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Phase III Study of Rituxan in Leukemia Meets its Goal.

BIOWORLD Today - Oct. 19, 2008
http://www.therapeuticsdaily.com/news/article.cfm?contenttype=sentryarticle&contentvalue=1857564&channelID=28
Byline: Catherine Hollingsworth, Staff Writer

Genentech Inc. and Biogen Idec Inc. said their investigational leukemia drug Rituxan (rituximab) passed a second Phase III study, meeting its primary goal of improving the period of time before the disease progresses compared to chemotherapy alone.

Rituxan combined with chemotherapy treatments fludarabine and cyclophosphamide improved progression-free survival in patients with previously treated CD20-positive chronic lymphocytic leukemia (CLL).

Earlier this year, another European Phase III study, CLL-8, showed a similar treatment combination improved PFS in patients with CLL who previously had not received treatment.

South San Francisco-based Genentech still is reviewing the data, the details of which will be presented at a future medical meeting.

An independent review of the primary endpoint is being conducted for U.S. regulatory purposes.

The study, known as REACH (Rituximab in the study of relApsed Chronic lympHocytic leukemia), is the largest ever in relapsed CLL. It is the first such study to show an improvement in progression-free survival, according to Genentech.

Rituxan, currently approved for rheumatoid arthritis and non-Hodgkin's lymphoma, has been associated with a life-threatening brain infection known as progressive multifocal leukoencephalopathy, or PML. But there were no new or unexpected safety signals reported in the leukemia study, Genentech said.

Genentech and Biogen Idec co-market Rituxan in the U.S., and Roche markets it as MabThera in the rest of the world, except Japan, where Rituxan is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd.

Cephalon Inc's chemotherapy agent Treanda (bendamustine HCl) is among the current treatments approved for CLL. That approval was based on a 301-patient study showing a higher overall response compared to standard chemo agent chlorambucil. That study also showed significantly longer progression-free survival (18 months vs. six months) and a longer-lasting response compared with another chemo agent chlorambucil (19 moths vs. seven months). (See BioWorld Today, March 21, 2008.)

A Cephalon-sponsored Phase II study will evaluate Treanda and Rituxan in elderly patients with CLL. Genentech is not involved with that trial.

Other currently available treatments for CLL include the monoclonal antibody Campath (alemtuzumab), which targets the CD52 antigen, and chemotherapy agents fludarabine and cyclophosphamide, according to the American Cancer Society. Known as the FR regimen, those two chemo drugs were studied alongside Rituxan in the Genentech-Biogen Idec Phase III study of relapsed leukemia patients.

The FR regimen also has been studied alongside another potential antibody for CLL: Genta Inc.'s DNA-based drug Genasense.]/i]

Berkeley Height, N.J.-based Genta filed an amended new drug application for Genasense following an appeal of a December 2006 approvable letter. FDA's action date on that resubmission is set for Dec. 3. (See BioWorld Today, July 15, 2008.)

The major goal of the Phase III Genasense study was to put relapsing leukemia patients into complete remission -- and that endpoint was "very solid," Raymond Warrell, CEO of Genta, told BioWorld Today.

Combining Genasense with the FR chemotherapy regimen significantly increased the complete remission rate, he said, with a median duration of almost two years longer than those on chemo.

Warrell contrasted the remission endpoint in the Genasense study with the progression-free survival (PFS) endpoint used in the Rituxan study. With PFS as the objective, he said, patients don't necessarily have to respond or show a benefit but must show a delay in the regrowth of the disease.

Danish biotech GenMab A/S and partner GlaxoSmithKline plc have a leukemia drug directed at the same target as Rituxan's -- the CD20 molecule on B cells. That product also met its endpoint in a Phase III pivotal study. (See BioWorld Today, Aug. 1, 2008.)

Richard Parks, a senior analyst with Piper Jaffray, wrote in a research note that "ofatumumab has shown compelling activity as a single agent."

There is a significant amount of Rituxan use as a single agent for CLL, he said, "despite limited evidence of activity" because many patients cannot tolerate myelosuppressive chemotherapy.

Geoffrey Nichol, senior vice president of product development at Medarex Inc., which has a Phase I antibody in development for CLL, told BioWorld Today that his company's product, which binds to CD19, may be expressed in more cells and in more patients than CD20, offering a possible advantage.