R&D Lessons from Pfizer?s New Breast Cancer Drug, PD-332,991

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Earlier this month, Pfizer reported extremely exciting phase 2 results regarding its experimental breast cancer medication, PD-332,991. As related by Bloomberg?s Michelle Fay Cortez, when PD-332,991 was combined with Novartis? drug, Femara, post-menopausal patients with estrogen receptor positive breast tumors showed no tumor progression for more than 26 months as compared to patients on Femara alone who had only 7.5 months of progression free survival.

PD-332,991 is a highly selective inhibitor of CDK4/6, a protein that plays a key role in cancer cell cycles. ?CDK4/6 has been hypothesized to have the potential to treat a variety of cancers and this result certainly confirms that potential in breast cancer. Dr. Richard Finn of UCLA?s Jonsson Comprehensive Cancer Center who led this study said that: ?The magnitude of this benefit is probably one of the largest with any new agent in breast cancer or perhaps any solid tumor.?

This compound emerged from a collaboration begun in the late 1990s between the Warner-Lambert/Parke-Davis R&D labs and Onyx Pharmaceuticals. As told by Dr. James A. Bristol, this collaboration involved equal efforts between the organizations.

?The structure of the arrangement between Parke-Davis and Onyx was a 50-50 split of responsibilities with somewhere between 10 ? 15 scientists contributed by each company. Parke-Davis contributed medicinal chemistry, ADME/PK, in vivo animal pharmacology (principally mouse xenografts) and drug safety. Onyx provided all in vitro biology, including preparation of human protein, cell biology and enzymology. Clinical development was the responsibility of Parke-Davis and subsequently Pfizer (after the 2000 merger).?

The Parke-Davis/Onyx deal is a typical one between a pharmaceutical company and a small biotech company. In general, the biotech company has technology that is attractive to a potential partner. However, both companies need each other to move projects forward. This same type of deal was done by Pfizer with Oncogene Sciences and led to the discovery of the lung cancer drug, Tarceva. The discovery of the Lupus drug, Benlysta, came from a similar aliance between ?GSK and Human Genome Sciences (the latter has recently been acquired by GSK). There are many other such examples. However, I believe that the key to the success behind these programs is that BOTH partners brought important expertise to the table.

Critics of Big Pharma often state that true innovation only comes from biotech and that the pharma company only develops the experimental drug. These examples show that this is not the case. Innovation is a shared quality in the majority of drug R&D stories.

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But the PD-332,991 also highlights a different issue in drug R&D. As I have stated in the past , major mergers take a toll on a company in many ways, particularly morale and productivity. PD-332,991 seems to have been a victim of such a scenario. This compound was nominated for development in Pfizer in 2002 and, according to Onyx?s website which charts milestones, this compound entered ?clinical development in 2004. Yet, according to data that Pfizer provides on its own website regarding its pipeline, PD-332,991 languished in Phase 1 until January, 2010, when it was finally advanced to phase 2. It normally only takes 12 months for a compound to proceed through phase 1 studies. Why did this compound lag in phase 1 for 6 years?

There are various reasons why this happened. ?A scientist from Onyx familiar with this program offered this explanation:

?Although I have no firsthand knowledge of what happened within Pfizer, my impression is that PD-332,991 may be a case study to follow up on your ?Nature Reviews Drug Discovery? article on the consequences of mergers for R&D. The integration of Agouron/Parke-Davis/Pfizer oncology programs, each of which, I believe, ?had a cell cycle project , probably took its toll. It may be a classical example of a good compound that didn?t happen to have a champion, or whose champion was not in a position to exert much influence in a larger process. However, these are all just impressions.?

I was part of the Pfizer R&D hierarchy until 2007, so I think this view has some merit. As a result of reorganizations in R&D, as well as major cost cutting initiatives, we made radical changes to the oncology group in 2006/2007. These disruptions undoubtedly slowed things down across the board with all of our programs. This experience is a reason for my souring on the use of mergers and acquisitions as a corporate growth strategy.

Another possibility for the slow clinical progress of PD-332,991 is that Pfizer was very focused on delivering its late-stage portfolio. During this period, Pfizer executed the phase 3 programs and got FDA approvals for new cancer indications for Sutent, Inlyta for kidney cancer, Xalkori for lung cancer and Bosulif for leukemia. Such a heavy load can divert both focus and resources from early stage programs like PD-332,991. One often thinks that Big Pharma has enormous resources that enables companies to move all programs aggressively. I think this example shows this not to be true. Nevertheless, one cannot help but think that the structure and personnel changes that occurred at Pfizer helped to delay the advance of PD-332,991.

The good news is that Pfizer is working closely with oncology experts to finalize the key phase 3 studies that will be conducted to get FDA approval for this exciting drug. ??We?re trying to move forward with a thoughtful, methodical approach? said Dr. Mace Rothenberg, Pfizer?s senior VP of oncology clinical development. ?My guess is that the phase 3 program will take a lot less time than phase 1 did ? and that is great news for breast cancer patients.

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Source: http://www.forbes.com/sites/johnlamattina/2012/12/20/rd-lessons-from-pfizers-new-breast-cancer-drug-pd-332991/

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