2 Trials Testing Oral Varoglutamstat Now Enrolling in US, Europe

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by Patricia Inacio PhD |

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Vivoryon Therapeutics is looking to enroll patients at different stages of Alzheimer’s disease for two ongoing, Phase 2 trials evaluating the safety and efficacy of its investigational oral treatment varoglutamstat.

The therapy candidate has shown evidence, in earlier trials, of improving cognition, memory, and attention in Alzheimer’s patients, with “encouraging results after only 12 weeks of treatment,” the company said in a press release.

The first trial, a Phase 2b study called VIVIAD (NCT04498650), is currently underway at a dozen clinical sites in Denmark, Germany, and the Netherlands. It is aiming to recruit 250 patients with mild cognitive impairment and mild dementia due to Alzheimer’s. Information on enrollment is available here.

Due to the COVID-19 pandemic and to avoid recruitment delays, additional clinical sites have been added in Germany and the Netherlands. Up to 10 more sites in Spain and Poland will be joining the study over the next weeks, the company said.

A complementary study — the first in the U.S. testing varoglutamstat — is underway at the University of California San Diego (UCSD) School of Medicine, under the coordination of the Alzheimer’s Disease Cooperative Study (ADCS). That Phase 2a/b study is called VIVA-MIND (NCT03919162).

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Its initial enrollment target is 180 patients, with early stages of Alzheimer’s disease. More information is available on the trial page. Eight additional clinical sites, which have already received regulatory approval, according to the company, are expected to join soon.

“We are following a diligently designed development strategy and making continued progress towards overcoming the challenges of drug development in AD [Alzheimer’s disease], moving varoglutamstat through clinical development as efficiently as possible,” said Ulrich Dauer, PhD, CEO of Vivoryon.

Alzheimer’s disease is characterized by amyloid plaques and tau tangles — clumps of two proteins that accumulate to toxic degrees inside brain neurons — that cause nerve cell death.

Varoglutamstat (PQ912), a small molecule taken as an oral pill, is able to block the activity of an enzyme called glutaminyl cyclase. This enzyme is present at abnormally high levels in the brains of Alzheimer’s patients and is known to play a role in the formation of a particularly toxic form of amyloid-beta, called the N3pE amyloid. Amyloid-beta is the protein that clumps into the toxic plaques that characterize Alzheimer’s.

N3pE amyloid acts as a seeding factor, promoting the aggregation, or clumping, of amyloid-beta; its levels correlate with cognitive decline.

Contrary to other therapeutics that work to reduce the levels of these amyloid-beta plaques, varoglutamstat — which targets N3pE amyloid — may act earlier and prevent their formation, according to Vivoryon.

Also, since glutaminyl cyclase is important for the stability and activity of the pro-inflammatory CCL2 protein, which also promotes tau protein aggregates — another hallmark of Alzheimer’s disease — varoglutamstat holds the potential to lessen neuroinflammation and cognitive decline.

In a first-in-human Phase 1 trial, which involved 205 healthy volunteers, varoglutamstat was found to be well-tolerated. In the subsequent SAPHIR Phase 2a trial (NCT02389413), with 120 patients in the early stages of  Alzheimer’s, treatment with varoglutamstat, twice daily for 12 weeks, or about three months, was deemed safe.

Moreover, exploratory efficacy measures in the SAPHIR trial supported the therapy’s potential to lessen disease hallmarks — and to enhance nerve cell communication and improve patients’ cognition, memory, and attention.

Based on these findings, the company then launched the two clinical trials underway in Europe and the U.S.

“Based on its mechanism of action and encouraging data from earlier clinical studies, we believe that varoglutamstat is differentiated from other drugs in development, with potential benefits as an oral agent, potentially reduced side effects, and cost, which would make it accessible to a large number of [Alzheimer’s] patients who are anxiously waiting for new treatment options,” said Howard Feldman, MD, director of the ADCS at UC San Diego, and the U.S. trial’s director.

In the VIVIAD Phase 2b study, in Europe, the first 90 patients will be randomly assigned to receive either varoglutamstat — at doses of 300 or 600 miligrams (mg) — or a placebo, given twice daily for 24 weeks, or about six months.

This will be followed by an interim analysis to evaluate the treatment’s safety and efficacy, and to determine the best dose of varoglutamstat for further trials. The remaining patients will then be treated with the selected dose of varoglutamstat, twice daily, or a placebo for a minimum of 48 weeks (about one year) and up to 96 weeks (close to two years).

The primary goal of the VIVIAD trial is to determine the therapy’s safety and cognitive efficacy assessed by the neuropsychological test battery (NTB) throughout the study period. Additional exploratory goals include cognitive tests, and functional electroencephalograms and MRI scans, as well as the evaluation of disease markers in the cerebrospinal fluid, which surrounds the brain and spinal cord.

The therapy’s long-term safety and tolerability, as well as its efficacy on brain activity, cognition, and activities of daily living, will be assessed as secondary goals.

The first interim results of the trial are expected by June 2022, and the final results by the end of 2023, according to the developer.

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The U.S. VIVA-MIND Phase 2 trial is divided into two parts. In its initial Phase 2a, 180 patients will be randomly assigned to receive either a placebo or a dose range of varoglutamstat – 150 mg to 600 mg – given twice daily.

Following an interim futility analysis, planned for the first half of 2023, and if predefined criteria are met, the trial will move into the second stage, called Phase 2b. An additional 234 patients will be enrolled — totaling 414 patients altogether — to test varoglutamstat at the previous selected dose for at least 72 weeks, or about 16 months.

The primary goal of Phase 2b is to assess changes from the trial’s start (baseline) up to 72 weeks in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), an established clinical tool that measures a combination of cognitive abilities and activities of daily living.

The VIVA-MIND trial, launched in September, is supported by a $15 million grant from the National Institute on Aging, part of the National Institutes of Health.

“More than 6 million patients are currently living with Alzheimer’s in the U.S. alone, and despite recent developments, a huge need remains for safe, widely available effective disease-modifying therapies,” Feldman said.

“We are excited to offer those eligible for VIVA-MIND the option to participate in a clinical trial investigating the potential benefits of varoglutamstat, a novel type of AD [Alzheimer’s disease] medication, designed to address several key disease mechanisms,” Feldman added.

By launching the two trials, Vivoryon expects to confirm that the potential cognitive improvements seen in the European trial will translate into an established clinical endpoint — in other words, reach the treatment goals — in patients in the U.S. trial, according to the company’s release.

To secure the supply of varoglutamstat for the U.S. trial, Vivoryon expanded its manufacturing capacity by implementing a second line of manufacturing with an additional partner.