CNM-Au8 May Be Responsible for Slower ALS Progression Seen in Phase 2 Trial

Note: This story was updated Sept. 21, 2021, to note that 18% of patients, not 80%, experienced increases in the MUNIX(4) sum score at some point during the study.

Participants in a placebo-controlled Phase 2 clinical trial of CNM-Au8, Clene Nanomedicine’s investigational oral therapy for amyotrophic lateral sclerosis (ALS), are showing several signs of slower disease progression than expected in the natural course of the disease, interim blinded data show.

Notably, a considerable proportion of participants demonstrated improvements in the health and functioning of motor neurons — the specialized nerve cells that control voluntary movement and are gradually lost in ALS — as well as slower functional and respiratory decline.

While it’s currently unknown if the observed benefits come from patients assigned to CNM-Au8 or from those on a placebo, Clene believes “these data support CNM-Au8’s potential to become a breakthrough for this devastating disease,” Rob Etherington, the company’s president and CEO, said in a press release.

“It is our hope that this encouraging blinded update from our RESCUE-ALS study, in the midst of ALS Awareness Month, reassures the ALS community that companies like Clene are working diligently to advance innovation in this space,” said Robert Glanzman, MD, Clene’s chief medical officer.

“We look forward to delivering unblinded top-line results by the end of this year,” Etherington added.

The findings were shared by Glanzman in the poster “A Blinded Interim Update on RESCUE-ALS: A Randomized, Placebo-Controlled, Phase 2 Study to Determine the Effects of CNM-Au8 to Slow Disease Progression in Amyotrophic Lateral Sclerosis,” at the European Network to Cure ALS (ENCALS) 2021 Annual Meeting, held virtually May 12–14.

Problems in mitochondria, the cell’s powerhouses, and oxidative stress — an imbalance between the production of oxygen-related toxic molecules and a cell’s ability to detoxify them — are two biological hallmarks of ALS.

CNM-Au8 is an oral liquid suspension of gold nanocrystals designed to improve nerve cells’ survival, function, and communication by supporting their energetic needs, while lowering oxidative stress.

The therapy has “a unique multi-modal mechanism of action that addresses ALS disease-related bioenergetic failure, oxidative stress, and impaired [protein balance],” Clene stated in the release.

Preclinical studies showed that CNM-Au8 improved nerve cell survival and motor neuron function in rodent models of ALS and other neurodegenerative diseases, such as multiple sclerosis, and Parkinson’s disease. The therapy also was found to be safe in healthy volunteers in a previous Phase 1 trial (NCT02755870).

These positive early findings supported the launch of the Phase 2 RESCUE-ALS study (NCT04098406), which is taking place in Australia and is partly funded by FightMND, an Australian nonprofit patient advocate group working to raise awareness about motor neuron disease (MND) in that country.

The trial is assessing CNM-Au8’s safety, effectiveness, pharmacokinetics (movement into, through, and out of the body), and pharmacodynamics (effects in the body) in 45 adults (26 men and 19 women) with early ALS.

Participants, with a mean age of 59.1 years, were assigned randomly to receive either a liquid suspension containing 30 mg of CNM-Au8, or a placebo, each morning for 36 weeks (about eight months), in addition to standard care therapies.

At study start, participants had already lost 25% of their function, Glanzman said in the presentation.

RESCUE-ALS’s main goal is to assess changes in the number, function, and health of motor neurons controlling hand, arm, leg, and feet muscles, using the Motor Unit Number Index score, or MUNIX(4) sum, which is a good predictor of clinical decline.

Secondary efficacy goals include changes in patient’s ability to perform daily life tasks — as assessed with the ALS Functional Rating Scale revised (ALSFRS-R) — and lung function, and quality of life.

As of March 15, results showed that about 18% of all participants had increases in the MUNIX(4) sum score at some point during the study, indicative of improved motor neuron survival and function, and another 18% had 25% or lower score drop through week 36.

This is in clear contrast with the expected continuous MUNIX score decline seen in the natural course of the disease.

In addition, the overall patient population had a mean lung function decline of 11% at week 24 and 18% at week 36, declines generally lower than anticipated based on data from previous trials (about 25% decline at nine months).

Further analysis revealed that patients showing MUNIX(4) sum improvements also had less disability and greater lung function.

Participants’ ALSFRS-R scores were found to be significantly associated with their MUNIX(4) sum scores and lung function.

These blinded data suggest that CNM-Au8 may have promising neuro-reparative properties that can help preserve motor neuron function in ALS patients.

These findings “support a disease-modifying potential of CNM-Au8 in the treatment of this devastating disease,” Glanzman said in the presentation.

The trial is expected to finish in August 2022. After completing the study, participants may enter an open-label extension study, in which all will receive CNM-Au8.

“Concurrent with our advancement of the RESCUE-ALS study, we are also advancing CNM-Au8 through the Phase 3 HEALEY ALS Platform trial,” Etherington said.

The first platform trial for ALS, HEALEY ALS (NCT04297683) is designed to assess multiple treatment candidates simultaneously to accelerate ALS therapies’ development. The study, which started enrolling ALS patients in August, will first evaluate CNM-Au8, UCB’s zilucoplan, and Biohaven Pharmaceuticals’ verdiperstat against a placebo.

A fourth candidate — Prilenia’s pridopidine — was added to the trial this January, and more are planned to be included as they become available. HEALEY ALS’s first results are expected in the first half of 2022.

“Through the parallel execution of these clinical programs, we aim to facilitate CNM-Au8’s clinical development and hopefully one day shift the paradigm in how we can treat and target the underlying bioenergetic deficits common to ALS patients,” Etherington said.