Avid Bioservices Inc (CDMO)

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This may be old news, but maybe not to all.

Two Oncology Drugs Deemed Breakthrough Therapies

New program is intended to speed the path to approval by boosting company–FDA interactions.

Swiss drugmaker Novartis announced in mid-March that its investigational compound LDK378, an inhibitor of anaplastic lymphoma kinase (ALK), received a “Breakthrough Therapy” designation from the U.S. Food and Drug Administration (FDA) for treatment of patients with ALK+ metastatic non–small cell lung cancer who cannot tolerate crizotinib (Xalkori; Pfizer) or whose disease progressed while taking it.

Novartis is the second company to reveal that one of its oncology drugs was granted the special status. In February, Janssen and Pharmacyclics received 2 Breakthrough Therapy designations for ibrutinib, a Bruton tyrosine kinase inhibitor under investigation for the treatment of patients with relapsed or refractory mantle cell lymphoma who have received prior therapy, and also for patients with Waldenstrom macroglobulinemia. The companies are collaborating to develop ibrutinib.

The Breakthrough Therapy program, introduced last summer under the mandate of the FDA Safety and Innovation Act, is intended to expedite the development and review of drugs that treat serious and life-threatening conditions and that have demonstrated substantial improvement over existing therapies on at least one clinically significant endpoint. Companies whose drugs earn this status are entitled to interact more frequently with the FDA to discuss the clinical trial design, ensure the collection of appropriate data, and streamline the drug development program.

As of March 13, the FDA had received 32 requests for Breakthrough Therapy designation, of which 9 have been granted and 10 denied; the remainder are pending review. The program is open to all types of drugs, not just anticancer agents. Vertex Pharmaceuticals announced in January that 2 of its drugs for cystic fibrosis earned the designation.

“Breakthrough Therapies allow us to take the most promising drugs—those that will have a transformative effect on the practice of oncology, the crème de la crème drugs—and task our review staff to move these applications quickly and have frequent interactions with the company,” explains Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

The new FDA program is the fourth to be introduced over the past 2 decades as part of the agency's commitment to make the drug approval process speedier and more fluid:

The Fast Track designation, reserved for drugs that treat serious diseases and fill an unmet medical need, includes more frequent meetings and correspondence with the FDA and rolling review of sections of its application for approval.

Accelerated Approval hastens approval of drugs for serious diseases that fill an unmet need through the use of surrogate endpoints in trials; later confirmatory trials must verify the anticipated clinical benefit.

Priority Review status may be granted to drugs that offer significant advances in treatment or provide a treatment for a condition for which no adequate therapy exists. The FDA aims to complete a Priority Review in 6 months rather than the standard review timeline of 10 months.

Breakthrough Therapy status conveys all the benefits of the Fast Track program and even more intensive FDA guidance.

The various designations are not mutually exclusive. For example, a drug can be declared a Breakthrough Therapy and receive Accelerated Approval and Priority Review.

Although the FDA will likely be more discriminating about which drugs receive the designation than it is with the Fast Track distinction, the specifics of the program aren't entirely clear yet, says Christopher-Paul Milne, DVM, MPH, JD, director of research at the Center for the Study of Drug Development at Tufts University in Boston, MA.

By law, the FDA must issue a draft “guidance document” before the end of 2013 to aid companies in preparing submissions and planning trials. The lack of such guidance now, however, isn't likely to deter many in industry from seeking the designation.

“It really shouldn't cost them much in the way of resources to apply,” notes Milne, adding that a Tufts survey completed several years ago found that the average time spent by companies preparing Fast Track materials was about 60 hours. Such an average isn't available yet for the new classification, but it's likely to be a relatively small investment of time—one that could get a drug to market months, or even years, sooner.

The designation may also boost a company's value. When the FDA takes that level of interest in a candidate drug, says Milne, “it certainly helps maintain investor interest.” –Suzanne Rose, with additional reporting by Megan Scudellari

What makes a “Breakthrough”?

According to the 2012 U.S. Food and Drug Administration (FDA) Safety and Innovation Act, a Breakthrough Therapy is a drug intended to “treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

However, the FDA has not yet issued guidance on what constitutes “substantial treatment effects” or the amount of data required for a drug to be considered a Breakthrough Therapy. Public data on 2 oncology drugs that have received the designation—LDK378 (Novartis) and ibrutinib (Janssen and Pharmacyclics) may offer some insight.

At last fall's European Society of Medical Oncology annual congress, researchers presented results of a phase I study of LDK378 in patients with ALK+ malignancies. Data showed an 80% response rate in patients with non–small cell lung cancer whose disease had progressed despite treatment with crizotinib (Xalkori; Pfizer). Novartis subsequently launched 2 phase II single-arm trials of LDK378: one in patients previously treated with chemotherapy and crizotinib and the other in patients with no previous exposure to the drug.

Ibrutinib was tested in a phase I trial of 56 patients with various relapsed or refractory B-cell lymphomas; 7 of 9 patients with mantle cell lymphoma and 3 of 4 patients with Waldenstrom macroglobulinemia responded to the drug. Data from a phase II trial of the drug in patients with mantle cell lymphoma were presented at the American Society of Hematology Annual Meeting in December 2012. Among the 110 patients who were evaluated for their response to treatment, 68% experienced a complete or partial response to the drug.

©2013 American Association for Cancer Research.
http://cancerdiscovery.aacrjournals.org/content/early/2013/03/28/2159-8290.CD-ND2013-008.abstract