SLS-005 Slows ALS Progression Better in Subgroup Without AMX0035, HEALEY ALS Platform Trial Shows
Despite the overall cohort not reaching statistical significance on the primary end point, a subgroup of patients on SLS-005 without AMX0035 performed better.
Raj Mehra, PhD
Newly announced topline findings from the SLS-005 (intravenous trehalose) regimen of the HEALEY ALS Platform trial showed that the agent failed to demonstrate statistical significance on the primary end point; however, it did perform significantly better in a subgroup of individuals who were not on concomitant AMX0035 (Relyrvio; Amylyx Pharmaceuticals).1,2
SLS-005 is a low molecule weight disaccharide that cross the blood brain barrier and is thought to stabilize proteins and activate autophagy through the activation of Transcription Factor EB (TFEB), a key factor in lysosomal and autophagy gene expression. After 24 weeks of treatment, a prespecified subgroup of patients with amyotrophic lateral sclerosis (ALS) on SLS-005 without AMX0035 showed a 22% improvement in ALS Functional Rating Scale (ALSFRS-R) assessment adjusted for mortality, with an 89% success probability.
The full analysis set included shared placebo from all regimens, including regimen E (RGE; n = 204) and RGE participants on SLS-005 (n = 120). The efficacy regimen only (ERO) population included 120 RGE SLS-005 and 41 RGE placebo participants. In total, 31 participants in the ERO population received AMX0035 during the study, thus confounding results from this population. The Efficacy Relyvrio Free (ERF) analyses, which excluded participants who initiated AMX0035 during the study, represented the participants who followed the protocol as envisioned. This group, comprised of 130 individuals, 99 on REG active and 31 on RGE placebo, made up 81% of ERO/RGE participants.
"The HEALEY platform is designed to detect signals of efficacy and we believe the observed signal and success probability is competitive to other recently FDA-approved therapies for ALS which also failed to achieve statistical significance when measured for function and mortality on similar primary and efficacy endpoints," Raj Mehra, PHD, chairman and chief executive officer at Seelos, said in a statement.1 "We plan to request a meeting with the FDA to discuss potential next steps for the program and will continue our potential partner discussions."
Using the full analysis set, treatment with the therapy resulted in a 13% improvement in function and mortality with an 88% success probability (vs the pre-specified 98%) on the overall population. Over the 6-month period, patients in the prespecified ERF data set demonstrated a slower rate of decline in ALSFRS-R slope (–0.80 vs –1.07 points per month, respectively) than placebo. In this specific subgroup, investigators reported a 25% slowing of slow vital capacity decline vs placebo (SLS-005: –11.5% vs placebo: –15.4%) at 24 weeks.
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HEALEY ALS, the first ever platform trial of ALS, also studies zilucoplan (regimen A; UCB), verdiperstat (B; Biohaven), CNM-Au8 (C; Clene Nanomedicine), and Pridopidine (D; Prilenia Therapeutics), in addition to SLS-005. In a head-to-head analysis of platform trial data, the 13% and 22% improvements seen in the full analysis set and ERF subgroup of SLS-005 were considered the greatest effects on function and mortality seen thus far.
When comparing SLS-005 to other approved ALS treatments, the therapy appeared to demonstrate better results on change in ALSFRS-R. For SLS-005 (n = 130), the change from baseline was –4.80 while those on placebo changed –6.42. In the edaravone (Radicava; MT Pharma), tofersen (Qalsody; Biogen), and AMX0035 trials, the change from baseline in ALSFRS-R scores were –5.01, –7.00, and –6.70, respectively, vs changes of –7.50, –8.10, and –9.62 for placebo in each study. Seelos noted that these analyses were for illustrative purposes only, and that no head-to-head trials with AMX0035 and/or tofersen have been conducted.
In terms of safety, treatment emergent adverse events (TEAEs) were similar between the placebo (n = 204) and SLS-005 (n = 120) groups, with 89.2% of patients in each group experiencing at least 1 TEAE. Between the 2 groups, there was a higher rate of serious TEAEs (15.8% vs 8.8%) and TEAEs leading to study drug withdrawal (11.7% vs 6.4%) in the SLS-005 group. Overall, death occurred in 7 patients (5.8%) on active drug and in 4 (2.0%) on placebo.
