New melanoma drug from BMS gets approval from FDA

It the first new drug to be approved for unresectable or metastatic melanoma in around 10 years and the first and only approved therapy for such cancer to demonstrate a significant improvement in overall survival

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PRINCETON, N.J.—Late Friday night saw Bristol-Myers Squibb Co. make the announcement that the U.S. Food and Drug Administration (FDA) had approved Yervoy (ipilimumab) for the treatment of patients with unresectable (inoperable) or metastatic melanoma, making it the first new drug to be approved for such cancer in around 10 years. Also, BMS reports that it is the first and only approved therapy for unresectable or metastatic melanoma to demonstrate a significant improvement in overall survival and notes that it is the first approved cancer immunotherapy for melanoma to target CTLA-4.

"Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient's life," says Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, noting that Yervoy's safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."

Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen or CTLA-4. CTLA-4 may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors. The drug is administered intravenously.

The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone. Those who received the combination of Yervoy plus the vaccine or Yervoy alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.

However, there is a caveat to all of this good news. As the FDA notes, common side effects that can result from autoimmune reactions associated with Yervoy use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis)—and severe to fatal autoimmune reactions were seen in 12.9 percent of patients treated with Yervoy. As the FDA reports, "Due to the unusual and severe side effects associated with Yervoy, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential side effects."

"Metastatic melanoma is one of the most aggressive forms of cancer and despite the rising incidence, no new treatments have been approved in more than a decade," says Lamberto Andreotti, CEO of Bristol-Myers Squibb. "Today's approval of Yervoy is an example of Bristol-Myers Squibb living its mission of developing and delivering innovative medicines that address the unmet needs of patients with serious diseases. It also represents a significant step forward in our commitment to deliver and execute against our differentiated and focused BioPharma strategy."

Noting that more than 14 years of research and development that went into making Yervoy a reality, BMS's CSO and president of R&D, Dr. Elliott Sigal, adds: "Yervoy is the first FDA-approved compound from our robust immuno-oncology pipeline, which comprises a variety of other compounds with the potential to harness the patient's immune system to fight cancer." The mechanism of action of ipilimumab's effect in patients with melanoma is indirect, he says, possibly through T-cell mediated anti-tumor immune responses.

James Wentworth, a healthcare analyst at Datamonitor, thinks there might be an uphill climb for Yervoy in the market and he wonders how long its star will shine once it hits its peak altitude.

"Initial uptake could be slow as physicians struggle to identify patients who are likely to benefit and not suffer life-threatening side effects," he says. "The Risk Evaluation and Mitigation Strategy (REMS) in collaboration with the FDA to inform patients and providers about patient monitoring and safety risks is likely to help improve uptake. However, the risk of severe side effects and onerous monitoring may prevent some physicians from prescribing Yervoy altogether."

"The revenue generated from Yervoy will be significantly increased by the approval in both first- and second-line unresectable or metastatic melanoma," Wentworth notes. "However, Yervoy's advantage as the first drug approved in over ten years in melanoma may be short lived with the anticipated launch of RG7204 (PLX4032; Plexxikon/Roche) in 2013 which has high response rates in BRAF positive patients and is well-tolerated in comparison. Yervoy will likely retain a small market share, but providers will likely choose the less toxic more effective RG7204 for BRAF positive patients."

Also putting a damper on the good news was the fact, as several market analysts have noted, that a full four-infusion course of induction therapy with Yervoy is priced at $120,000, which is about twice the consensus estimate of $50,000 to $60,000.

But while this drug may not be a home run for BMS in the long run, the approval is important for the treatment of melanoma, insists Dr. Thomas Gajewski, president of the Society for Immunotherapy of Cancer.

"This is a landmark advance for several reasons," Gajewski says. "First, this is a completely new way to treat cancer in the clinic, by blocking a key negative regulator of the anti-tumor immune response. Second, it is the first drug ever to show improved survival of metastatic melanoma patients. And third, we learned that clinical responses to immune therapies such as this one can take time, with patients sometimes showing disease progression prior to regression. This pattern will require significant education of the oncology community that will be utilizing these agents in the near future."

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