AL101 Safely Increases Progranulin Levels in Phase 1 Trial
IV injections led to greater progranulin gains than subcutaneous injections did
Multiple doses of AL101, Alector’s investigational treatment for neurodegenerative diseases such as Parkinson’s, safely increased progranulin levels in healthy volunteers, according to data from a Phase 1 clinical trial.
Low levels of progranulin, a protein critical for immune activity and cell survival in the nervous system, have been linked to Parkinson’s disease and other neurodegenerative conditions.
Intravenous (IV) injections of AL101 led to greater increases in progranulin compared with under-the-skin (subcutaneous; SC) injections, suggesting that IV administration may be the more appropriate route for future trials with people with neurodegenerative disease, according to Alector.
“Phase 1 study results demonstrated that AL101 elevated progranulin levels, and these results pave the way for exploring multiple indications and dosing schedules for AL101,” said Gary Romano, MD, PhD, chief medical officer of Alector, in a company press release.
The findings were presented in a poster, titled “Repeat IV and SC dosing of the Anti-Sortilin Antibody AL101,” at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference, in San Francisco, Nov. 29–Dec. 2.
AL101 is an antibody-based therapy that works by blocking sortilin, a receptor protein at the surface of cells of the nervous system where it regulates progranulin levels. By suppressing this receptor, AL101 is thought to increase progranulin, which may prevent nerve cell death and disease progression.
Alector, in partnership with GlaxoSmithKline (GSK), is developing the treatment for a number of conditions, including Parkinson’s disease, Alzheimer’s disease, and frontotemporal dementia, for which it earned orphan drug designation in the U.S.
“Human genetics have shown that even moderately reduced progranulin [levels] may lead to an increased risk of developing neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease,” Romano said. “We are excited to have the opportunity to test the hypothesis that increasing progranulin in the brain of patients suffering from these diseases may counteract disease [mechanisms].”
The Phase 1 trial (NCT04111666), which began dosing in early 2020, evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and bioavailability of single and multiple doses of AL101 against a placebo in 88 healthy volunteers, ages 18–65. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body. Pharmacodynamics is its effects on the body.
Participants were randomly assigned to receive a single IV injection (6–60 mg/kg) of either AL101 or a placebo, or a SC injection of AL101 (600 mg).
Results from the single-dose part of the trial, which were presented last year at CTAD 2021, showed the treatment was generally well tolerated, with mostly mild to moderate side effects. Moreover, AL101 was associated with a dose-dependent increase in progranulin in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord.
This year’s presentation showed results from the multiple-dose portion where 27 participants were randomly assigned to receive an IV injection of either AL101 (30 mg/kg; 11 people) or a placebo (three people) every four weeks for a total of four doses, or a 300 mg AL101 subcutaneous injection once every two weeks for a total of seven doses (13 people).
Most healthy volunteers were white and men, and their median age was 51 for the AL101 group and 36 for the placebo group.
The majority (85.2%) completed the treatment and 77.8% completed the study. Four of the six who did not complete the trial were lost to follow-up, while only one discontinued due to side effects.
Consistent with the findings from the single-dose portion, AL101 was measurable in the CSF after multiple doses with either route of administration. Progranulin blood and CSF levels were also raised, but a greater increase was seen with the IV treatment, multiple doses of which led to sustained elevations of progranulin in the blood, reaching 2.6 to three times higher than at the study’s start. In the CSF, levels were increased by about 1.8 times.
The treatment was again generally well tolerated, regardless of the mode of administration, with most side effects being mild to moderate in severity. The most frequently reported side effects among all participants were headache, back pain, COVID-19 infection, dizziness, injection site reactions, and neck pain.
A serious side effect, a heart attack, was reported in a man in the SC group who had undiagnosed heart disease, but this was deemed unrelated to the treatment.
“In this first-in-human phase 1 study, AL101 was found to be generally safe and well tolerated following multiple-dose IV [once-a-month] and SC [every-other-week] administrations,” the researchers wrote. “The pharmacokinetic/pharmacodynamic profile of AL101 following single and multiple IV doses supports future development with either a [once-a-month] dosing interval at 30 mg/kg or a [once-every-two-months] interval at a higher dose.”
The results also suggest the 300 mg SC dose, once every other week, “is not sufficient and further optimization of SC dose regimen is needed,” they wrote.
These findings, along with the treatment’s pharmacological profile, support developing AL101 for chronic neurodegenerative diseases. Alector and GSK, as part of their partnership, are also developing another progranulin-targeted treatment for neurodegenerative diseases called AL001 (latozinemab).
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