CNM-Au8 Displays Positive Topline Results in Multiple Sclerosis, Supportive of Phase 3 Trial

Benjamin Greenberg, MD, MHS, FANA, FAAN, CRND

CNM-Au8, an investigational treatment for relapsing multiple sclerosis (MS) consisting of a gold nanocrystal suspension, has shown positive topline results in the phase 2 VISIONARY-MS clinical trial (NCT03536559), meeting its primary and secondary end points without significant safety signals being reported.¹

All told, on Low Contrast Letter Acuity (LCLA) measures—the primary end point—the least squares (LS) mean difference was 3.13 (95% CI, –0.08 to 6.33; P = .056) compared with the placebo group in the clinically affected eye over 48 weeks of treatment. Analysis of the secondary end point of mean change in modified Multiple Sclerosis Functional Composite (mMSFC) scores showed an LS mean difference of 0.28 (95% CI, 2.83-23.94; P = .0207) compared with placebo.

Clene noted in its announcement that the full dataset from VISIONARY-MS will be reported on at an upcoming scientific congress. VISIONARY-MS was a randomized, double-blind, placebo-controlled trial that randomly assigned patients with stable MS with a history of chronic visual impairment (who are allowed disease-modifying therapy) in a 1:1:1 fashion to CNM-Au8 in doses of 15 mg/day or 30 mg/day, or placebo. Its execution was halted because of operational challenges related to COVID-19, enrolling 73 of 150 anticipated participants, thus the threshold for significance was set at P = .10 prior to database lock.

“These data are very encouraging to us in the MS research and treatment community as we work to address functional improvement in patients,” Benjamin Greenberg, MD, MHS, FANA, FAAN, CRND, professor and Cain Denius Scholar in Mobility Disorders, Department of Neurology, and Department of Pediatrics, UT Southwestern Medical Center, said in a statement.¹ “The MS community has been successful at limiting relapses, but we need therapies to address progression independent of relapse activity (PIRA). This study was designed as a proof-of-concept evaluation to establish that treatment of neuronal and glial energetic failure can support remyelination and neuroprotection in people living with MS. I am pleased to see the potential effectiveness of CNM-Au8 demonstrated in this trial.”

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Additional secondary outcomes included the LS mean difference in mMSFC average rank score (LS mean difference, 13.38; 95% CI, 2.83-23.94; P = .0138) and the time to first repeated clinical improvement to Week 48 (treatment: 45%; placebo: 29%; P = .3991). As well, CNM-Au8 showed favorable signs of consistent improvement across a variety of paraclinical biomarkers— multifocal visual evoked potentials (mfVEP) amplitude and latency, and optical coherence tomography—and MRI end points—magnetization transfer ratio and diffusion tensor imaging metrics. The results, Clene noted in its announcement, support the advancement of CNM-Au8 into phase 3 clinical development, as they offer “quantitative physiological evidence that supports the potential neuroprotective and remyelinating effects” of the therapy.

Robert Glanzman, MD, FAAN, chief medical officer, Clene, said in a statement,¹ "In this study, CNM-Au8 demonstrated neurological improvements in people with stable relapsing MS as adjunctive therapy to immunomodulatory DMTs. I am very impressed by the consistency of structural and functional improvements demonstrated by CNM-Au8 throughout the neuraxis. With these data, Clene looks forward to initiating a phase 3 clinical program in people with MS who are experiencing progression independent of relapse activity, the most urgent unmet medical need in MS today. We look forward to the next phase of clinical development.”

Earlier in 2022, Glanzmann presented 2 sets of data at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, held February 24-26, in West Palm Beach, Florida, that suggest the therapy has effects on brain bioenergetic metabolism.^2,3 Those presentations included findings from the phase 2 REPAIR-MS clinical trial (NCT03993171), which suggested that CNM-Au8 treatment resulted in improvements in the NAD+/NADH ratio, as well as NAD+ and NADH levels and homeostatic effects on brain bioenergetic phosphorous metabolites.² The second presentation offered an update on VISIONARY-MS, offering updates on LCLA and MSFC scores, as well as 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).³

Additionally, CNM-Au8 has been investigated in patients with amyotrophic lateral sclerosis (ALS), with Clene presenting interim data from the RESCUE-ALS clinical trial (NCT04098406) in July 2022. Those data show that treatment with CNM-Au8 resulted in significant survival benefit among those with ALS. Using unadjusted Kaplan-Meier survival analyses obtained for 43 of 45 participants, treatment with CNM-Au8 resulted in a 70% decreased risk of death compared with those initially randomized to placebo (log-rank HR, 0.301; 95% CI, 0.122-0.742; P = .0143).⁴

In RESCUE-ALS, patients with ALS were randomly assigned 1:1 to either 30-mg CNM-Au8 or placebo for 36 weeks during the double-blind period, followed by an open-label extension of up to 130 weeks of treatment. Participants in the placebo-treated group, who received either no treatment or a 9-month delay in treatment initiation with CNM-Au8, were compared with patients treated daily with study drug from randomization.

REFERENCES
1. Clene Reports Positive Topline Results for CNM-Au8® in the Phase 2 VISIONARY-MS Trial in Multiple Sclerosis. News release. Clene Nanomedicine. August 15, 2022. Accessed August 15, 2022. https://www.globenewswire.com/news-release/2022/08/15/2498070/0/en/Clene-Reports-Positive-Topline-Results-for-CNM-Au8-in-the-Phase-2-VISIONARY-MS-Trial-in-Multiple-Sclerosis.html
2. Glanzman RL, Ren J, Rynders A, Ho KS, Hotchkin M, Greenberg B. Improvement of Brain Energy Metabolism in Relapsing Multiple Sclerosis Patients - Results from Phase 2 REPAIR-MS Clinical Trial With CNM-Au8. Presented at ACTRIMS Forum; February 24-26, 2022; West Palm Beach, Florida. P100.
3. Glanzman RL, Beadnall H, Klistorner A, et al. VISIONARY-MS Update to a Phase 2 Clinical Trial of CNM-Au8, Catalytically Active Gold Nanocrystals Suspension, for the Treatment of Chronic Optic Neuropathy. Presented at ACTRIMS Forum; February 24-26, 2022; West Palm Beach, Florida. P113.
4. Clene reports significantly decreased mortality in RESCUE-ALS long-term open label extension trial. News release. Clene Nanomedicine. July 14, 2022. Accessed August 15, 2022. https://www.globenewswire.com/news-release/2022/07/14/2479565/0/en/Clene-Reports-Significantly-Decreased-Mortality-in-RESCUE-ALS-Long-Term-Open-Label-Extension-Trial.html