ANVS401 Improves Colonic Motility in Mouse Models of Early Parkinson’s

Investigational therapy ANVS401 (also known as Posiphen) reversed gastrointestinal dysfunction linked to early Parkinson’s in two mouse models of the disease.

Results of the study, “Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice,” were published in the American Journal of Neurodegenerative Disease.

Parkinson’s disease is characterized by aggregates of alpha-synuclein in the nervous system, particularly in dopamine-producing neurons in the brain. How these aggregates form in the first place, however, is not fully understood.

One proposed hypothesis is that the aggregates don’t initially form in the brain, but in the enteric nervous system (ENS) — the nervous system of the gut.

This is supported by the fact that gastrointestinal dysfunction can occur decades before the onset of motor symptoms. Common gastrointestinal symptoms include dysphagia (difficulty swallowing), gastroparesis (slow movement of the stomach muscles), longer gut transit time (time between ingestion of food and its excretion as feces), constipation, and difficulty with defecation.

ANVS401, developed by Annovis Bio (previously known as QR Pharma), is an oral medication that stops the production of alpha-synuclein protein. It does so by binding to SNCA mRNA — a molecule that serves as a template for protein production — and preventing it from being translated into alpha-synuclein by the cell’s protein-making machinery. (Translation is the process by which the genetic information contained within a gene, in this case SNCA, gives rise to a protein.)

Previous in vitro studies in human and rodent nerve cells have shown that ANVS401 can reduce alpha-synuclein protein levels in those cells. However, no preclinical studies of the effects of ANVS401 in animal models of Parkinson’s disease existed.

Now, researchers at the University of California San Francisco, in a study funded by the Michael J. Fox Foundation, tested the effectiveness of ANVS401 to reverse gastrointestinal dysfunction in two mouse models of SNCA-associated early Parkinson’s disease. 

“What we have here is a very early model of PD [Parkinson’s disease], where alpha-synuclein accumulates in the enteric nervous system and causes defects in gut motility,” the researchers wrote.

The team also studied ANVS401’s pharmacokinetics and pharmacodynamics — how the body affects a medicine and the interactions between the body and a medicine. 

The results showed that in both mouse models, ANVS401 prevented slowing in colonic motility (the amount of time it takes for material to move through the colon). This positive effect was kept for at least nine weeks after ANVS401 treatment was stopped.

“This may be indicative of the time it takes α [alpha]-synuclein to accumulate and cause gastrointestinal dysfunction,” the researchers wrote.

However, whole gut transit time — the time it takes for food to leave the stomach and go through the small bowel and colon  — was not changed by ANVS401 treatment. The weight of the mice also remained unchanged.

Importantly, while lower doses of ANVS401 (10 mg/kg) reduced the levels of alpha-synuclein in the gut of mice treated for 21 weeks, higher doses (50 and 65 mg/kg) reduced alpha-synuclein levels in the brain of mice treated for a much shorter period of time (21 days).

This suggests that ANVS401 acts over a longer period of time in the gut and may help researchers calculate its appropriate dose to be used in future clinical trials so the treatment can “be effective, and less probable to cause side effects.”

Overall, the data “are in agreement with the ability of Posiphen to reach the nervous system, and its mechanism of action, the translational inhibition of α [alpha]-synuclein,” the researchers wrote.

“ANVS401 lowered levels of α[alpha]-synuclein and normalized gut motility in two transgenic animal models of PD [Parkinson’s disease]. Together, these data are very exciting and provide strong support for moving forward in our development of ANVS401,” Maria Maccecchini, PhD, CEO of Annovis Bio said in a press release.

Annovis Bio now is planning a multi-center, randomized, double-blind, placebo-controlled Phase 2a trial evaluating the safety and tolerability of ANVS401 in patients with early Parkinson’s disease.

The compound already is being tested in a Phase 2 clinical trial (NCT02925650), called DISCOVER, in people with early stage or probable Alzheimer’s disease.