No SPA for Cabo Phase III in CRPC; Exelixis Plummets
By Tom Wall
BioWorld Today Contributing Writer
Exelixis Inc.'s stock plummeted 40.2 percent Tuesday following the South San Francisco biotech's announcement that it was unable to secure a special protocol assessment (SPA) from the FDA for its pivotal Phase III XL184-306 trial of cabozantinib (cabo) in end-stage castrate resistant prostate cancer (CRPC).
Exelixis said it has stopped pursuing the SPA and plans to initiate the '306 trial by the end of 2011 with pain as the primary efficacy endpoint, to be followed in the first half of 2012 by the Phase III XL184-307 trial to evaluate overall survival time. Exelixis had been trying to reach an agreement with the FDA on an SPA for the '306 trial using composite endpoints of pain reduction and bone scan response.
Exelixis shares (NASDAQ:EXEL) lost $3.11 to close Tuesday at $4.62.
The slide came just a week after Exelixis jumped 24.2 percent thanks to impressive results from a Phase III trial of cabozantinib in medullary thyroid cancer (MTC). But investors and analysts have focused on the drug's potential in the larger prostate cancer indication. (See BioWorld Today, Oct. 25, 2011.)
In a Form 8-K filed Monday, Exelixis said the company's decision to forego the dual endpoints and settle on just pain as the primary endpoint for the '306 trial was based on feedback from both the FDA and the European Medicines Agency. The company said it submitted the original '306 protocol and SPA request to the FDA in June. The FDA's initial response came in August, and the company said it responded a month later, "agreeing to substantially all of the FDA's requested changes to the protocol and resubmitting the request for a SPA."
But Exelixis said the FDA's subsequent response late last month raised several concerns about the '306 trial design and the SPA, including the ability to maintain blinding of the trial due to differences in toxicity profiles between cabozantinib and mitoxantrone; a view that the magnitude of pain improvement is modest and could represent a placebo effect or be attained with less toxicity by opioid therapy; a view that symptomatic improvement should be supported by evidence of antitumor activity, an acceptable safety profile and lack of survival decrement; and a recommendation that, if the company uses pain response as a primary efficacy endpoint, it should conduct two adequate and well-controlled trials to demonstrate effectiveness. The FDA also recommended that overall survival be the primary efficacy endpoint, the company said.
Exelixis said the '306 trial will be a double-blind trial enrolling 246 patients with CRPC that is metastatic to the bone, who are suffering from moderate to severe bone pain despite optimized narcotic medication and who have failed prior docetaxel and Zytiga (abiraterone, Johnson & Johnson) in no particular order. The '306 trial will be conducted in regions including the U.S., Canada and the UK. Patients will be randomized 1:1 to receive either cabozantinib or mitoxantrone/prednisone.
Alleviation of bone pain will be the primary endpoint, and that will be measured by comparing the percentage of patients in the two treatment arms who achieve a pain response at week nine that is confirmed at week 15. Overall survival will be a secondary endpoint of the '306 trial.
The company said the '307 trial, with a primary endpoint of overall survival, will be conducted in patients with CRPC with bone metastases who have failed prior docetaxel and abiraterone therapies. Patients will be randomized to receive cabozantinib at 60 mg daily or prednisone. The '307 trial is expected be executed globally and at non-overlapping sites with the '306 trial.
J.P. Morgan analyst Cory Kasimov said his firm lowered its average U.S. peak sales scenario for cabo in CRPC to $500 million a year from $900 million, pushed out timelines and lowered the probability of approval to 45 percent from 60 percent. He called the SPA news "a major negative development" that was particularly surprising given management's "unwavering confidence that an SPA would be granted."
"Although we questioned the commercial significance of the proposed composite endpoint in the pending SPA, we are still disappointed by this development," Kasimov wrote. "Now, with a less compelling regulatory pathway for CRPC, it is tough to become more constructive on the product's longer-term outlook in a rapidly evolving and highly competitive prostate cancer market."
He added that the FDA "made it abundantly clear that a single trial with a pain endpoint is not sufficient for approval. Our prevailing view has been that whatever the outcome of '306, cabo needs long-term survival data to be a viable competitor in the rapidly evolving CRPC market where five different drugs have already shown a survival benefit."
Biren Amin, of Jefferies & Co., estimated that top-line overall survival data from the '307 trial would be released in late 2014, with a new drug application filing in the first half of 2015 based on data from both the '306 and '307 trials. That would put possible approval in late 2015 or early 2016.
"We also estimate with both trials initiating, Exelixis will need to tap the equity markets in the 2013 time frame, and prior to Phase III data," Amin wrote.
Canaccord Genuity analyst George Farmer added that "demonstrating both a pain and overall survival benefit in two separate studies could be the best strategy for cabo positioning in a market of rapidly accumulating competing drugs, in our view. However, with cash expected to deplete in 2013, big patient numbers and extended timelines imply a need for additional financing to reach this goal."
The company ended the third quarter with cash of $313.1 million.
Farmer said his firm has lowered its price target for Exelixis shares to $6 from $7, reflecting "a cabo CRPC launch in 2016 but in a more concentrated market expected to be filled with competitive drugs."
Among the competitors is Algeta ASA, of Oslo, Norway, which in September released Phase III data showing Alpharadin-treated prostate cancer patients with bone metastases had a median survival of 14 months compared to 11.2 months for placebo. (See BioWorld Today, Sept. 27, 2011.)
Cabozantinib is an inhibitor of MET, RET and VEGFR2. It was previously included as part of a six-year option agreement between Exelixis and GlaxoSmithKline plc, which passed on the compound in 2008. Bristol-Myers Squibb Co. picked it up as part of a potential $740 million deal a few months later, but then handed back rights in 2010, citing an inability to reach agreement with Exelixis on the development plan. (See BioWorld Today, Oct. 24, 2008, and Dec. 15, 2008.)
Nevertheless, Exelixis has remained committed to cabozantinib by concentrating all of its resources on the drug and raising $165 million to push cabozantinib through clinical trials. (See BioWorld Today, Dec. 6, 2010, and March 11, 2011.)
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