Assistant Managing Editor

Ariad Pharmaceuticals Inc.'s odds of gaining approval of mTOR inhibitor ridaforolimus in sarcoma maintenance therapy went up considerably last week after the drug hit its primary endpoint in a special protocol assessment-conducted Phase III trial – even if the progression-free survival (PFS) numbers fell a little short of initial expectations.

Data from the 711-patient study, designated SUCCEED, showed a statistically significant 28 percent reduction in the risk of disease progression for patients on ridaforolimus vs. placebo, with a solid "p" value of 0.0001 and a hazard ratio of 0.72. Median PFS showed a 21 percent improvement in the treatment arm over placebo, but that translated to a mere 3.1 weeks, which, as one analyst pointed out on the company's conference call, is less of a treatment improvement than the FDA's Oncologic Drugs Advisory Committee typically likes to see. (See BioWorld Today, Jan. 19, 2011.)

SUCCEED was designed specifically to test ridaforolimus in patients with soft-tissue or bone sarcoma who had achieved a favorable response to chemotherapy, but were in a treatment vacuum – the so-called "watchful waiting" period. Ariad's drug went head-to-head against placebo, and the study had been 90 percent powered to detect a 33 percent increase in median PFS. (See BioWorld Today, Sept. 25, 2007.)

Yet the data generated from SUCCEED should be sufficient to support a new drug application. Partner Merck & Co. Inc., of Whitehouse Station, N.J., plans to file by the end of this year, and many analysts believe Ariad's ridaforolimus will fare well at the FDA.

After all, the drug has precedent in its favor, thanks to prior approvals of both Tarceva (erlotinib, Roche AG and Astellas Pharma) and Alimta (pemetrexed, Eli Lilly and Co.), both as maintenance therapies in non-small-cell lung cancer.

"Both Tarceva and Alimta were approved with PFS differences of less than 12 weeks," Ariad CEO Harvey J. Berger, told investors on the call. "So I don't think there's any single cut off for what is approvable."

Alimta gained approval for maintenance use in 2009, with a median PFS of four months for patients in the treatment arm vs. two months in the placebo group. And last year the FDA split with ODAC, after the panel's shocking negative 12 to 1 vote against Tarceva, approving the drug for maintenance in NSCLC based on only a one-month PFS improvement. (See BioWorld Today, April 20, 2010.)

That means Ariad's ridaforolimus looks to have a good chance at approval, though final regulatory clearance and commercial uptake could hinge on the drug's secondary endpoint data, which include overall survival (OS) and safety. Berger said those results are expected at an upcoming scientific conference and should show "at a minimum, some trends that are supportive" of approval.

The good news is that OS data shouldn't be as critical to ridaforolimus' success. Those data played a significant role during the Tarceva debate, as regulators questioned whether the drug showed greater benefit as a maintenance therapy or as a second- or third-line treatment for which it already was approved. But ridaforolimus is not approved in second- or third-line settings, so "similar questions will likely not apply," noted Leerink Swann analyst Howard Liang.

Should the drug reach market, J.P. Morgan analyst Cory Kasimov anticipates average peak sales in sarcoma of around $175 million. Under the terms of its Merck collaboration, Cambridge, Mass.-based Ariad will book a tiered, double-digit royalty.

But the SUCCEED win could have other implications for Ariad, as analysts anticipate Merck to accelerate development of ridaforolimus in other indications. The drug is designed to target mTOR, the protein that acts as a master switch in cancer cells. It works via the same mechanism as Pfizer Inc.'s Torisel, approved in kidney cancer, and Novartis AG's Afinitor, used to treat brain cancer and second-line kidney cancer, and ridaforolimus is in Phase II testing in endometrial, breast, NSCLC and prostate cancers.