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'Cabo' on Time for Exelixis, Fares Well; Wider Label Next?

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By Randy Osborne
Staff Writer

As expected, Exelixis Inc. won the FDA's nod for cabozantinib, a therapy for medullary thyroid cancer (MTC) – a less common form of the disease, originating in parafollicular C cells – but bigger revenue potential lies ahead, if the compound passes muster in metastatic prostate cancer, where Phase III trials are under way.

U.S. regulators gave approval late Thursday to Cometriq, or "cabo," as many know it, which inhibits tumor growth, metastasis and angiogenesis by targeting MET, VEGFR2 and RET. The only other approved therapy for MTC is Caprelsa (vandetanib), cleared in April 2011, which hits VEGFR, EGFR and the RET tyrosine kinase. London-based AstraZeneca plc has sold about $19 million worth of Caprelsa this year.

Exelixis submitted the new drug application (NDA) in late May, and many investors saw favorable writing on the wall recently when the FDA removed the drug from November's agenda for the meeting of the Oncologic Drugs Advisory Committee.

The NDA filing hinged on results from the Phase III EXAM trial in advanced MTC, conducted under a special protocol assessment (SPA) plan with the FDA, with progression-free survival (PFS) as the primary endpoint. In October 2011, Exelixis said top-line data showed cabo improved median PFS by 7.2 months. (See BioWorld Today, Oct. 25, 2011.)

The pivotal Phase III trial for cabo in the much larger market of metastatic castration-resistant prostate cancer (mCRPC) is called COMET-1, with a primary endpoint of overall survival in mCRPC patients who show disease progression after treatment with docetaxel and Zytiga (abiraterone acetate, Johnson & Johnson) and/or MDV3100 (enzalutamide, Medivation Inc.).

South San Francisco-based Exelixis also has the COMET-2 study in progress, which randomizes 246 mCRPC patients with pain palliation as the primary endpoint – chosen after Exelixis was unable to agree with the FDA on an SPA using the composite endpoints of pain reduction and bone scan response. (See BioWorld Today, Nov. 2, 2011.)

At the European Society for Medical Oncology meeting this fall, the company offered interim data on lower dose (40-mg) cabo in 51 mCRPC patients, and in 26 with baseline pain, the median maximal reduction was 49 percent, with a more than 30 percent decrease in the pain score recorded in 18 patients (or 69 percent), and 54 percent of patients backing off their use of narcotics.

Median PFS in the interim data was 4.1 months, and median treatment duration was 4.7 months. The lesser, 40-mg dose was better tolerated, and only a fourth of the studied patients needed an even lower dose.

Cowen and Co. analyst Eric Schmidt noted in a research report that COMET-1 began enrollment in the second quarter of this year, but "witnessed slower site activation during the third quarter, owing to administrative issues in Europe." Still, the activated sites are "enrolling at a healthy pace," and the company said it believes half the intended sites will be open by the end of the year.

Yet to come are pivotal trials in hepatocellular carcinoma and renal cell carcinoma. Also, the company's MEK inhibitor, GDC-0973, with partner Roche AG, of Basel, Switzerland, has entered a pivotal study in melanoma, and Exelixis maintains a "substantial" ownership of that program, Schmidt wrote.

Edward Tenthoff, analyst with Piper Jaffray, pointed in his research report to the company's "dramatically strengthened cash position," thanks to net proceeds of $416 million in equity and debt raised recently. Exelixis ended the third quarter of this year with about $675 million in cash, "which should last through potential [cabo] prostate cancer approval, he wrote. (See BioWorld Today, Aug. 7, 2012.)

The cabo approval announcement came after markets closed Thursday. Exelixis' shares (NASDAQ:EXEL) closed at $5.24, down 4 cents.