Troriluzole Fails to Ease Cognitive Impairments in Phase 2/3 Trial

Troriluzole, an investigational oral symptomatic treatment developed by Biohaven for Alzheimer’s disease, did not work better than a placebo in alleviating cognitive impairments and reducing brain volume loss in patients with mild-to-moderate disease, according to top-line data from a Phase 2/3 trial.

However, a subgroup analysis — performed in the subset of study patients with milder forms of Alzheimer’s — suggested troriluzole might help preserve cognitive abilities and brain volume in people at the earlier stages of the neurodegenerative disease.

Nevertheless, Biohaven now said that additional analyses will be needed to assess troriluzole’s potential value as a disease-modifying treatment for early Alzheimer’s.

The company said it plans to present full data from the trial at a future medical meeting. Such presentations would include biomarker data and other key secondary and exploratory study endpoints that are expected to become available in the coming months.

“Our goal was to efficiently assess whether troriluzole could benefit patients relatively late in the disease process with mild-to-moderate AD [Alzheimer’s disease]. This study was well-conducted but unfortunately it is clear from this preliminary analysis that troriluzole is not efficacious as a symptomatic treatment in a mixed population of patients with mild and moderate AD,” Vlad Coric, MD, CEO of Biohaven, said in a press release.

“We are awaiting additional biomarker data and other secondary analyses that will help inform whether troriluzole may provide benefit in early AD as a disease modifying agent,” Coric added.

Troriluzole (BHV-4157) is a precursor of riluzole, an oral therapy that has been approved to slow the progression of amyotrophic lateral sclerosis (ALS). This therapy was designed to control the activity of glutamate, one of the most abundant and important neural chemicals in the brain.

Although glutamate plays a key role in learning and memory by stimulating brain cells, abnormal sensitivity or excessively high levels of this brain chemical can damage and even destroy nerve cells.

Treatment with troriluzole lowers glutamate-mediated nerve cell stimulation by promoting the chemical’s reabsorption at synapses, the places where nerve cells contact and communicate with each other. The medication does this by increasing the production and activity of specialized molecule transporters, like EAAT2, in brain cells.

The T2 Protect AD (NCT03605667) trial sought to assess the safety and efficacy of troriluzole at easing cognitive impairments and reducing brain volume loss, a sign of Alzheimer’s progression, in a group of patients with mild to moderate forms of the disease.

Participants were randomly assigned to receive either oral capsules containing 280 mg of troriluzole, or a matched placebo, for 48 weeks (nearly one year).

The study’s main goals were evaluating the therapy’s effects on patients’ memory, reasoning, orientation, and language, as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11), as well as its effects on overall cognition and functioning, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB).

Additional secondary goals included assessing the effects of treatment on hippocampal brain volume, which was evaluated by brain MRI scans, as well as on key disease biomarkers, such as neurofilament light chain (a marker of nerve cell damage), tau, and amyloid proteins.

Earlier data from the study showed troriluzole had the potential to be superior to the placebo at improving patients’ cognition and reducing brain volume loss. These findings, which included data from 100 patients who were treated for at least six months, allowed the study to pass its interim futility analysis and continue dosing patients.

However, top-line data from the T2 Protect AD trial, now announced by Biohaven, showed that despite being safe and well-tolerated, troriluzole failed to show superiority over the placebo at improving cognition and lowering brain volume loss in the overall population of patients participating in the 48-week study.

Yet, a subgroup analysis performed only in a subset of patients with mild Alzheimer’s demonstrated that troriluzole led to some improvements in cognition and brain volume preservation at week 48.

Despite not being statistically significant compared with the placebo, these numerical improvements indicate troriluzole might be particularly beneficial for patients who are still at the early stages of Alzheimer’s. Yet, additional analyses will be needed to confirm this hypothesis.

“The topline data we released today only represent the early analyses that are available and multiple analyses including important biomarker data are expected in the near term,” said Irfan Qureshi, MD, vice president of neurology at Biohaven.

“Additional planned analysis of the clinical outcome scales and biomarkers will help to inform our long-term development plans for troriluzole in AD,” Qureshi said.

Biohaven is now planning to amend the trial’s long-term extension study, which is currently underway, to allow participants with mild Alzheimer’s to be able to continue treatment. This change will allow the company to continue gathering data on troriluzole’s potential health benefits for this patient population.

“We look forward to completing our analysis of the full dataset including all the clinical measures as well as the biomarker data to understand if further investigation of troriluzole in the early stages of Alzheimer’s disease is warranted,” said Howard Feldman, MD, professor of neurosciences at the University of California, San Diego, and director of UCSD’s Alzheimer’s Disease Cooperative Study.

The researchers expressed their appreciation of all of the efforts put forth by patients and researchers to complete the study.

“Successfully undertaking this trial during the COVID-19 pandemic has required a remarkable commitment of our participants, research site staff and Principal Investigators for which we express our gratitude,” Feldman said.