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Atrasentan/ Xinlay™: Abbott seeks FDA Approval for Prostate Cancer Drug

Phase III results show "delay in time to disease progression" for advanced prostate cancer patients with bone disease

December 14, 2004. Abbott Laboratories Inc. said on Tuesday it is seeking U.S. regulatory approval for a drug to treat advanced prostate cancer that has spread through the body.

Previously known by its generic name atrasentan, now given the trade name Xinlay™, the drug is an oral, non-hormonal, non-chemotherapy targeted anti-cancer agent.

Xinlay belongs to a class of compounds known as selective endothelin-A receptor antagonists, or SERAs. SERAs antagonize the effect of endothelin (ET-1), one of the proteins thought to be involved in the stimulation of the spread of cancer cells.

Xinlay™(atrasentan) has fast track review status at the U.S. Food and Drug Administration (FDA). Abbott will complete the NDA (new drug application) filing for Xinlay in metastatic hormone-refractory prostate cancer by year-end, ahead of the 2005 timetable predicted after its pivotal trial in the indication failed to reach statistical significance.

Abbott will continue to support studies of this drug in other cancers including kidney, ovarian, brain, and non-small-cell lung cancers.

One factor influencing choice of prostate cancer for study is the prevalence of hormonal ablation therapy (or chemical castration) for men with advanced prostate cancer. Preclinical tests on dogs showed that castration produces a change in the endothelin receptor density in the prostate and brain.

Xinlay™ (atrasentan) appears to be a generally well-tolerated. Commonest side effects are headache, peripheral edema (swollen limbs) and rhinitis (nasal congestion, "stuffy nose"). The question has been, is the drug as effective as theory suggested it could be?

How Xinlay™ came this far

In February 2003 atrasentan looked disappointing after Abbott disclosed that data from a late-stage trial showed a delay in progression of the disease that was not statistically significant.

Michael Carducci M.D.However, last summer in New Orleans at the American Society of Clinical Oncology (ASCO) annual meeting, Michael A. Carducci, M.D., an associate professor in oncology and urology at of Johns Hopkins Medical Institutions, presented findings based on pooled data from two clinical studies. Analysis of this pooled data looked more promising. The data showed a statistically significant delay in time to disease progression in men with metastatic, hormone refractory prostate cancer who took atrasentan compared to those who took placebo.

Analyzed separately the studies still did not show statistical significance.

Abbott Labs said the results "trended towards" showing positive effect. Company representative Perry Nisen, M.D. Ph.D., a drug development vice president, said: "These meta-analysis results are encouraging and show that atrasentan holds promise for the treatment of metastatic, hormone-refractory prostate cancer."

Now in the December 2004 issue of the journal Expert Opinion on Investigational Drugs, Dr. Carducci has published his results with focus on a Phase III study of atrasentan for prostate cancer.

"Biological and clinical activity in patients with prostate cancer," Carducci writes, "has been demonstrated in a Phase III clinical setting by the suppression of markers of biochemical and clinical prostate cancer progression, and by a delay in time to disease progression, especially in patients with bone disease."

More details about Xinlay™ (atrasentan)

Xinlay™ (atrasentan) belongs to a class of compounds known as selective endothelin-A receptor antagonists, or SERAs. SERAs antagonize the effect of endothelin (ET-1), one of the proteins thought to be involved in the stimulation of the spread of cancer cells.

Endothelin-1 is a small molecule that causes changes in blood vessels and helps regulate blood pressure. Researchers at the University of Pittsburgh explain that "the endothelins and their receptors--referred to as the endothelin (ET) axis- have key physiological functions in normal tissue, acting as modulators of vasomotor tone, tissue differentiation, development, cell proliferation and hormone production. Based on new data, the ET axis also functions in the growth and progression of various tumors.

By last June, atrasentan had been tested in Phase II and Phase III clinical trials in men with metastatic, hormone refractory prostate cancer. Another Phase III pivotal trial (M00-244) was testing it on men with prostate cancer that had not spread (non-metastatic). Also it was being tested in a Phase II trial (M01-366) in men with rising prostate-specific antigen (PSA) following prostate cancer surgery.

To sum up the drug's overall treatment effect in men with metastatic, hormone refractory prostate cancer, Abbott conducted a simple retrospective pooling of its two large, randomized, well-controlled clinical trials (M96-594 & M00-211) with a total patient population of 1,097 men.

Results pooled from two different atrasentan doses (2.5mg and 10mg) demonstrated a statistically significant delay in time to disease progression in the "intent to treat" analysis for men taking atrasentan vs. placebo.

The two individual studies pooled for the meta-analysis tested the same patient population with similar baseline demographics, used the same endpoint of time to disease progression (radiographic progression was more explicitly defined in the M00-211 protocol) and were placebo-controlled and double blind. Abbott conducted statistical tests to make sure the studies were comparable and on the overall treatment effect to support the rigor of the meta-analysis.

Side Effects

Atrasentan (10mg) was generally well tolerated in both studies among all patients. Comparing adverse events for atrasentan vs. placebo showed headache (21 percent vs. 13 percent), peripheral edema (39 percent vs. 13 percent), and rhinitis (34 vs. 14 percent) respectively.

Was this pooled data method a good way to study how the drug affects patients? According to Professor David Dearnaley, MD, FRCP, Institute of Cancer Research/Royal Marsden Hospital, "A meta-analysis is a useful tool in assessing modest but nevertheless clinically important treatment effects. The combined results from these studies are very encouraging and suggest atrasentan may be an exciting novel treatment option which targets the endothelin axis,"he said.

About the overall outlook for this drug, Dearnaley added: "These are the first trials to explore the benefit of the endothelin-A receptor antagonists in hormone refractory prostate cancer and give rise to optimism than an entirely different class of agents may be valuable after failure of conventional treatments."

Today in the company press release, John Leonard, M.D., vice president for global pharmaceutical development at Abbott Laboratories, said: "We are very excited about the possibility to bring the first of several Abbott --discovered oncology drugs to patients. We are looking at novel approaches to treat prostate cancer with the hope of providing additional treatment options to patients sooner."

Sources and links

Company press release: ABBOTT LABORATORIES ANNOUNCES INTENT TO SUBMIT NEW DRUG APPLICATION FOR XINLAY™ (ATRASENTAN) IN THE U.S. Dec 14, 2004

Atrasentan clinical trials Abbott Labs site

Review: Endothelin receptors as novel targets in tumor therapy Anna Bagnato and Pier Giorgio Natali
Journal of Translational Medicine 2004, 2 : 16    May 24, 2004 Full free text (open access)

Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Atrasentan An Endothelin Receptor Antagonist for Refractory Prostate Cancer Bernard A. Zonnenberg , Gerard Groenewegen , Todd J. Janus , Terri W. Leahy , Rod A. Humerickhouse , Jeffrey D. Isaacson , Robert A. Carr and Emile Voest Department of Internal Medicine, University Hospital, 3584 CX Utrecht, the Netherlands [B. A. Z., G. G., E. V.], and Abbott Laboratories, Abbott Park, Illinois

 

This page reported by J. Strax, last updated December 14, 2004

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Related News

FDA Agrees to File Abbott's New Drug Application for Xinlay (Atrasentan) to Treat Metastatic Hormone-refractory prostate cancer Feb 11, 2005

 

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Atrasentan: targeting the endothelin axis in prostate cancer. Expert Opin Investig Drugs. 2004 Dec; 13(12):1631-40. Jimeno A, Carducci M. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. See abstract below:

Endothelin axis deregulation triggers a series of events that lead to a profound deregulation in cancer cells, including key tumorigenic cellular events such as proliferation, invasion, escape from programmed cell death, new vessel formation, abnormal osteogenesis and the alteration of nociceptive stimuli.

Atrasentan is a novel agent that effectively targets this pathway and is able to inhibit and/or reverse several of those events. Biological and clinical activity in patients with prostate cancer has been demonstrated in a Phase III clinical setting by the suppression of markers of biochemical and clinical prostate cancer progression, and by a delay in time to disease progression, especially in patients with bone disease.

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