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Live Conference Coverage @Medcitynews Converge 2018 @Philadelphia: Promising Drugs and Breaking Down Silos

Reporter: Stephen J. Williams, PhD

Promising Drugs, Pricing and Access

The drug pricing debate rages on. What are the solutions to continuing to foster research and innovation, while ensuring access and affordability for patients? Can biosimilars and generics be able to expand market access in the U.S.?

Moderator: Bunny Ellerin, Director, Healthcare and Pharmaceutical Management Program, Columbia Business School
Speakers:
Patrick Davish, AVP, Global & US Pricing/Market Access, Merck
Robert Dubois M.D., Chief Science Officer and Executive Vice President, National Pharmaceutical Council
Gary Kurzman, M.D., Senior Vice President and Managing Director, Healthcare, Safeguard Scientifics
Steven Lucio, Associate Vice President, Pharmacy Services, Vizient

What is working and what needs to change in pricing models?

Robert:  He sees so many players in the onStevencology space discovering new drugs and other drugs are going generic (that is what is working).  However are we spending too much on cancer care relative to other diseases (their initiative Going Beyond the Surface)

Steven:  the advent of biosimilars is good for the industry

Patrick:  large effort in oncology, maybe too much (750 trials on Keytruda) and he says pharma is spending on R&D (however clinical trials take large chunk of this money)

Robert: cancer has gotten a free ride but cost per year relative to benefit looks different than other diseases.  Are we overinvesting in cancer or is that a societal decision

Gary:  maybe as we become more specific with precision medicines high prices may be a result of our success in specifically targeting a mutation.  We need to understand the targeted drugs and outcomes.

Patrick: “Cancer is the last big frontier” but he says prices will come down in most cases.  He gives the example of Hep C treatment… the previous only therapeutic option was a very toxic yearlong treatment but the newer drugs may be more cost effective and safer

Steven: Our blockbuster drugs could diffuse the expense but now with precision we can’t diffuse the expense over a large number of patients

President’s Cancer Panel Recommendation

Six recommendations

  1. promoting value based pricing
  2. enabling communications of cost
  3. financial toxicity
  4. stimulate competition biosimilars
  5. value based care
  6. invest in biomedical research

Patrick: the government pricing regime is hurting.  Alot of practical barriers but Merck has over 200 studies on cost basis

Robert:  many concerns/impetus started in Europe on pricing as they are a set price model (EU won’t pay more than x for a drug). US is moving more to outcomes pricing. For every one health outcome study three studies did not show a benefit.  With cancer it is tricky to establish specific health outcomes.  Also Medicare gets best price status so needs to be a safe harbor for payers and biggest constraint is regulatory issues.

Steven: They all want value based pricing but we don’t have that yet and there is a challenge to understand the nuances of new therapies.  Hard to align all the stakeholders together so until some legislation starts to change the reimbursement-clinic-patient-pharma obstacles.  Possibly the big data efforts discussed here may help align each stakeholders goals.

Gary: What is the data necessary to understand what is happening to patients and until we have that information it still will be complicated to determine where investors in health care stand at in this discussion

Robert: on an ICER methods advisory board: 1) great concern of costs how do we determine fair value of drug 2) ICER is only game in town, other orgs only give recommendations 3) ICER evaluates long term value (cost per quality year of life), budget impact (will people go bankrupt)

4) ICER getting traction in the public eye and advocates 5) the problem is ICER not ready for prime time as evidence keeps changing or are they keeping the societal factors in mind and they don’t have total transparancy in their methodology

Steven: We need more transparency into all the costs associated with the drug and therapy and value-based outcome.  Right now price is more of a black box.

Moderator: pointed to a recent study which showed that outpatient costs are going down while hospital based care cost is going rapidly up (cost of site of care) so we need to figure out how to get people into lower cost setting

Breaking Down Silos in Research

“Silo” is healthcare’s four-letter word. How are researchers, life science companies and others sharing information that can benefit patients more quickly? Hear from experts at institutions that are striving to tear down the walls that prevent data from flowing.

Moderator: Vini Jolly, Executive Director, Woodside Capital Partners
Speakers:
Ardy Arianpour, CEO & Co-Founder, Seqster @seqster
Lauren Becnel, Ph.D., Real World Data Lead for Oncology, Pfizer
Rakesh Mathew, Innovation, Research, & Development Lead, HealthShareExchange
David Nace M.D., Chief Medical Officer, Innovaccer

Seqster: Seqster is a secure platform that helps you and your family manage medical records, DNA, fitness, and nutrition data—all in one place. Founder has a genomic sequencing background but realized sequence  information needs to be linked with medical records.

HealthShareExchange.org :

HealthShare Exchange envisions a trusted community of healthcare stakeholders collaborating to deliver better care to consumers in the greater Philadelphia region. HealthShare Exchange will provide secure access to health information to enable preventive and cost-effective care; improve quality of patient care; and facilitate care transitions. They have partnered with multiple players in healthcare field and have data on over 7 million patients.

Innovacer

Data can be overwhelming, but it doesn’t have to be this way. To drive healthcare efficiency, we designed a modular suite of products for a smooth transition into a data-driven world within 4 weeks. Why does it take so much money to move data around and so slowly?

What is interoperatibility?

Ardy: We knew in genomics field how to build algorithms to analyze big data but how do we expand this from a consumer standpoint and see and share your data.

Lauren: how can we use the data between patients, doctors, researchers?  On the research side genomics represent only 2% of data.  Silos are one issue but figuring out the standards for data (collection, curation, analysis) is not set. Still need to improve semantic interoperability. For example Flatiron had good annotated data on male metastatic breast cancer.

David: Technical interopatabliltiy (platform), semantic interopatability (meaning or word usage), format (syntactic) interopatibility (data structure).  There is technical interoperatiblity between health system but some semantic but formats are all different (pharmacies use different systems and write different prescriptions using different suppliers).  In any value based contract this problem is a big issue now (we are going to pay you based on the quality of your performance then there is big need to coordinate across platforms).  We can solve it by bringing data in real time in one place and use mapping to integrate the format (need quality control) then need to make the data democratized among players.

Rakesh:  Patients data should follow the patient. Of Philadelphia’s 12 health systems we had a challenge to make data interoperatable among them so tdhey said to providers don’t use portals and made sure hospitals were sending standardized data. Health care data is complex.

David: 80% of clinical data is noise. For example most eMedical Records are text. Another problem is defining a patient identifier which US does not believe in.

 

 

 

 

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Allergan, Pfizer Deal Goes Through with Allergan Bigger Than Pfizer: But at What Cost to R&D?

Curator: Stephen J. Williams, Ph.D.

Just recently this site had a post entitled Pfizer Near Allergan Buyout Deal But Will Fed Allow It? 

Now, as Bloomberg reports the international deal between Allergan and Pfizer has gone through, resulting in a tax inversion and nary a discouraging word from the US Federal Government (their blessing for future tax inversions?).  And as Bloomberg Go guest speculate finally it may spark Congress to do something about it, or perhaps not.  For details see Bloomberg transcript below:

 

Pfizer Inc. and Allergan Plc agreed to combine in a record $160 billion deal, creating a drugmaking behemoth called Pfizer Plc with products from Viagra to Botox and a low-cost tax base.

QuickTake Tax Inversion

Pfizer will exchange 11.3 shares for each Allergan share, valuing the smaller drugmaker at $363.63 a share, according to a statement Monday. That’s a premium of about 27 percent above Allergan’s stock price on Oct. 28, before news of the companies’ discussions became public. Pfizer investors will be able to opt for cash instead of stock in the combined company in exchange for their shares, with as much as $12 billion to be paid out.

The transaction is structured so that Dublin-based Allergan is technically buying its much larger partner, a move that makes it easier for the company to locate its tax address in Ireland for tax purposes, though the drugmaker’s operational headquarters will be in New York. Pfizer Chief Executive Officer Ian Read will be chairman and CEO of the new company, with Allergan CEO Brent Saunders as president and chief operating officer, overseeing sales, manufacturing and strategy.

The deal will begin adding to Pfizer’s adjusted earnings starting in 2018 and will boost profit by 10 percent the following year, the companies said. Pfizer’s 11 board members will join four from Allergan, including Saunders and Executive Chairman Paul Bisaro.Pfizer dropped 2.1 percent to $31.51 at 9:34 a.m. in New York, while Allergan fell 2 percent to $306.17. The combined company will trade on the New York Stock Exchange.Pfizer said it will start a $5 billion accelerated share buyback program in the first half of 2016. The deal is expected to be completed by the end of next year.

Unprecedented Deal

Pfizer, based in New York, makes medications including Viagra, pain drug Lyrica and the Prevnar pneumococcal vaccine, and Allergan produces Botox and the Alzheimer’s drug Namenda. Together, barring any divestitures, the companies will be the biggest pharmaceutical company by annual sales, with about $60 billion. The deal will be unprecedented on many levels. It’s the largest acquisition so far this year. It’s the largest ever in the pharmaceutical world, eclipsing Pfizer’s purchase of Warner-Lambert Co. in 2000 for $116 billion. And if the new company is able to establish itself abroad for a lower tax rate, a controversial process called an inversion, it will be the largest such move in history. The U.S. Treasury Department has increasingly targeted such strategies, most recently announcing new guidance on how it will value assets owned by U.S. companies that undertake inversions. The U.S. has the highest tax rate for businesses in the world, at 35 percent, and is one of the only countries to tax corporate profits wherever they are earned. Previous moves by the U.S. Treasury have derailed other proposed inversions, including AbbVie Inc.’s plan to buy Ireland’s Shire Plc for an estimated $52 billion. Pfizer and Allergan’s deal appears structured to avoid the tax inversion rules.

Read has already reached out to lawmakers in both houses of Congress, including Senate Majority Leader Mitch McConnell, and is calling the White House Monday, according to a person with knowledge of the matter. His pitch is that that the deal will help the companies invest in more innovative drugs and that Pfizer Plc would have 40,000 U.S. employees at the close of the transaction.

Facilitate Split

An agreement may also facilitate the widely discussed potential for Pfizer to reconfigure itself by splitting the newly enlarged company into two: one focused on new drug development, the other on selling older medications. Pfizer said Monday it will decide on a potential separation by the end of 2018. Pfizer earlier this year bought Hospira Inc., the maker of generic drugs often administered in hospitals, in a transaction valued at about $17 billion. The deal bolstered Pfizer’s established-drugs business, which combines strong cash flow and slow growth. Allergan itself has been recently transformed, created through an acquisition by Actavis Plc that kept the Allergan name. The company agreed to sell its generics business to Israel’s Teva Pharmaceutical Industries Ltd. for about $40.5 billion and has been on a buying binge of its own. It now has more than 70 compounds in mid-to late-stage development.

But What About Pfizer R&D?  Will that be put on the Back Burner?

A little while ago this site posted a talk given by Pfizer on their foray into personalized medicine in

11/19/2015 8 a.m. Building a Personalized Medicine Company & Keynote: President, Worldwide R&D, Pfizer Inc. 11th Annual Personalized Medicine Conference, November 18-19, 2015, Harvard Medical School

Here Pfizer had emphasized its commitment to discoveries in the personalized medicine area however the emphasis on worldwide may have been a hint of what is to come.

Just a few days ago Allergan CEO wrote a guest post in Forbes  (edited by Matthew Herper)

Allergan CEO Brent Saunders: Here’s What I Really Think About R&D

There has been a lot of discussion about my views about pharmaceutical research and development. Let me cut to the chase. I’m pro-R&D, but I don’t believe that any single company can corner the market on innovation in even one therapeutic area. It doesn’t mean they shouldn’t do basic research where they have special insights, but even then they need to be open to the ideas of others. Innovation in healthcare is more important than ever. Other companies have had success with different models based on different capabilities, and we applaud every new drug approval. Here at Allergan, we’ve adopted a strategy we call “Open Science.” It is based on a simple concept: Sometimes great ideas come from places where they are least expected.

Allergan’s CEO goes on to stress innovation centers around academic centers such as in Boston and an emphasis on Alzheimer’s research and development but is this just shop talk or is there a agenda and strategy here?

It is known that Allergan has not felt that building big labs to support an R&D strategy was in their best interests but Derick Lowes Science blog In the Pipeline shows the changes in feeling about R&D, that Allergan is in fact pro-R&D they just don’t feel it is in their best interests to do it “in house”. (see Come to Think of It, Brent Saunders Likes R&D, Too! and the comments)

And check out CEO Saunder’s Twitter feed which gives some insight into his feeling on in house R&D.

Retweeted

on a R&D approach that can deliver big for patients.

This is all very interesting and might mean, with the size of this deal and that Allergan owns 40% of Pfizer, a massive sea-change in the way big pharma conducts R&D, possibly focusing on smaller “open-sourced” smaller players.

Our Open Science approach allows us to strategically invest in innovation and be more nimble so that we can increase our R&D efficiency. It has led to a robust pipeline of experimental medicines. We currently have 70 mid- to late-stage programs in the pipeline, and since 2009, we have successfully brought 13 new drugs and devices to the market.

It also allows us to invest in areas that other companies have abandoned, like central nervous system (CNS) treatments. In CNS, clinical development costs are higher, and market approval probability is lower. But treating these disorders can bring hope to patients of all ages. According to the Centers for Disease Control & Prevention, one in 68 children has autism spectrum disease. Alzheimer’s affects one in three people over the age of 85, based on data from the Chicago Health and Aging Project. Yet despite the 634 current open clinical trials for these diseases, there are no approved medicines for autism’s three core characteristics, nor drugs that treat Alzheimer’s underlying disease or delay its progression.

Other related articles published in this Open access Online Scientific Journal include the following:

On Allergan

https://pharmaceuticalintelligence.com/?s=Allergan

On Pfizer

https://pharmaceuticalintelligence.com/?s=Pfizer

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Are Cyclin D and cdk Inhibitors A Good Target for Chemotherapy?

 

Curator: Stephen J. Williams, Ph.D.

The U.S. Food and Drug Administration today granted accelerated approval to Ibrance (palbociclib) to treat advanced (metastatic) breast cancer inr postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have not yet received an endocrine-based therapy. It is to be used in combination with letrozole, another FDA-approved product used to treat certain kinds of breast cancer in postmenopausal women.

See Dr. Melvin Crasto’s blog posts on the announcement of approval of Ibrance (palbociclib) at

http://newdrugapprovals.org/2015/02/05/fda-approves-ibrance-for-postmenopausal-women-with-advanced-breast-cancer/

and about the structure and mechanism of action of palbociclib

http://newdrugapprovals.org/2014/01/05/palbociclib/

 

From the CancerNetwork at http://www.cancernetwork.com/aacr-2014/cdk-inhibitors-show-impressive-activity-advanced-breast-cancer

CDK Inhibitors Show Impressive Activity in Advanced Breast Cancer

News | April 08, 2014 | AACR 2014, Breast Cancer

By Anna Azvolinsky, PhD

Ibrance structure

 

Chemical structure of palbociclib

 

 

Palbociclib and LY2835219 are both cyclin-dependent kinase (CDK) 4/6 inhibitors. CDK4 and CDK6 are kinases that, together with cyclin D1, facilitate the transition of dividing cells from the G1 to the S (synthesis) phase of the cell cycle. Preclinical studies have shown that breast cancer cells rely on CDK4 and CDK6 for division and growth, and that selective CDK4/6 inhibitors can arrest the cells at this G1/S phase checkpoint.

The results of the phase II trial of palbociclib and phase I trial of LY2835219 both indicated that hormone receptor (HR)-positive disease appears to be the best marker to predict patient response.

LY2835219 Phase I Trial Demonstrates Early Activity

The CDK4/6 inhibitor LY2835219 has demonstrated early activity in heavily pretreated women with metastatic breast cancer. Nineteen percent of these women (9 out of 47) had a partial response and 51% (24 out of 47) had stable disease following monotherapy with the oral CDK4/6 inhibitor. Patients had received a median of seven prior therapies, and 75% had metastatic disease in the lung, liver, or brain. The median age of patients was 55 years.

All of the partial responses were in patients with HR-positive disease. The overall response rate for this patient subset was 25% (9 of 36 patients). Twenty of the patients with stable disease had HR-positive disease, with 13 patients having stable disease lasting 24 weeks or more.

Despite treatment, disease progression occurred in 23% of the patients.

These results were presented at a press briefing by Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, at the 2014 American Association for Cancer Research (AACR) Annual Meeting, held April 5–9, in San Diego.

The phase I trial of LY2835219 enrolled 132 patients with five different tumor types, including metastatic breast cancer. Patients received 150-mg to 200-mg doses of the oral drug every 12 hours.

The overall disease control rate was 70% for all patients and 81% among the 36 HR-positive patients.

The median progression-free survival (PFS) was 5.8 months for all patients and 9.1 months for HR-positive patients. Patnaik noted that the median PFS is still a moving target, as 18 patients, all with HR-positive disease, remain on therapy.

“The data are rather encouraging for a very heavily pretreated patient population,” said Patnaik during the press briefing.

Even though the trial was not designed to compare efficacy based on breast cancer subpopulations, the results in HR-positive tumors are particularly encouraging, according to Patnaik.

Common adverse events thought to be treatment-related were diarrhea, nausea, fatigue, vomiting, and neutropenia. These adverse events occurred in 5% or less of patients at grade 3 or 4 toxicity, except neutropenia, which occurred as a grade 3 or 4 toxicity in 11% of patients. Patnaik noted during the press briefing that the neutropenia was uncomplicated and did not result in discontinuation of therapy by any of the patients.

Palbociclib Phase II Data “Impressive”

The addition of the oral CDK4/6 inhibitor palbociclib resulted in an almost doubling of PFS in first-line treatment of postmenopausal metastatic breast cancer patients with HR-positive disease compared with a control population. The patients in this trial were not previously treated for their metastatic breast cancer, unlike the patient population in the phase I LY2835219 trial.

Patients receiving the combination of palbociclib at 125 mg once daily plus letrozole at 2.5 mg once daily had a median PFS of 20.2 months compared with a median of 10.2 months for patients treated with letrozole alone (hazard ratio = 0.488; P = .0004).

Richard S. Finn, MD, assistant professor of medicine at the University of California, Los Angeles, presented the data from the phase II PALOMA-1 trial at a press briefing at the AACR Annual Meeting.

A total of 165 patients were randomized 1:1 to either the experimental arm or control arm.

Forty-three percent of patients in the combination arm had an objective response compared with 33% of patients in the control arm.

Overall survival (OS), a secondary endpoint in this trial, was encouraging but the results are still preliminary, said Finn during the press briefing. The median OS was 37.5 months in the palbociclib arm compared with 33.3 months in the letrozole alone arm (P = .21). Finn noted that long-term follow-up is necessary to establish the median OS. “This first look of the survival data is encouraging. This is a front-line study, and it is encouraging that there is early [separation] of the curves,” he said.

No new toxicities were reported since the interim trial results. Common adverse events included leukopenia, neutropenia, and fatigue. The neutropenia could be quickly resolved and was uncomplicated and not accompanied by fever, said Finn.

Palbociclib is currently being tested in two phase III clinical trials: The PALOMA-3 trial is testing the combination of palbociclib with letrozole and fulvestrant in late-stage metastatic breast cancer patients who have failed endocrine therapy. The PENELOPE-B trial is testing palbociclib in combination with standard endocrine therapy in HR-positive breast cancer patients with residual disease after neoadjuvant chemotherapy and surgery.

References

  1. Patnaik A, Rosen LS, Tolaney SM, et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. American Association for Cancer Research Annual Meeting 2014; April 5–9, 2014; San Diego. Abstr CT232.
  2. Finn RS, Crown JP, Lang I, et al. Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer (PALOMA-1; TRIO-18). American Association for Cancer Research Annual Meeting 2014; April 5–9, 2014; San Diego. Abstr CT101.

– See more at: http://www.cancernetwork.com/aacr-2014/cdk-inhibitors-show-impressive-activity-advanced-breast-cancer#sthash.f29smjxi.dpuf

 

The Cell Cycle and Anti-Cancer Targets

 

graph_cell_cycle

 

From Cell Cycle in Cancer: Cyclacel Pharmaceuticals™ (note dotted arrows show inhibition of steps e.g. p21, p53)

For a nice video slideshow explaining a bit more on cyclins and the cell cycle please see video below:

 

Cell Cycle. 2012 Nov 1; 11(21): 3913.

doi:  10.4161/cc.22390

PMCID: PMC3507481

Cyclin-dependent kinase 4/6 inhibition in cancer therapy

Neil Johnson and Geoffrey I. Shapiro*

See the article “Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors” in volume 11 on page 2756.

See the article “CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy” in volume 11 on page 2747.

This article has been cited by other articles in PMC.

Cyclin-dependent kinases (CDKs) drive cell cycle progression and control transcriptional processes. The dysregulation of multiple CDK family members occurs commonly in human cancer; in particular, the cyclin D-CDK4/6-retinoblastoma protein (RB)-INK4 axis is universally disrupted, facilitating cancer cell proliferation and prompting long-standing interest in targeting CDK4/6 as an anticancer strategy. Most agents that have been tested inhibit multiple cell cycle and transcriptional CDKs and have carried toxicity. However, several selective and potent inhibitors of CDK4/6 have recently entered clinical trial. PD0332991, the first to be developed, resulted from the introduction of a 2-aminopyridyl substituent at the C2-position of a pyrido(2,3-d)pyrimidin-7-one backbone, affording exquisite selectivity toward CDK4/6.1 PD0332991 arrests cells in G1 phase by blocking RB phosphorylation at CDK4/6-specfic sites and does not inhibit the growth of RB-deficient cells.2 Phase I studies conducted in patients with advanced RB-expressing cancers demonstrated mild side effects and dose-limiting toxicities of neutropenia and thrombocytopenia, with prolonged stable disease in 25% of patients.3,4 In cyclin D1-translocated mantle cell lymphoma, PD0332991 extinguished CDK4/6 activity in patients’ tumors, resulting in markedly reduced proliferation, and translating to more than 1 year of stability or response in 5 of 17 cases.5

Two recent papers from the Knudsen laboratory make several important observations that will help guide the continued clinical development of CDK4/6 inhibitors. In the study by Dean et al., surgically resected patient breast tumors were grown on a tissue culture matrix in the presence or absence of PD0332991. Crucially, these cultures retained associated stromal components known to play important roles in cancer pathogenesis and therapeutic sensitivities, as well as key histological and molecular features of the primary tumor, including expression of ER, HER2 and Ki-67. Similar to results in breast cancer cell lines,6 the authors demonstrate that only RB-positive tumors have growth inhibition in response to PD0332991, irrespective of ER or HER2 status, while tumors lacking RB were completely resistant. This result underscores RB as the predominant target of CDK4/6 in breast cancer cells and the primary marker of drug response in primary patient-derived tumors. As expected, RB-negative tumors routinely demonstrated robust expression of p16INK4A; however, p16INK4A expression was not always a surrogate marker for RB loss, supporting the importance of direct screening of tumors for RB expression to select patients appropriate for CDK4/6 inhibitor clinical trials.

In the second study, McClendon et al. investigated the efficacy of PD0332991 in combination with doxorubicin in triple-negative breast cancer cell lines. Again, RB functionality was paramount in determining response to either PD0332991 monotherapy or combination treatment. In RB-deficient cancer cells, CDK4/6 inhibition had no effect in either instance. However, in RB-expressing cancer cells, CDK4/6 inhibition and doxorubicin provided a cooperative cytostatic effect, although doxorubicin-induced cytotoxicity was substantially reduced, assessed by markers for mitotic catastrophe and apoptosis. Additionally, despite cytostatic cooperativity, CDK4/6 inhibition maintained the viability of RB-proficient cells in the presence of doxorubicin, which repopulated the culture after removal of drug. These results reflect previous data demonstrating that ectopic expression of p16INK4A can protect cells from the lethal effects of DNA damaging and anti-mitotic chemotherapies.7 Similar results have been reported in MMTV-c-neu mice bearing RB-proficient HER2-driven tumors, where PD0332991 compromised carboplatin-induced regressions,8 suggesting that DNA-damaging treatments should not be combined concomitantly with CDK4/6 inhibition in RB-proficient tumors.

To combine CDK4/6 inhibition with cytotoxics, sequential treatment may be considered, in which CDK4/6 inhibition is followed by DNA damaging chemotherapy; cells relieved of G1 arrest may synchronously enter S phase, where they may be most susceptible to agents disrupting DNA synthesis. Release of myeloma cells from a prolonged PD0332991-mediated G1 block leads to S phase synchronization; interestingly, all scheduled gene expression is not completely restored (including factors critical to myeloma survival such as IRF4), further favoring apoptotic responses to cytotoxic agents.9 Furthermore, in RB-deficient tumors, CDK4/6 inhibitors may be used to maximize the therapeutic window between transformed and non-transformed cells treated with chemotherapy. In contrast to RB-deficient cancer cells, RB-proficient non-transformed cells arrested in G1 in response to PD0332991 are afforded protection from DNA damaging agents, thereby reducing associated toxicities, including bone marrow suppression.8

In summary, the current work provides evidence for RB expression as a determinant of response to CDK4/6 inhibition in primary tumors and highlights the complexity of combining agents targeting the cell cycle machinery with DNA damaging treatments.

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Notes

Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, Knudsen ES. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors Cell Cycle 2012 11 2756 61 doi: 10.4161/cc.21195.

McClendon AK, Dean JL, Rivadeneira DB, Yu JE, Reed CA, Gao E, Farber JL, Force T, Koch WJ, Knudsen ES. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy Cell Cycle 2012 11 2747 55 doi: 10.4161/cc.21127.

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Footnotes

Previously published online: www.landesbioscience.com/journals/cc/article/22390

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References

  1. Toogood PL, et al. J Med Chem. 2005;48:2388–406. doi: 10.1021/jm049354h. [PubMed] [Cross Ref]
  2. Fry DW, et al. Mol Cancer Ther. 2004;3:1427–38. [PubMed]
  3. Flaherty KT, et al. Clin Cancer Res. 2012;18:568–76. doi: 10.1158/1078-0432.CCR-11-0509. [PubMed] [Cross Ref]
  4. Schwartz GK, et al. Br J Cancer. 2011;104:1862–8. doi: 10.1038/bjc.2011.177. [PMC free article] [PubMed] [Cross Ref]
  5. Leonard JP, et al. Blood. 2012;119:4597–607. doi: 10.1182/blood-2011-10-388298. [PubMed] [Cross Ref]
  6. Dean JL, et al. Oncogene. 2010;29:4018–32. doi: 10.1038/onc.2010.154. [PubMed] [Cross Ref]
  7. Stone S, et al. Cancer Res. 1996;56:3199–202. [PubMed]
  8. Roberts PJ, et al. J Natl Cancer Inst. 2012;104:476–87. doi: 10.1093/jnci/djs002. [PMC free article] [PubMed] [Cross Ref]
  9. Huang X, et al. Blood. 2012;120:1095–106. doi: 10.1182/blood-2012-03-415984. [PMC free article] [PubMed] [Cross Ref]

Cell Cycle. 2012 Jul 15; 11(14): 2756–2761.

doi:  10.4161/cc.21195

PMCID: PMC3409015

Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors

Jeffry L. Dean, 1 , 2 A. Kathleen McClendon, 1 , 2 Theresa E. Hickey, 3 Lisa M. Butler, 3 Wayne D. Tilley, 3 Agnieszka K. Witkiewicz, 4 , 2 ,* and Erik S. Knudsen 1 , 2 ,*

Author information ► Copyright and License information ►

See commentary “Cyclin-dependent kinase 4/6 inhibition in cancer therapy” in volume 11 on page 3913.

This article has been cited by other articles in PMC.

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Abstract

To model the heterogeneity of breast cancer as observed in the clinic, we employed an ex vivo model of breast tumor tissue. This methodology maintained the histological integrity of the tumor tissue in unselected breast cancers, and importantly, the explants retained key molecular markers that are currently used to guide breast cancer treatment (e.g., ER and Her2 status). The primary tumors displayed the expected wide range of positivity for the proliferation marker Ki67, and a strong positive correlation between the Ki67 indices of the primary and corresponding explanted tumor tissues was observed. Collectively, these findings indicate that multiple facets of tumor pathophysiology are recapitulated in this ex vivo model. To interrogate the potential of this preclinical model to inform determinants of therapeutic response, we investigated the cytostatic response to the CDK4/6 inhibitor, PD-0332991. This inhibitor was highly effective at suppressing proliferation in approximately 85% of cases, irrespective of ER or HER2 status. However, 15% of cases were completely resistant to PD-0332991. Marker analyses in both the primary tumor tissue and the corresponding explant revealed that cases resistant to CDK4/6 inhibition lacked the RB-tumor suppressor. These studies provide important insights into the spectrum of breast tumors that could be treated with CDK4/6 inhibitors, and defines functional determinants of response analogous to those identified through neoadjuvant studies.

Keywords: ER, PD0332991, breast cancer, cell cycle, ex vivo

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Introduction

Breast cancer is a highly heterogeneous disease.14 Such heterogeneity is known to influence patient response to both standard of care and experimental therapeutics. In regards to biomarker-driven treatment of breast cancers, it was initially recognized that the presence of the estrogen receptor α (ER) in a fraction of breast cancer cells was associated with the response to tamoxifen and similar anti-estrogenic therapies.5,6 Since this discovery, subsequent marker analyses and gene expression profiling studies have further divided breast cancer into a series of distinct subtypes that harbor differing and often divergent therapeutic sensitivities.13 While clearly important in considering the use of several current standard of care therapies, these markers, or molecular sub-types, do not necessarily predict the response to new therapeutic approaches that are currently undergoing clinical development. Thus, there is the continued need for functional analyses of drug response and the definition of new markers that can be used to direct treatment strategies.

Currently, all preclinical cancer models are associated with specific limitations. It is well known that cell culture models lack the tumor microenvironment known to have a significant impact on tumor biology and therapeutic response.79 Xenograft models are dependent on the host response for the engraftment of tumor cells in non-native tissues, which do not necessarily recapitulate the nuances of complex tumor milieu.10 In addition, genetically engineered mouse models, while enabling the tumor to develop in the context of the host, can develop tumors that do not mirror aspects of human disease.10 Furthermore, it remains unclear whether any preclinical model truly represents the panoply of breast cancer subtypes that are observed in the clinic. Herein, we utilized a primary human tumor explant culture approach to interrogate drug response, as well as specific determinants of therapeutic response, in an unselected series of breast cancer cases.

Cell Cycle. 2012 Jul 15; 11(14): 2747–2755.

doi:  10.4161/cc.21127

PMCID: PMC3409014

CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy

  1. Kathleen McClendon, 1 , † Jeffry L. Dean, 1 , † Dayana B. Rivadeneira, 1 Justine E. Yu, 1 Christopher A. Reed, 1 Erhe Gao, 2 John L. Farber, 3 Thomas Force, 2 Walter J. Koch, 2 and Erik S. Knudsen 1 ,*

Author information ► Copyright and License information ►

See commentary “Cyclin-dependent kinase 4/6 inhibition in cancer therapy” in volume 11 on page 3913.

This article has been cited by other articles in PMC.

Go to:

Abstract

Triple-negative breast cancer (TNBC) is an aggressive disease that lacks established markers to direct therapeutic intervention. Thus, these tumors are routinely treated with cytotoxic chemotherapies (e.g., anthracyclines), which can cause severe side effects that impact quality of life. Recent studies indicate that the retinoblastoma tumor suppressor (RB) pathway is an important determinant in TNBC disease progression and therapeutic outcome. Furthermore, new therapeutic agents have been developed that specifically target the RB pathway, potentially positioning RB as a novel molecular marker for directing treatment. The current study evaluates the efficacy of pharmacological CDK4/6 inhibition in combination with the widely used genotoxic agent doxorubicin in the treatment of TNBC. Results demonstrate that in RB-proficient TNBC models, pharmacological CDK4/6 inhibition yields a cooperative cytostatic effect with doxorubicin but ultimately protects RB-proficient cells from doxorubicin-mediated cytotoxicity. In contrast, CDK4/6 inhibition does not alter the therapeutic response of RB-deficient TNBC cells to doxorubicin-mediated cytotoxicity, indicating that the effects of doxorubicin are indeed dependent on RB-mediated cell cycle control. Finally, the ability of CDK4/6 inhibition to protect TNBC cells from doxorubicin-mediated cytotoxicity resulted in recurrent populations of cells specifically in RB-proficient cell models, indicating that CDK4/6 inhibition can preserve cell viability in the presence of genotoxic agents. Combined, these studies suggest that while targeting the RB pathway represents a novel means of treatment in aggressive diseases such as TNBC, there should be a certain degree of caution when considering combination regimens of CDK4/6 inhibitors with genotoxic compounds that rely heavily on cell proliferation for their cytotoxic effects.

 

 

Click on Video Link for Dr. Tolaney slidepresentation of recent data with CDK4/6 inhibitor trial results https://youtu.be/NzJ_fvSxwGk

Audio and slides for this presentation are available on YouTube: http://youtu.be/NzJ_fvSxwGk

Sara Tolaney, MD, MPH, a breast oncologist with the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, gives an overview of phase I clinical trials and some of the new drugs being tested to treat breast cancer. This talk was originally given at the Metastatic Breast Cancer Forum at Dana-Farber on Oct. 5, 2013.

A great article on current clinical trials and explanation of cdk inhibitors by Sneha Phadke, DO; Alexandra Thomas, MD at the site OncoLive

 

http://www.onclive.com/publications/contemporary-oncology/2014/november-2014/targeting-cell-cycle-progression-cdk46-inhibition-in-breast-cancer/1

 

cdk4/6 inhibitor Ibrance Has Favorable Toxicity and Adverse Event Profile

 

As discussed in earlier posts and the Introduction to this chapter on Cytotoxic Chemotherapeutics, most anti-cancer drugs developed either to target DNA, DNA replication, or the cell cycle usually have similar toxicity profile which can limit their therapeutic use. These toxicities and adverse events usually involve cell types which normally exhibit turnover in the body, such as myeloid and lymphoid and granulocytic series of blood cells, epithelial cells lining the mucosa of the GI tract, as well as follicular cells found at hair follicles. This understandably manifests itself as common toxicities seen with these types of agents such as the various cytopenias in the blood, nausea vomiting diarrhea (although there are effects on the chemoreceptor trigger zone), and alopecia.

It was felt that the cdk4/6 inhibitors would show serious side effects similar to other cytotoxic agents and this definitely may be the case as outlined below:

(Side effects of palbociclib) From navigatingcancer.com

Palbociclib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • nausea
  • diarrhea
  • vomiting
  • decreased appetite
  • tiredness
  • numbness or tingling in your arms, hands, legs, and feet
  • sore mouth or throat
  • unusual hair thinning or hair loss

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

  • fever, chills, or signs of infection
  • shortness of breath
  • sudden, sharp chest pain that may become worse with deep breathing
  • fast, irregular, or pounding heartbeat
  • rapid breathing
  • weakness
  • unusual bleeding or bruising
  • nosebleeds

The following is from FDA Drug Trials Snapshot of Ibrance™:

 

See PDF on original submission and CDER review

original FDA Ibrance submission

original FDA Ibrance submission

CDER Review Ibrance

CDER Review Ibrance

 

4.3 Preclinical Pharmacology/Toxicology

 

For full details, please see Pharmacology/Toxicology review by Dr. Wei Chen The nonclinical studies adequately support the safety of oral administration of palbociclib for the proposed indication and the recommendation from the team is for approval. Non-clinical studies of palbociclib included safety pharmacology studies, genotoxicity

studies, reproductive toxicity studies, pharmacokinetic studies, toxicokinetic studies and repeat-dose general toxicity studies which were conducted in rats and dogs. The pivotal toxicology studies were conducted in compliance with Good Laboratory Practice regulation.

 

Pharmacology:

As described above, palbociclib is an inhibitor of CDK4 and CDK6. Palbociclib modulates downstream targets of CDK4 and CDK6 in vitro and induces G1 phase cell cycle arrest and therefore acts to inhibit DNA synthesis and cell proliferation. Combination of palbociclib with anti-estrogen agents demonstrated synergistic inhibition

of cell proliferation in ER+ breast cancer cells. Palbociclib showed anti-tumor efficacy in animal tumor model studies. Safety pharmacology studies with palbociclib demonstrated adverse effects on both the respiratory and cardiovascular function of dogs at a dose of 125mg/day (four times and 50-times the human clinical exposure

respectively) based on mean unbound Cmax.

 

General toxicology:

Palbociclib was studied in single dose toxicity studies and repeated dose studies in rats and dogs. Adverse effects in the bone marrow, lymphoid tissues, and male reproductive organs were observed at clinically relevant exposures. Partial to complete reversibility of toxicities to the hematolymphopoietic and male reproductive systems was demonstrated following a recovery period (4-12 weeks), with the exception of the male reproductive organ findings in dogs. Gastrointestinal, liver, kidney, endocrine/metabolic (altered glucose metabolism), respiratory, ocular, and adrenal effects were also seen.

 

Genetic toxicology:

Palbociclib was evaluated for potential genetic toxicity in in vitro and in vivo studies. The Ames bacterial mutagenicity assay in the presence or absence of metabolic activation demonstrated non-mutagenicity. In addition, palbociclib did not induce chromosomal aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. Palbociclib was identified as aneugenic based on kinetochore analysis of micronuclei formation in an In vitro assay in CHO-WBL cells. In addition, palbociclib was shown to induce micronucleus formation in male rats at doses 100

mg/kg/day (10x human exposure at the therapeutic dose) in an in vivo rat micronucleus assay.

 

Reproductive toxicology: No effects on estrous cycle and no reproductive toxicities were noticed in standard assays.

 

Pharmacovigilance (note please see PDF for more information)

Deaths Associated With Trials: Although a few deaths occurred during some trials no deaths were attributed to the drug.

Non-Serious Adverse Events:

(note a reviewers comment below concerning incidence of pulmonary embolism is a combination trial with letrazole)

 

fda ibrance reviewers SAE comment

 

Other article in this Open Access Journal on Cell Cycle and Cancer Include:

 

Tumor Suppressor Pathway, Hippo pathway, is responsible for Sensing Abnormal Chromosome Numbers in Cells and Triggering Cell Cycle Arrest, thus preventing Progression into Cancer

Nonhematologic Cancer Stem Cells [11.2.3]

New methods for Study of Cellular Replication, Growth, and Regulation

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

In Focus: Targeting of Cancer Stem Cells

 

 

 

 

 

 

 

 

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Pfizer Cambridge Collaborative Innovation Events: ‘The Role of Innovation Districts in Metropolitan Areas to Drive the Global an | Basecamp Business.

Reporter: Stephen J. Williams, Ph.D.

Monday, September 8 2014 5:30pm – 7:00pm Other Time Presented by:

Event Details:
Date/Time:
Monday, September 8, 2014, 5:30-7PM EDT
Venue: Pfizer Cambridge Seminar Room (ground floor)
Location: Pfizer Inc., 610 Main Street, Cambridge, MA 02139 . Click here for a map to the location
(Corner of Portland and Albany street, Cambridge, MA 02139)
RSVP: To confirm your attendance please RSVP online through this website. This is an ONLINE REGISTRATION-ONLY event (there will not be registration at the door).

The Role of Innovation Districts in Metropolitan Areas to Drive the Global and Local Economy: Cambridge/Boston Case Study

Join Pfizer Cambridge at our new residence for a fascinating evening led by Vise-President and Founding Director, Bruce Katz of Brookings Institution, followed by a networking reception with key partners in our new Cambridge residence; Boston-Cambridge big pharma and biotech, members of the venture capital community, renowned researchers, advocacy groups and Pfizer Cambridge scientists and clinicians.

Boston/Cambridge is one of most prominent biomedical hubs in the world and known for its thriving economy. Recent advances in biomedical innovation and cutting-edge technologies have been a major factor in stimulating growth for the city. The close proximity of big pharma, biotech, academia and venture capital in Boston/Cambridge has particularly been crucial in fostering a culture ripe for such innovation.

Bruce Katz will shed light on the state of the local and global economy and the role innovation districts can play in accelerating therapies to patients. Katz will focus on the success Boston/Cambridge has had thus far in advancing biomedical discoveries as well as offer insights on the city’s future outlook.

The Brookings Institution is a nonprofit public policy organization based in Washington, D.C. Mr. Katz is Founding Director of the Brookings Metropolitan Policy Program, which aims to provide decision makers in the public, corporate, and civic sectors with policy ideas for improving the health and prosperity of cities and metropolitan areas.

Agenda:

5:30-6PM      Registration/Gathering (please arrive by no later than 5:45PM EDT with a
                       government issued ID to allow sufficient time for security check)

6-7PM            Welcoming remarks by Cambridge/Boston Site Head and Group Senior 
                       Vice-President WorldWide R&D, Dr. Jose-Carlos Gutierrez-Ramos

                        Keynote speaker: Bruce Katz, 
                        Founding Director Metropolitan Policy Program
                        Vice-president, The Brookings Institution

7-8PM             Open reception and Networking

8PM                 Event ends

This May, Pfizer Cambridge sites are integrating and relocating our research and development teams into our new local headquarters at 610 Main Street, Cambridge, MA 02139. The unified Cambridge presence represents the opportunity to interlace Pfizer’s R&D capability in the densest biomedical community in the world, to potentially expand our already existing collaborations and to embark on forging possible new connections. These events will further drive our collective mission and passion to deliver new medicines to patients in need. Our distinguished invited guests will include leaders in the Boston-Cambridge venture capital and biotech community, renowned researchers, advocacy groups and Pfizer Cambridge scientists and clinicians.  

Online registration:
If you are experiencing issues with online registration, please contact: Cambridge_site_head@pfizer.com  



Hashtags: #bcnet-PCCIE

Monday, September 8 2014 5:30pm – 7:00pm Other Time

Location: Pfizer Inc.
610 Main St
Cambridge, MA 02139
Contact:
 

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Good and Bad News Reported for Ovarian Cancer Therapy

Reporter, Curator: Stephen J. Williams, Ph.D.

 

In a recent Fierce Biotech report

FDA review red-flags AstraZeneca’s case for ovarian cancer drug olaparib”,

John Carroll reports on a disappointing ruling by the FDA on AstraZeneca’s PARP1 inhibitor olaparib for maintenance therapy in women with cisplatin refractory ovarian cancer with BRCA mutation.   Early clinical investigations had pointed to efficacy of PARP inhibitors in ovarian tumors carrying the BRCA mutation. The scientific rationale for using PARP1 inhibitors in BRCA1/2 deficiency was quite clear:

  1. DNA damage can result in

1. double strand breaks (DSB)

  1.  DSB can be repaired by efficient homologous recombination (HR) or less efficient non-homologous end joining (NHEJ)

b. BRCA1 involved in RAD51 dependent HR at DSB sites

  1. In BRCA1 deficiency DSB repaired by less efficient NHEJ

 

 

2. single strand breaks, damage (SSB)

  1. PARP1 is activated by DNA damage and poly-ADP ribosylates histones and other proteins marking DNA for SSB repair
  2. SSB repair usually base excision (BER) or sometimes nucleotide excision repair (NER)

B. if PARP inhibited then SSB gets converted to DSB

C. in BRCA1/2 deficient background repair is forced to less efficient NHEJ thereby perpetuating some DNA damage pon exposure to DNA damaging agent

 

A good review explaining the pharmacology behind the rationale of PARP inhibitors in BRCA deficient breast and ovarian cancer is given by Drs. Christina Annunziata and Susan E. Bates in PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

(http://f1000.com/prime/reports/b/2/10/) and below a nice figure from their paper:

 

parpbrcadnadamage

 

 

 

 

 

 

 

(from Christina M Annunziata and Susan E Bates. PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer.  F1000 Biol Reports, 2010; 2:10.)  Creative Commons

Dr. Sudipta Saha’s post BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair discusses how BRCA1 affects the double strand DNA repair process, augments histone modification, as well as affecting expression of DNA repair genes.

Dana Farber’s Dr. Ralph Scully, Ph.D., in Exploiting DNA Repair Targets in Breast Cancer (http://www.dfhcc.harvard.edu/news/news/article/5402/), explains his research investigating why multiple DNA repair pathways may have to be targeted with PARP therapy concurrent with BRCA1 deficiency.

 

However FDA investigators voiced their skepticism of AstraZeneca’s clinical results, namely

  • Small number of patients enrolled
  • BRCA1/2 cohort were identified retrospectively
  • results skewed by false benefit from “underperforming” control arm
  • possible inadvertent selection bias
  • hazard ratio suggesting improvement in progression free survival but higher risk/benefit

The FDA investigators released their report two days before an expert panel would be releasing their own report (reported in the link below from FierceBiotech)

UPDATED: FDA experts spurn AstraZeneca’s pitch for ovarian cancer drug olaparib

in which the expert panel reiterated the findings of the FDA investigators.   The expert panel’s job was to find if there was any clinical benefit for continuing consideration of olaparib, basically stating

“This trial has problems,” noted FDA cancer chief Richard Pazdur during the panel discussion. If investigators had “pristine evidence of a 7-month advantage in PFS, we wouldn’t be here.”

The expert panel was concerned for the above reasons as well as the reported handful of lethal cases of myelodysplastic syndrome and acute myeloid leukemia in the study, although the panel noted these patients had advanced disease before entering the trial, raising the possibility that prior drugs may have triggered their deaths.

 

This was certainly a disappointment as ….

it was at last year’s ASCO (2013) that investigators at Perelman School of Medicine at the University of Pennsylvania and Sheba Medical Center in Tel Hashomer, Israel presented data showing that in 193 cisplatin-refractory ovarian cancer patients carrying a BRCA1/2 mutation, 31% had a partial or complete tumor regression. In addition the study also showed good response in pancreatic and prostate cancer with tolerable side effects.

 

See here for study details: http://www.uphs.upenn.edu/news/News_Releases/2013/05/domchek/

 

As John Carrol from FierceBiotech notes, the decision may spark renewed interest by Pfizer of a bid for AstraZeneca as the potential FDA rejection would certainly dampen AstraZeneca’s future growth and profit plans. Last month AstraZeneca’s CEO made the case to shareholders to reject the Pfizer offer by pointing to AstraZeneca’s potential beefed-up pipeline. AstraZeneca had projected olaparib as a potential $2 billion-a-year seller, although some industry analysts see sales at less than half that amount.

A company spokeswoman said the monotherapy use of olaparib for ovarian cancer assessed by the U.S. expert panel this week was only one element of a broad development program.

 

 

Please see a table of current oncology clinical trials with PARP1 inhibitors

at end of this post

 

However, on the same day, FierceBiotechreports some great news (at least in Europe) on the ovarian cancer front:

 

EU backs Roche’s Avastin for hard-to-treat ovarian cancer

As Arlene Weintraub   of FierceBiotech reports:

EU Committee for Medicinal Products for Human Use (CHMP) handed down a positive ruling on Avastin, recommending that the European Commission approve the drug for use in women with ovarian cancer that’s resistant to platinum-based chemotherapy. It’s the first biologic to receive a positive opinion from the CHMP for this hard-to-treat form of the disease.

Please see here for official press release: CHMP recommends EU approval of Roche’s Avastin for platinum-resistant recurrent ovarian cancer

 

EU had been getting pressure from British doctors to approve Avastin based on clinical trial results although it may be important to note that the EU zone seems to have an ability to recruit more numbers for clinical trials than in US. For instance an EU women’s breast cancer prevention trial had heavy recruitment in what would be considered a short time frame compared to recruitment times for the US.

 

Below is a table on PARP1 inhibitors in current clinical trials (obtained from NewMedicine’s Oncology KnowledgeBase™). nm|OK is a relational knowledgeBASE covering all major aspects of product development in oncolology. The database comprises 6 modules each dedicated in a specific sector within the oncology field.

 

PARP1 Inhibitors Currently in Clinical Trials for Ovarian Cancer

 

Developer and

Drug Name

Development Status & Location
– Indications
AbbVie

Current as of: March 27, 2014

PARP inhibitor: ABT-767

Phase I (begin 5/11, ongoing 2/14) Europe (Netherlands) – solid tumors with BRCA1 or BRCA2 mutations, locally advanced or metastatic • ovarian cancer, advanced or metastatic • fallopian tube cancer, advanced or metastatic • peritoneal cancer, advanced or metastatic
AstraZeneca
Affiliate(s):
· Myriad GeneticsCurrent as of: June 26, 2014Generic Name: Olaparib
Brand Name: Lynparza
Other Designation: AZD2281, KU59436, KU-0059436, NSC 747856
Phase I (begin 7/05, closed 9/08) Europe (Netherlands, UK, Poland); phase II (begin 6/07, closed 2/08, completed 5/09) USA, Australia, Europe (Germany, Spain, Sweden, UK), phase II (begin 7/08, closed 2/09) USA, Australia, Europe (Belgium, Germany, Poland, Spain, UK), Israel, phase II (begin 8/08, closed 12/09, completed 3/13) USA, Australia, Canada, Europe (Belgium, France, Germany, Poland, Romania, Spain, Ukraine, UK), Israel, Russia; phase II (begin 2/10, closed 7/10) USA, Australia, Canada, Europe (Belgium, Czech Republic, Germany, Italy, Netherlands, Spain, UK), Japan, Panama, Peru (combination); MAA (accepted 9/13) EU, NDA (filed 2/14) USA – ovarian cancer, advanced or metastatic, BRCA positive • ovarian cancer, recurrent, platinum sensitive • ovarian cancer, advanced, refractory, BRCA1 or BRCA2-associatedPhase I (begin 5/08, ongoing 5/12) USA; phase II (begin 7/08, closed 10/09) Canada – breast cancer, locally advanced, BRCA1/BRCA2-associated or hereditary metastatic or inoperable • ovarian cancer, locally advanced, BRCA1/BRCA2-associated or hereditary metastatic or inoperable • breast cancer, triple-negative, BRCA-positive • ovarian cancer, high-grade serous and/or undifferentiated, BRCA-positive

Phase I (begin 10/10, ongoing 1/13) USA (combination) – ovarian cancer, inoperable or metastatic, refractory • breast cancer, inoperable or metastatic, refractory

Phase III (begin 8/13) USA, Australia, Brazil, Canada, Europe (France, Italy, Netherlands, Poland, Russia, Spain, UK), Israel, South Korea, phase III (begin 9/13) USA, Australia, Brazil, Canada, Europe (France, Germany, Italy, Netherlands, Poland, Russia, Spain, UK), Israel – ovarian cancer, serous, high grade, BRCA mutated, platinum-sensitive, relapsed, third line, maintenance • ovarian cancer, serous or endometrioid, high grade, BRCA mutated, platinum responsive (PR or CR), maintenance, first line • primary peritoneal cancer, high grade, BRCA mutated, platinum responsive (PR or CR), maintenance • fallopian tube cancer, high grade, BRCA mutated, platinum responsive (PR or

BioMarin Pharmaceutical

Current as of: June 14, 2014

PARP inhibitor:

BMN-673, BMN673, LT-673

Phase I/II (begin 1/11, ongoing 3/14) USA – solid tumors, advanced, recurrent

Phase I (begin 2/13, closed 4/13, completed 5/14) USA – healthy volunteers

Phase I/II (begin 11/13) USA – solid tumors, relapsed or refractory, BRCA mutated, second line

BiPar Sciences

Current as of: April 16, 2009

Parp inhibitor:

BSI-401

Preclin (ongoing 4/09) – solid tumors
Clovis Oncology
Affiliate(s):
· University of Newcastle Upon Tyne
· Cancer Research Campaign Technology
· PfizerCurrent as of: June 21, 2014Generic Name: Rucaparib
Brand Name: Rucapanc
Other Designation: AG140699, AG014699, AG-14,699, AG-14669, AG14699, AG140361, AG-14361, AG-014699, CO-338, PF-01367338
Phase I (begin 03, completed 05) Europe (UK) (combination), phase I (begin 2/10, closed 11/13) Europe (France, UK) (combination) – solid tumors, advanced

Phase II (begin 12/07, closed 10/13) Europe (UK) – breast cancer, advanced or metastatic, in patients carrying BRCA1 or BRCA2 mutations • ovarian cancer, advanced or metastatic, in patients carrying BRCA1 or BRCA2 mutations

Phase I/II (begin 11/11, ongoing 6/14) USA, Europe (UK) – solid tumors, metastatic, with mutated BRCA • breast cancer, metastatic, HEr2 negative, with mutated BRCA

Sanofi

Current as of: June 03, 2013

Generic Name: Iniparib
Brand Name: Tivolza
Other Designation: BSI-201, NSC 746045, SAR240550

Phase I/Ib (begin 3/06, closed 3/10) USA (combination), phase I (begin 7/10, closed 11/10) USA, phase I (begin 9/10, ongoing 2/11) Japan (combination); phase Ib (begin 1/07, ongoing 1/11) USA (combination) – solid tumors, advanced, refractory
Phase II (begin 5/08, closed 1/09) USA – ovarian cancer, advanced, refractory, BRCA-1 or BRCA-2 associated • fallopian tube cancer, advanced, refractory, BRCA-1 or BRCA-2 associated • peritoneal cancer, advanced, refractory, BRCA-1 or BRCA-2 associated
Tesaro
Affiliate(s):
· MerckCurrent as of: May 18, 2014Generic Name: Niraparib
Other Designation: MK-4827, MK4827
Phase I (begin 9/08, closed 2/11) USA, Europe (UK) – solid tumors, locally advanced or metastatic • ovarian cancer, locally advanced or metastatic, BRCA mutant • chronic lymphocytic leukemia (CLL), relapsed or refractory • prolymphocytic leukemia, T cell, relapsed or refractory
Phase Ib (begin 11/10, closed 3/11, terminated 10/12) USA (combination) – solid tumors, locally advanced or metastatic • ovarian cancer, serous, high grade, platinum resistant or refractoryPhase III (begin 5/13, ongoing 5/14) USA – ovarian cancer, platinum-sensitive, high grade serous or BRCA mutant, chemotherapy responsive • fallopian tube cancer • primary peritoneal cancer
Teva Pharmaceutical Industries

Current as of: May 04, 2013

Designation:

CEP-9722

Phase I (begin 5/11, closed 11/12, terminated 10/13) USA, phase I (begin 6/09, closed 7/12, completed 1/12) Europe (France and UK) (combination) – solid tumors, advanced, third line
Phase I (begin 5/11, completed 1/13) Europe (France) (combination) – solid tumors, advanced • mantle cell lymphoma (MCL), advanced

 

 

Summary of Combination Ovarian Cancer Trials with Avastin (current and closed)

 

Indication in Development ovarian cancer, advanced, recurrent, persistent • ovarian cancer, progressive, platinum resistant, second line • fallopian tube cancer, progressive, platinum resistant, second line • primary peritoneal cancer, progressive, platinum resistant, second line
Latest Status Phase II (begin 4/02, closed 8/04) USA, phase II (begin 11/04, closed 10/05) USA; phase III (begin 10/09) Europe (Belgium, Bosnia and Herzegovina, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, Sweden), Turkey
Clinical History Refer to the Combination Trial Module for trials of Avastin in combination with various chemotherapeutic regimens.According to results from the AURELIA clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911), the median PFS in women with progressive platinum resistant ovarian, fallopian tube or primary peritoneal cancer treated with Avastin in combination with chemotherapy, was 6.7 months compared to 3.4 months in those treated with chemotherapy alone for an HR of 0.48 (range =0.38–0.60).. In addition, the objective response rate was 30.9% in women treated with Avastin compared to 12.6% in those on chemotherapy (p=0.001). Certain AE (Grade 2 to 5) that occurred more often in the Avastin arm compared to the chemotherapy alone arm were high blood pressure (20% versus 7%) and an excess of protein in the urine (11% versus 1%). Gastrointestinal perforations and fistulas occurred in 2% of women in the Avastin arm compared to no events in the chemotherapy arm (Pujade-Lauraine E, etal, ASCO12, Abs. LBA5002).A multicenter (n=124), randomized, open label, 2-arm, phase III clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911; http://clinicaltrials.gov/ct2/results?term=NCT00976911 ), dubbed AURELIA, was initiated in October 2009, in Europe (Belgium, Bosnia and Herzegovina, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, and Sweden), and Turkey, to evaluate the efficacy and safety of Avastin added to chemotherapy versus chemotherapy alone in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer with disease progression within 6 months of platinum therapy in the first line setting. The trials primary outcome measure is PFS. Secondary outcome measures include objective response rate, biological PFS interval, OS, QoL, and safety and tolerability. According to the protocol, all patients are treated with standard chemotherapy with IV paclitaxel (80 mg/m²) on days 1, 8, 15 and 22 of each 4-week cycle; or IV topotecan at a dose of 4 mg/m² on days 1, 8 and 15 of each 4-week cycle, or 1.25 mg/kg on days 1-5 of each 3-week cycle; or IV liposomal doxorubicin (40 mg/m²) every 4 weeks. Patients (n=179) randomized to arm 2 of the trial are treated with IV Avastin at a dose of 10 mg/kg twice weekly or 15 mg/kg thrice weekly concomitantly with the chemotherapy choice. Treatment continues until disease progression. Subsequently, patients are treated with the standard of care. Patients in arm 1 (n=182), on chemotherapy only may opt to be treated with IV Avastin (15 mg/kg) three times weekly. The trial was set up in cooperation with the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) and was conducted by the international network of the Gynecologic Cancer Intergroup (GCIG) and the pan-European Network of Gynaecological Oncological Trial Groups (ENGOT), under PI Eric Pujade-Lauraine, MD, Hopitaux Universitaires, Paris Centre, Hôpital Hôtel-Dieu (Paris, France). The trial enrolled 361 patients and was closed as of May 2012..Results were presented from a phase II clinical trial (protocol ID: CDR0000068839; GOG-0170D; NCT00022659) of bevacizumab in patients with persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer that was performed by the Gynecologic Oncology Group to determine the ORR, PFS, and toxicity for this treatment. Patients must have been administered 1-2 prior cytotoxic regimens. Treatment consisted of bevacizumab (15 mg/kg) IV every 3 weeks until disease progression or prohibitive toxicity. Between April 2002 and August 2004, 64 patients were enrolled, of which 2 were excluded for wrong primary and borderline histology and 62 were evaluable (1 previous regimen=23, 2 previous regimens=39). The median disease free interval from completion of primary cytotoxic chemotherapy to first recurrence was 6.5 months. Early results demonstrated that some patients had confirmed objective responses and PFS in some was at least 6 months. Observed Grade 3 or 4 toxicities included allergy (Grade 3=1), cardiovascular (Grade 3=4; Grade 4=1), gastrointestinal (Grade 3=3), hepatic (Grade 3=1), pain (Grade 3=2), and pulmonary (Grade 4=1). As of 11/04, 36 patients were removed from the trial, including 29 for disease progression and 1 for toxicity in 33 cases reported. Preliminary evidence exists for objective responses to bevacizumab (Burger R, et al, ASCO05, Abs. 5009).An open label, single arm, 2-stage, phase II clinical trial (protocol ID: AVF2949g, NCT00097019) of bevacizumab in patients with platinum resistant, advanced (Stage III or IV), ovarian cancer or primary peritoneal cancer for whom subsequent doxorubicin or topotecan therapy also has failed was initiated in November 2004 at multiple locations in the USA to determine the safety and efficacy for this treatment.A multicenter phase II clinical trial was initiated in April 2002 to determine the 6-month PFS of patients with persistent or recurrent ovarian epithelial or primary peritoneal cancer treated with bevacizumab (protocol ID: GOG-0170D, CDR0000068839, NCT00022659). IV bevacizumab is administered over 30-90 minutes on day 1. Treatment is repeated every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. A total of 22-60 patients will be accrued within 12-30 months. Robert A. Burger, MD, of Chao Family Comprehensive Cancer Center is Trial Chair.This trial was closed in August 2004.

 

 

Sources

http://www.fiercebiotech.com/story/fda-review-red-flags-astrazenecas-case-ovarian-cancer-drug-olaparib/2014-06-23

 

http://www.fiercebiotech.com/story/fda-experts-spurn-astrazenecas-pitch-ovarian-cancer-drug-olaparib/2014-06-25

 

http://www.fiercepharma.com/story/eu-backs-roches-avastin-hard-treat-ovarian-cancer/2014-06-27

 

In a followup to this original posting A Report From the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine entitled

Evolving Approaches in Research and Care for Ovarian Cancers

was generated in a ViewPoint piece in JAMA which discussed their Congressional mandated report on the State of the Science in Ovarian Cancer Research, titled

Ovarian Cancers: Evolving Paradigms in Research and Care 

highlights some of the research gaps felt by the committee in the current state of ovarian cancer research including:

  • consideration in research protocols of the multitude of histologic and morphologic subtypes of ovarian cancer, including the feeling of the committee that high grade serous OVCA originates from the distal end of the fallopian tube (espoused by Dr. Doubeau and Dr. Christopher Crum) versus originating from the ovarian surface epithelium
  • a call for expanded screening and prevention research with mutimodal screening including CA125 with secondary transvaginal screen
  • better patient education of the risk/benefit of genetic testing including BRCA1/2 as well as in consideration for PARP inhibitor therapy
  • treatments should be standardized and disseminated including more research in health outcomes and decision support for personalized therapy

This Perspective article can be found here: jvp160038

Some other posts relating to OVARIAN CANCER on this site include

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Ultrasound-based Screening for Ovarian Cancer

Dasatinib in Combination With Other Drugs for Advanced, Recurrent Ovarian Cancer

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

 

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Keynote Address Speaker and Panel Updates Announced

Reporter: Aviva Lev-Ari, PhD, RN

Scientific innovation is at the core of Big Pharma‘s business model, but continuous transformation critical to R&D momentum has been an ongoing, multi-year challenge. Big Pharma has struggled to manage costs while delivering on productivity. Unmet medical need remains a compelling scientific and business opportunity, as is development of truly differentiated medicines and orphan drugs.

 

R&D: Balancing Austerity and Innovation at the 23rd Annual PSA: The Pharmaceutical Strategy Conference, being held September 23-25, 2013 at the Millennium Broadway Hotel in New York City. Successful R&D leaders discuss their strategies for maintaining excellence and adaptability in the face of internal and external hurdles.

 

Matthias Evers, PhD (Moderator), Partner, McKinsey & Company 

George Yancopoulos, MD, PhD, President & CSO, Regeneron Pharmaceuticals

Rupert Vessey, SVP, R&D Strategy, Merck & Co., Inc.

JC Gutierrez-Ramos, SVP & Head of Biotherapeutics R&D, Pfizer

 

Keynote Address: Applying the Lessons of Philanthropy

Tadataka “Tachi” Yamada

Chief Medical and Scientific Officer

Takeda Pharmaceuticals

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Larry H. Bernstein, MD
Leaders in Pharmaceutical Innovation
https://pharmaceuticalintelligence.com/2013/03/02/cancer-drugs-proving-worth/

 

INSIGHT – Cancer drugs proving worth earlier in testing
By Bill Berkrot and Ransdell Pierson | Reuters – Mon, Feb 25, 20

 

http://ph.news.yahoo.com/insight-cancer-drugs-proving-worth-earlier-testing-060402726–finance.html?goback=%2Egde_72923_member_217729560/

 

NEW YORK (Reuters) – Michael Weitz was out of options. The Californian had endured chemotherapy, radiation and surgery but his lung cancer still spread to his bones and brain. He was  entered into a Phase I study – the earliest stage of human testing for a new medicine – of crizotinib. The drug works for about 4 percent of advanced lung cancer patients with a mutated form of a protein called ALK.

 

Weitz, now 55,  is cancer-free after three years of taking the drug now sold by Pfizer as Xalkori after an unusually swift development process.

 

It typically has taken a decade and $1 billion to bring a new treatment to market. But in the last two years a handful of cancer drugs – including Onyx Pharmaceutical Inc’s Kyprolis for multiple myeloma, Roche’s Zelboraf for melanoma, and Pfizer’s Xalkori – were approved in about half that time because of improved genetic screening, more definitive Phase I trials and the dire need for new, effective treatments.

 

“We hope to be able to shave years off the time it takes to get final approval and save hundreds of millions of dollars per drug,” said Robert Schneider, director of translational cancer research at New York University Cancer Institute.

 

Smoking lung cancer

Smoking lung cancer (Photo credit: Wikipedia)

High rates of lung cancer (indicated in this m...

High rates of lung cancer (indicated in this map by brown colors) are highly correlated with the Stroke Belt. (Photo credit: Wikipedia)

 

 

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