ALS Agent IPL344 Demonstrates Positive Slowing of Disease Progression in Phase 2a Trial

Ilana Cohen, vice president of R&D at Immunity

Recently announced topline data from a phase 2a trial (NCT03755167) showed that treatment with IPL344, an investigational agent developed by Immunity Pharma, resulted in statistically significant change in disease progression among patients with amyotrophic lateral sclerosis (ALS), with positive benefits in weight gain, respiration, and survival.¹

Over a 36-week treatment period, patients on once-daily IPL344 demonstrated a mean slope of decline on ALS Functional Rating Scale-Revised (ALSFRS-R) of –0.53, equating to a 48% slower disease progression (P = .028). After adjusting for disease state and rate-indicating covariates, the rate of progression improved even further, with a 64% slowing (P = .034). Notably, the therapy was well-tolerated for the study duration, with no major drug-related serious adverse events (AEs).

"We are excited that treatment with IPL344 was well tolerated in people with ALS and demonstrated encouraging signs of efficacy across multiple parameters. This data will soon be submitted for publication in a scientific journal," Ilana Cohen, vice president of R&D at Immunity, said in a statement.¹ "If confirmed in a subsequent larger phase 3 study, the magnitude of reduction in ALSFRS-R progression observed in this study is greater than that achieved with currently approved drugs."

The phase 1/2a open-label trial features 9 patients with probable or definite ALS who underwent a 28-day phase 1 dose-escalation portion, followed by an optional phase 2a portion. Conducted at the Hadassah Medical Center in Jerusalem, the trial evaluated the efficacy of once-daily ILP344 using outcomes of ALSFRS-R, slow vital capacity, weight, and survival, and comparing them with historical placebo from the PRO-ACT database and ceftriaxone study. Ceftriaxone, an FDA-approved beta-lactam antibiotic, failed to demonstrate clinical efficacy in a phase 3 study, with results published in 2014.²

IPL344, currently being developed as an intravenous injection, is a biologically active peptide that stimulates therapeutic cell-signaling processes including activation of the Akt pathway, which is down-regulated in neurodegenerative diseases. Despite ongoing post-treatment follow-up, additional findings from the study showed a median survival of 29 months on IPL344 vs 19 months for those on placebo from the ceftriaxone study, indicating a trend towards reduced risk of death favoring the agent (P = .13). In comparison to PRO-ACT placebo patients, those treated with IPL344 demonstrated statistically significant increase in body weight (P = .02).

Patients on IPL344 demonstrated a 44% slower reduction in average SVC loss per month vs historical placebo, which was considered non-significant (P = .15). In addition, among 6 patients who had neurofilament light (NfL) sampling past the initial dose-escalating phase, investigators observed a 20% mean reduction, suggesting decrease of neuronal injury following treatment. This is notable considering the FDA approved Biogen’s tofersen, an antisense oligonucleotide, as a treatment for SOD1-mediated ALS based on reductions in NfL as a surrogate biomarker.

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"These early-stage data support further development of IPL344 as a treatment for ALS, and merit further investigation in a large number of participants,” Eran Ovadia, chief executive officer, Immunity, said in a statement.¹ "We intend to progress PL344 to a pivotal clinical trial in ALS.”

Immunity announced first-in-human findings from the phase 1 portion of the trial at the 2022 Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) Meeting, with results showing that IPL344 was well-tolerated with no major safety concerns. All told, the mean ALSFRS-R slopes for IPL344 vs PRO-ACT pooled placebo revealed a 49% estimated difference (–1.03 vs –0.52; P = .027) that favored IPL344. After adjustment, the differences in slopes grew bigger (–1.02 vs –0.19; 81%; P = .026). In the analysis comparing IPL344 to pre-treatment lead-in rate, the model assumed that ALSFRS-R during the lead-in period had a linear trajectory that varies with patients, and it also had a different linear trajectory during treatment that also varies with patients.³

In comparison with the ceftriaxone study, the mortality analysis showed a 70% lowered risk of death with IPL334 (P = .13). Adjusted mean slopes for slow vital capacity were –1.2% per month with IPL334 vs –2.5% for PRO-ACT pooled placebo, a 51% estimated difference (P = .24). In terms of weight loss/gain, those on active drug showed adjusted mean slopes of +0.47 vs –0.39 for the PRO-ACT pooled placebo group (P = .026).

REFERENCES
1. Immunity Pharma announces positive top line results from phase 2a trial with IPL344 in ALS patients. News release. Immunity Pharma. January 17, 2024. Accessed January 22, 2024. https://www.prnewswire.com/news-releases/immunity-pharma-announces-positive-top-line-results-from-phase-2a-trial-with-ipl344-in-als-patients-302037139.html
2. Cudkowicz ME, Titus S, Kearney M, et al. Efficacy and safety of ceftriaxone for amyotrophic lateral sclerosis: results of a multi-stage, randomized, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2014;13(11):1083-1091. doi:10.1016/S1474-4422(14)70222-4.
3. Gotkine M, Schoenfeld D, Cohen I, et al. First in human phase 1/2a study evaluating the safety and efficacy of the Akt activator, IPL344 in ALS (NCT03652805; NCT03755167). Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 85