Expecting the first interim analysis result in June 2022
'Aren't all beta-amyloid-targeted therapies the same?'
The development of new drug candidate (varoglutamstat) for Alzheimer's disease targeting the specific enzyme called ‘glutaminyl cyclase (QC)’ is expected to accelerate.
According to the related industry, Vivoryon Therapeutics, a biopharmaceutical company developing innovative small molecule-based medicines for age-related disorders, is conducting two phase 2 clinical trials of its new drug candidate 'varoglutamstat (formerly PQ912)' for Alzheimer's disease.
In a public announcement on November 1st, the company said, “There are two clinical trials that will evaluate safety and efficacy.” “Varoglutamstat also provided evidence that it improves cognition, memory, and attention in Alzheimer's patients in the clinical trial conducted earlier. This is an encouraging result observed with only 12 weeks of treatment," he emphasized.
The first phase 2b clinical trial, the VIVIAD study (NCT04498650), is being conducted at 12 clinical sites in Denmark, Germany, and the Netherlands. A total of 250 patients with mild cognitive impairment and mild dementia due to Alzheimer's will be recruited for the trial.
In the study, the efficacy and safety of varoglutamstat will be weighed for about 6 months, starting with 300 or 600 mg (twice a day) for 90 patients who were initially recruited for the study. After that, the optimal dose is selected through an interim analysis, and improvement benefits are evaluated for at least 1 year and up to 2 years. The primary endpoint is the neuropsychological test battery (NTB). Other outcome measures include the CogState Brief Battery (CBB) and electroencephalography (EEG).
“To avoid delays in patient recruitment due to the COVID-19 pandemic, we have added clinical centers in Germany and the Netherlands,” the company said.
"The complementary study (first in the United States) evaluating varoglutamstat is also underway under the collaboration between the University of California, San Diego (UCSD) and the Alzheimer's Disease Cooperative Study (ADCS)." This phase 2 study was named VIVA-MIND study (NCT03919162). It plans to recruit 180 patients with early-stage Alzheimer's disease.
Varoglutamstat is an orally available small molecule and has the unique mechanism of action that blocks the activity of glutaminyl cyclase.
The glutaminyl cyclase is observed at abnormally high levels in the brains of Alzheimer's patients and actively intervenes in the transformation process of beta-amyloid protein by catalyzing the formation of toxic pyroglutamate-modified beta-amyloid peptides (N3pE amyloid). The level of N3pE amyloid is closely related to cognitive decline, by promoting the accumulation and aggregation of beta-amyloids. The glutaminyl cyclase also plays an important role in the activation and stabilization of pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2 protein) which induces the aggregation of tau proteins, another biomarker of Alzheimer's disease.
Therefore, by inhibiting the glutaminyl cyclase, varoglutamstat can reduce the amount of toxic N3pE amyloids and attenuate the CCL2 protein activity.
The company expects "the potential of varoglutamstat to improve neuroinflammation and cognitive decline will be significant." and also said "Unlike other therapeutic agents that act to lower beta-amyloid levels, varoglutamstat will act earlier by targeting N3pE amyloid, thereby preventing the aggregation of it in advance."
Donanemab also targets N3pE. But unlike varoglutamstat, donanemab recognizes N3pE amyloid in plaques itself to clear amyloid burden from the brain, rather than preventing aggregation or deposition of amyloid.
The company said, "The first interim analysis results of the VIVIAD study are expected to come out around June 2022. The final results will be available at the end of 2023."
"Based on the mechanism of action of varoglutamstat and encouraging data from earlier clinical trials, it has great differences from other drugs currently under development, such advantages as an oral drug, low incidence of side effects, and cost reduction."
Meanwhile, the SAPHIR study (NCT02389413), a phase 2a clinical trial, which was conducted earlier, attracted attention by supporting cognitive improvement benefits for early-stage Alzheimer's disease patients. Administration of varoglutamstat twice a day for 12 weeks to 120 patients with early Alzheimer's disease, improved patients' cognition, memory, and attention, and also interneuronal activities.
