#AANAM – AP-101 Raises No Safety, Tolerability Concerns in Phase 1 Trial

Editor’s note: The ALS News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

In a Phase 1 trial for amyotrophic lateral sclerosis (ALS), the investigational therapy AP-101 — designed to ease motor symptoms and increase survival in people with the neurodegenerative disease — was found to be safe and well-tolerated at all tested doses.

The most commonly reported adverse events, or side effects, were related to the spinal tap during patient screening, according to researchers.

The positive results from the ongoing trial (NCT03981536) will enable AL-S Pharma, the study sponsor, to design multiple-dose clinical studies to continue investigating the therapy’s potential in ALS patients. AL-S Pharma was jointly funded by Neurimmune and TVM Capital Life Science to develop AP-101.

The poster with the findings, titled “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),” was presented by Angela Genge, MD, of Mcgill University, at the American Academy of Neurology 2021 Virtual Annual Meeting. The AAN meeting is being held online April 17-22.

Mutations in the SOD1 gene, which carries the instructions to make the SOD1 enzyme, are estimated to cause up to 20% of cases of familial ALS and 1-2% of those of sporadic ALS. These mutations cause that SOD1 protein to build up and form clumps in neurons, ultimately leading to nerve cell death. 

AP-101 is a human monoclonal antibody designed to selectively target and reduce levels of the defective SOD1 protein. It has been found to alleviate motor symptoms and increase survival in a mouse model of ALS.

The therapy has received orphan drug designation from the U.S. Food and Drug Administration, the European Medicines Agency (EMA), and Swissmedic for the treatment of ALS, according to AL-S Pharma.

The ongoing, open-label trial was designed to investigate the safety and tolerability of AP-101 and to determine its maximum tolerable dose. A total of nine patients, whose symptoms started in the prior four years, were included in the trial. They were treated with a single intravenous (into-the-vein) infusion of AP-101 at doses of 100, 500, or 2,500 mg.

Each dose group included an initial patient who was observed for treatment-related toxicity or adverse events (side effects) for three weeks following the infusion before additional patients were recruited. The maximum tolerated dose was reached if two or more patients at any dose level experienced dose-limiting toxicities.

The primary goals of the trial are determining the safety and tolerability of a single AP-101 dose of up to 2,500 mg. The scientists are assessing adverse events and any abnormalities in vital signs, physical or neurological examinations, clinical lab tests, or electrocardiograms — which record the electrical signals in the heart — up to seven weeks after the infusion. 

To date, three patients have been recruited and dosed with a single infusion of AP-101 at each of the three dose levels. Of the nine study participants, eight have sporadic ALS and one (receiving a 2,500 mg dose) has familial ALS.

No dose-limiting toxicities or treatment-related safety and tolerability concerns have been reported so far. The spinal tap, also called a lumbar puncture, that was used during the patient screening process was associated with the most frequently reported adverse events. In that procedure, a needle is inserted between two vertebrae, also called lumbar bones, to remove a sample of the cerebrospinal fluid that surrounds the brain and spinal cord. 

The trial is ongoing with continued observation for treatment safety and pharmacokinetics — the movement of a drug into, through, and out of the body.

Additional study goals include the evaluation of AP-101 levels in the blood and cerebrospinal fluid, and the levels of defective SOD1. Other goals are changes in the ALS Functional Rating Scale and in slow vital capacity, a measure of respiratory function.