Perhaps Lilly’s early success with donanemab in Alzheimer’s disease had spurred a minor flurry of enthusiasm around Biohaven’s rival asset troriluzole. Clearly there had been hopes of success, however misplaced, otherwise Biohaven would not be off 15% today on its project’s failure, which some will say was highly foreseeable.
Troriluzole put to the test a somewhat broad theory, namely that excessive concentration of the neurotransmitter glutamate is responsible for a variety of CNS diseases, including Alzheimer’s. Not only did some analysts not buy this, as reflected in consensus sales estimates, troriluzole had already failed in three other neurology settings.
Most recently it flunked an obsessive compulsive disorder study, having earlier drawn blanks in spinocerebellar ataxia and generalised anxiety disorder, though Biohaven is pushing on in the first two settings.
Sellside consensus, according to EvaluatePharma, is for troriluzole to post 2026 revenues of $303m, of which Alzheimer’s accounted for $114m. With Biohaven yesterday revealing the unambiguous failure of the T2 Protect AD trial, at best those forecasts will be slashed, and some analysts are removing most troriluzole sales from their models.
The open-label phase II/III study had compared troriluzole against placebo in mild to moderate Alzheimer’s, but failed both its co-primary endpoints, 48-week Adas-Cog and CDR-Sum of Boxes scores, as well as a secondary MRI metric looking at hippocampal volume.
The best Biohaven could say about the data was that a subgroup of 48 subjects with mild Alzheimer’s showed a numerical benefit versus placebo on Adas-Cog and hippocampal volume, but even this did not hit nominal statistical significance. The company accepted that further trials would be necessary to demonstrate any benefit, and additional analyses will determine whether these are warranted.
Troriluzole is a prodrug of riluzole, which as Rilutek is approved for amyotrophic lateral sclerosis. It reduces levels of glutamate by augmenting the expression and function of excitatory amino acid transporters, which increase uptake of the neurotransmitter from synapses.
Biohaven had earlier argued that excessive glutamate levels in synapses, owing to overproduction and insufficient uptake and breakdown, had a range of deleterious downstream effects; unfortunately, it has been unable to prove that reversing this was relevant in a clinical trial setting.
Numerous other projects are in development targeting glutamate modulation, but none appears to be in development for dementia, according to EvaluatePharma. Earlier work included Aquestive Therapeutics’ oral film form of riluzole, Glialogix’s GLX1112 and Roche’s R449, but all appear now to be discontinued in Alzheimer’s.
Analysts at Mizuho and Leerink alike said Biohaven’s failure was not surprising, and stressed that the company’s investment case remained centred on its recently launched acute migraine treatment, Nurtec ODT.
Mizuho says uptake has been impressive, and expects additional approval in the second quarter in migraine prevention. Indeed, Nurtec ODT achieving consensus 2026 sales of $1.6bn seems more realistic than a win for troriluzole in Alzheimer’s ever was.