A Phase 1, Multicenter, Open Label, Single-Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of AP-101 in Familial and Sporadic Amyotrophic Lateral Sclerosis (ALS)
Angela Genge1, Maxime Berube-Desrosiers1, Lorne Zinman2, Christen Shoesmith3, Michael Salzman4, Robert Schott5, Paule Clermont5, Justus Bingham5, Emma Bowden5
1Mcgill University, 2Sunnybrook Health Sciences Centre, 3London Health Sciences Centre, 4ALS Pharma, 5Chorus, Eli Lilly
Objective:
To determine and safe and tolerable dose of AP-101.
Background:

Mis-folded SOD1 can be detected in the majority of ALS patients suggesting that SOD1 is a common pathogenic driver across familial and sporadic forms of ALS. AP-101 is a fully human IgG1 antibody with high affinity and selective binding to misfolded SOD1 protein. In transgenic mouse models of ALS, a murine version of AP-101 was able to attenuate loss of spinal cord motor neurons and prolong overall survival.

Design/Methods:

Given the rapidly fatal nature ALS  an efficient accelerated dose escalation study was performed using an open label oncology style 3+3 design (ClinicalTrials.gov Identifier: NCT03981536). AP-101 was administered to patients via intravenous infusion over 1 hour at increasing dose levels of 100, 500 or 2500mg. A sentinel patient was observed before recruitment of additional patients into the cohort. After observation for 3 weeks and in the absence of any drug related toxicity the next dose cohort was opened for recruitment. If any safety signal had been observed in the first 3 patients, an additional 3 patients would have been recruited at the same dose level. Dose limiting toxicities in 2 or more patients at any dose level would result in a declaration of maximum tolerated dose. The overall goal was to assess safety, tolerability, and pharmacokinetics of AP-101 after intravenous administration. Cerebral spinal fluid was also collected from patients

Results:

To date, no dose-limiting toxicities effects or any safety and tolerability concerns related to AP-101 have been observed. The most common adverse events are related to the lumbar puncture associated with patient screening. 

Conclusions:
Results will be used to guide the design of a proof-of-concept study to examine the efficacy potential for AP-101.