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Akt Activator IPL344 Demonstrates Safety, Signs of Efficacy in Phase 1/2 Study of ALS

By comparing results with pooled placebo groups from the PRO-ACT database, the data showed a 67% slower ALSFRS-R progression with IPL344.

Findings from the first in-human study (NCT03652805) of IPL344 (Immunity Pharma), an Akt activator, showed that the treatment was generally safe for patients with amyotrophic lateral sclerosis (ALS), and demonstrated signals of efficacy on the ALS Functional Rating Scale-Revised (ALSFRS-R) assessment.1

Led by Merit Cudkowicz, MD, MSc, director, Sean M. Healey & AMG Center for ALS, and chief of the Department of Neurology, Massachusetts General Hospital, the open-label study, divided into a 28-day dose escalation phase a voluntary long-term extension, showed that IPL344 was well-tolerated with no major safety concerns. Presented at the 2022 Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) Meeting, November 1-3, in Clearwater Beach, Florida, IPL344-treated patients had a 67% slower ALSFRS-R progression rate compared with the participants’ pre-treatment lead-in rate (P = .0001).

The phosphoinositide 3-kinases (Pi3K)-Akt pathway is an intracellular signal transduction pathway that promotes cell survival and growth by preventing neurodegeneration and apoptosis. Although dysfunction of this pathway is common in neurodegenerative disorders like ALS, studies have shown that higher Akt levels and/or activation in humans and certain cell types provide some protection from ALS as well as a slower progression rate of the disease and better overall survival.

IPL344, a short peptide shown to activate Akt independent of Pi3K, was assessed in a cohort of rapidly progressing ALS, defined by reductions of at least 0.55 points/month in ALSFRS-R prior to enrollment. Study results, which included safety, functional assessment, lung function, weight, and ALS-related events, were compared against the natural history of ALS as captured by the PRO-ACT database, including the pooled placebo groups from 16 studies included in the database and by the ceftriaxone study (NCT00349622; for end points where the PRO-ACT database was incomplete). When comparing to PRO-ACT, the analysis was against all patients included in the database with available data for the analyzed end point.

Patients were on IPL344 for an average of 11 months of treatment. 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.

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).

In terms of safety, of the treatment-related adverse events (TEAEs) observed, 2 were pneumonia complications, 2 catheter related AEs, 1 fall, and 1 drug-related hypersensitivity. Of those with pneumonia, 1 patient had tracheostomy and 1 patient died; however, neither was related to treatment. For the one case of drug-related hypersensitivity, this occurred in a patient enrolled for compassionate treatment after 12 months and was resolved with reduced infusion rate.

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REFERENCES
1. 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