Background

AL101 is a monoclonal antibody to sortilin (SORT1), a trans-Golgi sorting receptor abundantly expressed in the nervous system. This IgG1 antibody is being developed to treat Alzheimer’s disease. Alector is evaluating a different sortilin antibody, AL001, in a Phase 3 trial for frontotemporal dementia (FTD). According to information on Alector’s website, the two antibodies bind different parts of the sortilin protein (see slide 13 in Dec 2023 presentation). AL101 is claimed to have a longer half-life than AL001.

Both AL001 and AL101 have orphan drug designation from the U.S. FDA for the treatment of FTD.

Sortilin is important for neurotrophin signaling, lysosomal degradation, and APP metabolism. It negatively regulates levels of the lysosomal protein progranulin. Genetic mutations that reduce levels of the progranulin protein and induce lysosome dysfunction are a leading cause of frontotemporal dementia and amyotrophic lateral sclerosis. In animal models, loss of progranulin leads to inflammation and neurodegeneration (e.g., Yin et al., 2010). A progranulin polymorphism is associated with risk for AD and PD (Chen et al., 2015).

Both AL001 and AL101 are intended to increase progranulin levels by blocking sortilin, and thus improve lysosome function.

Findings

In December 2019, Alector began a Phase 1 first-in-human safety and tolerability study of AL101 in 88 healthy participants. The placebo-controlled study tested single and multiple ascending doses of intravenously or subcutaneously administered antibody, against a primary outcome of adverse events. Pharmacokinetics and bioavailability were also determined. The trial finished in June 2022.

Results of the single-dose part of the study were presented at the November 2021 CTAD conference (poster). The study enrolled 55 healthy adults averaging 40 years old, for single intravenous doses of 6, 15, 30, or 60 mg/kg or placebo, or a subcutaneous dose of 600 mg. The antibody was well tolerated, with mostly mild to moderate adverse events, the most frequent being headache, anemia, and procedural pain. One severe infusion reaction occurred in the 60 mg/kg IV dose group. Blood and CSF antibody levels were reported to be dose-proportional. Brain concentrations reached 0.1-0.7 percent of serum concentration. Blood levels of progranulin were elevated after all doses, and higher doses also resulted in increased CSF progranulin levels. The subcutaneous dose resulted in an approximately 50 percent increase in CSF progranulin that lasted for about one month. Multiple dose data were presented at the November 2022 CTAD conference, showing that biweekly 300 mg subcutaneous or monthly 30 mg/kg intravenous doses elicited mild to moderate adverse events. IV dosing resulted in sustained, 160 to 200 percent elevation of progranulin in plasma compared to placebo, and an 80 percent increase in CSF (press release). Subcutaneous dosing resulted in insufficient drug levels or progranulin elevation, requiring optimization.

In July 2021, Alector announced an agreement with GlaxoSmithKline to co-develop AL001 and AL101 (press release). 

In October 2023, a Phase 2 study  began to compare the safety and efficacy of two different doses of AL101 to placebo in 282 people with early Alzheimer’s disease. Participants who are amyloid-positive with mild cognitive impairment or mild dementia are to receive intravenous antibody infusions for 18 months. The primary outcome is change from baseline in the CDR-SB after 12, 15, or 18 months. Secondary outcomes span other standard measures of cognition or function including the iADRS, ADS-COG14, ADCS-ADL-MCI, and ADCOMS. The study is running worldwide through December 2026.

For details on AL101 trials, see clinicaltrials.gov.