Millennium, Looking to Fend Off Onyx, Awaits FDA Word on New Velcade

1/20/12Follow @xconomy

The drug that made Millennium into a biotech power is on the verge of getting a subtle but meaningful upgrade, just in time to help the company fend off a serious new competing therapy from South San Francisco-based Onyx Pharmaceuticals (NASDAQ: ONXX).

Cambridge, MA-based Millennium, the cancer drug unit of Takeda Pharmaceuticals, is awaiting word from the Food and Drug Administration on whether it can start marketing a new version of bortezomib (Velcade) that can be injected just underneath the skin. The U.S. drug regulatory agency has a deadline of Jan. 23 to complete its review of Millennium’s application for the subcutaneous form of the treatment, which would be a new option beyond the current version that’s given intravenously.

Ordinarily, this kind of application would be an incremental advance. But the FDA’s decision could mean a lot to Millennium, because the new subcutaneous form is not only faster and more convenient for hospitals to administer, but clinical trials show it causes less nerve damage in the fingers and toes than the conventional IV product. If the FDA agrees to allow Millennium to market the new version, then Millennium will have a stronger defense against emerging competition from Onyx Pharmaceuticals, which is angling for FDA clearance of a rival drug that has long claimed to have an advantage with its milder side effects.

The Millennium drug, approved by the FDA in 2003, generated $1.4 billion in worldwide sales in 2009, and is on pace to eclipse $3 billion by 2015, according to BCC Research. About 20,000 people are diagnosed with myeloma each year in the U.S., and 10,000 die from it annually, according to the American Cancer Society.

“There are all kinds of ramifications that will make this quite an attractive option for patients,” Deborah Dunsire, the CEO of Millennium, said last week in an interview at the JP Morgan Healthcare Conference in San Francisco.

The whole idea of packaging Velcade in a new way wasn’t something that came from Millennium scientists, and they didn’t expect it would make much difference. The idea for developing a subcutaneous form came after a nurse in France improvised when it was too difficult to find a vein in an elderly patient, Dunsire says. It turned out the patient did well on this improvised injection, and the doctor decided to try to study the new injection mode further, she says.

When Millennium got wind of some promising early results, it designed a study of 222 patients to compare those on standard Velcade with patients on the new subcutaneous version, to see if they were roughly the same. A subcutaneous version, after all, has a natural convenience advantage in that patients don’t have to spend as much time at the clinic to get it, and such a treatment can be delivered by a healthcare staffer with less training than registered nurses who need to handle IVs.

Results from the study, presented at the American Society of Hematology meeting in December 2010, showed that the subcutaneous form of Velcade had exactly the same ability to shrink tumors as the original, but was milder in terms of side effects. Peripheral neuropathy—a form of nerve damage in the fingers and toes that causes numbness and tingling—has long been a drawback for Velcade, and that often forces doctors to reduce its dose. But in this trial, researchers saw that only 6 percent of patients on subcutaneous Velcade had moderate to severe cases of peripheral neuropathy, compared with 16 percent on the standard form of the drug.

The difference surprised the people at Millennium, because it’s the same drug, manufactured the same way. “It goes to show you don’t necessarily know everything in development that you think you know,” Dunsire says.

If the FDA clears the new version of Velcade for sale, it could have a significant impact on Millennium’s business, Dunsire says. More patients might be started on Velcade, since there’s no concern about finding veins in elderly patients. Some patients at risk of peripheral neuropathy, who might have had their Velcade delayed, might be inclined to move ahead with treatment quickly now. Existing patients might be able to stay on Velcade longer if the side effect doesn’t pop up. And doctors may be more inclined to test out regular doses for “maintenance” therapy since the subcutaneous form will be more convenient on a regular basis than an IV.

Even though Millennium can’t yet promote the new version of Velcade, Dunsire says she’s heard that some physicians are converting their entire practice over to using the subcutaneous form of the drug because it saves the time of their nurses, and offers a better risk/benefit profile.

Perhaps most importantly, the milder side effect profile could help Millennium fight back against Onyx’s competing drug, carfilzomib, a proteasome inhibitor like Velcade. Onyx filed for FDA approval of that drug back in September, based on a trial of 266 patients. That study showed the Onyx drug could shrink tumors in half or more for 24 percent of patients, even after they had gotten at least two prior rounds of therapy, and no longer responded to Velcade. Less than 1 percent of patients on the Onyx drug in that study reported a moderate to severe case of peripheral neuropathy.

Dunsire, while having some words of respect for her competitor, said she’s confident the new form of Velcade will stack up well with the Onyx drug on the peripheral neuropathy score.

“Onyx has been very clear they think one of their advantages is less peripheral neuropathy,” Dunsire says. “But in the single-agent setting, in relapsed patients, Velcade seems to have more complete remissions. There’s more power in Velcade, but there’s definitely a higher rate of peripheral neuropathy. When you think about subQ [subcutaneous], you get the power of Velcade with the proven long-term survival of Velcade, and now you can mitigate the neuropathy. It starts to close that gap. That issue, if you will, is going away.”

Onyx CEO Tony Coles, also interviewed last week at the JP Morgan gathering, said he’s watching for the FDA’s Jan. 23 decision on the subcutaneous form of Velcade, but he declined to make any direct comparisons. He did say that Onyx is currently only seeking FDA approval among patients who have already been treated with Velcade and no longer respond to it. But Onyx clearly has its sights on challenging Velcade more broadly. Last month, the company touted results from a small study which showed 79 percent of new myeloma patients had complete remissions on the drug after 12 months of follow-up. About 24 percent of patients on the Onyx drug had some peripheral neuropathy, but those cases were graded as only mild to moderate in severity.

Dunsire says she believes the data behind the Onyx drug is good enough for it to become an FDA approved drug—the only question is whether it can win approval based on the current Phase II trial dataset, or whether another Phase III trial will be required first. Since no one has yet come up with a cure for multiple myeloma, there is a place for multiple drugs, she says. But she doesn’t see Onyx taking over the market that Millennium is so entrenched in.

While Onyx will have to wait until at least July for FDA clearance to sell carfilzomib, Millennium is working hard right now to remind doctors that its existing drug is standing up to the test of time—improved five-year survival data was released just last month. Even after the Onyx drug arrives, Dunsire says many doctors and patients will be inclined to stick with the one they know works, especially when its most significant drawback is being minimized.

“The thought that [Onyx's drug] will obliterate Velcade—it’s definitely not going to happen,” Dunsire says. “There will be a place for multiple agents. But the data for Velcade is so strong, it will be the first proteasome inhibitor used.”

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