Welcome to your weekly digest of approaching regulatory and clinical readouts. Roche is due to report phase II results with its novel autism candidate balovaptan by the end of next quarter; if these are positive accelerated approval might be within reach.
Balovaptan, an oral vasopressin 1a receptor agonist, is being studied in 5-17 year olds with high-functioning autism, defined as an IQ of 70 or more. The primary endpoints in the 340-patient Aviation study are safety and changes from baseline in the Vineland-II adaptive behaviour scale, which includes measures of communication, daily living skills, socialisation and motor skills.
A lack of options means that children on the autism spectrum are often treated with multiple psychotropic or antipsychotic drugs. This means that if balovaptan succeeds it should see good uptake – sales could peak at $3.5bn, according to Jefferies analysts.
However, the path to regulatory success might not be smooth. A previous phase II trial, Vanilla, failed to hit its primary endpoint, change in the SRS-2 scale. Roche claimed that it saw dose-dependent improvement on the secondary Vineland II score endpoint, even though only the middle 4mg dose hit nominal significance here.
Even without that upset, the odds are against balovaptan given the difficulty of finding druggable targets for autism. Little is known about the underlying biology of the disorder, and conducting meaningful research is complicated by the fact that multiple genes are involved – studies have identified over 200 different genetic mutations in autism patients, and environmental factors might play a part too.
Alongside Aviation, Roche is also running the longer open-label phase III Viaduct study, which is expected to read out in late 2020 or early 2021. Some believe that if the Aviation data show clear efficacy Roche might file before seeing phase III data. At present this looks like a big if.
|Selected late-stage autism treatments|
|Product||Company||Mechanism of action||2018||2024e|
|Vraylar||Allergan||Dopamine D2 & D3 agonist||487||1,353|
|Latuda||Sumitomo Dainippon Pharma||5-HT2A, 5-HT7 & dopamine D2 antagonist||1,691||753|
|Balovaptan||Roche||Vasopressin 1a receptor antagonist||-||246|
|Bumetanide||Servier||Solute carrier family 12 member member inhibitor||-||-|
|CM-AT||Curemark||Amylase, lipase & protease regulator||-||-|
|Serelsa||Autism Therapeutics||Selective 5-HT reuptake inhibitor||-||-|
Drop the pressure
OTX-TP, Ocular Therapeutix’s depot formulation of travoprost, should have little problem meeting the endpoint of its phase III trial. The glaucoma project must only prove its superiority to placebo, rather than an active comparator like timolol.
This is just as well for the company since in phase IIb OTX-TP failed against timolol control. Indeed, when the phase III design was announced the group’s stock jumped 39% (Glaucoma fans throw caution to the wind, February 18, 2016).
The 550 patients in the pivotal study had the minute implant placed in their tear ducts; once it is implanted it is designed to leach the prostaglandin analogue over three months before dissolving.
The trial is due to read out by mid-year, and will assess the effect of OTX-TP on intraocular pressure, sampled at 8am, 10am and 4pm at the two week visit, and at these same time points at the six-week and three-month visits. Beating placebo on this measure would be a step towards approval, assuming a clean safety profile.
But the FDA will only countenance approval if the pressure reduction is clinically meaningful. The definition of this is up for discussion, though as a guide timolol was approved on the basis of a reduction of around 7mmHg.
In the phase IIb trial OTX-TP reduced eye pressure by 4.8mmHg at two months and 5.2mmHg at three months. The figures for timolol were 6.4mmHg and 7.3mmHg respectively.
In any case a second phase III trial will have to be completed before Ocular can seek approval, and it will begin after the forthcoming data are evaluated. Only then will Ocular have to grapple with its real problem: how can it hope to sell an ocular implant that appears not to work as well as cheap and widely available generic eyedrops?