Fosigotifator Fails to Meet End Points in HEALEY-ALS Platform Trial

Merit Cudkowicz, MD, MSc

Topline data from regimen F of the HEALEY-ALS Platform trial revealed that fosigotifator (Calico Life Sciences), an investigational eIF2B activator, did not meet its primary end point of slowing disease progression in patients with amyotrophic lateral sclerosis (ALS). At the exploratory high dose, investigators observed between-group differences in end points of muscle strength, hinting that this target approach may need further investigation.¹

Over a 24-week treatment period, patients with ALS randomized to the primary dose (n = 155) demonstrated no statistically significant difference vs placebo on the primary end point of change in ALS Functional Rating Scale-Revised. Throughout that time, those in this treatment group also showed no difference in survival, as well as other secondary end points of respiratory and muscle strength. Encouragingly, the therapy was considered safe and well-tolerated, with no meaningful safety differences between doses.

"While the results of this regimen did not meet the trial’s primary or key secondary outcome measures for the primary dose at Week 24, the findings at the exploratory high dose on muscle strength in both upper and lower extremities and possibly in respiratory function suggest that this target and approach need additional investigation,” Merit Cudkowicz, MD, MSc, principal investigator and sponsor of the HEALEY-ALS Platform trial, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, said in a statement.¹ "We have additional pre-specified subgroup analyses and biomarker work pending from this regimen, as well as long term efficacy data from participants who continued in the active treatment extension period. We remain deeply committed to fully understanding the effects of fosigotifator in ALS, and will further evaluate the data before determining next steps."

Fosigotifator targets eIF2B, a guanine nucleotide exchange factor that is essential for protein synthesis and a key regulator of the integrated stress response (ISR). In addition to HEALEY-ALS, the therapy is being studied in another phase 1 trial (NCT04948645) of patients with ALS, as well as another phase 1b/2 open-label study (NCT05757141) of adults and pediatric patients with vanishing white matter (VWM) disease.

In regimen F of HEALEY-ALS, an additional 79 participants were given an exploratory high dose and compared with participants (n = 129) from the shared concurrent placebo cohort, which comprised placebo participants within the regimen (n = 76) and those from another concurrently enrolling regimen (n = 50). At the exploratory high dose, muscle strength endpoints measured by hand-held dynamometry (HHD) showed slower decline in the treatment group, with a 32% slower decline in upper extremity muscles compared to the shared placebo cohort (P = 0.014) and 37% slower compared to the regimen-only placebo group (P = 0.007).

In terms of lower extremities, those in the exploratory high dose fosigotifator group declined 62% slower than both the shared concurrent placebo cohort (nominal P = .037) and the regimen-only placebo group (P = .054). In addition, there was a potential signal towards slowing respiratory decline, measured by slow vital capacity, in this treatment group. Treatment-emergent adverse event (TEAE) rates were similar between the shared placebo group (88.7%) and the combined fosigotifator group (90.6%), with 26.2% and 25.2% of participants, respectively, experiencing treatment-related TEAEs.

READ MORE: DNL343 Falls Short of Primary End Point in Phase 2/3 HEALEY-ALS Platform Trial

Cudkowicz added, "Every step we take brings us closer to finding effective treatments. Our dedication to the ALS community is unwavering, and we will continue to explore innovative pathways in our research."

"We would like to extend our sincere gratitude to our participants, investigators, and staff who dedicated their time and expertise to this regimen,” Senda Ajroud-Driss, MD, a neurologist at Northwestern University and co-lead of regimen F, said in a statement.¹ "The trial has provided substantial clinical data so far around dosing and the upcoming biomarker data and subgroup analyses will contribute to future studies and help us better understand ALS."

The other phase 1 study of fosigotifator in patients with ALS is currently ongoing, with an expected completion date later this year. This 156-week, 2-part study, includes a 4-week, randomized, double-blind, placebo-controlled portion, followed by a 152-week active treatment extension during which all patients receive fosigotifator. Participants were required to have a confirmed diagnosis of familial or sporadic ALS, with symptom onset within 36 months before screening, an SVC of ≥50%, and the ability to swallow solids. Additionally, they needed a reliable caregiver and, if using standard ALS treatments, to be on a stable dose for at least 30 days before baseline.²

In June 2024, Calico announced that fosigotifator was accepted into the FDA’s Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program, underscoring the therapy’s potential in treating patients with VWM disease. The pilot program, created by the FDA’s Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER), is used to help further accelerate the development of novel drug and biological products for rare diseases.³

REFERENCES
1. Sean M. Healey & AMG Center Announces Update in ALS Platform Trial with Fosigotifator. News release. Sean M. Healey & AMG Center for ALS. January 6, 2025. Accessed January 7, 2025. https://www.massgeneral.org/neurology/als/news/healeyamg-announces-platform-trial-update-fosigotifator
2. A Phase 1 Study to Investigate the Safety and Pharmacokinetics of Fosigotifator in Patients With Amyotrophic Lateral Sclerosis. Clinicaltrials.gov. Updated September 19, 2024. Accessed January 7, 2025. https://www.clinicaltrials.gov/study/NCT04948645?cond=Fosigotifator&rank=4
3. Calico Life Sciences Announces that Fosigotifator (ABBV-CLS-7262) for Vanishing White Matter Disease has been Selected for the FDA START Pilot Program. News release. Calico Life Sciences. June 7, 2024. Accessed January 7, 2025. https://www.calicolabs.com/press/calico-life-sciences-announces-that-fosigotifator-abbv-cls-7262-for-vanishing-white-matter-disease-has-been-selected-for-the-fda-start-pilot-program/