BioWorld Financial Watch Editor
Goodbye, 2007: The year finished with a splutter of moderately bad, or somewhat good, or just plain confusing news from a handful of well-known players in the cancer space.
December's apparent Phase II blowup of the front-line melanoma drug ARRY-886 (also known as AZD-6244) from Array Biopharma Inc. - licensed to AstraZeneca plc, which conducted the study - dented Array's shares, as its overseas partner opted not to move ahead with Phase III trials. But the pharma firm set its trial bar high, and top-line results showed promising activity in a tough indication where plenty of others are working.
The on-paper fizzle recalled a failure earlier in the month with a compound for advanced melanoma: ipilimumab, from Medarex Inc. and Bristol-Myers Squibb Co., who said they would pursue a biologics license application next year for the compound despite missed primary endpoints in three pivotal trials, including one that was conducted under a special protocol assessment with the FDA.
Medarex took a 21 percent hit on the news that three trials known as 008, 022, and 007 missed their marks. Results from 008, performed under the SPA, were intended to rule out a best objective response rate lower than 10 percent, but "the totality of the data has always been an important consideration," noted Geoffrey Nichol, senior vice president of product development for Medarex, so the firms are forging ahead. He pointed to a long duration of response with ipilimumab, a fully human antibody that binds to cytotoxic T lymphocyte-associated antigen 4. Study 008 enrolled 155 patients to test the compound as a monotherapy at 10 mg/kg of ipilimumab in advanced melanoma patients whose disease progressed after standard treatment.
The Array/AstraZeneca news with ARRY-886 provided a peculiar contrast to news around the same time from Genitope Corp., which disclosed that its cancer vaccine MyVax missed its primary endpoint in a pivotal Phase III trial, failing to improve progression-free survival compared to control in patients with follicular B-cell non-Hodgkin's lymphoma. Whereas Array/AstraZeneca proved circumspect about data that left analysts unshocked, Dan Denny, Genitope's chairman and CEO, said during a conference call that he was "delighted" about MyVax's "successful" trial - a reaction called "outrageous" and "completely unwarranted" by analyst Jonathan Aschoff of Brean Murray, Carret & Co.
In the front-line Phase II melanoma study with ARRY-886, AstraZeneca - probably wanting to avoid a larger trial - hoped to show superiority rather than non-inferiority to Temodar (temozolomide), the standard-of-care alkylating agent from Schering-Plough Corp., and ARRY-886 missed that ambitious endpoint. The drug, however, performed comparably to Temodar. What's more, ARRY-886, targeting a key point in the Ras/Raf/MEK/ERK signaling pathway, is oral (like Temodar) with fewer side effects. The most common were mild rash, diarrhea, fatigue and vomiting at the maximum tolerated dose of 100 mg. Phase I patients developed dose-limiting toxicities at 200 mg and 300 mg.
Melanoma has proven a tough nut to crack. Among the Phase III blowups are CancerVax Corp.'s immunotherapy Canvaxin, Genta Inc.'s antisense Bcl-2 inhibitor Genasense (oblimersen) and the kinase inhibitor Nexavar (sorafenib) from Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp.
Apart from melanoma, two monotherapy signal searching studies of ARRY-886 in colorectal and non-small-cell lung cancer also failed to meet their primary endpoints of outperforming the standards of care in delaying disease progression. In the NSCLC trial, Array said the drug showed "very little difference" in activity compared to Eli Lilly & Co.'s chemotherapy drug Alimta (pemetrexed), though some analysts viewed that outcome as positive. The colorectal cancer control was F. Hoffmann-La Roche Ltd.'s Xeloda (capecitabine).
AstraZeneca is expected to offer more information during 2008. Meanwhile, the pharma firm has gained a vote of confidence in ARRY-886 from the National Cancer Institute, which is collaborating with AstraZeneca in Phase II trials against recurrent, low-grade ovarian, metastatic hepatocellular, and papillary thyroid cancers.
Results from all the trials are due at scientific meetings, and AstraZeneca said it's keeping the faith in MEK inhibitors. The company has licensed another in the class from Array, called ARRY-704. Not much is known about that Phase I-stage compound, except that the molecular structure is different from ARRY-886.
Pharma giant Pfizer Inc. has become a MEK inhibitor player as well, with its Phase II-stage PD 325901, which has shown a "decent efficacy signal," noted analysts at Leerink Swann, and could work against lung, colon and breast cancers, as well as melanoma. Pfizer's apparent success - so far, at least - made the Phase II setback for ARRY-886 that much more disappointing, Leerink noted in a research report.
At the start of 2007, Exelixis Inc. signed a $40 million-plus deal that gives Genentech Inc. optional rights to develop (and fund) beyond Phase I trials the clinic-ready MEK inhibitor XL518 for cancer. Exelixis, which filed the investigational new drug application for XL518 in December 2006, got $40 million in combined up-front money and milestone payments.
Around the same time, an early stage MEK-inhibitor candidate became part of Ardea Biosciences Inc.'s portfolio, when the firm (formerly IntraBiotics Pharmaceuticals Inc.) bought a set of preclinical programs from Valeant Pharmaceuticals International Inc. The FDA in October cleared Ardea to start Phase I testing of RDEA119, the first MEK drug to emerge from Ardea's program.
February's takeover by Caprion Pharmaceuticals Inc. of Ecopia Biosciences Inc. included a similar compound to be developed by the new company, known as Thallion Pharmaceuticals Inc.: the Phase I/II-stage ECO-4601 for various chemotherapy-refractory tumors.
Leerink Swann remained sanguine on Array shares, pointing to six clinical-stage compounds wholly owned by the firm - the most interesting of which is yet another MEK inhibitor, ARRY-162 for inflammation, due for a Phase II trial in the first quarter of 2008.
"The recent deal with [Celgene Corp.], drawing double-digit royalty on preclinical projects that only exist on the drawing board, provides clear external validation of Array's platform," Leerink analysts wrote in a report.
That agreement brought $40 million up front and could be worth much more in cancer and inflammatory disease, though Array CEO Robert Conway, calling the four-target pact "one of the biggest, I think, discovery deals in the history of the drug industry," pointed to "confusion" among some analysts. Celgene could pay as much as $200 million per drug in potential pre-commercialization milestone payments, and up to $300 million in payments related to further success, plus royalties. If two drugs hit all milestones, the deal means as much as $1 billion to Array.