CNM-Au8 Shows Significant Reductions in Neurofilament in HEALEY ALS Trial

Article

New data announced by Clene Nanomedicine suggested that the gold nanocrystal therapy reduced plasma neurofilament light chain, which principal investigator Merit Cudkowicz, MD, said, “help advance the design of a phase 3 trial.”

Merit Cudkowicz, MD, the chair of the neurology department and director of the Sean M Healey & AMG Center for ALS

Merit Cudkowicz, MD

New data from the ongoing HEALEY ALS platform trial (NCT04297683) from Regimen C, which is assessing Clene Nanomedicine’s investigational agent CNM-Au8 among patients with amyotrophic lateral sclerosis (ALS), suggest that the treatment resulted in statistically significant reductions in neurofilament light (NfL) compared with placebo after 24 weeks of therapy.1

CNM-Au8 is an oral suspension of gold nanocrystals developed by Clene in an attempt to restore neuronal health and function by increasing energy production and utilization. All told, in this analysis and across the full cohort of patients (n = 161) in Regimen C, the least-squares (LS) mean change in natural logarithm of plasma NfL was –0.024 (SE, 0.024) for patients on CNM-Au8 compared with 0.076 (SE, 0.042) among patients randomly assigned to placebo (LS mean difference, –0.100; SE, 0.048; P = .040).

“The totality of survival and time-to event data supports my belief that CNM-Au8 should move forward expeditiously into the next phase of clinical development,” Merit Cudkowicz, MD, the chair of the neurology department and director of the Sean M Healey & AMG Center for ALS, as well as the principal investigator of the HEALEY ALS trial, said in a statement.1 “These clinical and biomarker evidence from the phase 2 HEALEY ALS Platform trial will also help advance the design of a phase 3 trial to increase our confidence in how CNM-Au8 can delay the clinical course of this devastating neurodegenerative disease.”

In the CNM-Au8 treatment regimen of the trial, the 161 participants were randomly assigned in a 3:1 ratio, with 120 planned for randomization across 2 active arms (30 mg and 60 mg) and at least 40 planned in placebo. Participants included were at least 18 years old, had a diagnosis of sporadic or familial ALS, and had less than 36 months since onset of weakness prior to screening. Clene noted in its announcement that NfL serum samples specified as the primary blood matrix for analysis are undergoing analysis, and additional biomarker and long-term survival data are undergoing testing preparatory for analysis, with a goal of being reported later in 2023.1

READ MORE: Full Efficacy and Safety Results From Phase 3 LAVENDER Trial of Trofinetide Published

Sensitivity analyses also showed a consistent reduction in plasma NfL levels compared with placebo, particularly among a subset of individuals who are considered at greater risk for disease progression. These faster progressors—defined as those with a baseline pretreatment ALSFRS-R slope of greater than 0.45 points per month (post hoc, n = 107)—the difference of LS means was –0.144 (SE, 0.058; P = .014). Likewise, those with definite or probable ALS diagnosis per El Escorial criteria (n = 125) reported a difference of LS means was –0.124 (SE, 0.054; P = .023), and those with a higher mortality risk—defined as a baseline plasma NfL level above the median (n = 79)—reported a difference of LS means of –0.150 (SE, 0.068; P = .031).

“The statistically significant difference in plasma neurofilament levels, a key marker of neurodegeneration, is another independent indicator of slowed disease progression associated with CNM-Au8 treatment,” Benjamin Greenberg, MD, the head of Medical at Clene, said in a statement.1 “Results with CNM-Au8 treatment in multiple phase 2 trials in ALS previously showed 2 independent indicators of slowed disease progression—CNM-Au8 decreased time to clinical worsening and improved survival at the 30-mg dose. These independent pieces of evidence strongly support CNM-Au8 as a potential treatment for ALS.”

Larger overviews of the trial—including a breakdown of the platform trial experience thus far in ALS—were recently presented by Sabrina Paganoni, MD, PhD, an investigator at the Sean M Healey & AMG Center for ALS, at the 75th American Academy of Neurology Annual Meeting, held April 22 to 27, in Boston, Massachusetts. Data on the therapy’s potential in multiple sclerosis (MS) from the VISIONARY-MS trial, another area in which it is being investigated, were presented by Michael Barnett, PhD, MBBS, FRACP, senior academic at the University of Sydney.2

Additionally, just a month earlier, in March 2023, interim data from the HEALEY ALS trial on CNM-Au8 were announced by Clene, showing that the agent was tolerable and resulted in several meaningful delays in clinical worsening and increased survival benefit.3 In that announcement, also an analysis of the 24-week treatment period, patients with ALS treated with 30-mg CNM-Au8 demonstrated a 74% decreased risk on the composite end point of time to ALS clinical worsening (P = .035). This composite included the first instance of death, tracheostomy, initiation of permanent assisted ventilation for at least 22 hours per day, or placement of a feeding tube. Additionally, and concurrent with a lower hazard of ALS clinical worsening, individuals treated with 30-mg CNM-Au8 had a 98% decreased risk of death or permanently assisted ventilation (= .028), a 95% decreased risk of death (= .053), and a 74% decreased risk of feeding tube placement (= .035). As well, they reported a 63% decreased risk of assisted ventilation (= .058), an 84% decreased risk of ALS-related hospitalization (= .107), and a 69% decreased risk of all-cause hospitalization (= .065).3

Rob Etherington, Clene’s CEO, added to the statement that, “For the first time, the FDA has recently granted accelerated approval of another ALS therapy based upon plasma NfL as a biomarker predictive of clinical efficacy. Clene is exploring the possibility for an NDA filing. In addition to planning the global phase 3 ALS trial, we are preparing the complete CNM-Au8 clinical data package including our strong safety evidence, biomarker, survival, and time-to-event analyses for FDA regulatory discussion in the third quarter. We believe the benefit-risk framework for CNM-Au8 strongly favors a path to approval.”1

REFERENCES
1. Clene’s CNM-Au8® Shows Statistically Significant Difference in Plasma Neurofilament Light (NfL) levels in the HEALEY ALS Platform Trial. Neww release. Clene Nanomedicine. June 15, 2023. Accessed June 15, 2023. https://www.globenewswire.com/news-release/2023/06/15/2689404/0/en/Clene-s-CNM-Au8-Shows-Statistically-Significant-Difference-in-Plasma-Neurofilament-Light-NfL-levels-in-the-HEALEY-ALS-Platform-Trial.html
2. Barnett M, Beadnall H, Klistorner A, et al. VISIONARY-MS top-line results: a phase 2, randomized, double-blind, parallel-group, placebo-controlled study to assess the safety and efficacy of CNM-Au8, a catalytically active gold nonocrystal suspension in relapsing multiple sclerosis. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 004273
3. CNM-Au8 associated with delayed time to key clinical progression events at six months supporting a survival benefit in the Healey ALS Platform trial. News release. Clene Nanomedicine. March 9, 2023. Accessed June 15, 2023. https://www.globenewswire.com/news-release/2023/03/09/2623829/0/en/CNM-Au8-Associated-With-Delayed-Time-to-Key-Clinical-Progression-Events-at-Six-Months-Supporting-a-Survival-Benefit-in-the-Healey-ALS-Platform-Trial.html
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