Excerpt from the FDA Briefing Document (IMO, the reason for today's drop):
All approvals require evidence of effectiveness and safety from adequate and well controlled studies conducted with a well-defined population for which the therapy is beneficial, and adequate safety for the dose schedule identified.
Randomized controlled trials provide the best evidence for judging effectiveness and relative safety of a therapy.
Vion has not provided a randomized, well-controlled study demonstrating the efficacy or safety of laromustine as a single agent or in combination. The results from the two submitted single-arm studies were confounded by the fact that additional therapy was given with laromustine which obscures the treatment effect attributable to laromustine. In study CLI-043, patients achieving remission then received cytarabine consolidation. Thus the contribution of laromustine to the duration of remission cannot be determined. In the subset of patients selected from study CLI-033 who were pooled and analyzed for this NDA as "elderly, poor-risk, de novo AML," all received concurrent hydroxyurea. The applicant had postulated that the addition of hydroxyurea would enhance the effectiveness of laromustine. Given the lack of a comparator arm in this study, we cannot say with certainty whether the applicant’s hypothesis is correct. However, we can state that the use of hydroxyurea interfered with the ability of the trial to isolate the contribution of laromustine to the CR rate.
Safety concerns arose when during the conduct of the phase 2 studies and phase 3 trial, laromustine use was noted to be associated with a sometimes fatal pulmonary toxicity resembling BCNU pulmonary toxicity and requiring mechanical ventilation. The toxicity and its management are not well characterized and impose an additional burden on patients. In addition, the phase 3 study of laromustine with cytarabine had to be placed on hold for excess mortality, raising concerns about using laromustine in combination.
The applicant has chosen to submit the results from single arm studies as a pathway to accelerated approval. An accelerated approval requires that the applicant demonstrate that (a) the new therapy must show benefit to patients over existing treatments (available therapy) and that (b) confirmatory post-marketing studies should be underway to verify and describe the clinical benefit.
Issues that arise with developing a drug for the treatment of acute leukemia using a single arm trial and defining a study patient population without available therapy include: AML is primarily a disease of the elderly, with median age about 68 years in the U.S., and currently there is no universally agreed upon standard definition of an elderly patient who is not eligible to receive standard induction/consolidation treatment with agents such as cytarabine and daunorubicin. The unproven assumption is that elderly patients with AML, especially those with additional medical illnesses, are assumed not to benefit from standard, available therapy.
The eligibility criteria in the Vion studies characterize patients as "poor risk" based on age, ECOG performance status of 2, co-morbidities, or unfavorable cytogenetics. Although these characteristics have been used to varying degrees in other studies, these characteristics are vague; they lack newer information about molecular markers and more specific geriatric assessment tools. There is evidence that some older patients do as well as younger patients with standard available therapy such as induction chemotherapy (3+7) or with low-dose cytarabine schedules. Previous FDA approvals in the treatment of AML in adult patients have been based on Phase III randomized trials (daunomycin, cytarabine and the combination of iadarubicin and cytarabine). In the controlled trials for cytarabine and anthracyclines, endpoints of survival as well as response rate were used.
Thus far, approvals of agents to treat acute leukemia relying on single arm trial data have been problematic. ODAC reviewed the Zarnestra® application and did not recommend approval. During the ODAC meeting, several issues were raised including the low response rate and whether the patients enrolled on the study could have received standard therapy, since a number of them actually did so subsequently. A subsequent randomized study designed to confirm clinical benefit for regulatory purposes showed no survival advantage for Zarnestra® therapy over supportive care alone. Evidence for the efficacy and safety of laromustine as a single-agent has not been provided. Studies CLI-033 and CLI-043 are confounded by the additional agents used, HU and cytarabine respectively, so that estimation of the complete remission rate and the durations of remissions resulting from laromustine are confounded and not well characterized. There is evidence also for a unique toxicity involving the lung, which does not occur with the standard agents currently used for AML therapy, and use of laromustine in the patients proposed by the applicant, who have pre-existing cardio-pulmonary co-morbidity, is very concerning.
Evidence from study CLI-037 indicates that laromustine cannot be combined safely with concurrent cytarabine induction therapy in the regimen tested. There was an apparent decrease in median overall survival on the laromustine arm: 176 days for the cytarabine arm and 128 days for the laromustine plus cytarabine arm. This detrimental effect on overall survival must be further examined in adequate and well-controlled randomized studies with survival as a primary outcome to assure the safety and efficacy of laromustine. Single arm study results cannot offset the inferior survival observed in the randomized, controlled trial.
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