West Coast Editor
The top-line failure of Allos Therapeutics Inc.'s Phase III trial with Efaproxyn for brain cancer that has metastasized from the breast lets the company - and investors - set the compound aside, in favor of the more-promising PDX, a dihydrofolate reductase (DHFR) inhibitor in Phase II trials against relapsed or refractory peripheral T-cell lymphoma (PTCL).
"Efaproxyn was an inherently risky development candidate because it had to be given in combination with [radiation therapy], and that made Phase II data very difficult to assess," noted Pablo Cagnoni, chief medical officer for Westminster, Colo.-based Allos, during a conference call.
"We don't believe this is a matter of an underpowered study," he added, pointing to a 4.8 percent differential between the arms in response rate in the brain, which "calls into serious question the biological activity of Efaproxyn."
PDX, on the other hand, is given as a single agent, and has shown "clear evidence [of efficacy] not only in lymphomas but also in solid tumors," Cagnoni said.
Paul Berns, president and CEO of Allos, said PDX is one member in a class of anti-folates with a "rich history in the oncology as well as the autoimmune therapeutic space."
So much is PDX considered a value driver for the stock that Allos' shares (NASDAQ:ALTH) first rose on the bad Efaproxyn news, trading as high as $6.75, though the price dropped to $5.63, a gain of only 2 cents, by the market's closing Tuesday.
Called ENRICH, the pivotal study tested Efaproxyn (efaproxiral, designed to sensitize hypoxic tumor areas) in combination whole-brain radiation therapy. Results missed the primary endpoint of improvement in overall survival, compared to patients getting only radiation, according to a stratified log rank analysis of overall survival (8.5 months vs. 7.5 months; hazard ratio 0.87, p-value = 0.23).
Charles Duncan, analyst with JMP Securities, called the failure "not a huge surprise." Efaproxyn missed all the secondary endpoints, too, and Allos is dropping the program, which puts still more chips on PDX (pralatrexate). The small-molecule chemotherapy agent's target, DHFR, is a folate-dependent enzyme that's involved in building DNA.
The Phase II trial with PDX, known as PROPEL, is an international, multicenter, open-label, single-arm pivotal study designed under a special protocol assessment plan with the FDA. One hundred evaluable patients with PTCL are being sought at 35 centers across the U.S., Canada and Europe - 23 sites are open so far - and the primary endpoint of the study is objective response rate (complete and partial response). Secondary endpoints include duration of response, progression-free survival and overall survival.
An interim analysis is expected in the second half of this year, after 35 patients finish at least one cycle of treatment. At least four responses must show up for the trial to keep going, and enrollment could finish by the third quarter of next year.
Cagnoni said Allos will know full data on responses for the first 35 patients at the interim analysis, but will publicly share only whether the four-response threshold has been reached.
Based on previous cancer-drug approvals, he said, a 20 percent response rate would be satisfying, "with some durability in some of those responses, which I think is going to be an important issue."
PTCLs comprise a diverse group of blood cancers that account for 10 percent to 15 percent of all cases of non- Hodgkin's lymphoma, or about 6,700 patients. The average five-year survival rate for PTCL patients is about 25 percent, and no approved drugs exist for first-line or relapsed or refractory PTCLs. Most PTCL patients get CHOP-type chemo (cyclophosphamide, doxorubicin, vincristine and prednisone), but it usually quits working.
Allos' stock rise after the Efaproxyn fizzle somewhat recalls Denver-based Myogen Inc.'s Phase III experience two years ago with the capsule version of the heart-failure drug enoximone, let go in favor of ambrisentan for pulmonary arterial hypertension, which went on to greater things.
On the failure of enoximone capsules, Myogen took a hit, but the stock climbed steadily afterward on hopes for ambrisentan. Foster City, Calif.-based Gilead Sciences Inc., which paid $2.5 billion for Myogen, won approval this week for the endothelin A receptor antagonist. (See BioWorld Today, June 19, 2007.)
Others with news lately in the PTCL space include Branford, Conn.-based CuraGen Corp., which said first data from a Phase II trial with its histone deacetylase inhibitor, belinostat, as monotherapy generated partial and complete responses, and CuraGen said the PTCL arm of the study will be expanded, along with the cutaneous T-cell lymphoma arm (CTCL).
At the American Society of Clinical Oncology meeting earlier this month, Gloucester Pharmaceuticals Inc., of Cambridge, Mass., offered interim Phase II data for its HDAC inhibitor romidepsin, also directed at CTCL as well as PTCL. In the PTCL group, three of 39 patients achieved a complete response. A partial response showed up in eight. In the CTCL patient group, four of 70 patients achieved a complete response. A partial response was seen in 18.
Allos plans a Phase I/IIa trial with PDX in non-Hodgkin's lymphoma and Hodgkin's disease, with enrollment starting at the end of this month. The drug is being tested at an earlier stage in non-small-cell lung cancer, for which it could enter Phase II as soon as the fourth quarter of this year.
Meanwhile, full data from the brain-cancer trial with Efaproxyn "need to be presented," Cagnoni said, and will be offered at an upcoming scientific conference. "I think there are some nuggets here that are important for the medical community to know about," he said.
David Clark, Allos' vice president of finance, said the firm continues to expect $34 million to $38 million in spending this fiscal year, and had about $75.5 million in cash at the end of the first quarter.
The ENRICH outcome "does not materially impact our estimated cash use for the second half of 2007," he said, and the company has enough to get through the first quarter of 2009.