FDA Clears Way for Phase 2 Trial of AV-101 for Levodopa-Induced Dyskinesia

VistaGen Therapeutics will begin a Phase 2 clinical trial to evaluate its lead candidate AV-101 as a potential treatment to reduce dyskinesia (abnormal involuntary movements) induced by levodopa in patients with Parkinson’s disease, after the U.S. Food and Drug Administration (FDA) cleared the company’s investigational new drug (IND) application.

Parkinson’s is characterized by the loss of neurons that produce the neurotransmitter dopamine. Treatment with levodopa, or L-DOPA — a precursor to dopamine — is one of the gold standards for Parkinson’s. However, as the disease progresses, patients need larger doses.

Dyskinesia — sudden, involuntary movement — is one of the complications of long-term levodopa therapy that affects many patients with advancing Parkinson’s.

Amantadine (brand names Gocovri, Symmetrel, Symadine) can be used to treat dyskinesia, though it is often accompanied by side effects such as depression and cognitive impairment.

Amantadine acts on a specific part of NMDA (N-methyl-D-aspartate) receptors  — molecular structures involved in neuronal communication — in the brain, enhancing dopamine levels.  AV-101 is an oral NMDA receptor antagonist (inhibitor) that acts on a different part of the receptor.

Preclinical data from a non-human, primate model of Parkinson’s showed that AV-101 lessened dyskinesia without affecting the timing, extent, or duration of the therapeutic benefits of levodopa. Researchers observed none of the adverse effects with AV-101 often associated with amantadine, such as hallucinations, dizziness, and falls.

In a Phase 1b clinical study performed in collaboration with Baylor College of Medicine, researchers tested AV-101’s potential in seven healthy U.S. military veteran volunteers. Participants were randomly assigned a single (either high or low) dose of AV-101 (720 mg or 1440 mg) or a placebo.

The results showed that the higher dose of AV-101 could block NMDA activity, confirming the therapy’s target engagement. Moreover, both doses were well tolerated, without any adverse side effects.

“Current drug treatment options for levodopa-induced dyskinesia, or LID, may cause serious side effects, including hallucinations and sedation,” VistaGen CEO Shawn Singh said in a press release. “In all clinical studies to date, AV-101 has not been associated with any psychotomimetic [inducing psychotic alteration of behavior and personality] side effects or drug-related serious adverse events.”

“With its exceptional safety profile, recently successful preclinical studies in the leading primate model for LID, and the successful Phase 1b NMDAR target engagement clinical study conducted by Baylor College of Medicine in healthy volunteer U.S. military veterans, we are excited by AV-101’s potential as a novel therapy for LID,” Singh said.

VistaGen said it also received a notice of allowance from the U.S. Patent and Trademark Office covering to the use of AV-101 for levodopa-induced dyskinesia. The patent, once issued, will be in effect until at least 2034, the company said.