UPDATED: FDA review challenges Amgen on a questionable T-Vec study

In the lead-up to Wednesday's FDA advisory committee meeting on Amgen's ($AMGN) cancer-killing virus talimogene laherparepvec (T-Vec), the Big Biotech relied heavily on what it said were clear signs of a durable response in the latest clinical trial with a near miss on survival stats that the company felt shouldn't prevent an approval for treating melanoma. But an internal FDA review of Amgen's study of the dual-acting cancer vaccine/viral therapy, released Monday morning, raises more red flags for this drug, presenting some thorny questions for the company's regulatory team to answer.

Of particular concern:

278 subjects dropped out of the study, leading the FDA to question whether investigator bias--focusing on crafting positive final data--had something to do with those decisions. "Subject or investigator bias regarding the relative benefit of talimogene laherparepvec and the control may have influenced the determination that it was in the best interest of the subject to stop treatment or to be given other therapy for melanoma," noted the FDA.

The review--which rules out an accelerated approval under the rules of the approval game--notes that there is "uncertainty regarding the meaningfulness of the observed responses," with a small size in baseline lesions and a move by investigators to add patients as durable responders after the initial 6-month period for assessing responses.

Is there clear evidence of a systemic response to the drug, which is designed to spur an immune response as it targets and kills cancer cells? That's hard to determine based on the data presented, says the FDA review. "Although there is a scientific basis to support the possibility that systemic effects may occur, the evidence in Study 005/05 that talimogene laherparepvec had a systemic effect was limited and difficult to quantitate."

The review also raises questions of investigator bias in assembling the final data, excluding some patients--cherry-picking would be another way of phrasing it--in a way that may have skewed the final outcomes, in which overall survival missed the bar for success in any case. Says the FDA: "Thus the survival results are not robust, and the conduct of the study with regard to a relatively small number of subjects, potentially subject to investigator bias, could have had substantial impact on the results of the survival analysis."

"Uncertainty regarding the clinical meaningfulness of the Study 005/05 primary endpoint results, in the absence of a clear effect on overall survival, raises concern regarding both the existence and the magnitude of an overall benefit of talimogene laherparepvec," the review concludes.

Dr. Richard Pazdur

Amgen does have one big factor in its favor. The FDA has become quite accommodating when it comes to approving new cancer therapies, provided the registration study doesn't raise the ire of oncology chief Richard Pazdur. Even if the therapy is approved, though, this kind of review raises serious questions about its market potential, particularly as several new melanoma therapies have hit the market in the past few years.

Amgen, though, isn't about to back away from T-Vec at this stage of the game.

"We look forward to discussing the monotherapy data for talimogene laherparepvec at the joint FDA advisory committee meeting on Wednesday," said Dr. Sean Harper, executive vice president of R&D at Amgen, in a statement this morning. "The results from the Phase III OPTiM clinical trial showed that talimogene laherparepvec, an oncolytic immunotherapy, demonstrated a statistically significant improvement in the primary endpoint--durable response rate--which was associated with clinical benefit to patients. Even with the remarkable recent advances in the melanoma field, there is still a need for additional treatment options. If approved, talimogene laherparepvec would represent an entirely new class of agent for the treatment of metastatic melanoma."

Amgen acquired T-Vec, a re-engineered virus designed to destroy cancer cells while spurring an immune response, in a $1 billion buyout of BioVex, a 2009 Fierce 15 company. The biotech has been aiming at a big year for new drug approvals, determined to shake off critics of its R&D strategy. But the recent approval of the heart drug ivabradine was dogged by comparisons with Novartis' big LCZ696, which is widely expected to get an approval later this year. Amgen is also in a close race with Sanofi ($SNY)/Regeneron ($REGN) on a new PCSK9 drug.

While not solely a cancer vaccine, T-Vec's mixed results in the clinic do nothing to raise the prospects for a field that's been littered with a series of trial failures and a big market setback for Provenge.