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Mar 20, 2013

Amgen Melanoma Drug Meets Phase III Endpoint

  • Amgen said its cancer drug candidate talimogene laherparepvec (TVEC) met its primary endpoint in a Phase III clinical trial evaluating its safety and efficacy against later stages of melanoma compared to subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF).

    According to top-line results released yesterday by Amgen, TVEC led to complete or partial response lasting continuously for at least six months—a “durable response rate” (DRR)—of 16% of patients tested with the drug candidate during the trial, versus 2% in patients treated with GM-CSF. Also, an interim analysis conducted with the DRR analysis showed an overall survival trend favoring TVEC over GM-CSF.

    More detailed safety and efficacy data will be submitted to the American Society of Clinical Oncology for presentation at its 2013 Annual Meeting, set for May 31–June 4 in Chicago.

    TVEC is based on a herpes simplex virus type 1 (HSV-1) that has been modified to selectively replicate in tumor cells without harming healthy cells. TVEC represents a new class of therapy against melanoma because it combines local with systemic effects against tumors. That effect is believed to be achieved through the functional deletion of two key genes (ICP34.5 and ICP47) from HSV-1, which deprives it of the proteins normally used for circumventing the body’s response to infections, followed by the addition of the human GM-CSF gene.

    When injected directly into tumors, TVEC selectively replicates until the membrane of the cancer cells rupture or lyse, destroying these cells and releasing the viruses that have been replicated. The released viruses, in turn, invade more tumor cells—a cycle that continues until the weakened virus encounters healthy cells. During replication, TVEC also induces the tumor to produce GM-CSF—a white blood cell growth factor that attracts and activates the cells required for a systemic immune response.

    "A high unmet need exists in melanoma and we believe the innovative mechanism of action of talimogene laherparepvec may offer a promising approach for these patients," Sean E. Harper, M.D., Amgen’s executive vp of research and development, said in a statement.

    The trial (NCT00769704) was the first late-stage clinical test of TVEC, and involved more than 400 patients with unresected stage IIIB, IIIC, or IV melanoma. Patients were randomized 2:1 to receive TVEC intralesionally every two weeks or GM-CSF subcutaneously for the first 14 days of each 28-day cycle. Treatment could last for up to 18 months.

    During the trial, the most frequent adverse events observed were fatigue, chills, and pyrexia. The most common serious adverse events included pyrexia as well as disease progression, and cellulitis.

    TVEC was originally developed by BioVex Group, now a subsidiary of Amgen following acquisition in 2011 for $425 million up-front, plus up to $575 million tied to its drug candidates achieving eight regulatory and sales milestones.

    According to Amgen’s Form 10-K annual report for 2012, filed February 27 with the U.S. Securities and Exchange Commission, those milestones include the filing of a Biologics License Application with the FDA, which would trigger a $125 million payment; the first commercial sale in both the U.S. and European Union following receipt of marketing approval, which includes use of the product in specified patient populations; and upon achieving undisclosed “specified” levels of sales within specified periods of time.

    “Amgen is ideally positioned to leverage the potential of OncoVEX in multiple solid tumor indications given their impressive oncology franchise and expertise in biologics manufacturing and development," Philip Astley-Sparke, then BioVex’s president and CEO, and now president, U.S., for gene therapy developer uniQure, said in a statement when the deal was announced.

    At the time, Amgen said the deal would benefit the company by enabling it to bring TVEC, already by then in late-stage development, to market in a few years. Amgen's executive vp, research and development at the time was Roger M. Perlmutter, M.D., Ph.D., who on March 7 was named by Merck & Co. as its new executive vp and president of Merck Research Laboratories.


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