Pfizer has become more effective at controlling the development risk of investigational compounds with novel mechanisms of action, Global Research & Development President John LaMattina asserted Nov. 30.

"I think we have gotten better working with what we call internally...Quadrant IV compounds - totally unprecedented areas both in terms of efficacy and safety," LaMattina said during an analyst meeting in Groton, Conn.

LaMattina's comments came just two days before Pfizer announced the termination of its clinical development program for torcetrapib/atorvastin due to an increased mortality risk; torcetrapib, which was designed to raise HDL cholesterol, would have been the first cholesteryl ester transfer protein inhibitor (see ¹ Also see "Pfizer’s Lipitor Extension Shot Down By Failure Of Torcetrapib Silver Bullet" - Pink Sheet, 11 December, 2006.).

LaMattina said the main reason Pfizer has improved its ability to deal with first-in-class compounds is that the firm is bringing better compounds into the clinic.

"Many times in our history we have lost compounds in Phase II, not because we tested the mechanism and the mechanism didn't work, but because the compound we had wasn't robust enough to really demonstrate efficacy," he explained.

"With a number of compounds that we have talked about today, that is no longer the case," he added.

In addition, "we know a lot more about biology than we did 10 or 12 years ago," he noted.

Pfizer Senior VP-Worldwide Research & Technology Martin Mackay said the key to developing compounds with novel mechanisms is moving them quickly into early clinical efficacy trials.

"Probably the most important thing, particularly with an unprecedented mechanism, is to get through Phase I quickly and then be able to test it in Phase II...and look for early signals," he said.

Mackay noted that historically 60 percent of compounds drop out of development before reaching clinical trials.

"Being able to find the right...chemical-type characteristics for safety and being able to test efficacy, this has improved [so] now 70 percent to 80 percent of compounds normally get into first-in-humans," he said. "That alone makes a difference in testing untested medical mechanisms."

LaMattina also highlighted the importance of decreasing the number of compounds that fall out of development between Phase II and Phase III.

"What's startling in the industry is that that attrition rate in going from Phase II into Phase III is roughly about 75 percent - three-quarters of the compounds that start Phase II drop out before Phase III," he said.

"We think that we can really move that needle," he maintained. "You only have to get an improvement by about 10 percent and you get a tremendous increase....Our early signs are pretty good right now."

LaMattina and Mackay's statements came in response to a question regarding the potential for high attrition in Pfizer's pipeline due to a large number of compounds employing novel mechanisms of action.

LaMattina acknowledged that "compounds that are totally novel tend to have a higher attrition rate," but said he is "encouraged" by positive proof-of-concept trials with Pfizer's candidates.

The exec pointed to the Janus Kinase 3 (JAK-3) inhibitor CP-690,550, which is in Phase II trials in rheumatoid arthritis, as one example of a compound with a novel target that has demonstrated efficacy in trials. It "is not just a study that's been done in rheumatoid arthritis in about 20 patients, it was a pretty robust study with 260 patients," he noted.

In a Phase II trial, approximately 60 percent of CP-690 patients experienced ACR 20 responses, a response rate similar to or higher than those seen with Abbott's TNF inhibitor Humira (adalimumab), Pfizer said.

"This is a pretty remarkable finding and we believe this is a game changer in the treatment of autoimmune disease, particularly RA," LaMattina said. "Getting from large molecule infusion therapies to a once or twice a day pill...I think will be very well received when we try that on patients."

Pfizer is developing CP-690 as a disease modifying agent; the firm has not decided whether to study it in combination with or head-to-head to an anti-TNF agent in Phase III.

LaMattina said similarly strong activity in proof-of-concept studies makes him confident about the compounds with unprecedented mechanisms in the company's oncology portfolio.

Pfizer's late-stage oncology portfolio includes a number of agents with novel mechanisms of action including an anti-CLA4 monoclonal antibody (CP-675,206) and a toll-like receptor 9 agonist (PF-3,512,676) (see ² Also see "Pfizer Looks To Combination Regimens To Maximize Oncology Pipeline Value" - Pink Sheet, 11 December, 2006.).

"When you take a compound and put it in...patients who have failed every other [treatment option] and get a robust response, it's going to be a good indicator," he said.

In addition to the JAK-3 and oncology agents, other compounds with novel mechanisms in Pfizer's pipeline include CCR5 antagonist maraviroc for HIV, CB-1 antagonist CP-945,598 and an MTP inhibitor for obesity, a PDE-10 inhibitor for schizophrenia and RAGE inhibitor TTP488 for Alzheimer's disease.

"Will we see a degree of attrition" with first-in-class compounds, "absolutely, but I think our prospects are better than ever before," LaMattina said.

While Pfizer's late-stage pipeline includes a large number of compounds with unproven mechanisms of action, LaMattina cited some line extensions, which generally are lower risk, as offering significant market potential.

"Some line extensions actually represent major regulatory filings," he said, citing Sutent (sunitinib) in breast and non-small cell lung cancer and Lyrica (pregabalin) in fibromyalgia as examples. Sutent is currently approved for gastrointestinal/stromal tumors and renal cell carcinoma; Lyrica has claims for neuropathic pain and seizures.

"The value of an individual line extension like these can rival a stand-alone new molecular entity," he said.

- Andrew Kasper

Pfizer Better Able To De-Risk First-In-Class Compounds, R&D Head Says

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