Welcome to your weekly digest of approaching regulatory and clinical readouts. Waylivra should theoretically be approved by its August 30 PDUFA date for the rare hereditary disorder familial chylomicronaemia syndrome (FCS), thanks to the paucity of treatments options for the disease, in which patients lack the enzymes to clear fatty triglycerides from blood plasma.
Getting Waylivra to this point has not been plain sailing for Ionis's Akcea subsidiary, despite its clear efficacy. While the phase III Approach study showed a 77% reduction in triglyceride levels versus an 18% increase for the placebo group, concerns have been raised about the risk of thrombocytopenia. More than half of the patients taking Waylivra saw significant drops in platelet levels; this was not seen in the placebo group. And so far four patients have experienced grade 4 thrombocytopenia.
A May adcom vote was close, coming out 12-8 in favour of approval.
To mitigate what many believe will be a very strict REMs programme, Ionis has proposed platelet monitoring of patients, as well as the more immediate measure of dose skipping if platelet levels are seen to be declining.
Ionis is looking into a remote electronic platelet-monitoring system for Tegsedi, its treatment for polyneuropathy associated with hereditary transthyretin amyloidosis, approved in Europe, and this could reasonably be extended to cover patients taking Waylivra.
Even with the company’s efforts to allay the safety concerns raised at the adcom, Waylivra could struggle to meet its $412m 2024 consensus sellside forecasts. Some analysts also see a very slow sales ramp-up owing to the potential difficulty of identifying FCS patients.
|Approach extension study||NCT02658175|
Mixing it up
Thankfully for Intra-Cellular Therapies the FDA decided in 2017 that dog physiology was different from that of humans. This put an end to some of the toxicity concerns from a canine study that had been hanging over Intra-Cellular’s antipsychotic project lumateperone/ITI-077.
Scroll forward, and the next big event on the horizon is readout of the phase III monotherapy 401 study in bipolar depression, due in the second half of the year. Until now much of the investor focus for lumateperone has been on its use in schizophrenia, where a rolling NDA submission was started in June.
The group will be hoping that the 401 bipolar depression study, testing 40mg and 60mg doses against placebo, is indisputably positive following the mixed results seen so far in schizophrenia.
Lumateperone is a dopamine receptor phosphoprotein modulator, and provides selective and simultaneous modulation of serotonin, dopamine and glutamate, three neurotransmitters implicated in severe mental illness.
Schizophrenia accounts for $549m of lumateperone’s $1.23bn forecast sales in 2024, according to data from EvaluatePharma, but bipolar comes in a close second with consensus of $439m. There is a third indication: Intra-Cellular is also due to report an interim analysis of a phase III trial of lumateperone in agitation in patients with dementia in the second half of this year.
Should 401 disappoint, a second bite at the bipolar cherry will come in the form of another monotherapy trial, 404, due to read out in 2019. Intra-Cellular hopes to file lumateperone for treating bipolar on the back of both studies in the second half of next year; a failure in either could force it to conduct further trials.
That said, the FDA has historically taken a flexible approach to CNS drugs owing to the lack of options for patients, allowing some products to be filed or approved despite clinical failures.