Science + Technology

Astellas, Medivation to develop, commercialize MDV3100 for treatment of prostate cancer

The companies will use a compound developed in UCLA laboratories

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Astellas Pharma Inc. of Japan and California's Medivation Inc. have announced a global agreement to develop and commercialize MDV3100, a chemical compound developed in UCLA science laboratories that is now Medivation's investigational drug for the treatment of prostate cancer.
 
MDV3100 is currently being evaluated in the Phase 3 AFFIRM clinical trial in men with castration-resistant prostate cancer who were previously treated with docetaxel-based chemotherapy.

Michael Jung, UCLA professor of chemistry and biochemistry and a researcher at UCLA's Jonsson Comprehensive Cancer Center, and his research group designed and synthesized the molecule that became MDV3100.

The molecule was tested in biology research that was conducted in the UCLA departments of medicine, urology and pharmacology by Charles Sawyers and his research group; Sawyers has since moved to Memorial Sloan-Kettering Cancer Center in New York, where he serves as chair of the human oncology and pathogenesis program. Medivation Inc. tested MDV3100 in clinical trials.

"This pharmaceutical offers the promise of extended life for patients with prostate cancer, and I am proud that it was developed in a collaborative research effort at UCLA by world-class scientists led by Michael Jung and Charles Sawyers," said UCLA Chancellor Gene D. Block. "While treatment is still in the testing phase, the path to approval looks quite promising."

"It is very encouraging that Medivation has decided to collaborate with Astellas on the development of MDV3100 for the treatment of prostate cancer," said Jung, who is also a member of the California NanoSystems Institute (CNSI) at UCLA. "I am hopeful that this new agreement will help the process of approval of this new drug, which potentially could help many men with prostate cancer. This is indeed good news."

The companies will collaborate on a comprehensive development program that will include additional studies to develop MDV3100 for both late- and early-stage prostate cancer. Subject to receipt of regulatory approval, the companies will jointly commercialize MDV3100 in the United States. Astellas will have responsibility for developing and commercializing MDV3100 outside the United States.

Prostate cancer is the most common non-skin cancer among men in the United States, according to the American Cancer Society. More than 2 million American men have prostate cancer — the second leading cause of cancer death among men after lung cancer. In 2009, an estimated 192,000 new cases are expected to be diagnosed, and approximately 27,000 men are expected to die from the disease.

MDV3100, a new generation of oral anti-androgen, which shows different pharmacological profiles from current anti-androgens, has been shown in preclinical studies to provide more complete suppression of the androgen receptor pathway than bicalutamide, the most commonly used anti-androgen. MDV3100 slows growth and induces cell death in bicalutamide-resistant cancers through three complementary actions: It blocks testosterone binding to the androgen receptor, impedes movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation), and inhibits binding to DNA.
 
Research published in the journal Science earlier this year demonstrated that MDV3100 has shown considerable promise in early clinical trials involving patients with castration-resistant prostate cancer, or CRPC, whose disease has become resistant to current drugs.

In September 2009, Medivation began enrolling patients in a randomized, placebo-controlled, double-blind, multinational Phase 3 clinical trial known as AFFIRM. This trial is evaluating MDV3100 at a dose of 160 mg taken orally once daily versus placebo in men with castration-resistant prostate cancer who were previously treated with docetaxel-based chemotherapy. This trial is expected to enroll approximately 1,200 patients at sites in the United States, Canada, Europe, South America, Australia and South Africa.
 
Medivation previously announced interim safety and efficacy results from an ongoing Phase 1-2 clinical trial of MDV3100 at the American Society of Clinical Oncology (ASCO) annual meeting in May 2009. The interim results showed that MDV3100 was associated with anti-tumor activity in patients who had become resistant to bicalutamide or other standard anti-androgen treatments, including both patients who had failed prior chemotherapy and patients who were chemotherapy naive. Anti-tumor activity was demonstrated by reductions in prostate-specific antigen (PSA) levels, improvement or stabilization in tumors that had spread to soft tissue or bone, and a decrease in circulating tumor cells, which has been associated in published literature with improved survival in patients with castration-resistant prostate cancer. MDV3100 was generally well tolerated in this trial at doses up to and including 240 mg a day, with fatigue being the most frequently reported adverse event.
 
In an article published April 9, 2009, in the online edition of the journal Science, Sawyers, Jung and other chemists and biologists at UCLA and colleagues at several other institutions, including Memorial Sloan-Kettering Cancer Center, described the development and testing of two novel compounds, MDV3100 and RD162, which block the androgen receptor in CRPC cells, and reported results from a clinical trial in which MDV3100 was found to lower PSA levels — a marker for tumor growth — in men with CRPC.
 
The UCLA patents for both compounds were licensed by the pharmaceutical company Medivation Inc., which chose to test MDV3100 in clinical trials.
 
Prostate cancer becomes resistant to currently approved anti-androgen drugs when cancer cells begin to increase production of the androgen receptor, Sawyers said. When the level of androgen receptors on the cells' surface reaches a certain level, the drugs that originally suppressed the cancer actually begin to stimulate cancer growth. Sawyers and his colleagues therefore set out to design a new generation of drugs that can block the androgen receptor without this unwanted side effect, even when levels of the receptor are high.

In addition to Sawyers' and Jung's teams, researchers from the Oregon Health and Science University, the University of Washington and Medivation contributed to the research.

This research was supported by the National Institutes of Health, the U.S. Department of Defense, the Prostate Cancer Foundation and Medivation and was conducted through the Prostate Cancer Clinical Trials Consortium.

For more information about Jung, visit www.chem.ucla.edu/~jung/home.html.

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