CNM-Au8 Meets Primary End Point in Phase 2 Parkinson Disease, Multiple Sclerosis Studies

Robert Glanzman, MD, FAAN

Positive topline results announced today from the phase 2 REPAIR clinical trials showed that treatment with CNM-Au8 (Clene Nanomedicine), an aqueous suspension of catalytically active, clean-surfaced, faceted gold nanocrystals, significantly improved brain energetic metabolism in patients with multiple sclerosis (MS) as well as those with Parkinson disease (PD).¹

REPAIR includes REPAIR-MS (NCT03993171) and REPAIR-PD (NCT03815916), 2 sequential group studies that examine the brain metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who have been diagnosed with MS within 15 years of screening or in patients with PD who have been diagnosed within 3 years of screening. Participants received orally delivered CNM-Au8 daily each morning for 12 weeks.

Phosphorous magnetic resonance spectroscopy (P-MRS), an innovative noninvasive brain imaging technique, was used to semiquantitatively measure central nervous system (CNS) energic metabolites at baseline, prior to administration of drug, and at the end of the study period. All told, the results for the primary end point, the mean change in the brain ratio of oxidized nicotinamide adenine dinucleotide (NAD+) to reduced nicotinamide adenine dinucleotide (NADH), demonstrated a statistically significant increase by an average of 0.589 units (10.4%) following the 12-week treatment period (paired t-test, P = .037).

"We believe the REPAIR program represents a critical breakthrough for Clene, demonstrating that catalytically active CNM-Au8 improves energy production and utilization in the brains of people with Parkinson disease and multiple sclerosis. Using a novel, noninvasive brain imaging approach, the study demonstrated that a key driver of cellular ATP [adenosine triphosphate] energy production, the ratio of NAD+/NADH, was significantly increased in the brains of patients after 3 months of daily CNM-Au8 oral administration,” Robert Glanzman, MD, FAAN, chief medical officer, Clene Nanomedicine, said in a statement.¹ "Remarkably, the data also show a significant rebalancing of brain ß-ATP levels in these patients, a metabolic response to treatment that suggests improved ATP energy efficiency. Our next step will be to demonstrate that these brain energetic changes result in clinically meaningful results in patients with Parkinson disease and multiple sclerosis."

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Key secondary end points were also concordant with the primary end point. Investigators observed an increase in NAD+ fraction (P = .026) and decrease in NADH fraction (P = .026) from baseline. Additionally, a consistent statistical trend toward improvement in the NAD+/NADH ratio in both REPAIR-PD (P = .11) and REPAIR-MS (P = .14), respectively.

The investigational agent also demonstrated an ability to achieve homeostatic equilibrium across essential energetic metabolites, including ATP, intracellular phosphorous (Pi[in]), phosphocholine (PC), and phosphorylation potential index (ß-ATP/ADP*Pi[in]). By the end of the 12-week treatment period, percent change from baseline for these metabolites and indices was significantly inversely correlated with baseline levels, such that participants with relatively lower baseline levels demonstrated increases, and subjects with relatively higher baseline levels demonstrated a rebalancing effect with levels decreased to the baseline population mean.

In both REPAID-PD and REPAIR-MS, respectively, this relationship was observed both on an integrated and independent basis for metabolites including ß-ATP (r2= 0.82, P <.0001; r2= .71, P = .0011), phosphorylation potential (r2 = .72, P = .00002; r2 = .68, P = .0019), PC (r2= .78, P <.00001; r2 = .54, P = .0095) and Pi[in] (r2= .42, P = .017; r2 = .48, P = .018). Clene noted that the drug had a consistent homeostatic effect on multiple other phosphorous energetic metabolites, adding that those data will be revealed at a later meeting.

CNM-Au8 was found to be well-tolerated within the study cohort, with all treatment-emergent adverse events (AEs) predominately mild and unrelated to study drug. There were no serious AEs or treatment discontinuations related to AEs in either study. Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the primary safety end point in REPAIR-PD, showed no worsening with treatment of CNM-Aug.

Patients in REPAIR-MS showed consistent improvements in the modified MS functional composite, which includes 4 scales of Symbol Digit Modalities Test, low contrast letter acuity, 9-hole peg test, and timed 25-foot walk test.

"Clene is a company driven to pioneer the development of cellular energy-enhancing nanotherapeutics for the treatment of neurodegenerative diseases,” Rob Etherington, chief executive officer, Clene, said in a statement.¹ "We believe the study results also strongly support Clene’s ongoing phase 2 and phase 3 clinical programs investigating how CNM-Au8’s neuro-reparative and neuroprotective properties may impact disease progression in amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson disease, and may be broadly applicable to the treatment of neurodegenerative diseases."

The company previously reported interim data from its phase 2 VISIONARY-MS trial (NCT03536559) in February, which showed that CNM-Au8 has potential as a promoter of neurological improvement in patients with stable MS who are on disease-modifying therapy.² The investigational agent is also part of the HEALEY ALS (amyotrophic lateral sclerosis) platform trial, which is the first of its kind in the disease, and evaluates multiple treatments for patients with ALS across 54 sites in the Northeast ALS Consortium in conjunction with the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.³

Glanzman sat down with NeurologyLive in March to discuss those VISIONARY-MS trial data, which were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis Forum 2021. Listen to his comments below, as he details the implications for what the findings mean to the clinical community.

REFERENCES

1. Clene reports positive top-line results from its phase 2 REPAIR clinical trials in Parkinson disease and multiple sclerosis. News release. August 5, 2021. Accessed August 5, 2021. https://www.globenewswire.com/news-release/2021/08/05/2275392/0/en/Clene-Reports-Positive-Top-line-Results-from-its-Phase-2-REPAIR-Clinical-Trials-in-Parkinson-s-Disease-and-Multiple-Sclerosis.html

2. Glanzman RL, Beadnall H, Barnett M, et al. VISIONARY-MS: Update to a Phase 2 clinical trial of catalytic gold nanocrystals, CNM-Au8, for the treatment of chronic optic neuropathy. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P050.

3. Sean M. Healey & AMG Center for ALS at Mass General receives “May Proceed” notice for three drugs in first ALS platform trial. News release. Massachusetts General Hospital. January 22, 2020. Accessed August 5, 2021 massgeneral.org/neurology/als/news/2020-01-22-Healey-ALS-platform-trial-may-proceed.