CVN424 Shows Promise as Levodopa Add-on Therapy, Phase 2 Data Show

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by Patricia Inácio, PhD |

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CVN424 as add-on therapy | Parkinson's News Today | illustration of oral therapies

Using Cerevance’s oral CVN424 as an add-on therapy for Parkinson’s motor symptoms led to a significant and meaningful dose-dependent reduction in “off” time — periods when symptoms reappear or worsen — data from a Phase 2 study show.

The trial also met its safety objectives, according to a company press release. Moreover, Cerevance reported that CVN424 worked “without troublesome dyskinesia,” the uncontrolled, involuntary movements associated with long-term use of standard levodopa therapies.

“We are delighted to report these results which we believe demonstrate that CVN424 can provide a significant improvement for patients,” said Brad Margus, CEO of Cerevance.

Parkinson’s disease is characterized by the loss of nerve cells (neurons) that produce the neurotransmitter dopamine, a chemical messenger essential for muscle control. Levodopa, a precursor to dopamine, has long been one of the mainstay treatments for Parkinson’s.

However, over time, patients experience off time, or periods of the day when Parkinson’s symptoms return despite ongoing medication. These symptoms often include tremor and dyskinesia, which can impact patients’ quality of life.

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CVN424 is small molecule designed to penetrate the brain and modulate the activity of specific nerve cells in the striatum, a brain region involved in voluntary movement control. The experimental therapy selectively targets the dopamine D2 receptor-dependent, indirect pathway associated with Parkinson’s. This is thought to result in the positive effects of levodopa but without its adverse effects.

“For more than 50 years, physicians have relied on therapeutics that work by directly increasing dopaminergic signaling,” said Karl Kieburtz, MD, president of Clintrex, a company that works with pharmaceuticals to develop new treatments for brain diseases.

“This new mechanism holds great promise for treating the motor fluctuations eventually experienced by all Parkinson’s disease patients, as well as potential for treating patients in the earlier stages of the disease,” Kieburtz said.

The Phase 2 trial (NCT04191577), launched in 2019, involved approximately 135 adults, ages 30 to 80, with Parkinson’s disease. Enrolled participants had experienced at least a mean of two hours or more per day of “off” time despite treatment with levodopa and other medications.

Each was randomly assigned to one of two doses of CVN424 — a low or a high dose — or a matching placebo, taken once daily for four weeks.

The results showed the effects of the add-on therapy were dose-dependent. At the high dose, CVN424 treatment led to a 1.3-hour reduction in off time compared with a placebo, a statistically significant difference. This was accompanied by enhancement of levodopa effects, known as “on-time,” without dyskinesia.

CVN424 also reduced daytime sleepiness when compared with the placebo, which sets it apart from other current add-on therapies for levodopa, according to Cerevance. Daytime sleepiness was measured by the Epworth Sleepiness Scale, a self-administered questionnaire.

The lower dose of CVN424 also led to a meaningful reduction in “off” time and an increase in on time without dyskinesia, when compared with placebo, the company said.

Nausea, vomiting and headache were the most common adverse reactions, experienced by two participants (4%) on the high dose.

Margus called the improvements for patients “significant,” and noted there was “little exacerbation of dopaminergic side effects.”
The company now expects to conduct Phase 2/3 clinical trials to further establish the therapeutic potential of CVN424 as an add-on therapy. In parallel, it aims to evaluate its potential as a single therapy for those diagnosed with early Parkinson’s who have not yet been treated with levodopa.

“We look forward to rapidly advancing CVN424 into several larger clinical studies aimed at obtaining regulatory approval,” Margus said.

CVN424 was developed using Cerevance’s proprietary NETSseq platform technology. Originally designed at Rockefeller University, in New York, it conducts a comprehensive analysis of the messages encoded by specific cell types of the human brain.

Researchers analyze the cell’s specific transcriptome and epigenome to unveil new therapeutic targets. Of note, the transcriptome is the entire set of gene transcripts — messenger RNA molecules constituting copies of the DNA sequence used to build proteins — in a human or animal. The epigenome comprises all external modifications to DNA to turn genes on or off that do not change the actual DNA sequence.

“CVN424’s positive results demonstrate the power of the deep, cell-type-specific transcriptional and epigenetic data we are generating by applying our NETSseq platform technology to thousands of post-mortem human brain tissue samples,” said Mark Carlton, PhD, chief scientific officer of Cerevance.

“These data also increase the confidence we have in our pipeline of additional programs against novel targets identified by our approach,” he added.