12:00 AM
Jun 01, 2009
 |  BioCentury  |  Regulation

Accelerate, or not

Arzerra ofatumumab from Genmab A/S and partner GlaxoSmithKline plc would appear to be a classic example of why accelerated approval was created. With last Friday's 10-3 vote by the Oncologic Drugs Advisory Committee to recommend approval of Arzerra to treat chronic lymphocytic leukemia, the question now is whether FDA will follow ODAC's advice or be swayed by the lack of consistency on reported results for the surrogate endpoint of objective response rate.

Granting accelerated approval would provide the anti-CD20 mAb to a highly refractory population of CLL patients who have failed multiple drugs, and allow the companies to generate revenues in the five years it will take to complete two ongoing Phase III trials.

But if FDA decides to wait for the data, there's a good chance that another anti-CD20 mAb will be approved ahead of Arzerra. Last month, Biogen Idec Inc. and Roche submitted a pair of sBLAs to FDA for Rituxan, including one for first-line treatment of CLL and the other for relapsed CLL.

While GSK contends that Rituxan is unlikely to be a competitor in the refractory population, Arzerra would be Genmab's first product on the market, so the biotech potentially has the most to lose from any regulatory delay or possible competition from Rituxan.

Genmab also argues its anti-CD20 compound is competitively advantaged, and in any case says it can weather any potential setbacks, having refocused its pipeline last year in order to reduce its R&D spend and create a sustainable company (see BioCentury, Oct. 20, 2008).

Which population

There is no cure for CLL. The disease, which is the most common leukemia in the U.S., is characterized by the accumulation of CD5-, CD20- and CD23-positive lymphocytes.

The median age at CLL diagnosis is 72 years, with over half of patients living more than 10 years. However, survival for high risk patients is only about two or three years.

There are five approved drugs for CLL. But no matter which treatment patients receive, they typically relapse within about two years. As a result, patients move from regimen to regimen until they become refractory to all the available drugs.

Doctors also use a number of off-label salvage regimens, including CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), to treat patients who have relapsed frequently and/or are refractory to the other treatments.

In designing the Phase I1I trial that is the basis for the Arzerra BLA, the companies and FDA disagreed on the CLL population that would qualify for accelerated approval based on the requirement that these patients have an unmet medical need.

GSK applied for accelerated approval in double refractory (DR) patients based on interim results from the open-label, single-arm Hx-CD20-406 study. DR patients are refractory to both Campath and fludarabine.

According to the pharma's briefing documents, DR patients have low response rates (about 20%) and toxicities of up to 60% on salvage therapies, resulting in median survival of eight months.

But GSK thinks Arzerra also should be approved for patients with bulky (at least 1 lymph node > 5cm) fludarabine-refractory (BFR) CLL. According to the company, these patients do not do well on Campath, and when given other salvage therapies have response rates of about 26%, with median survival of 14 months.

According to FDA's briefing documents,...

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