ALS Trial Falls Short of Primary Goal - Calico

Fosigotifator is a eukaryotic initiation factor 2B (eIF2B) activator in development by Calico in collaboration with AbbVie for the treatment of ALS and other disorders of the central nervous system.

A total of 155 participants were randomized to the primary dose, 79 to the exploratory high dose, and 126 participants were in the shared concurrent placebo cohort which includes placebo participants within this regimen (76) combined with placebo participants from another concurrently enrolling regimen (50). The primary analysis was the comparison of the primary dose to the shared concurrent placebo cohort. There were also pre-specified analyses of the exploratory high dose group to the shared concurrent placebo cohort and each dose to the regimen-only placebo group.  

At the primary dose, the trial did not meet its primary endpoint, evaluating ALS disease progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival from baseline through 24 weeks or key secondary endpoints of respiratory and muscle strength.  

At the exploratory high dose, endpoints of muscle strength, as measured by hand-held dynamometry (HHD) were different between the active and placebo groups in both upper and lower extremities. In the upper extremity muscles, the exploratory high dose treatment group declined 32% slower than the shared concurrent placebo cohort (nominal p =0.014) and 37% slower when compared to the regimen-only placebo group (nominal p=0.007). In the lower extremity muscles, the exploratory high dose treatment group declined 62% slower than both the shared concurrent placebo cohort (nominal p =0.037) and the regimen-only placebo group (nominal p=0.054). In addition, there was a potential signal towards slowing respiratory functional decline as measured by the slow vital capacity (SVC) in the participants taking the exploratory high dose.  

Overall, fosigotifator was found to be safe and well-tolerated with no meaningful safety differences between doses. Treatment emergent adverse event (TEAE) rates were comparable between the shared concurrent placebo group (89.7%) and combined fosigotifator group (90.6%). Similarly, 26.2% and 25.2% of participants experienced TEAEs which were considered treatment-related in the shared concurrent placebo group and the combined fosigotifator group, respectively.  

“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. 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,” says Merit Cudkowicz, MD, MSc, principal investigator and sponsor of the HEALEY ALS Platform Trial, director of the Sean M. Healey & AMG Center for ALS, chair of the Department of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at Harvard Medical School. “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.”  

“Although these results were disappointing, the study has yielded important insights into fosigotifator’s potential bioactivity in people with ALS that supports further investigation,” said Bill Cho, M.D., Head of Clinical Sciences at Calico. “We are grateful to the participants and our collaborators who have made this trial possible. We remain committed to investigating the potential of fosigotifator as a much needed treatment option for people living with ALS and for other disorders, including vanishing white matter disease and major depressive disorder which each test different scientific hypotheses.”

Overall, fosigotifator was found to be safe and well-tolerated, with results showing that treatment-emergent adverse events were similar among all treatment groups.

The HEALEY ALS Platform Trial is a patient-centric clinical trial designed in collaboration with the Northeast ALS Consortium (NEALS) to accelerate the development of breakthrough treatments for persons with ALS by testing multiple drugs (regimens) at the same time with efficient use of patient, scientific, and operational resources. So far, seven regimens have been included in the trial and more regimens will become available soon, with the goal of adding approximately three regimens per year. Data derived from the trial, if positive, could be used to support the potential approval of an investigational medication. Moreover, results from the trial, even when negative, can advance current knowledge related to the mechanisms underlying ALS and aid in the development of new biomarkers, laying the foundation for new avenues of scientific inquiry.