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Posts Tagged ‘Bristol-Myers Squibb’


From Thalidomide to Revlimid: Celgene to Bristol Myers to possibly Pfizer; A Curation of Deals, Discovery and the State of Pharma

 

Curator: Stephen J. Williams, Ph.D.

Updated 6/24/2019

Updated 4/12/2019

Updated 2/28/2019

Lenalidomide (brand name Revlimid) is an approved chemotherapeutic used to treat multiple myeloma, mantle cell lymphoma, and certain myedysplastic syndromes.  It is chemically related to thalidomide analog with potential antineoplastic activity. Lenalidomide inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells.  It is usually given with dexamethasone for multiple myeloma. Revlimid was developed and sold by Celgene Corp.  However, recent news of deals with Bristol Myers Squib

 

Revlimid Approval History

FDA Approved: Yes (First approved December 27, 2005)
Brand name: Revlimid
Generic name: lenalidomide
Dosage form: Capsules
Company: Celgene Corporation
Treatment for: Myelodysplastic SyndromeMultiple MyelomaLymphoma

Revlimid (lenalidomide) is an immunomodulatory drug indicated for the treatment of patients with multiple myeloma, transfusion-dependent anemia due myelodysplastic syndromes (MDS), and mantle cell lymphoma.

Development History and FDA Approval Process for Revlimid

Date Article
Feb 22, 2017  FDA Expands Indication for Revlimid (lenalidomide) as a Maintenance Treatment for Patients with Multiple Myeloma Following Autologous Hematopoietic Stem Cell Transplant (auto-HSCT)
Feb 18, 2015  FDA Expands Indication for Revlimid (lenalidomide) in Combination with Dexamethasone to Include Patients Newly Diagnosed with Multiple Myeloma
Jun  5, 2013  FDA Approves Revlimid (lenalidomide) for the Treatment of Patients with Relapsed or Refractory Mantle Cell Lymphoma
Oct  3, 2005 Revlimid PDUFA Date Extended Three Months By FDA
Sep 14, 2005 FDA Oncologic Drugs Advisory Committee Recommends Revlimid for Full Approval
Sep 13, 2005 FDA and Celgene Revlimid Briefing Documents for Advisory Committee Meeting Available Online
Jun 21, 2005 FDA Grants Priority Review for Revlimid NDA for Treatment of Low- and Intermediate- Risk MDS With Deletion 5q Chromosomal Abnormality
Jun  7, 2005 Revlimid (lenalidomide) New Drug Application Accepted for Review by FDA
Apr  8, 2005 Revlimid New Drug Application Submitted to FDA for Review

 

 

 

 

M&A Deals Now and On The Horizon

  1. Right before the 2019 JP Morgan Healthcare Conference and a month before Bristol Myers quarterly earings reports, Bristol Myers Squib (BMY) announes a $74 Billion offer for Celgene Corp.  From the Bristol Myers website press realease:

Bristol-Myers Squibb to Acquire Celgene to Create a Premier Innovative Biopharma Company

  • Highly Complementary Portfolios with Leading Franchises in Oncology, Immunology and Inflammation and Cardiovascular Disease
  • Significantly Expands Phase III Assets with Six Expected Near-Term Product Launches, Representing Greater Than $15 Billion in Revenue Potential
  • Registrational Trial Opportunities and Early-Stage Pipeline Position Combined Company for Sustained Leadership Underpinned by Cutting-Edge Technologies and Discovery Platforms
  • Strong Combined Cash Flows, Enhanced Margins and EPS Accretion of Greater Than 40% in First Full Year
  • Approximately $2.5 Billion of Expected Run-Rate Cost Synergies to Be Achieved by 2022
THURSDAY, JANUARY 3, 2019 6:58 AM EST

NEW YORK & SUMMIT, N.J.,–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE:BMY) and Celgene Corporation (NASDAQ:CELG) today announced that they have entered into a definitive merger agreement under which Bristol-Myers Squibb will acquire Celgene in a cash and stock transaction with an equity value of approximately $74 billion. Under the terms of the agreement, Celgene shareholders will receive 1.0 Bristol-Myers Squibb share and $50.00 in cash for each share of Celgene. Celgene shareholders will also receive one tradeable Contingent Value Right (CVR) for each share of Celgene, which will entitle the holder to receive a payment for the achievement of future regulatory milestones. The Boards of Directors of both companies have approved the combination.

The transaction will create a leading focused specialty biopharma company well positioned to address the needs of patients with cancer, inflammatory and immunologic disease and cardiovascular disease through high-value innovative medicines and leading scientific capabilities. With complementary areas of focus, the combined company will operate with global reach and scale, maintaining the speed and agility that is core to each company’s strategic approach.

Based on the closing price of Bristol-Myers Squibb stock of $52.43 on January 2, 2019, the cash and stock consideration to be received by Celgene shareholders at closing is valued at $102.43 per Celgene share and one CVR (as described below). When completed, Bristol-Myers Squibb shareholders are expected to own approximately 69 percent of the company, and Celgene shareholders are expected to own approximately 31 percent.

“Together with Celgene, we are creating an innovative biopharma leader, with leading franchises and a deep and broad pipeline that will drive sustainable growth and deliver new options for patients across a range of serious diseases,” said Giovanni Caforio, M.D., Chairman and Chief Executive Officer of Bristol-Myers Squibb. “As a combined entity, we will enhance our leadership positions across our portfolio, including in cancer and immunology and inflammation. We will also benefit from an expanded early- and late-stage pipeline that includes six expected near-term product launches. Together, our pipeline holds significant promise for patients, allowing us to accelerate new options through a broader range of cutting-edge technologies and discovery platforms.”

Dr. Caforio continued, “We are impressed by what Celgene has accomplished for patients, and we look forward to welcoming Celgene employees to Bristol-Myers Squibb. Our new company will continue the strong patient focus that is core to both companies’ missions, creating a shared organization with a goal of discovering, developing and delivering innovative medicines for patients with serious diseases. We are confident we will drive value for shareholders and create opportunities for employees.”

“For more than 30 years, Celgene’s commitment to leading innovation has allowed us to deliver life-changing treatments to patients in areas of high unmet need. Combining with Bristol-Myers Squibb, we are delivering immediate and substantial value to Celgene shareholders and providing them meaningful participation in the long-term growth opportunities created by the combined company,” said Mark Alles, Chairman and Chief Executive Officer of Celgene. “Our employees should be incredibly proud of what we have accomplished together and excited for the opportunities ahead of us as we join with Bristol-Myers Squibb, where we can further advance our mission for patients. We look forward to working with the Bristol-Myers Squibb team as we bring our two companies together.”

Compelling Strategic Benefits

  • Leading franchises with complementary product portfolios provide enhanced scale and balance. The combination creates:
    • Leading oncology franchises in both solid tumors and hematologic malignancies led by Opdivo and Yervoy as well as Revlimid and Pomalyst;
    • A top five immunology and inflammation franchise led by Orencia and Otezla; and
    • The #1 cardiovascular franchise led by Eliquis.

The combined company will have nine products with more than $1 billion in annual sales and significant potential for growth in the core disease areas of oncology, immunology and inflammation and cardiovascular disease.

  • Near-term launch opportunities representing greater than $15 billion in revenue potential. The combined company will have six expected near-term product launches:
    • Two in immunology and inflammation, TYK2 and ozanimod; and
    • Four in hematology, luspatercept, liso-cel (JCAR017), bb2121 and fedratinib.

These launches leverage the combined commercial capabilities of the two companies and will broaden and enhance Bristol-Myers Squibb’s market position with innovative and differentiated products. This is in addition to a significant number of lifecycle management registrational readouts expected in Immuno-Oncology (IO).

  • Early-stage pipeline builds sustainable platform for growth. The combined company will have a deep and diverse early-stage pipeline across solid tumors and hematologic malignancies, immunology and inflammation, cardiovascular disease and fibrotic disease leveraging combined strengths in innovation. The early-stage pipeline includes 50 high potential assets, many with important data readouts in the near-term. With a significantly enhanced early-stage pipeline, Bristol-Myers Squibb will be well positioned for long-term growth and significant value creation.
  • Powerful combined discovery capabilities with world-class expertise in a broad range of modalities. Together, the Company will have expanded innovation capabilities in small molecule design, biologics/synthetic biologics, protein homeostasis, antibody engineering and cell therapy. Furthermore, strong external partnerships provide access to additional modalities.

Compelling Financial Benefits

  • Strong returns and significant immediate EPS accretion. The transaction’s internal rate of return is expected to be well in excess of Celgene’s and Bristol-Myers Squibb’s cost of capital. The combination is expected to be more than 40 percent accretive to Bristol-Myers Squibb’s EPS on a standalone basis in the first full year following close of the transaction.
  • Strong balance sheet and cash flow generation to enable significant investment in innovation. With more than $45 billion of expected free cash flow generation over the first three full years post-closing, the Company is committed to maintaining strong investment grade credit ratings while continuing its dividend policy for the benefit of Bristol-Myers Squibb and Celgene shareholders. Bristol-Myers Squibb will also have significant financial flexibility to realize the full potential of the enhanced late- and early-stage pipeline.
  • Meaningful cost synergies. Bristol-Myers Squibb expects to realize run-rate cost synergies of approximately $2.5 billion by 2022. Bristol-Myers Squibb is confident it will achieve efficiencies across the organization while maintaining a strong, core commitment to innovation and delivering the value of the portfolio.

Terms and Financing

Based on the closing price of Bristol-Myers Squibb stock on January 2, 2019, the cash and stock consideration to be received by Celgene shareholders is valued at $102.43 per share. The cash and stock consideration represents an approximately 51 percent premium to Celgene shareholders based on the 30-day volume weighted average closing stock price of Celgene prior to signing and an approximately 54 percent premium to Celgene shareholders based on the closing stock price of Celgene on January 2, 2019. Each share also will receive one tradeable CVR, which will entitle its holder to receive a one-time potential payment of $9.00 in cash upon FDA approval of all three of ozanimod (by December 31, 2020), liso-cel (JCAR017) (by December 31, 2020) and bb2121 (by March 31, 2021), in each case for a specified indication.

The transaction is not subject to a financing condition. The cash portion will be funded through a combination of cash on hand and debt financing. Bristol-Myers Squibb has obtained fully committed debt financing from Morgan Stanley Senior Funding, Inc. and MUFG Bank, Ltd. Following the close of the transaction, Bristol-Myers Squibb expects that substantially all of the debt of the combined company will be pari passu.

Accelerated Share Repurchase Program

Bristol-Myers Squibb expects to execute an accelerated share repurchase program of up to approximately $5 billion, subject to the closing of the transaction, market conditions and Board approval.

Corporate Governance

Following the close of the transaction, Dr. Caforio will continue to serve as Chairman of the Board and Chief Executive Officer of the company. Two members from Celgene’s Board will be added to the Board of Directors of Bristol-Myers Squibb. The combined company will continue to have a strong presence throughout New Jersey.

Approvals and Timing to Close

The transaction is subject to approval by Bristol-Myers Squibb and Celgene shareholders and the satisfaction of customary closing conditions and regulatory approvals. Bristol-Myers Squibb and Celgene expect to complete the transaction in the third quarter of 2019.

Advisors

Morgan Stanley & Co. LLC is serving as lead financial advisor to Bristol-Myers Squibb, and Evercore and Dyal Co. LLC are serving as financial advisors to Bristol-Myers Squibb. Kirkland & Ellis LLP is serving as Bristol-Myers Squibb’s legal counsel. J.P. Morgan Securities LLC is serving as lead financial advisor and Citi is acting as financial advisor to Celgene. Wachtell, Lipton, Rosen & Katz is serving as legal counsel to Celgene.

Bristol-Myers Squibb 2019 EPS Guidance

In a separate press release issued today, Bristol-Myers Squibb announced its 2019 EPS guidance for full-year 2019, which is available on the “Investor Relations” section of the Bristol-Myers Squibb website at https://www.bms.com/investors.html.

Conference Call

Bristol-Myers Squibb and Celgene will host a conference call today, at 8:00 a.m. ET to discuss the transaction. The conference call can be accessed by dialing (800) 347-6311 (U.S. / Canada) or (786) 460-7199 (International) and giving the passcode 4935567. A replay of the call will be available from January 3, 2019 until January 17, 2019 by dialing (888) 203-1112 (U.S. / Canada) or (719) 457-0820 (International) and giving the passcode 4935567.

A live webcast of the conference call will be available on the investor relations section of each company’s website at Bristol-Myers Squibb https://www.bms.com/investors.html and Celgene https://ir.celgene.com/investors/default.aspx.

Presentation and Infographic

Associated presentation materials and an infographic regarding the transaction will be available on the investor relations section of each company’s website at Bristol-Myers Squibb https://www.bms.com/investors.html and Celgene https://ir.celgene.com/investors/default.aspx as well as a joint transaction website at www.bestofbiopharma.com.

2.  Then through news on Bloomberg and some other financial sites on a possible interest of a merged Celgene-Bristol Myers from Pfizer as well as other pharma groups

Here’s How John Paulson Is Positioning His Celgene/Bristol Trade

Billionaire John Paulson sees a 10 percent to 20 percent chance that Bristol-Myers Squibb Co. receives a takeover bid and he’s positioning his Celgene Corp. trade based on that risk, he said in an interview on Mike Samuels’ “According to Sources” podcast.

Bristol-Myers “is vulnerable and it has an attractive pipeline to several potential acquirers,” Paulson said in the podcast released Monday. “It’s a reasonable probability,” he said. “You have to be prepared someone may show up. It’s an attractive spread, but you can’t take that big a position.”

John Paulson

Photographer: Jin Lee/Bloomberg

Paulson has the Celgene/Bristol-Myers trade as a 3 percent portfolio position, though his firm is short a pharma index rather than Bristol-Myers for about half of the position. If an activist did show up, it would likely blow out the spread from its current $13.85 to probably $20 and, if an actual bid arrived, he said the spread could move out to $40.

“I just don’t feel comfortable being short Bristol in this environment,” Paulson said. “You can sort of get the same economics by shorting an index, maybe even do better because, since Bristol came down, if the pharma sector goes up, Bristol may go up more than the pharma sector, which would increase the profitability on the Celgene. ”

Celgene fell as much as 2.2 percent on Tuesday, its biggest intraday drop since Dec. 27. Bristol-Myers also sank as much as 2.2 percent, the most since Jan. 9.

The question of whether Bristol-Myers receives a hostile takeover offerhas been the top issue for investors since the Celgene deal was announced. The drugmaker was pressured in February 2017 to add three new directors after holding talks with activist hedge fund Jana Partners LLC. The same month, the Wall Street Journal reported that Carl Icahn had taken a stake and saw Bristol-Myers as a takeover target.

Pfizer Inc., AbbVie Inc. or Amgen Inc. “make varying amounts of sense as suitors, though we see many barriers to someone making an offer,” Credit Suisse analyst Vamil Divan wrote in a note earlier this month. AbbVie and Amgen “have the balance sheet strength and could look to beef up their oncology presence.”

CNBC’s David Faber said Jan. 3 — the day the Celgene deal was announced — that there had been “absolutely” no talks between Bristol-Myers and potential acquirers.

Jefferies analyst Michael Yee wrote in note Tuesday that he doesn’t expect an unsolicited offer for Bristol-Myers to “thwart” its Celgene purchase. He sees the deal spread as “quite attractive” again at the current range of 18 percent to 20 percent after it had earlier narrowed to 11 percent to 12 percent.

Paulson managed about $8.7 billion at the the beginning of November.

From StatNews.com at https://www.statnews.com/2019/01/22/celgene-legacy-chutzpah-science-drug-pricing/

 

Nina Kjellson was just two years out of college, working as a research associate at Oracle Partners, a hedge fund in New York, when a cabbie gave her a stock tip. There was a company in New Jersey, he told her, trying to resurrect thalidomide, a drug that was infamous for causing severe birth defects, as a treatment for cancer.

Kjellson was born in Finland, where the memory of thalidomide, which was given to mothers to treat morning sickness but led to babies born without arms or legs, was particularly raw because the drug hit Northern Europe hard. But she was on the hunt for new cancer drugs, and her interest was piqued. She ended up investing a small amount of her own money in Celgene. That was 1999.

Since then, Celgene shares have risen more than 100-fold; the company became one of the largest biotechnology firms in the world. Earlier this month, rival Bristol-Myers Squibb announced plans to purchase Celgene for $74 billion in cash and stock.

Reflecting on a company she watched for two decades, Kjellson, now a venture capitalist at Canaan Partners in San Francisco, marveled at the “grit and chutzpah” that it took to push thalidomide back onto the market. “The company started taking off,” she remembered, “but not without an incredible reversal.” Celgene faced resistance from some thalidomide victims, and the Food and Drug Administration was lobbied not to revive the drug. In the end, she said, it built a golden egg and became a favorite partner of smaller biotech companies like the ones she funds. And it populated the rest of the pharmaceutical industry with its alumni. “If I had a nickel for every company that says we want to do Celgene-like deals,” she said, “I’d have better returns than from my venture career.”

But there’s another side to Celgene. When the company launched thalidomide as a treatment for leprosy in 1998, it cost $6 a pill. As it became clear that it was also an effective cancer drug, Celgene slowly raised the price, quadrupling it by the time it received approval for an improved molecule, Revlimid. Then, it slowly increased the price of Revlimid by a total of 145 percent, according to Sector & Sovereign LLC, a pharmaceutical consultancy.

Revlimid now costs $693 a pill. In 2017, Revlimid and another thalidomide-derived cancer drug represented 76 percent of Celgene’s $12.9 billion in annual sales. Kjellson gives the company credit for guts in science, for taking a terrible drug and resurrecting it. But it also had chutzpah when it came to what it charged.

A pioneer in ‘modern pricing’

How did the price of thalidomide, and then Revlimid, increase so much? Celgene explained it in a 2004 front-page story in the Wall Street Journal. “When we launched it, it was going to be an AIDS-wasting drug,” Celgene’s chief executive at the time, John Jackson, said. “We couldn’t charge more or there would have been demonstrations outside the company.” But once Celgene realized that the drug was a cancer treatment, the company decided to slowly bring thalidomide’s price more in line with other cancer medicines, such as Velcade, a rival medicine now sold by the Japanese drug giant Takeda. In 2003, it cost more than twice as much as thalidomide. “By bringing [the price] up every year, it was heading toward where it should be as a cancer drug,” Jackson told the Journal.

Thalidomide was not actually approved as a myeloma treatment until 2006. That same year, Revlimid, which causes less sleepiness and nerve pain than thalidomide, was approved, and Barer, the chemist behind Celgene’s thalidomide strategy, took over as chief executive. He made good on thalidomide’s promise, churning out one blockbuster after another. In 2017 Revlimid generated $8.2 billion. Another cancer drug derived from thalidomide, Pomalyst, generated $1.6 billion. Otezla, a very different drug also based on thalidomide’s chemistry, treats psoriasis and psoriatic arthritis. Its 2017 sales: $1.3 billion.

With persistent price increases, quarter after quarter, Celgene pioneered something else: what Wall Street calls “modern pricing.” Cancer drug prices have risen inexorably.

 

Updated 2/28/2019

From FiercePharma.com

BMS’ largest investor condemns Celgene deal—and it’s music to activists’ ears

Activist investor Starboard Value is officially rallying the troops against Bristol-Myers Squibb’s $74 billion Celgene deal, and thanks to a big investor’s thumbs-down, it’ll have more support than some expected. But the question is whether it’ll be enough to scuttle the merger.

Starboard CEO Jeffrey Smith penned a letter (PDF) to Bristol-Myers’ shareholders on Thursday labeling the transaction “poorly conceived and ill-advised.” It intends to vote its shares—which number 1.63 million, though the hedge fund is seeking more—against the deal, and it wants to see other shareholders do the same. It’ll be filing proxy materials “in the coming days” to solicit “no” votes from BMS investors, Smith said.

Starboard picked up its stake early this year after the deal was announced, BMS confirmed last week, but until now, the activist fund hasn’t been forthcoming about its intentions. But the timing of its reveal is likely no coincidence; just Wednesday, Wellington Management—which owns about 8% of Bristol-Myers’ shares and ranked as its largest institutional shareholder as of earlier this week—came out publicly against the “risky” buyout.

But while “we believe it is possible at least one other long-term top-five [shareholder] may disagree with the transaction, too,” RBC Capital Markets’ Michael Yee wrote in his own investor note, he—as many of his fellow analysts do—still expects to see the deal go through. “We think the vast majority of the acquirer holder base that would not like the deal already voted by selling their shares earlier, leaving investors who are mostly supportive of the deal,” he wrote.

Meanwhile, Starboard has been clear about one other thing: It wants board seats. It’s nominated five new directors, including CEO Smith, and investors will vote on that group at an as-yet-unscheduled meeting. Thing is, that meeting will take place after BMS investors vote on the Celgene deal in April, so Starboard will have to rally sufficient support against the deal if it wants to see them installed.

The “probability of a third-party buyer for Bristol-Myers Squibb” before the April vote is “very low,” BMO Capital Markets analysts wrote recently, adding that “we do not believe a potential activist can change that.” Barclays analysts agreed Wednesday, pointing to a “lack of realistic, potential alternatives that could collectively provide a similar level of upside.”

Updated 4/12/2019

Bristol-Myers Squibb Shareholders Approve Celgene Tie-Up

Three quarters of Bristol-Myers Squibb shareholders vote to approve the deal with Celgene, paving the way for the largest pharmaceutical takeover in history.

Bristol-Myers Squibb (BMY – Get Report) on Friday announced that it had secured enough shareholder votes to approve its roughly $74 billion takeover of Celgene (CELG – Get Report) , putting the company closer to finalizing the largest pharmaceutical merger in history.

More than 75% of Bristol-Myers shareholders voted to approve the deal, according to a preliminary tally announced by Bristol-Myers on Friday.

Bristol-Myers’ position took a positive turn in late March after an influential shareholder advisory group recommended investors vote in favor of the cancer drug specialist’s takeover,  and a key activist dropped its opposition to the deal.

Institutional Shareholder Services recommended the deal, which had been challenged by key Bristol-Myers shareholders Starboard Value and Wellington Management, ahead of Friday’s vote.

 

Updated 6/24/2019

Bristol Myers agrees to sell off Celgene blockbuster psoriasis and arthritis drug Otezla to satisfy FTC in hopes to speed up merger

By SY MUKHERJEE

June 24, 2019

Happy Monday, readers!

Bristol-Myers Squibb hasn’t exactly had a pristine path to its proposed acquisition of Celgene. Sure, the legacy pharma giant racked up more than 75% of shareholder votes to approve the $74 billion acquisition following a quickly-quashed rebellion from some activist naysayers. But the company hit another hurdle in its Celgene acquisition quest that sent Bristol Myers stock tumbling nearly 7.5%, a $6 billion erasure in market value.

The reason(s)? For one, Bristol-Myers Squibb reported an unfortunate clinical trial result from a late-stage study of its cancer immunotherapy superstar Opdivo in liver cancer. For another—BMS made a somewhat surprising announcement that it would spin off Celgene’s blockbuster psoriasis and arthritis drug Otezla, slated to rake in nearly $2 billion in sales this year alone, in order to address Federal Trade Commission (FTC) antitrust concerns over the M&A.

That means the Bristol-Myers Celgene deal may not close until early 2020, rather than the originally expected timeline by the end of this year.

“Bristol-Myers Squibb reaffirms the significant value creation opportunity of the acquisition of Celgene,” the firm said in a statement. “Together with $2.5 billion of cost synergies, a compelling pipeline and a strong portfolio of marketed products, the company continues to expect growth in sales and earnings through 2025.”

Investors can be a fickle bunch. For now, though, they don’t seem particularly pleased at the decision to lop off one of Celgene’s tried and true cash cows.

 

Additional posts on Pharma Mergers and Deals on this Open Access Journal include:

Live Conference Coverage Medcity Converge 2018 Philadelphia: Clinical Trials and Mega Health Mergers

First Annual FierceBiotech Drug Development Forum (DDF). Event covers the drug development process from basic research through clinical trials. InterContinental Hotel, Boston, September 19-21, 2016.

Pfizer Near Allergan Buyout Deal But Will Fed Allow It?

New Values for Capital Investment in Technology Disruption: Life Sciences Group @Google and the Future of the Rest of the Biotech Industry

Mapping the Universe of Pharmaceutical Business Intelligence: The Model developed by LPBI and the Model of Best Practices LLC

 

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37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 8, 2019: Deals and Announcements

Reporter: Stephen J. Williams, Ph.D.

From Biospace.com

JP Morgan Healthcare Conference Update: FDA, bluebird, Moderna and the Price of Coffee

Researcher holding test tube up behind circle of animated research icons

Tuesday, January 8, was another busy day in San Francisco for the JP Morgan Healthcare Conference. One interesting sideline was the idea that the current government shutdown could complicate some deals. Kent Thiry, chief executive officer of dialysis provider DaVita, who is working on the sale of its medical group to UnitedHealth Group this quarter, said, “We couldn’t guarantee that even if the government wasn’t shut down, but we and the buyer are both working toward that goal with the same intensity if not more.”

And in a slightly amusing bit of synchrony, U.S.Food and Drug Administration (FDA)Commissioner Scott Gottlieb’s keynote address that was delivered by way of video conference from Washington, D.C., had his audio cut out in the middle of the presentation. Gottlieb was talking about teen nicotine use and continued talking, unaware that his audio had shut off for 30 seconds. When it reconnected, the sound quality was reportedly poor.

Click to search for life sciences jobs

bluebird bio’s chief executive officer, Nick Leschlygave an update of his company’s pipeline, with a particular emphasis on a proposed payment model for its upcoming LentiGlobin, a gene therapy being evaluated for transfusion-dependent ß-thalassemia (TDT). The gene therapy is expected to be approved in Europe this year and in the U.S. in 2020. Although the price hasn’t been set, figures up to $2.1 million per treatment have been floated. Bluebird is proposing a five-year payment program, a pledge to not raise prices above CPI, and no costs after the payment period.

Eli Lilly’s chief executive officer David Ricks, just days after acquiring Loxo Oncologyoffered up projections for this year, noting that 45 percent of its revenue will be created by drugs launched in 2015. Those include Trulicity, Taltz and Verzenio. The company also expects to launch two new molecular entities this year—nasal glucagons, a rescue medicine for high blood sugar (hyperglycemia), and Lasmiditan, a rescue drug for migraine headaches.

CNBC’s Jim Cramer interviewed Allergan chief executive officer Brent Saunders, in particular discussing the fact the company’s shares traded in 2015 for $331.15 but were now trading for $145.60. Cramer noted that the company’s internal fundamentals were strong, with multiple pipeline assets and a strong leadership team. Some of the stock problems are related to what Saunders said were “unforced errors,” including intellectual property rights to Restasis, its dry-eye drug, and Allergan’s dubious scheme to protect those patents by transferring the rights to the Saint Regis Mohawk Tribe in New York. On the positive side, the company’s medical aesthetics portfolio, dominated by Botox, is very strong and the overall market is expected to double.

One of the big areas of conversation is so-called “flyover tech.” Biopharma startups are dominant in Boston and in San Francisco, but suddenly venture capital investors have realized there’s a lot going on in between. New York City-based Radian Capital, for example, invests exclusively in markets outside major U.S. cities.

“At Radian, we partner with entrepreneurs who have built their businesses with a focus on strong economics rather than growth at all costs,” Aly Lovett, partner at Radian, told The Observer. “Historically, given the amount of money required to stand up a product, the software knowledge base, and coastal access to capital, health start-ups were concentrated in a handful of cities. As those dynamics have inverted and as the quality of living becomes a more important factor in attracting talent, we’re not seeing a significant increase in the number of amazing companies being built outside of the Bay Area.”

“Flyover companies” mentioned include Bind in Minneapolis, Minnesota; Solera Health in Phoenix, Arizona; ClearDATA in Austin, Texas; Healthe, in Eden Prairie, Minnesota; HistoSonics in Ann Arbor, Michigan; and many others.

Only a month after its record-breaking IPO, Moderna Therapeutics’ chief executive officer Stephane Bancelspent time both updating the company’s clinical pipeline and justifying the company’s value despite the stock dropping off 26 percent since the IPO. Although one clinical program, a Zika vaccine, mRNA-1325, has been abandoned, the company has three new drugs coming into the clinic: mRNA-2752 for solid tumors or lymphoma; mRNA-4157, a Personalized Cancer Vaccine with Merck; and mRNA-5671, a KRAS cancer vaccine. The company also submitted an IND amendment to the FDA to add an ovarian cancer cohort to its mRNA-2416 program.

One interesting bit of trivia, supplied on Twitter by Rasu Shrestha, chief innovation officer for the University of Pittsburgh Medical Center, this year at the conference, 33 female chief executive officers were presenting corporate updates … compared to 19 men named Michael. Well, it’s a start.

And for another bit of trivia, Elisabeth Bik, of Microbiome Digest, tweeted, “San Francisco prices are so out of control that one hotel is charging the equivalent of $21.25 for a cup of coffee during a JPMorgan conference.”

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

36th Annual J.P. Morgan HEALTHCARE CONFERENCE January 8 – 11, 2018

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California

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Collaboration With Bristol Myers Squib Led to Successful Launch of Ono Pharmaceutical’s Cancer Immune Therapy (Opdivio®)

Reporter: Stephen J. Williams, Ph.D.

Updated 7/25/2019

Below are excerpts and a great story on the origins on Opdivo and its early marketing troubles and eventual success when Bristol Myers partnered with a small Japanese pharma, Ono Pharmaceuticals.

As seen in Biospace News 

Ten years ago, representatives from Japan’s Ono Pharmaceutical Co. went from hospital to hospital, attempting to convince doctors to test a new product under development: drugs that helped the body’s immune system fight cancer. Nobody would listen.

Immuno-therapy was another fad, they were told. The treatment probably offered no bigger benefit than eating mushrooms to fight cancer, one critic opined. Another said he’d shave his head if it worked.

 

Read at Bloomberg

 

Source: http://www.biospace.com/News/how-a-150000-drug-created-with-bristol-myers/411159/source=TopBreaking

From Bloomberg

This $150,000 Cancer Treatment Saved a Pharma Company

 

By  Natasha Khan natashakhanhk

Ten years ago, representatives from Japan’s Ono Pharmaceutical Co. went from hospital to hospital, attempting to convince doctors to test a new product under development: drugs that helped the body’s immune system fight cancer. Nobody would listen.

Immuno-therapy was another fad, they were told. The treatment probably offered no bigger benefit than eating mushrooms to fight cancer, one critic opined. Another said he’d shave his head if it worked.

Ono’s Chief Executive Officer Gyo Sagara says he received plenty of apologies when Opdivo, the drug the Japanese company worked on with Bristol-Myers Squibb Co., got the green light from regulators. The drug’s approval in Japan 20 months ago was the first worldwide in a new class of cancer treatments called PD-1 inhibitors.

It is among a string of therapies coming to market in the immuno-oncology category – medicines that help the body combat cancer rather than directly attacking the cancer cells themselves. The influential Science journal called cancer immunotherapy the “breakthrough of the year” in 2013, and the biggest global pharmaceutical companies are rushing into the field.

“They found the treasure of the century,” said Fumiyoshi Sakai, a health-care analyst with Credit Suisse, who boosted his target price for the stock to 25,000 yen in mid February. Ono’s shares closed at an all-time high of 22,605 yen on Thursday after climbing more than 70 percent over the past year.

The drug is pumping fresh life into Ono, which for years has battled slumping sales, patent expirations and rising competition from cheaper generics. Analysts now forecast that the Japanese company — among the biggest makers of specialty pharmaceuticals in Asia with a market cap of about $23 billion — will more than double annual revenue to about $3 billion by fiscal year end March 2018.

For the average U.S. patient, Opdivo costs about $12,500 a month, or $150,000 for a year of therapy. Bloomberg Intelligence says that consensus analyst estimates suggest that by 2020, Bristol-Myers and Ono’s Opdivo could have global sales of $9.5 billion and Merck & Co.’s Keytruda $5.1 billion.

Source: http://www.bloomberg.com/news/articles/2016-03-03/drugmaker-wins-big-in-japan-as-its-gamble-leads-to-150-000-drug

Updated 7/25/2019

From cnbc.com

https://www.cnbc.com/2019/07/24/bristol-myers-releases-mixed-opdivo-lung-cancer-results.html

Bristol-Myers releases mixed Opdivo lung cancer results

Bristol-Myers released mixed results on Wednesday from trials testing the survival benefit of its immunotherapy Opdivo in combination with either chemotherapy or its other immuno-oncology drug, Yervoy, as an initial treatment for advanced lung cancer.

The U.S. drugmaker said that Opdivo combined with chemotherapy failed to extend overall survival more than chemotherapy alone in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

The result sent Bristol-Myers shares 3% lower in extended trading, as it is likely to further solidify the domination of rival drug Keytruda from Merck as an initial treatment for advanced lung cancer, by far the most lucrative oncology market.

Both multibillion-dollar sellers are already approved for lung and several other types of cancer.

Opdivo did demonstrate an improvement in overall survival in combination with Yervoy in lung cancer patients whose tumors expressed at least 1% of the PD-L1 protein that the drug is designed to target. That accounts for about 70% of NSCLC patients, the company said.

Official company press release can be seen here:

https://news.bms.com/press-release/rd-news/bristol-myers-squibb-provides-update-part-2-checkmate-227

PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE: BMY) today announced that Part 2 of the Phase 3 CheckMate -227 trial did not meet the primary endpoint of overall survival (OS) with Opdivo® (nivolumab) plus chemotherapy versus chemotherapy in patients with first-line non-squamous non-small cell lung cancer (NSCLC), regardless of PD-L1 status (HR 0.86; 95% CI 0.69-1.08). The median OS for patients treated with Opdivo plus chemotherapy was 18.83 months vs. 15.57 months for chemotherapy, and the landmark one-year OS was 67.3 percent vs. 59.2 percent, respectively. In an exploratory analysis of patients with first-line squamous NSCLC, the median OS was 18.27 months for Opdivo plus chemotherapy vs. 11.96 months for chemotherapy (HR 0.69; 95% CI 0.50-0.97). No new safety signals were observed. The company will share complete findings from this trial at an upcoming medical meeting.

“While this is not the outcome we had hoped for, the Opdivo plus chemotherapy one-year landmark overall survival in the non-squamous population was consistent with the experimental arms in previously-reported trials of IO/chemotherapy combination regimens,” said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. “We thank the patients and investigators who participated in this trial.”

Bristol-Myers Squibb also announced that Part 1a of the CheckMate -227 trial met the co-primary endpoint of OS, demonstrating a statistically significant benefit for Opdivo plus low-dose Yervoy® (ipilimumab) versus chemotherapy in patients whose tumors express PD-L1 ≥1%. Additional information can be found at www.bms.com.

Other related articles in this Open Access Journal include:

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

Monoclonal Antibody Therapy and Market

PD1 Inhibitor atezolizumab may show promise in bladder cancer in patients with high PDL1 expression

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

 

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Myocardial Infarction: The New Definition After Revascularization

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/31/2014

Myocardial Ischemia Symptoms

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/07/29/myocardial-ischemia-symptoms/

 

VIEW VIDEO

Gregg Stone, MD

Co-DIrector, Medical Research & Education Division Cardiovascular Research Foundation

http://www.medpagetoday.com/Cardiology/MyocardialInfarction/42256?xid=nl_mpt_DHE_2013-10-15&goback=%2Egmr_4346921%2Egde_4346921_member_5795830612724035588#%21

Primary source: Journal of the American College of Cardiology
Source reference: Moussa I, et al “Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI)” J Am Coll Cardiol2013; 62: 1563-1570.

Additional source: Journal of the American College of Cardiology
Source reference:White H “Avatar of the universal definition of periprocedural myocardial infarction” J Am Coll Cardiol 2013; 62: 1571-1574.

Moussa reported that he had no conflicts of interest.

Stone is a consultant for Boston Scientific, Eli Lilly, Daiichi Sankyo, and AstraZeneca. The other authors reported relationships with Guerbet, The Medicines Company, Bristol-Myers Squibb/Sanofi, Merck, Maya Medical, AstraZeneca, Abbott Vascular, Regado Biosciences, Janssen Pharma, Lilly/Daiichi Sankyo, St. Jude Medical, Medtronic, Terumo, Bridgepoint/Boston Scientific, Gilead, Boston Scientific, Eli Lilly, and Daiichi Sankyo.

White is co-chairman for the Task Force for the Universal Definiton of Myocardial Infarction; has received research grants from sanofi-aventis, Eli Lilly, The Medicines Company, the NIH, Pfizer, Roche, Johnson & Johnson, Schering-Plough, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb; and has served on advisory boards for AstraZeneca, Merck Sharpe & Dohme, Roche, and Regado Biosciences.

WASHINGTON, DC — A “clinically meaningful” definition of MI following PCI or CABG is urgently needed to replace the arbitrarily chosen “universal definition” proposed in recent years that has no relevance to patients and may be muddying clinical-trial results. Those are the conclusions of a new expert consensus document released Monday by the Society of Cardiovascular Angiography and Interventions (SCAI)[1].

The notion of a “universal definition of MI” was first proposed in 2000 and updated in 2007 and 2012. The 2012 document defines a PCI-related MI as an increase in cardiac troponin (cTn) of more than five times the upper limit of normal (ULN) during the first 48 hours postprocedure plus specific clinical or ECG features. Post-CABG, the definition is a cTn increase of >10 times the ULN, plus different clinical or ECG features.

The problem, lead author Dr Issam Moussa (Mayo Clinic, Jacksonville, FL) told heartwire , is that these cutoffs were arbitrarily chosen and not based on any hard evidence that these biomarker levels spelled a poor prognosis. Moreover, “overnight, the rate of MI went from 5% following these procedures to 20% to 30%!” he said.

The SCAI committee, in its new document, focuses on post-PCI procedures and highlights the importance of acquiring baseline cardiac biomarkers and differentiating between patients with elevated baseline CK-MB (or cTn) in whom biomarker levels are stable or falling, as well as those in whom it hasn’t been established whether biomarkers are changing.

SCAI’s Proposed Clinically Meaningful MI Definitions

Group Definition
Normal baseline CK-MB CK-MB rise of >10x ULN or >5x ULN with new pathologic Q-waves in at least 2 contiguous leads or new persistent left bundle branch block
OR
In the absence of baseline CK-MB, a cTn rise of >70x ULN or a rise of>35 ULN plus new pathologic Q-waves in at least 2 contiguous leads or new persistent left bundle branch block
Elevated baseline biomarkers that are stable or falling A CK-MB or cTn rise that is equal (by an absolute increment) to the definitions described for patients with normal CK-MB at baseline.
Elevated baseline biomarkers that have not been shown to be stable or falling A CK-MB or cTn rise that is equal (by an absolute increment) to the definitions described for patients with normal CK-MB at baseline
Plus
New ST-segment elevation or depression
Plus
New-onset or worsening heart failure or sustained hypotension or other signs of a clinically relevant MI.

Moussa is quick to emphasize that these new clinically meaningful definitions have limited evidence to support them—and most of what exists supports CK-MB definitions, not cTn—but that the new document is based on the best scientific evidence available.

“We don’t want to come out with a definitive statement” saying this is the final word on MI definitions,” he stressed. “There is more science that needs to be done and there remains more uncertainty. We framed this to be inclusive and also to open the field for discussion.”

His hope is that this will lead to important changes in how patients are managed and money is spent. Currently, patients with clinically meaningless biomarker elevations may become unnecessarily panicked over news that they’ve had a “heart attack,” while hospital stays may be extended and further tests ordered on the basis of these results.

Moussa et al’s proposal also has important implications for clinical trials, he continued. Currently, for studies that include periprocedural MIs as an individual end point or as part of a composite end point, the very high number of biomarker-defined “MIs” collected in the trial could potentially overwhelm the true impact of any given therapy. “You are really using an end point that is truly not relevant to patients. . . . This could really affect the whole hypothesis.”

He’s expecting some push-back from cardiologists and academics, particularly those who championed the need for the universal definition in the first place, but believes most people will welcome a clinically meaningful definition.

“I think many in the medical community will accept this because they have not really been using the universal definition in their day-to-day practice anyhow.” What’s more, the National Cardiovascular Data Registry (NCDR) does not include the reporting of MI postangiography, in part because of concerns that the universal definition of MI overestimates the true incidence of this problem. “I think many in the community will look at this definition as more reflective of the true incidence of MI after angioplasty, and if it’s accepted, they are more likely to report it to databases like NCDR and use it to reflect quality-of-care processes.”

http://www.medscape.com/viewarticle/812533?nlid=35983_2105&src=wnl_edit_medp_card&uac=93761AJ&spon=2

  • ESC/ACCF/AHA/WHF Expert Consensus Document

Circulation.2012; 126: 2020-2035  Published online before print August 24, 2012,doi: 10.1161/​CIR.0b013e31826e1058

Third Universal Definition of Myocardial Infarction

  1. Kristian Thygesen;
  2. Joseph S. Alpert;
  3. Allan S. Jaffe;
  4. Maarten L. Simoons;
  5. Bernard R. Chaitman;
  6. Harvey D. White
  7. the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction
  1. *Corresponding authors/co-chairpersons: Professor Kristian Thygesen, Department of Cardiology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark. Tel: +45 7846-7614; fax: +45 7846-7619: E-mail: kristhyg@rm.dk. Professor Joseph S. Alpert, Department of Medicine, Univ. of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245037, Tucson AZ 85724, USA, Tel: +1 520 626 2763, Fax: +1 520 626 0967, E-mail: jalpert@email.arizona.edu. Professor Harvey D. White, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, 1030 Auckland, New Zealand. Tel: +64 9 630 9992, Fax: +64 9 630 9915, E-mail: harveyw@adhb.govt.nz.

Table of Contents

  • Abbreviations and Acronyms. . . . . . . . . . . . . . . . . . . .2021

  • Definition of Myocardial Infarction. . . . . . . . . . . . . . .2022

  • Criteria for Acute Myocardial Infarction. . . . . . . . . . . .2022

  • Criteria for Prior Myocardial Infarction. . . . . . . . . . . .2022

  • Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2022

  • Pathological Characteristics of Myocardial Ischaemia and Infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2023

  • Biomarker Detection of Myocardial Injury With Necrosis. . .2023

  • Clinical Features of Myocardial Ischaemia and Infarction. . .2024

  • Clinical Classification of Myocardial Infarction. . . .2024
    • Spontaneous Myocardial Infarction (MI Type 1). . . .2024

    • Myocardial Infarction Secondary to an Ischaemic Imbalance (MI Type 2). . . . . . . . . . . . . . . . . . . . . . . .2024

    • Cardiac Death Due to Myocardial Infarction (MI Type 3). .2025

    • Myocardial Infarction Associated With Revascularization Procedures (MI Types 4 and 5). . . . . . . . . . . . . . . . . . …

New Definition for MI After Revascularization

Published: Oct 14, 2013 | Updated: Oct 15, 2013

By Todd Neale, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

The Society for Cardiovascular Angiography and Interventions (SCAI) has released a new definition for myocardial infarction (MI) following coronary revascularization aimed at identifying only those events likely to be related to poorer patient outcomes.

In the new criteria — published as an expert consensus document inCatheterization and Cardiovascular Interventions and the Journal of the American College of Cardiology — creatine kinase-myocardial band (CK-MB) is the preferred cardiac biomarker over troponin, and much greater elevations are required to define a clinically relevant MI compared with the universal definition of MI proposed in 2007 and revised in 2012.

Also, the new definition uses the same biomarker elevation thresholds to identify MIs following both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), whereas the universal definition has different thresholds for events following the two procedures.

“What we’ve really tried to emphasize in this classification scheme is the primary link between biomarker elevations and prognosis,” according to Gregg Stone, MD, of Columbia University Medical Center and the Cardiovascular Research Foundation in New York City, one of the authors of the document.

“In the universal definition of MI, they even acknowledged that their criteria were arbitrary,” Stone said in an interview. “We’ve tried to reduce the arbitrariness of the cutoff values that we selected so that the researcher, academician, clinician, hospital administrator, etc., can be confident that these levels that we’re recommending are the ones that are associated with a worse prognosis for patients suffering periprocedural complications.”

The Change

The existing universal definition for MI defines events following PCI according to an increase in cardiac troponin to greater than five times the 99th percentile upper reference limit (URL) within 48 hours when baseline levels are normal, with confirmation by electrocardiogram (ECG), imaging, or symptoms.

For CABG-related MI, the increase must be more than 10 times the 99th percentile URL within 48 hours when baseline levels are normal, with confirmation by ECG, angiography, or imaging.

But, Stone and colleagues wrote, the relationship between that degree of troponin elevation after a revascularization procedure and prognosis is not as strong as the association between a CK-MB elevation and patient outcomes.

Using a small elevation in troponin to define a post-procedure MI could find myocardial necrosis that is unlikely to be associated with poor clinical outcomes, which could have far-reaching implications, they wrote.

“Widespread adoption of an MI definition not clearly linked to subsequent adverse events such as mortality or heart failure may have serious consequences for the appropriate assessment of devices and therapies, may affect clinical care pathways, and may result in misinterpretation of physician competence,” they wrote.

To address that issue, the expert panel convened by SCAI sought to define clinically relevant MI after PCI or CABG.

A clinically relevant MI is defined in the new document based on an increase of at least 10 times the upper limit of normal in the level of CK-MB within 48 hours after a revascularization procedure when baseline levels are normal.

When the CK-MB level is not available, then an increase in troponin I or T of at least 70 times the upper limit of normal can be used to define a clinically relevant MI, according to the authors.

However, if an ECG shows new pathologic Q-waves in at least two contiguous leads or a new persistent left bundle branch block, then the thresholds can be lowered to at least five times and at least 35 times the upper limit of normal for CK-MB and troponin, respectively.

Further guidance is provided for identifying clinically relevant post-procedure MIs when the cardiac biomarker levels are elevated at baseline.

Dueling Definitions

Co-chairman of the Task Force for the Universal Definition of Myocardial Infarction, Harvey White, DSc, of Auckland City Hospital in Auckland, New Zealand, noted some limitations of the new definition, including the lack of a requirement for ischemic symptoms.

“Ischemic symptoms have always been a basic tenet of the diagnosis of MI, and it should be no different for a [PCI-related] MI,” he wrote in an accompanying editorial.

In addition, with the use of such large elevations in biomarker levels in the new definition, “there will be very few PCI-related events identified, and an opportunity to improve patient outcomes may be lost,” he wrote.

Troponin should remain the preferred biomarker over CK-MB, White argued, pointing to variability in and analytical issues with CK-MB assays, the need for sex-specific cutoffs for CK-MB levels, the need for higher thresholds of CK-MB to determine abnormalities because all individuals have circulating levels of the biomarker, and the reduced sensitivity and specificity of CK-MB.

Also, he said, CK-MB is becoming increasingly unavailable at medical centers.

“With CK-MB becoming obsolete, troponin will become the gold standard, and CK-MB will no longer have a role in defining PCI injury and infarction in clinical practice,” White wrote.

Stone admitted that troponin ultimately might be preferable to CK-MB because of its greater specificity, although the evidence does not yet support it.

“I think there’s a general desirability to move to troponins, although when you look at the data that’s out there it’s much stronger correlating CK-MB elevations to subsequent prognosis,” he said. “I think a lot of the troponin elevations are just noise or troponins are just too sensitive.”

Room for Both?

White noted in his editorial that “the rationale for the SCAI definition has been well articulated by its authors and may be appropriate in an individual trial, but it should not supplant the universal definition of MI,” he wrote.

When asked whether the new definition would replace the universal definition, Stone said there is a place for both sets of criteria.

“We would propose the clinically relevant definition be the one that is used to make most substantial decisions right now, [such as] trade-offs between efficacy and safety for new drugs and devices, in judging hospital systems and physicians, etc.,” he said. “But I do think there’s value in both, and they will both continue to evolve over time as new data becomes evident.”

http://www.medpagetoday.com/Cardiology/MyocardialInfarction/42256?xid=nl_mpt_DHE_2013-10-15&goback=%2Egmr_4346921%2Egde_4346921_member_5795830612724035588#%21 

Articles citing 

Third Universal Definition of Myocardial Infarction

  • Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary interventionEur Heart J. 2013;0:eht369v1-eht369

  • The role of myeloperoxidase (MPO) for prognostic evaluation in sensitive cardiac troponin I negative chest pain patients in the emergency departmentEuropean Heart Journal: Acute Cardiovascular Care. 2013;2:203-210,
  • Coronary artery bypass grafting or percutaneous revascularization in acute myocardial infarction?Interact CardioVasc Thorac Surg. 2013;0:ivt381v1-ivt381,
  • Ischemic Conditioning as an Adjunct to Percutaneous Coronary InterventionCirc Cardiovasc Interv. 2013;6:484-492,
  • High sensitivity cardiac troponin in patients with chest painBMJ. 2013;347:f4222,
  • Chest Pain and Palpitations: Taking a Closer LookCirculation. 2013;128:271-277,
  • An Updated Definition of Stroke for the 21st Century: A Statement for Healthcare Professionals From the American Heart Association/American Stroke AssociationStroke. 2013;44:2064-2089,
  • Factors Influencing the 99th Percentile of Cardiac Troponin I Evaluated in Community-Dwelling Individuals at 70 and 75 Years of AgeClin. Chem.. 2013;59:1068-1073,
  • Detection and management of asymptomatic myocardial injury after noncardiac surgeryEuropean Journal of Preventive Cardiology.2013;0:2047487313494294v1-2047487313494294,
  • Postoperative Troponin Screening: A Cardiac Cassandra?Circulation. 2013;127:2253-2256,
  • Remote Ischemic Preconditioning Improves Outcome at 6 Years After Elective Percutaneous Coronary Intervention: The CRISP Stent Trial Long-term Follow-upCirc Cardiovasc Interv. 2013;6:246-251,
  • Outcomes for Clinical Studies Assessing Drug and Revascularization Therapies for Claudication and Critical Limb Ischemia in Peripheral Artery DiseaseCirculation. 2013;127:1241-1250,
  • Prevalence, Incidence, and Implications of Silent Myocardial Infarctions in Patients With Diabetes MellitusCirculation. 2013;127:965-967,
  • 2013 ACCF/AHA Key Data Elements and Definitions for Measuring the Clinical Management and Outcomes of Patients With Acute Coronary Syndromes and Coronary Artery Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards)Circulation. 2013;127:1052-1089,
  • Clin. Chem.. 2013;59:574-576,
  • Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Prevention of Spontaneous Myocardial Infarction in Subjects With Stable Ischemic Heart DiseaseCirculation. 2013;127:769-781,
  • Frequency of Myocardial Infarction and Its Relationship to Angiographic Collateral Flow in Territories Supplied by Chronically Occluded Coronary ArteriesCirculation. 2013;127:703-709,
  • The Power of More Than OneCirculation. 2013;127:665-667,
  • The curious life of the biomarkerJournal of the American Dental Association. 2013;144:126-128,
  • Persistent Increases in Cardiac Troponin Concentrations As Measured with High-Sensitivity Assays after Acute Myocardial InfarctionClin. Chem.. 2013;59:443-445,
  • 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice GuidelinesCirculation. 2013;127:e362-e425,

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Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Ischemic Assessment (Diagnostics) – Change in Paradigm: The RIGHT vessel not ALL vessels

Reporters: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

The evaluation of coronary artery disease (blocked arterial blood supply to heart muscle) by stress tests is functional: is there enough blockage to starve a region of muscle when demand is high? By starvation we mean ischemia – insufficient supply to meet metabolic demands as expressed by consequent functional impairment, e.g., metabolic, electric, mechanical. In the catheterization laboratory, the evaluation is primarily anatomic – is there a bite missing in the silhouette of a coronary artery consistent with a significant impediment to blood delivery beyond the lesion? Half of all heart attacks are due to such lesions. The other half derive from non-obstructive but unstable lesions that may crack, bleed into the vessel wall, and suddenly clot,  blocking the blood flow. Coronary lesions that restrict blood delivery sufficient to cause demand ischemia (insufficient blood supply to meet high demands) cause angina pectoris.

The focus of flow reserve is to add an assessment of functional significance to anatomic lesions observed at catheterization. The widespread practice of deciding on intervention based on percent diameter reduction imposed by a lesion is obviously flawed. The flow limitation imposed by a lesion depends on its length and shape (entrance and exit effects on flow pattern), not merely the diameter reduction expressed as a percent, that is currently deemed the decision-making “degree of stenosis.” In the midst of a medical emergency heart attack, the target of intervention is the culprit lesion, the one that best explains why a region of muscle is dying. In that case, timely intervention is potentially life saving and does not depend on or wait for measurements. In the non-emergent setting, it is much harder to establish benefit from intervention. If a lesion is flow limiting and explanatory for angina pectoris, then intervention to relieve obstruction offers pain relief and may improve exertion tolerance. In relatively rare circumstances (3-vessel obstruction, left main obstruction) intervention may avoid heart attack and extend life expectancy, but with as good or better outcomes from bypass surgery. Most elective catheter interventions (balloon angioplasty, stent placement) have failed  to establish improved life expectancy or even superiority over medication. Furthermore, stent placement obligates use of strong anti-platelet medications (e.g., aspirin plus clopidogrel) that elevate risk of serious bleeding and stroke. Therefore it is reasonable to require further evidence that a coronary lesion is obstructive and consequential that just percent stenosis (narrowing) as indication for intervention. Fractional flow reserve offers such confirmation of lesion significance.

Fractional flow reserve may prove useful also in the definition of heart attack (myocardial infarction): New Definition of MI Unveiled, Fractional Flow Reserve (FFR) CT for Tagging Ischemia

June 21, 2013

Recorded: May 23, 2013

VIEW VIDEO

http://www.theheart.org/editorial-program/1550783.do?utm_medium=email&utm_source=20130704_heartwire&utm_campaign=newsletter

The use of FFR is relatively widespread in Europe, while its usage is beginning to catch up in the US. But for what reasons? Drs Roxana Mehran,Justin Davies, and Ron Waksman gathered recently to share their thoughts on the role of functional assessment in the cath lab, to evaluate FFR and its alternatives, and discuss what testing the future might hold for the optimal detection of culprit lesions.

Host

Roxana Mehran MD
Professor of Medicine, Divisions of Cardiology and Health Evidence and Policy
Director, Interventional Cardiovascular Research and Clinical Trials
The Zena and Michael A Wiener Cardiovascular Institute
Icahn School of Medicine at Mount Sinai
New York, NY

Dr Mehran has served as an advisor or consultant for AstraZeneca Pharmaceuticals, Regado Biosciences, Abbott Cardiovascular Systems, Janssen (Johnson & Johnson), Merck, and Maya Medical. She has received grants for clinical research from Bristol-Myers Squibb, Sanofi, the Medicines Company, and Lilly/DSI.

Guests

Justin Davies MBBS PhD
Consultant Interventional Cardiologist
Hammersmith Hospital
Imperial College
London, United Kingdom

Dr Davies has served as an advisor or consultant for Volcano and Medtronic. He has served as a speaker or a member of a speakers’ bureau for Medtronic and has received grants for clinical research from Volcano, Medtronic, and Abbott.

Ron Waksman MD
Director, Clinical Research and Advanced Education
MedStar Cardiovascular Research Network/Cleveland Clinic Heart and Vascular Institute
Clinical Professor of Medicine (Cardiology)
Georgetown University
Washington, DC

Dr Waksman has served as a speaker or a member of a speakers’ bureau for AstraZeneca Pharmaceuticals, Boston Scientific, and Medtronic.

Roxana Mehran, MD: Hello. My name is Roxana Mehran from Mount Sinai

School of Medicine in New York. It’s my pleasure to welcome you to this editorial

program in which we will look into how FFR usage differs in Europe vs the United

States.

I’m joined by my colleagues Justin Davies from Imperial College London and, of

course, Ron Waksman, an old friend, from the Washington Hospital Center in

DC. Welcome.

Ron Waksman, MD: Thank you.

Dr Mehran: We thought today we’d have a conversation about fractional flow

reserve and the use of functional studies in guiding our interventional

procedures. This has become a very interesting and important modality that has

been incorporated, now, more and more into the cath lab.

Let’s begin, Justin. Maybe you could tell us: what is FFR? How do we use it?

What do you think about it? How important is it to have? Does every cath lab

need to have FFR?

Justin E Davies, MD: I think that it provides cath labs with an objective measure

of stenosis assessment that is quick and relatively easy to use. Often you find

people don’t come to cath labs with preprocedural ischemic assessment, so it

enables a physician in the lab to see if there is ischemia and to effectively

document that. It has clearly got a good, strong evidence base, which has been

developed over a number of years with the founding studies of DEFER and

FAME—and FAME-2, now, which has led to the technique getting into guidelines

and which has propelled its use to widespread practice.

Dr Mehran: There’s no question that functional assessment is quite important,

but what do you think about patients coming into the cath lab, especially in the

United States, without an ischemic assessment? How often are you seeing that

and would you even use [FFR] in a patient who has got a 90% stenosis or 80%

stenosis, Ron?

Dr Waksman: I think we are in a period of transformational culture, now, in terms

of appropriate-use criteria and justifying every lesion that we are doing. I think

that interventional cardiologists are on the defensive—because we have to justify

almost any angioplasty that we are doing, especially with an intermediate lesion.

I think physicians are more flexible in using FFR and looking it as guidance to

support their decision-making.

I would say, still, if it is a 90% lesion even without a functional test I don’t think it

is required, but the 90% is on the eyes of the beholder, so you know that if you

take it to the core lab it is not going to be probably 90%, it is usually going to be

less than that.

And as you know, we have been scrutinized by looking at films and, again, [we

need to] justify. It is true that in the past the algorithm was having a functional

test and going to the cath lab. But this [step] has delayed things, and now people

presenting with some chest discomfort, [who] have risk factors, they sometimes

would be sent to the cath lab as the first method of assessment. I think we have

to take this more carefully and incorporate a functional ischemic assessment in

the cath lab—especially when those lesions are not necessarily unambiguous,

we don’t clearly know that they would derive ischemia.

Dr Mehran: It seems like that is really the way to go. You talked to us about

FAME, FAME-2, [that FFR is] the only modality in the cath lab that actually

improves hard end points like death and MI. I think that was how it got into the

guidelines, obviously. Very important studies. But at what cost? Can we afford to

do this in every single patient who presents with, let’s say, multivessel disease,

as they did in FAME?

Dr Davies: I think, actually, that this is a tremendous opportunity because I think

for us as cardiologists, as Ron said, it is very easy to get yourself into a little bit of

a hole stenting lesions that are not as significant as you may think, and I think

this obviously provides a justification and a safety net for people to deploy stents.

But also I think increasingly going forward when you are taking on potentially

more challenging techniques and you have got three-vessel disease, [FFR]

enables us to assess multivessel disease and perhaps convert a three-vessel

PCI into a two- or [even] a single-vessel PCI, which may move them from getting

a CABG to angioplasty.

Dr Mehran: So actually decreasing the number of stents. Reducing your

devices—hopefully even radiation exposure and contrast media. If you actually

just do an FFR and say, okay, I am done. But you know that we have all

[discussed]: if you want to treat the lesion you use an IVUS; if you don’t want to

treat the lesion you use an FFR. What do you think about that, Ron? Is that

something that is going on in your lab?

Dr Waksman: No. We try to stay away [from that]. I know that is said. But I

would still think that FFR is oversold. For the controversy, I would [argue] that

those studies were investigator-sponsored studies and I don’t think the data are

so relevant today. In DEFER there was a balloon angioplasty. Even in FAME-1, it

was with first-generation stents, and it was not really practice to go after every

lesion.

I think we have to take these [data] with a grain of salt. To my view, not

everything is definitive. Nevertheless, we do see uptake of the FFR usage in the

lab and for something that used to be under 3% in the US—only a couple of

years ago—it is now reaching up to 20%. More and more people are using [FFR].

There are other modalities that you can use. I think that we try to do a conversion

between the anatomical [minimum lumen area] (MLA) to the IVUS / FFR. It is

controversial, but it is another option. I think we need to learn to use the tool

when we really need it, not to be obsessed with it.

Often, we would have a scenario [where] a patient presents with chest pain. It is

classical angina. It is relieved by nitroglycerin. You have what you think is about

70% lesion in the proximal LAD and then you stick [in] the FFR wire and you get

0.81. Then you have a problem. You can repeat the study. You shoot another

adenosine and now it is 0.79. Then you shoot another one and it is 0.80. It is very

hard for me when you have a binary number to make a decision [based] on that

number. I don’t think we should lose our clinical judgment. It is a nice tool, but

don’t abuse it. Use it when it is really helpful.

Dr Davies: I will share my view. I have to say I agree wholeheartedly with Ron.

To me, if you ask them what are the most important numbers in FFR, people will

say: 0.80 or 0.75. Actually, I think the two most important numbers are 0 when it

is completely occluded and 1. As you get nearer to 0.80 you know that you are

approaching a place where it is going to be likely ischemia and a high probability

of events. Ron is absolutely right. If you have a type A, 90% lesion and you have

an FFR of 0.81—I know [that] in the US you are in difficulties, at the moment,

with these kinds of lesions. I think with the commonsense kind of medical

entirety/holistic approach that would say you should probably stent these people.

Dr Mehran: But isn’t that just so important? Those are really important points

because it is not about the dichotomous number of 0.80 or 0.75. It is about the

clinician and what they feel the scenario is and how it all fits together.

Dr Waksman: I would say even though it is getting very hard to support by

studies but I may not have an 80% or 70% lesion. I would rather have an FFR of

0.92 or 0.96 than 0.81.

Dr Davies: Absolutely.

Dr Mehran: Of course.

Dr Waksman: If I have the choice. You also have to realize that the stents of

today are not the stents of yesterday. I think we see [many fewer] events. I think

that the price of stenting and the likelihood that we would have events is much

lower than in the past. So even if we deviate a little bit, it I don’t think we do an

injustice to the patients [or] put them at high risk. I would challenge that if you

would [do] the same study today as DEFER, with the new second-generation

stents, I am not sure that the results would be the same—as robust—as they

were in the past. As a matter of fact, if you are looking even [at] FAME-2, at the

two groups—[those who] were medically treated and those who were

[interventionally] treated, the curves were actually very similar. I would challenge

that you [would not be replicating these results] with second-generation [stents].

You have to be taking [FFR] when you really need. I don’t think [that]

systematically you go [to] every lesion and if it meets the criteria of 0.80, you

don’t treat. If it is less, you treat.

Dr Davies: And there are some people who see this as a weakness, but we

don’t do that in any other form of medicine we practice, and I see it as a strength

that you get a continuous range of values. I think the one thing, which we have

also done, is using these techniques purely as an outcome base. But really if you

look back they were designed to describe ischemia and chest pain, so really it is

a very good tool for seeing if chest pain is genuine and if it is likely to benefit from

a stent.

Dr Mehran: That’s right.

Dr. Davies: And that hasn’t been thoroughly explored since the original studies.

Dr Mehran: Those are really excellent points. Now, we have alternatives to FFR.

We talked a little bit about IVUS, but we also know now that, Justin, you have

done a lot of the work on [instantaneous wave-free ratio] iFR. Maybe you can just

tell us: what is iFR? How is it different from FFR and where are we in that? Do

you believe it will replace FFR?

Dr Davies: iFR is a technique which is very similar to perform as FFR. You use

the same pressure wire. It is a software change in the console that essentially

allows us to make a measurement of stenosis severity over a particular phase of

the cardiac cycle without the need for a drug. It typically takes a few seconds to

measure and is very quick.

There have been, to date, about 3000 patients studied, in five clinical trials,

which—with the exception of one study—have all shown, essentially, the same

findings.

And we know at the EuroPCR meeting this was, again, replicated this week. At

the moment, we are in a situation where we are advocating the use of a hybrid

approach, similar to the big RESOLVE study, which essentially says that if you

are above an iFR threshold of 0.93 you are safe to defer and below 0.86, to treat.

That gives you about a 90% to 95% agreement with FFR and overall

classification, and the ADVISE-II study shows it saves about 70% of adenosine.

There are potentially quite marked savings in the cath lab.

I think this is out there in clinical practice—in a limited release, in terms of certain

labs around the world on three continents. The general experience has been

very, very good from people in terms of just facilitating the use of physiology.

What I mean by that: I take centers that were relatively small users of FFR and

they found they have done the same number of cases in three months as they

would have done over the whole year. If you ask them why, it’s because it lowers

the burden of doing [the cases]. I think if we then move on to doing triple-vesseldisease

assessment I think it takes five seconds of each.

Dr Mehran: I think there is no question that taking away the adenosine is music

to a lot of people’s ears. We all know that adenosine is not being given perfectly

right in certain laboratories. It really should be an intravenous injection. There is

time needed for nurses to put it together, to put in the IV, the intra-arterial

[injection] has been refuted, etc.

But when I look at iFR I start to think that we are pushing ourselves toward what

Ron was just talking about. I think the validations need to take place. It would be

great to have technology that is well validated, studied, that actually correlates

with events without adenosine. I think that part of it is brilliant. But are we there

today?

Dr Davies: We have had a very good response taking the stuff from the research

lab into the cath lab, so this is what we are using this as a tool, certainly, within

the framework of studies. I think now we are in a position to do large studies. I

will give you an example: we asked all of the investigators who have got these

machines if they are willing to contribute to analysis at the time of PCI. [In the

space of] for four weeks—most of them only had the device that length of time,

they managed to get together 400 cases. [This shows that] doing very large

studies of 1500 or 2000 patients is extremely feasible and very easy to do.

Dr Mehran: I hope you are designing them and actually performing them.

Ron, what do you think about iFR? I love to hear your scrutiny.

Dr Waksman: I think it hasn’t been validated, obviously. I [would] like to get rid of

the adenosine. But I like to see reproducibility of any test. Again, I would say, we

don’t have to lose our brains just because we have numbers. We have a patient

in front of us. He has symptoms and we have lesions that we have to treat.

Obviously if you have a proximal lesion, it’s going to behave differently than a mid

or distal vessel. We know that, for example, if you look at most of the studies, at

just a circumflex of FFR. Most of them will be above 8.0. But you take most

proximal LADs, they probably would fit more into the predictability of ischemia vs

nonischemia. We have to, again, use our brains when we use the numbers and

understand what they mean.

I think that there will be other technologies that [will] try to be alternatives to

FFR—not that FFR is necessarily bad, but there are other ways that you can do

it. There is the heart flow option with a CT. I still think that IVUS is an option.

Not all of them are ideal, but it gives you a variety of options. The message is: we

are trying to treat only the vessels that need to be treated. I think that can also

change the paradigm of treatment. For example, we may turn “three vessel” to

“one vessel” and change the whole syntax score and move patients from CABG

to PCI—which is very attractive for interventional cardiologists.

One other thing that is interesting: recently I heard that SJ Park was presenting a

systematic use on all patients with FFR—which is amazing! It is over 70%. It was

not a randomized study but what he did show by systematically using FFR in his

practice [is that] he reduced, by a lot, the number of PCIs, the number of stents,

and the outcome of those patients was good. You have to compare it in a

randomized fashion. What would be the alternative? And that is the challenge.

You really have to show [efficacy] in a randomized clinical trial. I recognize there

were studies in the past, but they have limitations. I think we [are] moving to

another phase that this has to be tested.

Dr Mehran: Quickly touching on what you just said about noninvasive functional

assessments. More and more we are getting patients who come in with a

multislice CT. Can we use that technology to actually do some of the functional

assessment right then and there? The DEFACTO trial, in my mind, is a negative

study. Where are we with that technology?

Dr Davies: You are absolutely right to say a lot of these patients have CTs and it

is a question of whether we can use information from that CT. As Ron said, there

is HeartFlow technology, which enables you to effectively get a noninvasive

preprocedural virtual FFR measurement. Certainly from a theoretical perspective,

it should be possible to do these calculations. I think the problem that the

HeartFlow team has is translating the computational flow dynamic theory in a

perfect research environment into the clinical practice of getting good-quality

CTs. I think there is probably more work in progress to see that really translate.

Dr Mehran: That’s right.

Dr Waksman: But what we are seeing in the US right now is [that] there is a

decline in the nuclear test and there is increased uptake in FFR. There is a

change in paradigm because of many reasons. Some of them have nothing to do

with medicine. It is more the reimbursement. Because reimbursement went down

on nuclear tests, we see less nuclear tests being performed. Now we are getting

the patients actually to be assessed in the lab and we get [to have] more

confidence with FFR or other technologies. I think we are shifting the traditional

assessment of ischemia, which was in the old days was nuclear or dobutamine

echo, more into those [tests performed] in the lab. And I do believe that the fact

that studies were negative is not the end of the story. We still have to fine-tune.

This is all about software validation and finding the sweet spot. What is the

window that allows you to get good matching? That you can feel comfortable

[with]?

Dr Mehran: So great technology to look forward to in the future. We are looking

for that kind of noninvasive assessment of functional studies. Let’s now turn to

why we are really here, which is about the regional differences of FFR. In the UK,

in Europe, in the United States, are there regional differences? Let’s better

understand that. And, if so, why? Justin, maybe you could tell us about the UK

and Europe?

Dr Davies: I think [FFR penetration] is somewhere between 15% and 20% of

cases in the UK, which is very high on a worldwide basis. I think some of that has

to do with reimbursement and some of it is to do with the way that doctors are

reimbursed, as well. In terms of the UK, if we put a stent in or not, it has no net

effect on the income to ourselves. So it is very easy for us to follow guidelines

and, in fact, if we don’t, [we] get rapped around the knuckles and told off for not

doing so. I think that is a strong incentive to do it.

I think there are obviously differences from us in other parts of the world with

regard to the reimbursement—the cost of the bits of kit and the availability of the

kit. In some labs around the world, and some territories, getting adenosine is

simply not possible or it is [so] outrageously expensive that people would just say

I am not going to make this measurement and they defer to angiography or, as

Ron said, to IVUS.

Dr Mehran: It seems like the penetration is a little bit the same between the UK

and US? What do you think about the United States?

Dr Waksman: Not yet. I would actually take from what Justin just said. I think

that the main motivation in Europe for the penetration of FFR was monetary. It

was actually to save money to the operator, to the cath lab. This never was the

case in the US. I think the in the US of the uptick is more related to

the appropriateness[-criteria guidelines] and to be on the defensive. The

interventionalist now has to defend himself for every procedure [he is] doing and

to have a backup [as to] why they did this procedure. That was not the case in

the European continent, [where] the main drive was to reduce overall costs on

the capitation system. I always had a problem with that because this is the way

that it was presented and I think that we should give the best to our patients.

We also have to realize that the reason for the uptick could be because of

appropriateness. We actually learned to turn this into a helpful tool for us [and] to

use it not just for those ancillary decisions—that probably should not be related to

the patient (whether it is a cost or whether it is appropriateness), but [also for]

what [it is] really good [for]: to see how we can utilize [it] to do the right procedure

to the right vessel. So it’s another tool.

But as I mentioned before, I think we are seeing an uptick. I don’t think we are

crossing the 20% and we are not as broad as in Europe. When are we going to

get there? It is a question of how much push we are going to see, but one thing

you see [now is] more companies providing FFR systems. That means that there

will be more reps in the labs and more opportunities, and that is usually what will

populate the usage of the device. I have no doubt that we are going to continue

to see an increase.

Dr Davies: It is interesting. I know from the US, and some of the data there,

there is a big difference between diagnostic use of FFR and actually the PCI use.

It is almost used in the US to justify PCI, and I think the angiography use is

somewhere around 3%. If you take that study that SJ Park has just done and you

compare that 70% percent that he was doing with the 3%, there is obviously a

huge potential.

Dr Mehran: Isn’t it interesting that maybe the driving force of doing a functional

assessment in the lab is different in the UK vs the US or Europe vs the United

States? I believe that at the end of the day they both will come to the same

conclusion of doing the right procedure to the right patient, making the correct

diagnosis, treating the right lesion for the right patient, but at the end of the day

actually decreasing costs. While maybe we are seeing in the United States that

appropriate-use criteria is why we are doing this, it has, perhaps, to do with

capitation, as well, for us in the United States, and enhancing the cost in the

system, hopefully, with this kind of functional assessment?

Dr Waksman: I think there is one more important collateral benefit from using

the FFR. That I would say is that we are changing the paradigm. In the old days

we thought we have to treat all the three vessels; we have to have complete

revascularization. I think FFR taught us that actually we may not need to treat all

the three vessels. That is a big advantage of technology. As we are using it we

are starting to see maybe we just have to treat the culprit lesion and move on

and then leave the others either on medical therapy or not treat them at all. That

is a huge change in paradigm.

Dr Mehran: This has been a fantastic conversation among the three of us, and I

just want to close and I want you each to close for me. What do you think is the

future of FFR? What should we be looking forward to as alternatives and what

incorporation of functional assessment in the cath lab as we move to the next

decade of interventional cardiology. Ron?

Dr Waksman: I think that the FFR will continue to grow. I think that there is a

good future for iFR without the adenosine, the wireless, and better wires that you

can use. I think you [could] incorporate an IVUS probe in them—FFR on an IVUS

probe, so you can do both. I think that the combination of anatomical and

physiological [testing] is important. We learned that with IVUS you can optimize

the outcome of the PCI, not only just determine whether you treat or not. So the

future is there. We are coming to do more sophisticated PCIs, and these data will

help us to get better outcomes and also to triage the patients to what should be

the treatment of choice. In the long run—even though the short run shows

reduction of the PCIs—if we use [FFR] carefully it will open us or enable us to do

more complex patients and meet the outcome that is expected.

Dr Mehran: That’s great. Justin?

Dr Davies: I would agree with Ron’s thoughts and also extend them to say I think

we will be doing more of these measurements, but I also think we should be

doing more smartly. As we discussed earlier, if you get these very borderline

lesions in patients who clearly have angina, then this is an indication for treating

your patient and looking at the patient as a whole.

I think we are really going to embrace technology. Medicine is always a little bit

behind the kind of technological leaps compared with smartphones, for instance.

I think techniques such as the HeartFlow technique, techniques such as the ones

we have been working on with iFR, I think will continue to move forward. I think

whereas we only today have discussed things from the purely diagnostic single

ischemic perspective, I think within one or two years you are going to have

techniques freely available in the cath lab that enable us to coregister the

FFR/iFR images onto angiogram in real time, enable you to plan PCI by selecting

which lesions may or may not benefit from therapy, even before you deploy a

stent. I think this, in the SYNTAX era, where we know the potential benefits of

minimizing angioplasty, like Ron said, will really facilitate our practice, and I

suppose the most important thing is lead to the better results for our patients.

Dr Mehran: I think that you both did a beautiful job telling us about the current

and the future technology and even if there are regional differences, at the end of

the day what we are trying to do is use the functional assessment to enhance

outcomes for our patients with cardiovascular disease, to make the right

diagnostic and therapeutic choices in these patients. And the combination of

these technologies that currently exists and hopefully will exist in the future will

absolutely get us there.

Thank you so much for your time this morning and I hope our audience enjoys

this conversation as I did. Thank you.

SOURCES

http://media.theheart.org/pdf/FFR-state-of-the-nation.pdf

http://www.theheart.org/editorial-program/1550783.do?utm_medium=email&utm_source=20130704_heartwire&utm_campaign=newsletter

On this Open Access Online Scientific Journal the following articles published cases and results on Tools for Ischemic Assessment

 Advanced CT Reconstruction: Plaque Estimation Algorithm for Fewer Errors and Semiautomation

https://pharmaceuticalintelligence.com/2013/04/18/advanced-ct-reconstruction-plaque-estimation-algorithm-for-fewer-errors-and-semiautomation/

Detection and quantification of myocardial perfusion … – MDLinx

https://pharmaceuticalintelligence.com/2013/05/16/detection-and-quantification-of-myocardial-perfusion-mdlinx/

CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC

https://pharmaceuticalintelligence.com/2013/05/16/ct-angiography-ccta-reduced-medical-resource-utilization-compared-to-standard-care-reported-in-jacc/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

https://pharmaceuticalintelligence.com/2012/08/09/coronary-ct-angiography-versus-standard-evaluation-in-acute-chest-pain/

Stress CMR for CAD Matches Prognostic Utility of More Established Techniques – TCTMD

https://pharmaceuticalintelligence.com/2013/06/26/stress-cmr-for-cad-matches-prognostic-utility-of-more-established-techniques-tctmd/

Accurate Identification and Treatment of Emergent Cardiac Events

https://pharmaceuticalintelligence.com/2013/03/15/accurate-identification-and-treatment-of-emergent-cardiac-events/

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

https://pharmaceuticalintelligence.com/2013/04/25/contributions-to-vascular-biology/

Revascularization: PCI, Prior History of PCI vs CABG

https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Accurate Identification and Treatment of Emergent Cardiac Events

https://pharmaceuticalintelligence.com/2013/03/15/accurate-identification-and-treatment-of-emergent-cardiac-events/

Read Full Post »


Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/29/2018

 

HDL-C: Is It Time to Stop Calling It the ‘Good’ Cholesterol? – Medscape – Jul 27, 2018.

 

In Eli Lilly’s Pipeline: DISCONTINUING Evacetrapib, a CETP inhibitor that’s meant to boost HDL

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/10/12/in-eli-lillys-pipeline-discontinuing-evacetrapib-a-cetp-inhibitor-thats-meant-to-boost-hdl/

 

On April 3, 2012 we published

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme.

LCAT, an enzyme in the bloodstream, is a key component in the reverse cholesterol transport (RCT) system, which is thought to play a major role in driving the removal of cholesterol from the body and may be critical in the management of high-density lipoprotein (HDL) cholesterol levels.  The LCAT enzyme could also play a role in a rare, hereditary disorder called familial LCAT deficiency (FLD) in which the LCAT enzyme is absent.

https://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

On April 4, 2013, the next day, a new study was published on a novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects was published on Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Writer’s VIEWS:

    • AstraZeneca acquisition of AlphaCore represents its market entry into the CETP inhibitor segment via an acquisition where the company did not have presence or inhouse research. The results of the second study will position Merck at a superior position upon completion of Phase III Clinical Trials for Anacetrapib
    • If Biologics will help increase HDL in wide market penetration, the market share of Statins will be negatively impacted. Patent expiration and generic market availability of Statin erode future profits
    • Anacetrapib in in Phase III clinical Trial, if successfully completed — will be the FIRST biologics to use CETP inhibition biology of lipid metabolism in the quest to fight atherosclerosis by improving CVD outcomes
    • A connection between this two events and cites in Disclosure, AstraZeneca, Merck, supporting the research of Christopher P Cannon on the study on Anacetrapib.
    • Full Article PDF file was published in Research Reports in Clinical Cardiology, one of the Journals on Beall’s list publisher, where scientists pay to have the article been published, Dove Press, on its Web site says, “There are no limits on the number or size of the papers we can publish.” See reference for Beall’s list publishers http://www.nytimes.com/2013/04/08/health/for-scientists-an-exploding-world-of-pseudo-academia.html?pagewanted=1&_r=0&emc=eta1

Study Goals:

  • testing the hypothesis that CETP inhibition may reduce atherosclerotic outcomes. 
  • answer important questions regarding the role of CETP in the biology of lipid metabolism and atherosclerosis.

Research Reports in Clinical Cardiology, 4 April 2013 Volume 2013:4 Pages 39 – 53

Dylan L Steen,1 Amit V Khera,2 Christopher P Cannon1

1TIMI Study Group, Cardiovascular Division, 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Disclosure

Dr Cannon is a member of the advisory boards of and has received grant support from Alnylam, Bristol-Myers Squibb, Pfizer, and CSL Behring; has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; and is a clinical advisor to Automated Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper.

Abstract: Despite major advances in cardiovascular care in recent decades, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Statins have been shown to reduce cardiovascular events by 25%–40% in a dose-dependent fashion; yet additional therapies are needed to reduce vascular disease progression and acute thrombotic events. In addition to low-density lipoprotein cholesterol (LDL-C) reduction, other lipid risk factors, such as low high-density lipoprotein cholesterol (HDL-C), have created interest as therapeutic targets to lower cardiovascular risk. However, the absence of compelling data for incremental benefit of non-LDL-centric therapies in the statin era has limited their clinical use. A novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects. While in vitro and animal data for CETP inhibition have been encouraging, the initial enthusiasm for the class has been tempered by the failure of two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III trials to reduce cardiovascular outcomes. Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Keywords: anacetrapib, cholesteryl ester transfer protein, cholesteryl ester transfer protein inhibitor, atherosclerosis

  • Niacin, which augments HDL-C by 20%–25%, recently failed to lower atherosclerotic events in both the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH)6 and Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials.7,8
  • Lp(a) lowering has not yet been evaluated in randomized controlled trials, but observational and genetic (including Mendelian randomization) analyses have demonstrated an independent association of increased Lp(a) levels with increased CV events, suggesting Lp(a) lowering may confer benefit.9
  • surprising failure of the first two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III outcomes trials has somewhat tempered this initial excitement and forced a re-evaluation of the complex effects of CETP inhibition on lipid metabolism and vascular biology.
  • Anacetrapib results in near-complete CETP inhibition with more pronounced lipid effects than its predecessors and is currently in a Phase III study for secondary prevention of coronary events. If successful it is likely that anacetrapib will also be considered for statin-intolerant patients and for primary prevention in patients who require LDL-C lowering beyond statin monotherapy
  • Human CETP is a 476-residue, 74 kDa, hydrophobic glycoprotein primarily secreted by the liver and adipose tissue.13 CETP was first cloned in 1987.14 The structure of CETP allows formation of a tunnel with the opening on one end interacting with HDL and the other with a very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), or LDL particle. The hydrophobic central cavity of this tunnel is large enough to allow transfer of neutral lipids (eg, cholesteryl esters [CEs], triglycerides [TGs]) from donor to acceptor particles, but conformational changes may occur to accommodate larger lipoprotein particles. The concave surface of CETP matches the curvature of the HDL particles to which it is primarily bound in the bloodstream.15,16
  • The overall effect of CETP is a net transfer of CE from HDL to these apolipoprotein B (apoB)-containing particles and TG to HDL and LDL
  • An important driver of the transfer of CE from HDL to apoB-containing particles is the production of CE from free cholesterol within HDL by lecithin acetyltransferase (LCAT).17

    The role of CETP in reverse cholesterol transport.

    Beginning in the peripheral tissues, free cholesterol is predominantly taken up by small “immature” HDL particles (eg, pre-β-HDL) via the ABCA1 transporter. Alternatively, it can be taken up by larger “mature” HDL particles (eg, HDL2) via the ABCG1 transporter. LCAT converts free cholesterol into cholesteryl ester, which is then shuttled to apoB-lipoproteins (eg, LDL, VLDL) in exchange for triglycerides. Only a minority of cholesteryl ester is delivered directly to the liver by HDL via the SR-BI; the majority is delivered indirectly to the liver by apoB-lipoproteins via the LDL recepter.

    Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; LCAT, lecithin acetyltransferase; apoB, apolipoprotein B; LDL, low-density lipoprotein; VLDL, very low density lipoprotein; SR-BI, scavenger receptor-BI; FC, free cholesterol; CE, cholesteryl ester.

  • One of the interesting questions in CETP deficiency is whether the HDL particles produced by potent CETP inhibition are functional. Regardless of whether reverse cholesterol transport is increased, the initial steps of cholesterol efflux from foam cells may be one of the key anti-atherogenic functions of HDL.5
  • This increased efflux is related to the very high content of LCAT and apoE in these large HDL particles, presumably driving net cholesterol efflux by promoting cholesterol esterification.36
  • effect of CETP deficiency on liver uptake of cholesteryl ester, an important downstream step in a reverse cholesterol transport. These studies suggest that there may be increased CE uptake via SR-BI as well as through a high affinity of large apoE-rich HDL for LDL receptors.20
  • meta-analysis established that three CETP genotypes were not only associated with decreased CETP activity and increased HDL but also with a lower risk of myocardial infarction (MI). For example, for each allele inherited, individuals with the TaqIB polymorphism had lower mean CETP activity (−8.6%), higher mean HDL-C (4.5%), higher mean apoA-I (2.4%), and an odds ratio for coronary disease of 0.95 (95% confidence intervals [CI], 0.92, 0.99). Similar associations were found for the other two CETP genotypes.40
  • Subsequent studies have confirmed that genetic variants leading to reduced CETP activity and its corresponding anti-atherogenic lipid profile are associated with reduced atherosclerotic outcomes.41–43
  • In ILLUSTRATE, an inverse association between HDL-C achieved and the primary endpoint of atheroma volume (r = −0.17, P , 0.001) was found. In addition, the highest quartile of HDL-C achieved (.86 mg/dL) demonstrated atheroma regression, suggesting that there may be a “threshold effect” to HDL-C elevation.68
  • Other CETP inhibitors:

Dalcetrapib
was developed by Hoffmann–La Roche until May 2012. It did not raise blood pressure and did raise HDL, but it showed no clinically meaningful efficacy.

Evacetrapib 

is under development by Eli Lilly & Company.
Torcetrapib
was developed by Pfizer until December 2006 but caused unacceptable increases in blood pressure and had net cardiovascular detriment.
Anacetrapib At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg. Merck performed a dose-ranging study of anacetrapib, with the results presented in 2009.

Anacetrapib 

Anacetrapib is a 3,5-bis-trifluoromethyl-benzene derivative with similar binding properties to CETP as torcetrapib. The compound was developed when it was found that a substitution modification of the oxazolidinone ring increased its potency for CETP inhibition in a transgenic mouse model.85 In terms of its pharmacokinetics and pharmacodynamics, anacetrapib is rapidly absorbed with a time-to-peak plasma concentration of about 4 hours. The oral bioavailability of anacetrapib is poor, with only about 20% being absorbed; however at this exposure, LDL-C is reduced up to 40% and HDL-C increased up to 140%. It is recommended that anacetrapib be taken with food (ie, low-fat diet) to increase drug exposure (and efficacy) as well as compliance.86

Anacetrapib is highly protein bound (eg, CETP) in the plasma (.99.5%). It is cleared by oxidative metabolism via Cytochrome P450 3A4 (CYP3A4) with excretion of the metabolites via the biliary/fecal route. Only a trace amount is eliminated by urinary excretion.87 Importantly, while anacetrapib is a sensitive CYP3A4 substrate, anacetrapib neither inhibits nor induces CYP3A4 activity. No meaningful interactions have been found between anacetrapib and simvastatin, digoxin, or warfarin.86 Anacetrapib in part to its redistribution to adipose tissue has a long terminal half-life.88

In terms of safety endpoints, anacetrapib demonstrated no increase in side effects (including myalgia), drug-related adverse effects, adverse events leading to drug discontinuation, or other important safety endpoints, such as BP, electrolyte, aldosterone, creatinine kinase, or transaminase levels. A very small increase in C-reactive protein of undetermined significance was seen with anacetrapib, which notably was also reported with torcetrapib and dalcetrapib in their Phase III studies. It is unknown whether this is a class effect as the small sample size in the evacetrapib Phase II study limits evaluation of small C-reactive protein changes.

It is expected that the REVEAL (the Phase III) population will also have lower starting LDL-C levels, both because statin-intolerant subjects will not be enrolled and because of more stringent lipid entry criteria. The final major difference is that the primary endpoint in REVEAL is focused on coronary events, while ACCELERATE has a broader primary endpoint. A broader primary endpoint along with a slightly higher risk population will allow for a shorter follow-up duration and much smaller sample size in ACCELERATE.

Conclusion

  • CETP remains a valid target and that the lipid changes resulting from its inhibition may be protective. The biology of CETP inhibition is complex, and questions remain regarding which lipid changes (eg, reductions in LDL and Lp(a), increases in HDL) are most likely to be important and whether there are still unknown effects that may negate any overall clinical benefit.
  • if potent CETP inhibition is found to be beneficial, it is still unclear whether this effect will be homogeneous or vary based on individual metabolism.
  • anacetrapib-induced HDL (especially the apoE-rich HDL2 particles) may have an enhanced ability for reverse cholesterol transport without any known adverse effects. Importantly, if a threshold effect for HDL-C augmentation exists, the vast majority of patients taking anacetrapib would be expected to cross it.
  • Despite a difficult beginning for the class of CETP inhibitors, anacetrapib and evacetrapib hold promise as future therapies for patients with atherosclerosis
REFERENCES

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–1681.

2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–1504.

3. Steinberg D. The rationale for initiating treatment of hypercholesterolemia in young adulthood. Curr Atheroscler Rep. 2013;15(1):296.

4. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. the framingham study. Am J Med. 1977;62(5):707–714.

5. Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA. The HDL hypothesis: Does high-density lipoprotein protect from atherosclerosis? J Lipid Res. 2010;51(8):2058–2073.

6. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–2267

7. Armitage J, Baigent C, Chen Z, Landray M. Treatment of HDL to reduce the incidence of vascular events HPS2-THRIVE. Available from: http://clinicaltrials.gov/ct2/show/NCT00461630. Updated 2010. Accessed February 1, 2012.

8. Merck announces HPS2-THRIVE study of TREDAPTIVE (extended-release Niacin/Laropriprant) did not achieve primary endpoint. Available from: http://www.mercknewsroom.com/press-release/prescription-medicine-news/merck-announces-hps2-thrive-study-tredaptive-extended-relea. Updated 2012. Accessed December 31, 2012.

9. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: A rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol. 2012;60(8):716–721.

10. Brown ML, Inazu A, Hesler CB, et al. Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature. 1989;342(6248):448–451.

11. Inazu A, Brown ML, Hesler CB, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323(18):1234–1238.

12. Ohtani R, Inazu A, Noji Y, et al. Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects. Clin Chim Acta. 2012;413(5–6):537–543.

13. Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: At the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J. 2010;31(2):149–164.

14. Drayna D, Jarnagin AS, McLean J, et al. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature. 1987;327(6123): 632–634.

15. Qiu X, Mistry A, Ammirati MJ, et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol. 2007;14(2):106–113.

16. Zhang L, Yan F, Zhang S, et al. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat Chem Biol. 2012;8(4):342–349.

17. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: A novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160–167.

18. Niesor EJ. Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism. Curr Opin Lipidol. 2011;22(4):288–295.

19. Arai T, Tsukada T, Murase T, Matsumoto K. Particle size analysis of high density lipoproteins in patients with genetic cholesteryl ester transfer protein deficiency. Clin Chim Acta. 2000;301(1–2):103–117.

20. Yamashita S, Sprecher DL, Sakai N, Matsuzawa Y, Tarui S, Hui DY. Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency. J Clin Invest. 1990;86(3):688–695.

21. Ikewaki K, Nishiwaki M, Sakamoto T, et al. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest. 1995;96(3):1573–1581.

22. Millar JS, Brousseau ME, Diffenderfer MR, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipo­protein B100 metabolism in humans. Arterioscler Thromb Vasc Biol. 2006;26(6):1350–1356.

23. Rosenson RS, Brewer HB Jr, Davidson WS, et al. Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation. 2012;125(15):1905–1919.

24. Foger B, Chase M, Amar MJ, et al. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem. 1999;274(52):36912–36920.

25. Hayek T, Masucci–Magoulas L, Jiang X, et al. Decreased early athero­sclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J Clin Invest. 1995;96(4):2071–2074.

26. MacLean PS, Bower JF, Vadlamudi S, et al. Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice. Arterioscler Thromb Vasc Biol. 2003;23(8):1412–1415.

27. Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature. 1993;364(6432):73–75.

28. Plump AS, Masucci–Magoulas L, Bruce C, Bisgaier CL, Breslow JL, Tall AR. Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol. 1999;19(4):1105–1110.

29. Westerterp M, van der Hoogt CC, de Haan W, et al. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggra­vates atherosclerosis in APOE*3-leiden mice. Arterioscler Thromb Vasc Biol. 2006;26(11):2552–2559.

30. Tanigawa H, Billheimer JT, Tohyama J, Zhang Y, Rothblat G, Rader DJ. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation. 2007;116(11): 1267–1273.

31. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res. 2004;45(9):1594–1607.

32. Khera AV, Wolfe ML, Cannon CP, Qin J, Rader DJ. On-statin choles­teryl ester transfer protein mass and risk of recurrent coronary events (from the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 [PROVE IT-TIMI 22] study). Am J Cardiol. 2010;106(4):451–456.

33. Evans GF, Bensch WR, Apelgren LD, et al. Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholester­olemic hamsters: Effects on HDL subspecies, quantity, and apolipo­protein distribution. J Lipid Res. 1994;35(9):1634–1645.

34. Rittershaus CW, Miller DP, Thomas LJ, et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2000;20(9):2106–2112.

35. Sugano M, Makino N, Sawada S, et al. Effect of antisense oligonucle­otides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J Biol Chem. 1998;273(9): 5033–5036.

36. Matsuura F, Wang N, Chen W, Jiang XC, Tall AR. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest. 2006;116(5):1435–1442.

37. Curb JD, Abbott RD, Rodriguez BL, et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coro­nary heart disease in the elderly. J Lipid Res. 2004;45(5): 948–953.

38. Moriyama Y, Okamura T, Inazu A, et al. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med. 1998;27(5 Pt 1): 659–667.

39. Zhong S, Sharp DS, Grove JS, et al. Increased coronary heart disease in Japanese–American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996;97(12): 2917–2923.

40. Thompson A, Di Angelantonio E, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activ­ity, lipid levels, and coronary risk. JAMA. 2008;299(23):2777–2788.

41. Ridker PM, Pare G, Parker AN, Zee RY, Miletich JP, Chasman DI. Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18 245 initially healthy women from the women’s genome health study. Circ Cardiovasc Genet. 2009;2(1):26–33.

42. Voight BF, Peloso GM, Orho–Melander M, et al. Plasma HDL cho­lesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet. 2012;380(9841):572–580.

43. Johannsen TH, Frikke–Schmidt R, Schou J, Nordestgaard BG, Tybjaerg–Hansen A. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol. 2012;60(20):2041–2048.

submit your manuscript | http://www.dovepress.com Dovepress Dovepress 51 Anacetrapib for coronary heart disease Research Reports in Clinical Cardiology 2013:4

44. Clark RW, Ruggeri RB, Cunningham D, Bamberger MJ. Descrip­tion of the torcetrapib series of cholesteryl ester transfer pro­tein inhibitors, including mechanism of action. J Lipid Res. 2006;47(3):537–552.

45. Ranalletta M, Bierilo KK, Chen Y, et al. Biochemical characterization of cholesteryl ester transfer protein inhibitors. J Lipid Res. 2010;51(9): 2739–2752.

46. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350(15):1505–1515.

47. Clark RW, Sutfin TA, Ruggeri RB, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: An initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol. 2004;24(3):490–497.

48. McKenney JM, Davidson MH, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Am Coll Cardiol. 2006;48(9): 1782–1790.

49. Morehouse LA, Sugarman ED, Bourassa PA, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclero­sis in New Zealand White rabbits. J Lipid Res. 2007;48(6): 1263–1272.

50. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21): 2109–2122.

51. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356(16):1620–1630.

52. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADI­ANCE 2 study): A randomised, double-blind trial. Lancet. 2007;370(9582):153–160.

53. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13): 1304–1316.

54. Hu X, Dietz JD, Xia C, et al. Torcetrapib induces aldosterone and cor­tisol production by an intracellular calcium-mediated mechanism inde­pendently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150(5):2211–2219.

55. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompa­nied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154(7):1465–1473.

56. DePasquale M, Cadelina G, Knight D, et al. Mechanistic studies of blood pressure in rats treated with a series of cholesteryl ester transfer protein inhibitors. Drug Develop Res. 2009;70(10.1002/ddr.20282):35.

57. Clerc RG, Stauffer A, Weibel F, et al. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010;28(8): 1676–1686.

58. Sofat R, Hingorani AD, Smeeth L, et al. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation. 2010;121(1): 52–62.

59. Blasi E, Bamberger M, Knight D, et al. Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure. J Cardiovasc Pharmacol. 2009;53(6):507–516.

60. Connelly MA, Parry TJ, Giardino EC, et al. Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition. J Cardiovasc Pharmacol. 2010;55(5):459–468.

61. Simic B, Hermann M, Shaw SG, et al. Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33(13):1615–1624.

62. Westerterp M, Koetsveld J, Tall AR. Cholesteryl ester transfer protein inhibition: A dysfunctional endothelium. J Cardiovasc Pharmacol. 2010;55(5):456–458.

63. Guerin M, Le Goff W, Duchene E, et al. Inhibition of CETP by torce­trapib attenuates the atherogenicity of postprandial TG-rich lipoproteins in type IIB hyperlipidemia. Arterioscler Thromb Vasc Biol. 2008;28(1): 148–154.

64. Yvan–Charvet L, Matsuura F, Wang N, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27(5): 1132–1138.

65. Tall AR. The effects of cholesterol ester transfer protein inhibition on cholesterol efflux. Am J Cardiol. 2009;104(Suppl 10):39E–45E.

66. Tchoua U, D’Souza W, Mukhamedova N, et al. The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse choles­terol transport. Cardiovasc Res. 2008;77(4):732–739.

67. Briand F, Thieblemont Q, Andre A, Ouguerram K, Sulpice T. CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. Clin Transl Sci. 2011;4(6):414–420.

68. Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: Insights from ILLUSTRATE (investigation of lipid level management using coronary ultrasound to assess reduction of atherosclerosis by CETP inhibition and HDL elevation). Circulation. 2008;118(24):2506–2514.

69. Fryirs MA, Barter PJ, Appavoo M, et al. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol. 2010;30(8):1642–1648.

70. Barter PJ, Rye KA, Tardif JC, et al. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Circulation. 2011;124(5):555–562.

71. Funder JW. Aldosterone, hypertension and heart failure: Insights from clinical trials. Hypertens Res. 2010;33(9):872–875.

72. Kuivenhoven JA, de Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combina­tion with pravastatin in type II dyslipidemia. Am J Cardiol. 2005;95(9): 1085–1088.

73. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406(6792):203–207.

74. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: A randomized phase II dose-response study. Circulation. 2002;105(18):2159–2165.

75. Niesor EJ, Magg C, Ogawa N, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010;51(12): 3443–3454.

76. Derks M, Anzures–Cabrera J, Turnbull L, Phelan M. Safety, tolerability and pharmacokinetics of dalcetrapib following single and multiple ascending doses in healthy subjects: A randomized, double-blind, placebo-controlled, phase I study. Clin Drug Investig. 2011;31(5):325–335.

77. Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): Results from a 48-week trial. Eur Heart J. 2010;31(4):480–488.

78. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalce­trapib on atherosclerotic disease using novel non-invasive multimo­dality imaging (dal-PLAQUE): A randomised clinical trial. Lancet. 2011;378(9802):1547–1559.

79. Luscher TF. Effects of dalcetrapib on vascular function: Results of phase IIb dal-VESSEL study. Available from: http://www.escardio.org/about/press/press-releases/esc11-paris/Pages/HL1-dal-VESSEL.aspx. Updated 2011. Accessed February 1, 2012.

80. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: Efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158(6):896–901. e3.

81. Miller R. Roche stops dalcetrapib trial for lack of benefit. Available from: http://www.theheart.org/article/1395141.do. Updated 2012. Accessed June 21, 2012.

82. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–2099.

83. Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP Inhibitor evacetrapib administered as monotherpay or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099-2109.

84. Eli Lilly and Company. A study of evacetrapib in high-risk vascular disease (ACCELERATE); NCT01687998. Available from: http://www.clinicaltrials.gov/ct2/show/study/NCT01687998?term=evacetrapib&rank=3. Updated 2012. Accessed November 17, 2012.

85. Smith CJ, Ali A, Hammond ML, et al. Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: Modifica­tions of the oxazolidinone ring leading to the discovery of anacetrapib. J Med Chem. 2011;54(13):4880–4895.

86. Gutstein DE, Krishna R, Johns D, et al. Anacetrapib, a novel CETP inhibitor: Pursuing a new approach to cardiovascular risk reduction. Clin Pharmacol Ther. 2012;91(1):109–122.

87. Kumar S, Tan EY, Hartmann G, et al. Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. Drug Metab Dispos. 2010;38(3):474–483.

88. Dansky HM, Bloomfield D, Gibbons P, et al. Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia. Am Heart J. 2011;162(4): 708–716.

89. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157(2):352–360. e2.

90. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: Two double-blind, randomised placebo-controlled phase I studies. Lancet. 2007;370(9603):1907–1914.

91. Krauss RM, Wojnooski K, Orr J, et al. Changes in lipoprotein subfrac­tion concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res. 2012;53(3): 540–547.

92. Krishna R, Bergman AJ, Green M, Dockendorf MF, Wagner JA, Dykstra K. Model-based development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor. AAPS J. 2011;13(2): 179–190.

93. Yvan–Charvet L, Kling J, Pagler T, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30(7):1430–1438.

94. Castro–Perez J, Briand F, Gagen K, et al. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. J Lipid Res. 2011;52(11):1965–1973.

95. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib. Am Heart J. 2009;158(4):513–519. e3.

96. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406–2415.

97. Davidson M, Liu SX, Barter P, et al. Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib. J Lipid Res. 2013;54(2):467–472.

98. Brinton E, Liu S, Stepanavage M, et al. Lipid-modifying effects of anacetrapib in patients with lower versus higher baseline levels of HDL-C, LDL-C, and TG: Pre-specified subgroup analyses of the DEFINE (determining the efficacy and tolerability of CETP INhibition with AnacEtrapib) trial. Circulation. 2011;124:A9649.

99. Gotto A, Cannon C, Shah S, et al. Lipid modifying effects of anacetrapib: Pre-specified subgroup analyses. Circulation. 2011;124: A15035.

100. Bowman L. REVEAL: Randomized EValuation of the effects of anacetrapib through lipid-modification. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01252953?term=anacetrapib&rank=4. Updated 2011. Accessed June 25, 2012.

101. Cannon CP. High-density lipoprotein cholesterol as the Holy Grail. JAMA. 2011;306(19):2153–2155 Research Reports in Clinical Cardiology 2013:4

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Reporter: Aviva Lev-Ari, PhD, RN

German firm Alacris Theranostics today announced a deal with GlaxoSmithKline for the application of Alacris’ Modcell System for drug stratification.

The technology, which was developed at the Max Planck Institute for Molecular Genetics and is licensed exclusively to Alacris, will be used by GSK for early stage cancer drug discovery. GSK will provide Alacris with preclinical biology data from a cancer drug discovery project. Alacris will apply its systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial,” and then suggest cancer cell lines, as well as cancers, that may be likely responders to the inhibitor.

The process will be based on whole-genome and transcriptome data integrated in Alacris’ cancer model ModCell.

Financial terms of the deal were not disclosed.

Based in Berlin, Alacris develops personalized medicine approaches directed at cancer. Its ModCell approach is based on next-generation sequencing and kinetic pathway information, as well as mutation and drug databases.

SOURCE:

http://www.genomeweb.com//node/1153161?hq_e=el&hq_m=1408239&hq_l=2&hq_v=e1df6f3681

 

What is the strategy of the Competition

Foundation Medicine, AstraZeneca to ID Genetic Mutations for Cancer Drug Development

November 12, 2012

NEW YORK (GenomeWeb News) – Foundation Medicine today announced a deal with AstraZeneca aimed at predicting a patient’s response or resistance to targeted medicines.

The firms are partnering to identify genomic mutations in cancer-related tumor genes that may prove helpful to AstraZeneca in developing new therapies for patients. Foundation Medicine also was granted right of first negotiation for developing potential diagnostic products.

According to Susan Galbraith, vice president and head of the AstraZeneca Oncology Innovative Medicines Unit, the collaboration will allow the drug firm to “identify tumor-specific defects and alterations that can be used for patient segmentation.”

Financial and other terms of the agreement were not disclosed.

“We are helping companies like AstraZeneca achieve deeper insight into their programs and trials with our unique cancer expertise and our ability to provide genomic information that can impact clinical treatment decisions,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement. “Together, we expect to enable a more individualized, targeted approach to cancer drug development and clinical trials.”

The partnership is the most recent in a string of deals that Cambridge, Mass.-based Foundation Medicine has forged in recent months with drug firms. It follows a collaboration with Eisai last month, Clovis Oncologyin August, and Novartis in June.

SOURCE:

Life Tech to Partner with Bristol-Myers Squibb for CDx Development

September 17, 2012

NEW YORK (GenomeWeb News) – Life Technologies said today that it would collaborate with Bristol-Myers Squibb to develop companion diagnostics. Initially, the companies will partner on an oncology project with the option to expand collaborative efforts across a range of disease areas.

Life Tech will utilize a variety of its technology platforms including both next-generation and Sanger sequencing instruments, qPCR, flow cytometry, and immuno-histochemistry.

“The pharmaceutical industry is increasingly turning its focus to discovering and delivering targeted, personalized medications,” Life Tech’s President of Medical Sciences, Ronnie Andrews, said in a statement. “As more and more targeted drugs come onto the market in the next decade, there will be a growing need for diagnostics that can help predict which patients will benefit from which drugs.”

The agreement is part of Life Tech’s strategy to expand and develop its diagnostic business through both internal development and also partnerships and acquisitions.

Internally, the company has said that it plans to build out its medical sciences business across multiple technologies and develop assays across five disease areas: oncology, inherited disease, neurological disorders, transplant diagnostics, and infectious diseases.

In addition, in July it acquired direct-to-consumer genomic testing company Navigenics, which gave Life Tech access to its CLIA certified laboratory.

SOURCE:

http://www.genomeweb.com/sequencing/life-tech-partner-bristol-myers-squibb-cdx-development

 

Life Tech, Boston Children’s Hospital to Develop Sequencing Workflows on Ion Proton in CLIA Lab

June 20, 2012

NEW YORK (GenomeWeb News) – Life Technologies said today that it will collaborate with Boston Children’s Hospital to develop next-generation sequencing workflows in a CLIA and CAP certified laboratory.

As part of the collaboration, the hospital plans to purchase Life Tech’s Ion Proton, a benchtop, semiconductor sequencing machine.

David Margulies, director of the Gene Partnership Program at Boston Children’s Hospital, said in statement that the deal is an “important first step toward providing informed, personalized care for patients whose conditions are difficult to treat.”

The deal is Life Tech’s second announced this week to develop sequencing protocols for the Ion Proton in collaboration with a children’s hospital. Earlier this week, it said it would work with the Hospital for Sick Children in Toronto, which has launched a new Centre for Genetic Medicine and plans to install four Proton machines.

Paul Billings, Life Tech’s chief medical officer, commented in a statement that these kinds of partnerships are “essential to our medical sciences strategy as we seek to assist researchers in discovering improved diagnostics and treatments for genetic conditions.”

In a separate announcement today, Life Tech said that it is collaborating with the University of North Texas Health Science Center’s Institute of Applied Genetics to use the firm’s Ion Personal Genome Machine system to further the center’s forensic DNA research. Life Tech said that it will collaborate with the center to train forensic analysts in applying next-gen sequencing to their research.

Foundation Medicine, Novartis Ink New Deal for Clinical Oncology Programs

June 07, 2012

NEW YORK (GenomeWeb News) – Foundation Medicine today said it and Novartis have reached a new agreement to use Foundation’s clinical grade, next-generation sequencing to support the drug firm’s clinical oncology programs.

The three-year agreement builds on a 2011 deal between the firms and calls for the use of Foundation Medicine’s molecular information platform across many of Novartis’ Phase 1 and Phase 2 oncology clinical programs. The initial collaboration generated “very interesting” data, and this type of tumor genomic profiling has become an important part of Novartis’ clinical trials, Foundation Medicine said.

Foundation Medicine’s sequencing capabilities allow for the rapid analysis of hundreds of cancer-related genes from formalin-fixed, paraffin-embedded tumor samples, and earlier this year its laboratory in Cambridge, Mass., gained Clinical Laboratory Improvement Amendments certification. Novartis plans to use the technology to align clinical trial enrollment and outcome analysis with the genomic profile of patient tumors, accelerating the development of Novartis’ portfolio of targeted cancer therapeutics and expanding treatment options for patients.

Foundation Medicine added that it may develop additional diagnostic products from the partnership.

“The comprehensive molecular assessment of Novartis’ Oncology clinical trial samples is expected to help to bring potentially lifesaving therapies to the right patients more quickly, and we expect that the wealth of molecular information will help fundamentally improve the way cancer is understood and treated,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement.

Financial and other terms of the deal were not disclosed.

SOURCE:

Carestream Teams with Beatson Institute on Molecular Imaging Efforts

May 14, 2012
NEW YORK (GenomeWeb News) – Carestream Molecular Imaging announced today that it will collaborate with the Beatson Institute for Cancer Research on preclinical imaging approaches in oncology.

The partners will use Carestream’s Alibri trimodal imaging system, which combines PET, SPECT, and CT modalities in one platform. The system is being used by the Beatson Institute in its research into cancer cell behavior, as well as the development of new therapeutic, diagnostic, and prognostic tools.

The Beatson Institute, which is a core-funded institute of Cancer Research UK and is based in Glasgow, Scotland, said the Carestream technology would be used by its own researchers, as well as its close collaborators including the West of Scotland Cancer Center.

“The combination of PET, SPECT, and CT technologies in one instrument provides investigators at our institutions the flexibility to support research programs across many areas of cancer research such as biomarker, theranostics, and drug development,” Kurt Anderson, research professor and director of the Beatson Advanced Imaging Resource, said in a statement.

 

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Reporter: Aviva Lev-Ari, PhD, RN

Ten Biotech Powerhouses Such as Abbott Laboratories (ABT),AstraZeneca PLC (AZN) Unite to Form TransCelerate BioPharma Inc. to Accelerate the Development of New Meds

TransCelerate – New Non-Profit Organization to Speed Pharmaceutical R&D,  headquartered in Philadelphia

“This initiative is complementary to efforts of CTTI, and we look forward to working with TransCelerate BioPharma to improve the conduct of clinical trials.”
As shared solutions in clinical research and other areas are developed, TransCelerate will involve industry alliances including:

9/19/2012 9:29:28 AM

PHILADELPHIA, Sept. 19, 2012 /PRNewswire/ — Ten leading biopharmaceutical companies announced today that they have formed a non-profit organization to accelerate the development of new medicines. Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson, Pfizer, Genentech a member of the Roche Group, and Sanofi launched TransCelerate BioPharma Inc. (“TransCelerate”), the largest ever initiative of its kind, to identify and solve common drug development challenges with the end goals of improving the quality of clinical studies and bringing new medicines to patients faster.

 

Through participation in TransCelerate, each of the ten founding companies will combine financial and other resources, including personnel, to solve industry-wide challenges in a collaborative environment. Together, member companies have agreed to specific outcome-oriented objectives and established guidelines for sharing meaningful information and expertise to advance collaboration.

“There is widespread alignment among the heads of R&D at major pharmaceutical companies that there is a critical need to substantially increase the number of innovative new medicines, while eliminating inefficiencies that drive up R&D costs,” said newly appointed acting CEO of TransCelerate BioPharma, Garry Neil, MD, Partner at Apple Tree Partners and formerly Corporate Vice President, Science & Technology, Johnson & Johnson. “Our mission at TransCelerate BioPharma is to work together across the global research and development community and share research and solutions that will simplify and accelerate the delivery of exciting new medicines for patients.”

Members of TransCelerate have identified clinical study execution as the initiative’s initial area of focus. Five projects have been selected by the group for funding and development, including: development of a shared user interface for investigator site portals, mutual recognition of study site qualification and training, development of risk-based site monitoring approach and standards, development of clinical data standards, and establishment of a comparator drug supply model.

As shared solutions in clinical research and other areas are developed, TransCelerate will involve industry alliances including Clinical Data Interchange Standards Consortium (CDISC), Critical-Path Institute (C-Path), Clinical Trials Transformation Initiative (CTTI), Innovative Medicines Initiative (IMI), regulatory bodies including the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), and Contract Research Organizations (CROs).

Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research, said, “We applaud the companies in TransCelerate BioPharma for joining forces to address a series of longstanding challenges in new drug development. This collaborative approach in the pre-competitive arena, utilizing the collective experience and resources of 10 leading drug companies and others to follow, has the promise to lead to new paradigms and cost savings in drug development, all of which would strengthen the industry and its ability to develop innovative and much-needed therapies for patients.”

“These leading pharmaceutical companies are in a position to significantly influence changes in the way that clinical trials are done, so that better answers about the benefits and risks of drugs and other therapies are provided in a more efficient manner,” said Robert Califf, MD, Co-Chair of CTTI and Director of the Duke Translational Medicine Institute. “This initiative is complementary to efforts of CTTI, and we look forward to working with TransCelerate BioPharma to improve the conduct of clinical trials.”

TransCelerate BioPharma evolved from relationships fostered via the Hever Group, a forum for executive R&D leadership to discuss relevant issues facing the industry and solutions for addressing common challenges. TransCelerate was incorporated in early August 2012 and will file for non-profit status this fall. The Board of Directors includes R&D heads of ten member companies. Membership in TransCelerate is open to all pharmaceutical and biotechnology companies who can contribute to and benefit from these shared solutions. TransCelerate’s headquarters will be located in Philadelphia, PA.

http://news.bms.com/press-release/rd-news/ten-pharmaceutical-companies-unite-accelerate-development-new-medicines-0&t=634836499683795253

 

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Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

Reporter: Aviva Lev-Ari, PhD, RN

 

Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

Udo Hoffmann, M.D., M.P.H., Quynh A. Truong, M.D., M.P.H., David A. Schoenfeld, Ph.D., Eric T. Chou, M.D., Pamela K. Woodard, M.D., John T. Nagurney, M.D., M.P.H., J. Hector Pope, M.D., Thomas H. Hauser, M.D., M.P.H., Charles S. White, M.D., Scott G. Weiner, M.D., M.P.H., Shant Kalanjian, M.D., Michael E. Mullins, M.D., Issam Mikati, M.D., W. Frank Peacock, M.D., Pearl Zakroysky, B.A., Douglas Hayden, Ph.D., Alexander Goehler, M.D., Ph.D., Hang Lee, Ph.D., G. Scott Gazelle, M.D., M.P.H., Ph.D., Stephen D. Wiviott, M.D., Jerome L. Fleg, M.D., and James E. Udelson, M.D. for the ROMICAT-II Investigators

N Engl J Med 2012; 367:299-308 July 26, 2012

BACKGROUND

It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes.

METHODS

In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes.

RESULTS

The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65).

CONCLUSIONS

In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.)

Supported by grants from the National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022) and the National Institutes of Health (UL1RR025758, K23HL098370, and L30HL093896, to Dr. Truong).

Dr. Gazelle reports receiving consulting fees from GE Healthcare; Dr. Hauser, receiving consulting fees from Astellas and the Harvard Clinical Research Institute; Dr. Hoffmann, receiving grant support from the American College of Radiology Imaging Network, Bracco Diagnostics, Genentech, and Siemens Healthcare on behalf of his institution; Dr. Nagurney, receiving grant support from Alere (Biosite), Brahms Diagnostica (Fischer), and Nanosphere on behalf of his institution; Dr. Truong, receiving grant support from St. Jude Medical and Qi Imaging on behalf of her institution and travel support from Medconvent and the Society of Cardiac Computed Tomography; Dr. Wiviott, receiving consulting fees from Arena Pharmaceuticals, AstraZeneca, Bayer, Bristol-Myers Squibb, and Ortho-McNeil, grant support from AstraZeneca, Daiichi Sankyo, Eli Lilly, and Merck and Schering-Plough on behalf of his institution, and lecture fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, and Schering-Plough; and Dr. Udelson, being on the scientific advisory board of Lantheus Medical Imaging. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

SOURCE INFORMATION

The authors’ affiliations are listed in the Appendix.

Address reprint requests to Dr. Hoffmann at Massachusetts General Hospital, Cardiac MR PET CT Program, 165 Cambridge St., Suite 400, Boston, MA 02114, or at uhoffmann@partners.org.

 

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Curator: Aviva Lev-Ari, PhD, RN

For IP and Legal aspects of Biosimilars, go to:

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

Thus, projection of Sales for Biosmilars as % of top 100 U.S. Pharmaceutical will receive a special meaning and an expected enhanced market share for 2012 year end and beyond 2012.

Biosimilars are occupying the Following ranking in the U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales: 10, 11, 12 13, 15, 24, 27, 29, 33, 35, 39, 57, 58, 62, 65, 70,  72, 74, 90, 98, 99. In addition the following biosimilars did not make the Top 100 list:

Biosimilar Drugs by US Sales – not included in the Top 100 Drug List 

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca  $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer $1.4 billion

U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales – Small Molecule Drugs (in green) and Biosimilars (in red)

The following is a list of the top 100 pharmaceutical drugs by retail sales in 2012, listed by U.S. sales value and drug name. Last updated: July 2012 (updated quarterly)

http://www.drugs.com/stats/top100/sales

Rank Drug

Sales ($000)

   
1 PlavixBristol-Myers Squibb Company

1,620,790

Stats

2 NexiumAstraZeneca Pharmaceuticals

1,395,981

Stats

3 AbilifyOtsuka Pharmaceutical Co.

1,340,200

Stats

4 SingulairMerck & Co., Inc.

1,238,134

Stats

5 SeroquelAstraZeneca Pharmaceuticals

1,161,141

Stats

6 Advair DiskusGlaxoSmithKline

1,139,182

Stats

7 CrestorAstraZeneca Pharmaceuticals

1,117,904

Stats

8 CymbaltaEli Lilly and Company

1,029,262

Stats

9 atorvastatinGeneric Drug

952,407

Stats

10 HumiraAbbott Laboratories

928,124

 

Stats

11 RemicadeCentocor Ortho Biotech, Inc

899,453

 

Stats

12 EnbrelAmgen Inc.

890,135

 

Stats

13 NeulastaAmgen Inc.

849,971

 

Stats

14 LipitorPfizer Inc

840,715

Stats

15 RituxanGenentech, Inc

756,875

 

Stats

16 CopaxoneTeva Pharmaceuticals

748,585

Stats

17 AtriplaGilead Sciences, Inc.

694,901

Stats

18 OxyContin

662,876

Stats

19 SpirivaBoehringer Ingelheim Pharmaceuticals, Inc

659,818

Stats

20 AvastinGenentech, Inc

632,183

Stats

21 ActosTakeda Pharmaceuticals North America, Inc

630,970

Stats

22 JanuviaMerck & Co., Inc.

583,603

Stats

23 TruvadaGilead Sciences, Inc.

546,098

Stats

24 LantusSanofi-Aventis

520,584

Stats

25 DiovanNovartis Corporation

509,615

Stats

26 LexaproForest Pharmaceuticals, Inc

491,053

Stats

27 EpogenAmgen Inc.

489,570

 

Stats

28 LyricaPfizer Inc

458,171

Stats

29 Lantus SolostarSanofi-Aventis

448,388

 

Stats

30 enoxaparinGeneric Drug

442,263

Stats

31 EloxatinSanofi-Aventis

431,928

Stats

32 CelebrexPfizer Inc

430,993

Stats

33 HerceptinGenentech, Inc

425,687

 

Stats

34 Diovan HCTNovartis Corporation

415,475

Stats

35 LucentisGenentech, Inc

409,547

 

Stats

36 SynagisMedImmune, Inc

396,556

Stats

37 NamendaForest Pharmaceuticals, Inc

391,638

Stats

38 GleevecNovartis Corporation

391,072

Stats

39 AvonexBiogen Idec

388,623

 

Stats

40 VyvanseShire US Inc

387,167

Stats

41 olanzapineGeneric Drug

385,867

Stats

42 IncivekVertex Pharmaceuticals

371,349

Stats

43 One Touch Ultra

366,294

Stats

44 SuboxoneReckitt Benckiser Pharmaceuticals Inc.

338,840

Stats

45 methylphenidateGeneric Drug

337,211

Stats

46 ZetiaMerck & Co., Inc.

328,653

Stats

47 AndroGelAbbott Laboratories

311,850

Stats

48 ProvigilCephalon, Inc.

303,029

Stats

49 LidodermEndo Pharmaceuticals

301,354

Stats

50 TriCorAbbott Laboratories

298,834

Stats

51 SymbicortAstraZeneca Pharmaceuticals

290,669

Stats

52 CombiventBoehringer Ingelheim Pharmaceuticals, Inc

285,487

Stats

53 ProAir HFATeva Pharmaceuticals

284,647

Stats

54 Seroquel XRAstraZeneca Pharmaceuticals

282,416

Stats

55 amphetamine/dextroamphetamineGeneric Drug

275,447

Stats

56 NasonexMerck & Co., Inc.

274,748

Stats

57 NovologNovo Nordisk Inc.

266,305

 

Stats

58 ProcritJanssen Pharmaceuticals, Inc

264,190

 

Stats

59 AlimtaEli Lilly and Company

263,024

Stats

60 ViagraPfizer Inc

260,678

Stats

61 GeodonPfizer Inc

260,514

Stats

62 Rebif

258,088

 

Stats

63 budesonideGeneric Drug

257,243

Stats

64 NiaspanAbbott Laboratories

255,383

Stats

65 HumalogEli Lilly and Company

244,587

 

Stats

66 Flovent HFAGlaxoSmithKline

241,552

Stats

67 LovazaGlaxoSmithKline

239,845

Stats

68 LevemirNovo Nordisk Inc.

239,576

Stats

69 Adderall XRShire US Inc

239,097

Stats

70 NeupogenAmgen Inc.

238,427

 

Stats

71 ReyatazBristol-Myers Squibb Company

238,151

Stats

72 AranespAmgen Inc.

231,643

 

Stats

73 metoprololGeneric Drug

231,395

Stats

74 NovoLog FlexPenNovo Nordisk Inc.

227,228

 

Stats

75 VytorinMerck & Co., Inc.

218,215

Stats

76 JanumetMerck & Co., Inc.

212,596

Stats

77 IsentressMerck & Co., Inc.

211,526

Stats

78 escitalopramGeneric Drug

210,171

Stats

79 CialisEli Lilly and Company

206,996

Stats

80 AciphexEisai Corporation

203,097

Stats

81 PradaxaBoehringer Ingelheim Pharmaceuticals, Inc

201,065

Stats

82 SolodynMedicis Pharmaceutical Corporation

198,909

Stats

83 fentanylGeneric Drug

197,350

Stats

84 ZyprexaEli Lilly and Company

194,460

Stats

85 VelcadeTakeda Pharmaceuticals North America, Inc

188,583

Stats

86 RestasisAllergan, Inc

188,501

Stats

87 LunestaSunovion Pharmaceuticals Inc.

187,941

Stats

88 acetaminophen/hydrocodoneGeneric Drug

185,374

Stats

89 PrezistaJanssen Pharmaceuticals, Inc

182,859

Stats

90 PegasysGenentech, Inc

181,693

 

Stats

91 ZyvoxPfizer Inc

179,523

Stats

92 Prevnar 13Wyeth

179,085

Stats

93 LovenoxSanofi-Aventis

178,957

Stats

94 BenicarDaiichi Sankyo

174,619

Stats

95 VESIcareAstellas Pharma US

174,524

Stats

96 Ventolin HFAGlaxoSmithKline

172,707

Stats

97 OrenciaBristol-Myers Squibb Company

172,202

Stats

98 BetaseronBayer Healthcare Pharmaceuticals

172,143

 

Stats

99 ErbituxBristol-Myers Squibb Company

171,513

 

Stats

100 DexilantTakeda Pharmaceuticals North America, Inc

171,179

Stats

Source: IMS Health (Midas).

Biosimilars Drugs by US Sales – not included in the Top 100 Drug List 

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca  $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer $1.4 billion

2011 US Sales vs. 2008 US Sales (in Billions) for Top Selling Biologics

Source for 2008 Sales

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf 

Source for 20011, Q1 2012 Sales

http://www.drugs.com/stats/top100/sales

Drug Name,  2008 Sales, Year approved , Indication

[i.e. Drug Name Enbrel,  2008 Sales $8.0B, Year approved 1998 , Indication RA]

Enbrel $8.0 1998 — RA, psoriatic arthritis, or ankylosing spondylitis indication

Q1 2012 12 (1) $890,135 1.92% 823 -4.63%
Q4 2011 11 (1) $873,343 1.67% 863 1.77%
Q3 2011 12 (1) $858,997 1.27% 848 -2.97%
Q2 2011 13 (2) $848,230 3.77% 874 3.19%
Q1 2011 11 $817,401 847

http://www.drugs.com/stats/enbrel

Remicade $7.9 1998 — RA & Chron’s Disease

Q1 2012 11 (2) $899,453 10.04% 1,556 10.04%
Q4 2011 13 (3) $817,365 -7.02% 1,414 -9.82%
Q3 2011 10 $879,054 1.52% 1,568 1.03%
Q2 2011 10 (2) $865,903 7.61% 1,552 7.11%
Q1 2011 12 $804,699 1,449

http://www.drugs.com/stats/remicade

Humira $7.3 2002  — treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis

Q1 2012 10 $928,124 2.50% 546 -2.85%
Q4 2011 10 (1) $905,527 3.18% 562 2.55%
Q3 2011 11 (3) $877,641 3.95% 548 3.01%
Q2 2011 14 $844,296 6.32% 532 2.31%
Q1 2011 14 $794,076 520

http://www.drugs.com/stats/humira

Rituxan $7.3 1997 — cancer medicines to treat non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Q1 2012 15 (1) $756,875 -1.91% 547 -0.91%
Q4 2011 14 (2) $771,622 6.96% 552 4.74%
Q3 2011 16 $721,408 -1.77% 527 -1.86%
Q2 2011 16 (4) $734,378 7.26% 537 5.09%
Q1 2011 20 $684,666

http://www.drugs.com/stats/rituxan

Second Quarter 2012 Highlights: RITUXAN(R) (rituximab) revenues from our unconsolidated joint business arrangement were $285 million for the quarter, an increase of 31% year-over-year. As previously disclosed, during the second quarter of 2011 our share of RITUXAN revenues from unconsolidated joint business was reduced by approximately $50 million to reflect our share of damages and interest that might be awarded in relation to an intermediate decision in Genentech, Inc.’s ongoing arbitration with Hoechst GmbH

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

Herceptin $5.7 1998 —  treat metastatic breast cancer that has progressed after treatment with other chemotherapy

Q1 2012 33 $425,687 -0.06% 155
Q4 2011 33 (2) $425,931 7.61% 155 4.73%
Q3 2011 31 (1) $395,804 -0.64% 148 -0.67%
Q2 2011 32 (4) $398,348 3.62% 149 1.36%
Q1 2011 36 $384,428 147

http://www.drugs.com/stats/herceptin

Lantus $5.1 2000 — long-acting form of the hormone insulin.

Q1 2012 29 (5) $448,388 9.81% 3,737 7.32%
Q4 2011 34 $408,336 8.54% 3,482 7.07%
Q3 2011 34 (2) $376,208 4.53% 3,252 6.00%
Q2 2011 36 (5) $359,907 7.80% 3,068 8.30%
Q1 2011 41 $333,878 2,833

http://www.drugs.com/stats/lantus-solostar

Epogen/Procrit $5.1 1989Anemia, low RBC

Worldwide, sales of the two drugs – sold under the brand names Epogen, Procrit and Aranesp – exceeded $9 billion in 2005 for Amgen and Johnson & Johnson, their makers.  Johnson & Johnson, which sells epoetin under the brand names Procrit in the United States and Eprex everywhere else, reported sales of $2.4 billion in the first nine months of 2006, down slightly from 2005.

Amgen Recalls Anemia Medications for Glass Fragments09/24/2010 – Drug-makers Amgen (AMGN) and Johnson & Johnson (JNJ) are voluntarily recalling two brandsof an injectable anemia medication because vials containing the drug may have tiny glass flakes. The drug, Epoetin alfa, is marketed under the brand names Epogen and Procrit.Known as lamellae, the glass fragments are created by the interaction of the drug with glass vials during storage, Amgen said in a statement announcing the recall. The recall is being conducted in cooperation with the Food and Drug Administration, Amgen said.

Latest study shows anemia drugs Epogen, Aranesp and Procrit cause strokes, says FDA

Posted on January 7, 2010

Anemia drugs sold by Amgen and Johnson & Johnson have been reported to cause strokes when prescribed in high doses, according to an article from the FDA, recently published in the The New England Journal of Medicine. The law firm of Aylstock, Witkin, Kreis & Overholtz is investigating the FDA’s recent announcement.

The FDA commentary said the latest study and previous studies “raise major concerns” about the use of these drugs to treat anemia caused by kidney disease. The drugs are also used to treat anemia caused by chemotherapy. Studies over the past several years have revealed a link between the drugs and heart attacks, strokes, and other problems.

Amgen’s anemia drugs include Epogen and Aranesp. Johnson & Johnson sells anemia drug Procrit, which is produced by Amgen. The drugs are designed to raise red blood cell levels, to promote delivery of oxygen to body tissues.

http://www.awkolaw.com/news/heart-attacks/anemia-drugs-epogen-aranesp-procrit-cause-strokes-says-fda/

Epogen / Procrit / Aranesp: The July 2012 News Report Which Tells Story Of Big Pharma Profits Over Patient Safety And Drug Efficacy

Once The FDA Started Paying Attention The Writing On The Wall Became Apparent, Albeit Too Late For Some

(Posted by  at DrugInjuryWatch.com)

This lengthy and well-presented news report, “Anemia drugs made billions, but at what cost?”, written by Peter Whoriskey and published July 19, 2012 by The Washington Post (free registration required), is a must-read for anyone with a concern or interest in how larger pharmaceutical companies might put corporate profits ahead of patient safety and drug efficacy.

Here is an excerpt from this Washington Post article which will give you a sense of what went on that, in hindsight, is so disturbing:

For years, a trio of anemia drugs known as Epogen, Procrit and Aranesp ranked among the best-selling prescription drugs in the United States, generating more than $8 billion a year for two companies, Amgen and Johnson & Johnson. Even compared with other pharmaceutical successes, they were superstars. For several years, Epogen ranked as the single costliest medicine under Medicare: U.S. taxpayers put up as much as $3 billion a year for the drugs.

The trouble, as a growing body of research has shown, is that for about two decades, the benefits of the drug — including “life satisfaction and happiness” according to the FDA-approved label — were wildly overstated, and potentially lethal side effects, such as cancer and strokes, were overlooked.

Last year, Medicare researchers issued an 84-page study declaring that among most kidney patients, the original and largest market for the drugs, there was no solid evidence that they made people feel better, improved their survival or had any “clinical benefit” besides elevating a statistic for red blood cell count.

As for some of the key events which led up to this revelation of sorts, we start with a June 24, 2011 FDA press release, “FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents — Cites increased risk of cardiovascular events when used to treat chronic kidney disease”, which included the following:

The U.S. Food and Drug Administration today recommended more conservative dosing guidelines for Erythropoiesis-Stimulating Agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD) because of the increased risks of cardiovascular events such as stroke, thrombosis, and death….

Procrit —  (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012 58 (3) $264,190 -2.13% 295 -4.22%
Q4 2011 55 (2) $269,937 3.58% 308 3.01%
Q3 2011 53 (12) $260,610 -21.61% 299 -21.32%
Q2 2011 41 (7) $332,466 7.04% 380 5.56%
Q1 2011 48 $310,606 360

http://www.drugs.com/stats/procrit

Epogen —  (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012 27 (7) $489,570 -24.54% 555 -17.04%
Q4 2011 20 (2) $648,794 4.67% 669 3.40%
Q3 2011 22 (2) $619,828 -13.96% 647 -18.41%
Q2 2011 20 (1) $720,376 3.32% 793 4.48%
Q1 2011 19 $697,224 759

http://www.drugs.com/stats/epogen

Neulasta $4.2 2002 — used to prevent neutropenia, a lack of certain white blood cells caused by receiving chemotherapy. stimulates the bone marrow and promotes the growth of white blood cells called neutrophils

Q1 2012 13 (1) $849,971 3.33% 331 1.53%
Q4 2011 12 (2) $822,578 4.59% 326 3.49%
Q3 2011 14 (1) $786,464 -3.86% 315 -5.69%
Q2 2011 15 $818,068 4.04% 334 3.41%
Q1 2011 15 $786,288 323

http://www.drugs.com/stats/neulasta

Novolog $3.7 2000 —  Insulin aspart is a fast-acting form of insulin. NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

Q1 2012 57 (6) $266,305 5.67% 2,980 3.72%
Q4 2011 63 (3) $252,015 0.97% 2,873 -0.48%
Q3 2011 60 (1) $249,591 -0.96% 2,887 -2.66%
Q2 2011 61 (5) $252,010 3.16% 2,966 -0.70%
Q1 2011 66 $244,297 2,987

http://www.drugs.com/stats/novolog

Erbitux $3.6 2004 — used to treat cancers of the colon and rectum. It is also used to treat head and neck cancer.

Q1 2012 99 (2) $171,513 2.30% 266 3.91%
Q4 2011 97 (7) $167,657 -0.15% 256 0.79%
Q3 2011 90 (3) $167,909 -2.48% 254 -1.93%
Q2 2011 93 (2) $172,185 -0.89% 259 -0.38%
Q1 2011 95 $173,735 260

http://www.drugs.com/stats/erbitux

Aranesp $3.2 2001 — Anemia, low RBC,  (darbepoetin alfa) is a man-made form of a protein that helps your body produce red blood cells. 

Q1 2012 72 (6) $231,643 -5.86% 293 -7.86%
Q4 2011 66 (15) $246,056 -6.07% 318 -3.64%
Q3 2011 51 (3) $261,967 -10.25% 330 -11.29%
Q2 2011 48 (3) $291,873 -1.03% 372 -1.33%
Q1 2011 51 $294,912 377

http://www.drugs.com/stats/aranesp

The article reports on the decline of worldwide sales of Aranesp drug from Thousand Oaks, California-based Amgen Inc. as of the second quarter of 2007. According to Amgen, the 10% decrease of Aranesp worldwide sales was due to the reimbursement issues related to the anemia drug and the drop of U.S. demand for drug, in which the U.S. Aranesp reported sales in the second quarter of 2007 was only $578 million from $713 million in 2006.

http://connection.ebscohost.com/c/articles/26375335/amgen-posts-lower-aranesp-sales

1/24/2011, Amgen boosts prices to offset Aranesp sales

Amgen is hiking prices to make up for the shrinking sales volume of its anemia drug Aranesp. Bloomberg reports that Amgen raised the price tag on Aranesp itself by 4.4 percent, but also marked up the white-blood-cell-boosting meds Neulasta and Neupogen by 2.9 percent.

http://www.fiercepharma.com/story/amgen-boosts-prices-offset-aranesp-sales/2011-01-24

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant)

BioScience core franchises include: Hemophilia, Biotherapeutics, BioSurgery and Vaccines. BioScience products represent approximately 45 percent of Baxter’s annual sales, totaling $5.7 billion in 2010.

2007 Outlook – Sales within Baxter’s BioScience business totaled $1.2 billion, an increase of 18 percent from the same period last year. This growth was driven by record sales of ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM) for the treatment of hemophilia A, antibody therapy products, including GAMMAGARD LIQUID(TM) [Immune Globulin Intravenous (Human)] (IVIG) 10% Solution for the treatment of primary immunodeficiencies, specialty plasma therapeutics and biosurgery products. Medication Delivery sales increased 7 percent to $1.0 billion, with increased sales of infusion systems, intraveneous solutions and parenteral nutrition products, along with accelerated growth in the company’s drug delivery business. Renal sales increased 6 percent to $537 million reflecting accelerating gains in peritoneal dialysis patients globally.

Lucentis $2.7 2006 intraocular injection. (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A).

Date Range Sales Rank Sales ($000) Units (000)
Q1 2012 35 (5) $409,547 -6.89% 224 -5.88%
Q4 2011 30 (2) $439,867 2.44% 238 2.59%
Q3 2011 28 (2) $429,393 1.13% 232 0.87%
Q2 2011 30 (3) $424,611 0.95% 230 1.32%
Q1 2011 33 $420,635 227

http://www.drugs.com/stats/lucentis

http://www.gene.com/gene/about/ir/historical/product-sales/lucentis.html

Lucentis brought in $1.7 billion for Roche last year, according to data compiled by Bloomberg.Alimera Sciences Inc. (ALIM), based in Alpharetta, Georgia, and Psivida Corp. (PSDV) also are developing a diabetic macular edema treatment known as Iluvien. The FDA has twice rejected Iluvien, most recently in November.

The FDA pooled results from two Roche clinical trials and found 39 percent of patients who used the 0.3 milligram dose were able to read three additional lines of letters on an eye chart after two years compared to 41 percent who had the same effect on the 0.5 milligram dose, according to an FDA staff report released July 24.

Genentech recommended approval of the 0.3 milligram dose in its application to the FDA since there isn’t evidence of additional benefit of the higher dose, Terence Hurley, a spokesman for the company, said in an e-mail.

Patients who received the monthly injection also were significantly more likely than those who received fake doses of the drug to achieve 20/40 vision, enough eyesight to drive.

http://www.bloomberg.com/news/2012-07-26/roche-s-lucentis-backed-by-fda-panel-for-diabetic-blindness-1-.html

Avonex $2.6 1996 —  Multiple Sclerosis, a form of protein called beta interferon that occurs naturally in the body. Interferons help the body fight viral infections. Avonex is used to treat patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability. This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 39 (1) $388,623 2.22% 130 -3.70%
Q4 2011 38 (5) $380,189 0.19% 135 -2.17%
Q3 2011 33 $379,457 -0.05% 138 -1.43%
Q2 2011 33 (4) $379,639 2.45% 140 -1.41%
Q1 2011 37 $370,570 142

http://www.drugs.com/stats/avonex

Second-quarter net income surged 34 percent to $386.8 million, or $1.61 a share, from $288 million, or $1.18, a year earlier, the Weston, Massachusetts-based company said today in a statement. Earnings excluding some items of $1.82 topped by 26 cents the average of 21 analysts’ estimates (BIIB) compiled by Bloomberg. Revenue beat estimates by about $90 million.

Biogen said profit this year is expected to be more than $6.20 a share, 5 cents higher than its May 1 forecast (BIIB). The company has been increasing sales of Avonex, Rituxan and Tysabri, another MS therapy, while developing new medicines to introduce to the market.

http://www.businessweek.com/news/2012-07-24/biogen-second-quarter-profit-rises-as-avonex-sales-increase

AVONEX(R) (interferon beta-1a) revenues increased 16% year-over-year to $762 million.

Novolin $2.5 1991  —  Novolin R (insulin regular) is a short-acting form of human insulin, Diabetes, Type 1 Type 2

Date Range Sales Rank Sales ($000) Units (000)
Q1 2012 74 (2) $227,228 8.96% 2,489 13.81%
Q4 2011 76 (4) $208,552 10.19% 2,187 6.73%
Q3 2011 80 (6) $189,267 4.15% 2,049 4.92%
Q2 2011 86 (7) $181,733 3.71% 1,953 29.60%
Q1 2011 93 $175,235 1,507
http://www.drugs.com/stats/novolog-flexpen
Novo Nordisk launches iPhone app Posted 17th September 2010, 15:11:54
An iPhone app has been launched by Novo Nordisk in the US which lets healthcare staff check dosage guidelines for diabetes patients.

Novo Dose provides product-specific data for the company’s insulin analog agents Levemir (insulin detemir), NovoLog (insulin aspart) and NovoLog Mix (insulin aspart protamine/insulin aspart injectable).

Combined sales of the three medications increased by 24% last year, feeding a double-digit growth in Novo Nordisk sales and profits.

Novo Dose, the second diabetes app created by the industry, tells professionals when and how to dose the drugs, how to titrate and provides information on the blood glucose goals of patients.

Commenting on the new technology, Anup Kumar Sabharwal, an endocrinologist at the University of Miami Clinics’ Diabetes Research Institute, said: “This is where modern medicine is headed.”

Humalog $2.2 1996  Humalog is used to treat type 1 (insulin-dependent) diabetes in adults. Insulin lispro is a fast-acting form of insulin. It is usually given together with another long-acting insulin. It works by lowering levels of glucose in the blood. Humalog is also used together with oral (taken by mouth) medications to treat type 2 (non insulin-dependent) diabetes in adults.

Q1 2012 65 $244,587 -2.70% 2,570 -3.85%
Q4 2011 65 (2) $251,367 3.78% 2,673 2.81%
Q3 2011 63 (4) $242,208 -0.75% 2,600 -1.78%
Q2 2011 67 (5) $244,050 4.83% 2,647 1.15%
Q1 2011 72 $232,809 2,617

http://www.drugs.com/stats/humalog

Pegasys $2.0 2002 — (peginterferon alfa-2a) is made from human proteins that help the body fight viral infections. Pegasys is used to treat chronic hepatitis B or C. It is often used together with another medication called ribavirin (Copegus, Rebetol, RibaPak, Ribasphere, RibaTab).

Q1 2012 90 (1) $181,693 3.92% 87 3.57%
Q4 2011 91 () $174,833 84

http://www.drugs.com/stats/pegasys

Rebif $1.7 2002 — (interferon beta-1a) is a protein identical to one found in the body. Interferon beta-1a is made from human proteins. Interferons help the body fight viral infections. Rebif is used to treat relapsing multiple sclerosis (MS). This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 62 (1) $258,088 -0.21% 540 -9.09%
Q4 2011 61 (7) $258,643 0.43% 594 -0.34%
Q3 2011 54 (5) $257,535 1.48% 596 -1.49%
Q2 2011 59 (2) $253,780 0.25% 605 -0.66%
Q1 2011 61 $253,143 609

http://www.drugs.com/stats/rebif

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease.

Last year Genzyme was forced to temporarily close its manufacturing plant in Boston due to a viral contamination. The interruption lead to shortages of two key drugs: Cerezyme for Gaucher disease and Fabrazyme for Fabry disease.

That crisis sent the company’s stock price plummeting from nearly $84 in 2008 to a low earlier this year of $45.39. Sanofi’s offer to acquire the company for $18.5 billion, or $69 a share — along with a 14 percent rise in the NYSE Arca Biotech Index since late July — have helped the shares rebound.

But Genzyme is now on a mission to prove to shareholders that it is worth more than Sanofi is offering, and executives told investors on a conference call that the third quarter marks the beginning of its financial turnaround.

Third-quarter sales of Cerezyme, the company’s top drug, rose to $179.8 million from $93.6 million a year earlier, beating analysts’ average forecast of $175 million.

“In the third quarter we saw our financial recovery start to take effect, and we expect that this will accelerate during the fourth quarter as Cerezyme patients are able to return to normal dosing levels and we begin to increase shipments of Fabrazyme,” Genzyme CEO Henri Termeer said in a statement.

Cerezyme is the principal drug for Gaucher patients. In the first quarter of 2012 Genzyme (now part of Sanofi (SNY))reported Cerezyme sales of 149 million euros (approx. $194 million), up 5.8% from the same quarter of the previous year. The other supplier Shire (SHPGY) reported $72 million in Vpriv sales, up 22%. There is now a third supplier, Pfizer (PFE), teamed up with the Israeli company Protalix Biotherapeutics (PLX), whose product was approved by the FDA in May 2012. Elelyso (taliglucerase alfa) is now available in the US.
Product Cerezyme
2009 2010 2011
 Total 793 720 885
 Ann. Growth Total -9% 23%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=15461&componentID=1002

Tysabri $1.4 2004 — Multiple Sclerosis by Elan and Biogen

Global in-market sales of TYSABRI in the second quarter of 2012 were $395 million, an increase of 2% over the second quarter of 2011. The total was comprised of $211 million in U.S. sales and $184 million in sales outside the U.S.

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011.
ITALIAN DISPUTE

Elan derives its revenue almost exclusively from Tysabri and it reported total sales for the three months to June 30 of $288 million, up 6 percent on a year ago once sales from its since-divested drug delivery business are omitted.

That compared to the $299 million forecast by four analysts surveyed by Reuters and was driven by in-market sales of Tysabri that rose 2 percent year-on-year to $395 million, also shy of the $419 million expected by analysts.

Biogen, which detailed the sales numbers when it reported second quarter results on Tuesday, attributed the softer-than-expected Tysabri sales to a dispute with the Italian government over pricing.

The number of patients on Tysabri rose 4 percent to 69,100, maintaining Elan and Biogen’s 10 to 12 percent share of the MS drug market in the face of competition from Swiss drugmaker Novartis AG’s Gilenya treatment, the first multiple sclerosis pill to come on the market.

The average addition of 185 new patients per week was the highest quarterly run-rate since the fourth quarter of 2009.

http://in.reuters.com/article/2012/07/25/elan-idINL6E8IP1VV20120725

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk —

Generic Name:   eptacog alfa
Product NovoSeven
2009 2010 2011
 Total 1,324 1,431 1,559
 Ann. Growth Total 8% 9%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&id=13483&lType=modData&componentID=1002

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca

Product Synagis
2009 2010 2011
 Total 1,042 906 570
 Ann. Growth Total -13% -37%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=91&componentID=1002

Neupogen $1.3 1991 —  (filgrastim) is a man-made form of a protein that stimulates the growth of whiteblood cells in your body. White blood cells help your body fight against infection. Neupogen is used to treat neutropenia, a lack of certain white blood cells caused by cancer,bone marrow transplant, receiving chemotherapy, or by other conditions.

Q1 2012 70 $238,427 0.06% 170 -2.86%
Q4 2011 70 (5) $238,289 0.16% 175 10.76%
Q3 2011 65 (5) $237,915 0.69% 158 0.64%
Q2 2011 70 (4) $236,294 2.51% 157 0.64%
Q1 2011 74 $230,515 156

http://www.drugs.com/stats/neupogen

Betaseron $1.2 1993 — (interferon) is made from human proteins. Interferons help the body fight viral infections. Betaseron is used to treat relapsing multiple sclerosis (MS). Betaseron will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 98 (1) $172,143 2.93% 67 -10.67%
Q4 2011 99 (12) $167,236 -3.76% 75 -5.06%
Q3 2011 87 (2) $173,769 -2.89% 79 -2.47%
Q2 2011 89 (4) $178,938 -2.17% 81 -7.95%
Q1 2011 85 $182,908 88

http://www.drugs.com/stats/betaseron

Humulin $1.1 1992 Insulin Human by Eli Lilly 

Product Humulin R
2009 2010 2011
 Total 1,022 1,089 1,249
 Ann. Growth Total 7% 15%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=12399&componentID=1002

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer

Product Kogenate
2009 2010 2011
 Total 1,238 1,332 1,496
 Ann. Growth Total 8% 12%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=11681&componentID=1002

Conclusion

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

REFERENCES

http://www.wolfgreenfield.com/files/2426_biosimilars_2_final_pdf.pdf

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