No drug has been approved to treat acute myeloid leukemia in four decades. As two specialists in the field wrote a couple years ago, “We indeed regularly administer the same chemotherapy regimens that became standard care for AML in the 1970s, back when each of us was playing Little League baseball.”
South San Francisco, CA-based Sunesis Pharmaceuticals (NASDAQ: SNSS) thinks it can end the shutout, even though its candidate disappointed in a Phase 3 trial this year.
Investors bailed out when the news hit in October. Patients taking its drug vosaroxin combined with the chemotherapy cytarabine demonstrated median survival rates of 7.5 months, 19 percent longer than the patients who were given cytarabine and a placebo. But that difference wasn’t statistically significant, and so the trial, dubbed VALOR, failed to hit its primary endpoint.
All patients in the trial had AML that had relapsed (returned after a remission) or was refractory (not responding to other treatments).
However, data released in conjunction with the American Society of Hematology’s annual conference in San Francisco show that certain subsets of patients in the large trial saw a statistically significant survival benefit.
Farhad Ravandi, a principal investigator in the trial and a leukemia specialist at MD Anderson Cancer Center in Houston, pointed out that people over 60—two-thirds of the 711 patients enrolled in VALOR—saw a 30 percent difference in survival rates between the vosaroxin and the placebo group, a statistically significant figure.
This type of post-study subgroup analysis sometimes raises eyebrows—especially when the original endpoints weren’t met—but Ravandi told Xconomy that the benefit to the over-60 patients was also medically significant. (Ravandi has taken research funding from Sunesis and has other ties to the company, as disclosed in his ASH abstract.)
Compared to a solid tumor cancer that metastasizes, AML has a relatively high long-term survival or cure rate—about 40 percent of all people diagnosed, with the better outcomes weighted toward younger patients who are better suited to hold up to the initial chemotherapy and potential bone-marrow transplants. That’s one reason it’s hard to get a drug approved for it, Ravandi says; the bar is fairly high.
But once the disease relapses, the prognosis is bad; for those over 60 who relapse, it’s “abysmal,” says Ravandi. “That’s typically the group likely to do worse at the time of relapse. It’s difficult to improve their outcomes. In VALOR, the subgroup over 60 had a clear benefit.”
They were also the biggest population in the 711-person trial. Recruiting such a large group of patients for the trial wasn’t cheap. Sunesis CEO Daniel Swisher (pictured above) put the price tag of the trial around $100 million, and in 2012 Sunesis sold off future royalties of the drug to a hedge fund to help foot the bill. But if regulators buy the argument about the older population, the investment could end up paying off.
When the top-line negative data were first released earlier this fall, Sunesis officials insisted they would press on and ask European regulators for approval.
Now, with the more detailed data revealed, Swisher says the company will go to the FDA in the first quarter of 2015. (Investors still aren’t enthused. At market close Friday, shares were $2.21 each, down 74 percent from its 52-week high.)
Swisher plans to point regulators to other data that might be overshadowed by the failure to meet the primary endpoint. For example, the patients in the vosaroxin arm (of all ages) saw a doubling of “complete response”—disappearance of cancer from the patient—compared to the placebo arm.
Complete response isn’t a gold-standard criterion, as relapse is always a possibility. But the vosaroxin group also showed little to no increase in early death in the month or two after starting treatment. Previous AML candidates have raised the complete response rate but also boosted early mortality (and have not received FDA approval), says Swisher. In FDA guidance issued about five years ago, that was not an acceptable trade-off. The agency also said it wanted to see randomized, controlled data, which Sunesis has provided with its 711 patients split in two sets.
When asked if regulators could look at the benefit in the elderly population and restrict the label to that age group, Swisher says it wouldn’t be unprecedented. “But having a broader discussion than one just about just the over-60 population is important for us,” he says: “We don’t want to put the cart in front of the horse” by suggesting what the regulators could or should do.
There was more AML news today at the hematology meeting. Agios Pharmaceuticals (NASDAQ: AGIO) added to the impressive Phase 1 data for its pill, AG-221, that’s being tested in AML patients with a mutation in an enzyme called IDH2. With the strong results—25 of 45 patients have had partial or complete responses—Agios plans to jump ahead to a Phase 3 trial.
Even if that drug sails through, it will benefit a limited number of AML patients. IDH2-positive people account for 9 to 13 percent of all AML cases. The American Cancer Society estimates nearly 19,000 new AML cases in the U.S. alone this year—nearly a third of all leukemias—and Sunesis CEO Swisher says the count is low.
Some of them will benefit greatly from the standard chemotherapy and bone marrow transplants (although in terms of side effects and serious risk, there’s nothing standard about either). Others will need an alternative. Sunesis seems determined to press its case that vosaroxin should be one.