Pfizer’s late-stage portfolio has suffered another serious hit with the news that the firm is halting development of its experimental melanoma compound tremelimumab.

The New York-based drugs giant announced the discontinuation of a Phase III trial of tremelimumab in patients with advanced melanoma after the review of interim data showed that the drug would not demonstrate superiority to standard chemotherapy. However, Pfizer said it will work with patients to see if they are benefiting from treatment with tremelimumab and should continue on the drug.

Charles Baum, oncology chief at Pfizer Global Research, said that while the news is disappointing, the firm remains committed to investigating new treatment options for patients with melanoma, “a high risk area of research with significant unmet medical need". He added that “we continue to focus on additional studies involving tremelimumab alone and in combination with other therapies which are currently ongoing in patients with several types of cancer".

The bad news about tremelimumab is particularly disappointing seeing as it comes at a time when Pfizer has been stating its desire to become a major player in oncology. It also recently acquired the cancer specialist Serenex.

As for the larger picture, Pfizer is hoping to fill the gaps in its pipeline caused by the losses of patent protection by 2012 on drugs that make up one-third of its revenue, notably the cholesterol blockbuster Lipitor (atorvastatin). However it has suffered a number of disappointments in the last year or two.

Last June, the firm discontinued a Phase III development programme in advanced non-small cell lung cancer for PF-3512676 in combination with cytotoxic chemotherapy. Most high-profile, however, was the abrupt termination of Pfizer's high-density lipoprotein booster torcetrapib at the end of 2006, news which wiped over $21 billion off the value of the firm.

Good news, bad news for Celebrex
Meantime, the risk of cardiovascular adverse events with Celebrex (celecoxib), Pfizer’s COX-2 inhibitor, depends on the daily dose especially in higher-risk patients. This was the conclusion of the Cross Trials Safety Assessment, reported at the American College of Cardiology meeting, writes Sue Lyon in Chicago.

Concerns about cardiovascular risk with coxibs led to the withdrawal of Merck’s Vioxx (rofecoxib) in late 2004, followed two months later by the termination of the APC study, designed to assess whether Celebrex could reduce the risk of colorectal cancer. The Cross Trials Safety Assessment therefore has some good news for Pfizer, in providing prescribers with some reassurance when prescribing Celebrex to patients at low cardiovascular risk.

The Cross Trials Safety Assessment was a meta-analysis of six trials including 7950 patients and comparing Celebrex and placebo in conditions other than arthritis. Celebrex-associated cardiovascular risk was lowest for the 400mg daily dose, roughly doubling for 200 mg twice daily and trebling for 400mg twice daily. This risk was present regardless of baseline aspirin use, and appeared to increase in patients at high cardiovascular risk at the start of Celebrex treatment.

Presenting the study in Chicago, lead investigator Dr Scott Solomon, Brigham and Women’s Hospital, Boston, USA, recommended caution in prescribing Celebrex to patients at higher cardiovascular risk, and considered that the results supported the American Heart Association’s recent recommendation to give the lowest possible dose of Celebrex especially in this patient group.

“While the daily doses [of Celebrex] tested were higher than those typically used for osteoarthritis patients, they are directly relevant to rheumatoid arthritis, acute pain, dysmenorrhoea and familial adenomatous polyposis (an inherited condition that increases colorectal cancer risk), as well doses currently being tested for non-arthritic conditions. Our data provide strong evidence of a dose-related and regimen-related risk, but cannot address whether lower doses would lead to lower cardiovascular risk or whether non-selective NSAIDs would also be associated with a similar risk,” he added.

Dr Solomon’s reservations suggest that important questions about the cardiovascular safety of Celebrex and non-selective NSAIDs will only be answered when results are available from long-term clinical trials such as PRESTIGE. In the meantime, prescribers will have to balance potential cardiovascular risks against the need to treat the pain and disability experienced by patients with arthritis.