Mechanistic data from the phase 2 REPAIR-MS trial support blinded efficacy data from the VISIONARY-MS trial, suggesting that Clene Nanomedicine’s investigational CNM-Au8 has the potential to drive clinically meaningful improvements in recognized MS functional end points.
Data from pair of poster presentations on the investigational disease-modifying treatment for multiple sclerosis (MS), CNM-Au8 (Clene Nanomedicine), suggest that the agent has effects on brain bioenergetic metabolism, offering support for the nanotherapeutic's development.1,2
The first poster included data from the phase 2 REPAIR-MS clinical trial (NCT03993171), which suggested that CNM-Au8 treatment resulted in improvements in the NAD+/NADH ratio—the primary end point—as well as NAD+ and NADH levels—the secondary end point—and homeostatic effects on brain bioenergetic phosphorous metabolites—the exploratory end points.1
The second poster offered an update on the phase 2 VISIONARY-MS clinical trial (NCT03536559), which showed that at each visit—weeks 12, 24, 36, and 48—the overall study population, who were randomized 2:1 to active CNM-Au8 or placebo, reported mean improvements in the primary end point, low contrast letter acuity (LCLA; P <.0001), as well as averaged Multiple Sclerosis Functional Composite (MSFC) scores (P <.0001). Additional improvements were observed in the MSFC domains, including Symbol Digit Modalities Test (P <.0001), 9-Hole Peg Test (9HPT) dominant-hand (P <.001), and 9HPT nondominant hand (P <.002). All patients in the study were stable, with chronic optic neuropathy, and currently being treated with disease-modifying therapy.2
Both sets of results were presented by Robert Glanzman, MD, FAAN, chief medical officer, Clene Nanomedicine, at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, held February 24-26, in West Palm Beach, Florida.
“The results of the REPAIR-MS trial demonstrate the ability of CNM-Au8 to enter the brain and address energetic failure, a key driver in the pathophysiology of MS and other neurodegenerative diseases,” Glanzman said in a statement.3 “These mechanistic results support the blinded interim VISIONARY-MS data, which we believe suggest that CNM-Au8 has the potential to drive clinically meaningful improvements in recognized MS functional endpoints when administered in addition to standard of care. We look forward to sharing the unblinded data from VISIONARY-MS in the second half of 2022 that will help inform the design of our next clinical trial in MS patients.”
The data from the prespecified integrated analysis on brain energy metabolism across REPAIR-MS and its twin trial, REPAIR-PD (NCT03815916), showed that there was a statistically significant increase of 10.4% (0.589 U) in brain NAD+/NADH ratio following 12 weeks of treatment with CNM-AU8 (P = .037). The REPAIR-MS trial alone demonstrated an improvement of 14.3% (0.8296 U; P =.14).1
REPAIR-MS also incorporated a third high-resolution magnetic resonance spectroscopy (31P-MRS) scan following a 6-week washout period, which resulted in a return to baseline in mean NAD+/NADH ratio levels following the withdrawal of CNM-Au8 treatment. The exploratory end points showed that CNM-Au8 administration resulted in normalization of several critical biomarkers, including ß-ATP levels (r2 = 0.71; P = .001) and phosphorylation potential (r2 = 0.68; P = .002).2
The aforementioned REPAIR-PD trial is one of the sequential group studies examining the brain metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients with Parkinson disease who have been diagnosed within 3 years of screening. Participants received orally delivered CNM-Au8 daily each morning for 12 weeks. In August 2021, Clene announced that the therapy had achieved the primary end point in both trials.4
CNM-Au8 is also being assessed in amyotrophic lateral sclerosis (ALS) in the phase 2 RESCUE-ALS trial (NCT04098406), which announced topline results in November 2021 that showed that the investigational agent did not meet its primary or secondary end points in change of Motor Unit Number Index (MUNIX) biomarker and forced vital capacity, but did show a MUNIX efficacy signal after 12 weeks of treatment.5 Change in MUNIX, a neurophysiological biomarker that estimates the number of functioning lower motor neurons serving selected muscles, was found to be nonsignificant at the end of the treatment period; however, investigators noted an efficacy signal observed at week 12 (P = .057). In a subset of patients with limb onset ALS, which accounts for approximately 70% of the ALS population, CNM-Au8 showed a significant treatment effect in MUNIX at week 12 (P = .057), with a trend for improvement at week 36 (P = .0741).
Clene is expected to report results from the HEALEY ALS Platform Trial, which involves several different investigational agents, including CNM-Au8, in the second half of 2022.
At the ACTRIMS Forum 2021, NeurologyLive® spoke with Glanzman about the potential of CNM-Au8 as a novel therapeutic approach to MS. Watch below to hear him offer insight from an earlier readout of these data and to share his perspective on the drug’s ability to make an impact on the disease landscape.
For more coverage of ACTRIMS Forum 2022, click here.