Since initiating its Phase 3 study in AML in December 2010, Sunesis Pharmaceuticals, Inc. (NASDAQ:SNSS) has been widely followed by the investment community. Over the past two years, the company has been successful in raising roughly $100 million of debt and equity in order to finance the development of vosaroxin in the Valor study, which today serves as the biggest late stage study in AML.
The Valor study is Sunesis Pharmaceuticals' multi-national, randomized, double-blind, placebo-controlled, pivotal Phase 3 study evaluating vosaroxin in combination with cytarabine for patients with relapsed/refractory (R/R) AML.
When last September the Data and Safety Monitoring Board (DSMB) recommended expanding the sample size of the study based on interim data that suggested a "promising" outcome, vosaroxin garnered even more investor attention. In light of growing interest in the promising drug, we have decided to take a deeper look into the Valor study.
Valor Trial Design And Alpha Spend
At the analyst meeting in October 2012, Sunesis provided an update on the adaptive design of the study that allows for a potential one-time sample size increase of the patient population. Based on its review, the DSMB recommended the Valor study increase the sample size to 675 patients for a 90% statistical power to detect a 30% overall survival difference (5 months versus 6.5 months) with an HR of 0.77. The DSMB concluded that the interim data indicated a "promising" outcome - ruling out futility and an "unfavorable" scenario, but falling short of a "favorable" result.
Based on the nuances of statistical analysis, ruling out both favorable and unfavorable scenarios for a promising outcome strongly suggests that vosaroxin was closer to non-inferiority and in need of a larger sample size in order to show a statistically significant treatment difference. It was a smart idea by management to utilize the first interim analysis of Valor as a proxy for a randomized Phase 2 study whereby it could better estimate the sample size needed to demonstrate a clinical effect. Powering the study has thus been the main factor in influencing its "promising" outcome.
Doing so and taking an unblinded interim look, however, also comes at a cost. The main drawback to unblinding efficacy data is the fact that it comes at the expense of the study's alpha; in the Valor study, pre-specified at ρ<0.05 based on initial assumptions. In this case, the interim look at the data by the DSMB has cost the study an amount of alpha that has not been publicly disclosed by the company. Without knowing how much alpha has been spent it thus becomes difficult to calculate the level of significance, the statistical hurdle, and ultimately, the probability of a superiority outcome.
When the Phase 3 Dacogen study (DACO-16) failed in early 2012 it was because the study had spent its entire alpha. Although Dacogen did not demonstrate superiority at the pre-specified level of significance (ρ<0.05), it did when all of the patients had died, justifying approval. Upon interpreting the final data, the FDA Oncologic Drug Advisory Committee (ODAC) (pdf), however, rendered the ρ=0.037 recorded by the sponsor un-interpretable since the alpha hurdle had been raised to ρ<0.0107 after the study had been unblinded prior to final data. In the context of the recent failure of the Dacogen study, the amount of alpha spent is an important consideration in determining the success of the Valor study.
Conducted by the United Kingdom's National Cancer Research Institute (NCRI), the Less Intensive 1 study (LI-1) currently enrolls six different investigational drugs including vosaroxin in comparison to the same control of low-dose cytarabine (LDAC). The initial stage endpoint is complete remission (CR) for five treatments and one-year survival for sapacitabine. Vosaroxin is currently being dosed in two arms: one in combination with LDAC and the other as a single agent. If vosaroxin meets the pre-specified criteria set by the protocol, the NCRI may elect to move the drug to the second stage of the study with overall survival as the primary endpoint.
The excitement surrounding the LI-1 study and its potential in giving vosaroxin access to the frontline setting might well be true. The "Pick-A-Winner" platform, however, has historically proven to be questionable in demonstrating improvement in overall survival. At ASH in 2012, Sanofi/Genzyme's clofarabine failed to improve overall survival even though it nearly doubled the CR rate. Even in the hopeful event that vosaroxin improves overall survival, it still remains unclear if the LI-1 trial design is submissible for approval by the FDA or EMA since it challenges the rules of simultaneous randomization. Some arms of the study have completed enrollment while others have yet to start, compromising the probability that the patient is assigned to the drug's investigational arm at the same time as the control arm. LI-1 is thus more an observational/registry study than a traditional randomized one, casting doubt on its ability to "pick-a-winner" that improves overall survival.
AML Competitive Landscape
The competitive landscape in AML, today, is crowded if anything. There have been no new agents approved for frontline treatment for more than forty years. The last breakthrough happened in 1969 with the approval of cytarabine followed by idarubicin in 1990, but only as a combination drug with Ara-C in the 7+3 regimen.
There are currently five players competing in the race to become the first-in-class treatment for the small subset of patients with relapsed/refractory (R/R) AML and include Sunesis Pharmaceutical's vosaroxin currently in Phase 3, Clavis Pharma's (CLAV:OL) elacytarabine also in Phase 3, privately-held Ambit BioSciences' quizartinib (which just last week had all rights and considerations returned back to the company from Astellas), Celator Pharmaceuticals' CPX-351 and Cell Therapeutic's (NASDAQ:CTIC) tosedostat all in Phase 2.
While the prospect of vosaroxin winning FDA approval would be a major and much-welcomed breakthrough for AML patients and hematology-focused biotech companies in general, we remain on the sidelines until we gain more clarity.