Researchers for Ionis’ $IONS majority-owned spinout Akcea will have plenty of persuading to do this week if they ever expect to get their drug volanesorsen on the market.
The FDA internal review came out today, reflecting the same deep concerns that analysts have expressed about the safety of a drug that has been linked with repeated instances of sudden and dangerous drops in platelet counts. Platelets are needed to trigger the clotting that stops bleeding.
Akcea’s shares $AKCA immediately tumbled 15% on the negative tone of the internal review.
In a memo to the advisory committee meeting on Thursday, James Smith, the deputy director of the Division of Metabolism and Endocrinology Products, spotlighted a general agreement that the drug has a clearly positive effect on regulating plasma triglyceride for patients with rare cases of familial chylomicronemia syndrome. That’s a surrogate endpoint for the disease.
But is the benefit really worth the risk of bleeding? That’s the big question that the developers face this week. Regulators are also somewhat perplexed by Akcea’s wish to switch the dosing regimen and their platelet monitoring strategy to something that was never tested in the clinical trials.
From Smith’s note:
Although the reviews highlight several safety/tolerability issues, the primary focus for both the applicant and the reviewers has been the risk of thrombocytopenia (low blood platelet counts) and resulting potential for serious bleeding….(S)ome patients can exhibit a rapid and unpredictable reduction in platelets to extremely low levels. In CS6, no patients assigned to placebo had a platelet count fall below 100,000/uL compared with 18 (55%) of 33 patients assigned to volanesorsen…Switching to biweekly dosing and/or dose interruptions have not always led to a sufficiently timely recovery of platelet count; some patients have required treatment with prednisone, hospitalization, and/or administration of IVIG. To date, serious bleeding events have not been observed in this relatively limited safety database, but the reviewers highlight a higher risk of non-serious bleeding-related adverse events with volanesorsen (e.g., epistaxis, petechiae). Some of these events occurred at platelet levels where spontaneous bleeding would be unexpected, suggesting the possibility of an abnormality of platelet function as well as an effect on platelet count.
Ionis reported a little more that a year ago that it had achieved its efficacy endpoint in Phase III. But five patients were forced out of the trial due to a threatening decline in platelet counts. Grade 4 thrombocytopenia occurred in three patients, which ended after they stopped dosing. There were no withdrawals due to platelet counts after the company began monitoring the side effect.
If they do get an approval, says Smith, it will have to come with a REMS. But right now, that looks like the best case scenario.
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