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

Posted in Cancer - General, Cancer and Current Therapeutics, Drug Development Process, Health Economics and Outcomes Research, Patents, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Uncategorized, tagged Bristol-Myers Squibb, Celgene, Drug Price Competition and Patent Term Restoration Act, health costs, Mergers and acquisitions, Multiple myeloma, Pfizer, pharma deals, Revlimid, thalidomide on January 25, 2019| Leave a Comment »

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 Syndrome, Multiple Myeloma, Lymphoma

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

By

Joshua Fineman

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.”

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/

Celgene, sold for $74 billion, leaves a legacy of chutzpah in science and drug pricing

By MATTHEW HERPER @matthewherper

JANUARY 22, 2019

 

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.

M. Corey Goldman from TheStreet.com

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

Source: http://fortune.com/2019/06/24/bms-celgene-stock-brainstorm-health/

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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Myocardial Infarction: The New Definition After Revascularization

Posted in Abdominal Aorta, Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Atherogenic Processes & Pathology, Bio Instrumentation in Experimental Life Sciences Research, CABG, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Carotid Artery, Cerebrovascular and Neurodegenerative Diseases, Frontiers in Cardiology and Cardiovascular Disorders, Heart Transplant, Heart-Lung Transplant, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Medical Devices R&D and Inventions, Mitral Valve: Repair and Replacement, Origins of Cardiovascular Disease, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, Thoracic Aorta, Valves & Tools, tagged AstraZeneca, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Johnson & Johnson, Journal of the American College of Cardiology, myocardial infarction on October 15, 2013| Leave a Comment »

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

http://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 

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Third Universal Definition of Myocardial Infarction

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Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools for Ischemic Assessment

Posted in Atherogenic Processes & Pathology, Frontiers in Cardiology and Cardiovascular Disorders, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Origins of Cardiovascular Disease, PCI, Pharmacotherapy of Cardiovascular Disease, tagged Bristol-Myers Squibb, Cardiology, FFR, Fractional Flow Reserve, Imperial College London, Justin Davies, Ron Waksman, Roxana Mehran on July 4, 2013| 2 Comments »

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

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

Detection and quantification of myocardial perfusion … – MDLinx

http://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

http://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

http://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

http://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

http://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

http://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

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

Revascularization: PCI, Prior History of PCI vs CABG

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

Accurate Identification and Treatment of Emergent Cardiac Events

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

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Biosimilars: Financials 2012 vs. 2008

Posted in BioSimilars, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Uncategorized, tagged Abbott Laboratories, Amgen, AstraZeneca, Bao-Lu, Biologic, Biologic License Application, Biosimilar, biosimilars, Biotechnology and Pharmaceuticals, Bristol-Myers Squibb, Chemistry, European Union, Food and Drug Administration, GlaxoSmithKline, Manufacturing and Controls (CMC), New Drug Application, Pharmaceuticals, United States on July 30, 2012| 5 Comments »

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

http://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

http://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 1989 — Anemia, 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.

09/24/2010 – 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.

http://www.dailyfinance.com/2010/09/24/amgen-recalls-epogen-procrit-glass-anemia-drugs/

http://healthfully.org/dnd/id9.html

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 Tom Lamb 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….

http://www.drug-injury.com/druginjurycom/2012/07/epogen-procrit-aranesp-stroke-thrombosis-death-side-effects-safety-risks-benefits-efficacy-fda.html

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.

http://www.drugs.com/news/baxter-s-fourth-quarter-financial-results-exceed-expectations-5128.html

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.

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

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.

 http://www.reuters.com/article/2010/10/20/us-genzyme-idUSTRE69J2S520101020

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.

http://seekingalpha.com/article/694801-gaucher-disease-the-fight-for-market-share

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.

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

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

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

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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