AT-1501 (anti-CD40L) is an experimental treatment to treat amyotrophic lateral sclerosis (ALS). The treatment was originally being developed by Anelixis Therapeutics, a subsidiary of the ALS Therapy Development Institute (ALS TDI), before Anelixis was purchased by Novus Therapeutics who are continuing its development.

How AT-1501 works

ALS is a progressive neurodegenerative disease for which there is currently no cure. The symptoms of the disease are caused by damage to and death of motor neurons (nerve cells that control the movement of muscles). While the exact cause of the disease is unknown, researchers think that the immune system may contribute to its progression by causing inflammation in the nervous system, leading to damage of motor neurons. 

AT-1501 is an antibody against a protein called CD40 ligand (CD40L). Antibodies are proteins designed to bind to and block a particular target. CD40L is found on the surface of some immune cells; it is a protein that is involved in regulating the immune response and that can trigger inflammation in the spinal cord. Research has shown that the CD40L pathway is overactive in ALS patients.

The exact mechanism of AT-1501 in ALS is unknown, but it is thought that by inhibiting CD40L, the potential therapy could block or delay the activation of the damaging inflammatory immune response. This could delay the onset or slow the progression of ALS symptoms and increase survival. 

AT-1501 in clinical trials

AT-1501 has been through extensive preclinical studies with positive results.

For example, a preclinical study using a mouse model of ALS has shown that AT-1501 significantly increased the time until disease onset in the animals, increased their survival, and improved their body weight, compared with mice that were given a placebo. The results of this study were published in the scientific journal Nature Genetics.

In the wake of these results, studies testing the safety of AT-1501 in non-human primates were performed in 2017. These studies also produced positive results for safety, and AT-1501 was then tested in a Phase 1 clinical trial in humans.

The trial enrolled healthy volunteers as well as eight ALS patients to test the safety and tolerability of the treatment. Results of the trial showed that all dose levels tested in the trial were well-tolerated. The pharmacokinetics, or how the treatment moves through the body, worked as the researchers predicted. 

Following the results of the Phase 1 trial, a new Phase 2a trial (NCT04322149) has been initiated by Novus.  The trial is recruiting 54 adult patients with ALS to take part in the open label, multidose study at Johns Hopkins University Medical Center in Baltimore, Maryland. Additional trial sites in California, Georgia, and Indiana will be opening soon. Participants in the study will receive one of three increasing intravenous (IV) doses of AT-1501 once every two weeks for 11 weeks. The patients will then continue to be monitored for safety and tolerability for another eight weeks (19 weeks total). Novus announced in November 2020 that the first patient had been dosed in the trial. The study is estimated to conclude in October 2021.

Other information

AT-1501 has received orphan drug designation from the U.S. Food and Drug Administration (FDA). Orphan drug designation provides benefits to companies such as tax credits for clinical trials while they are developing treatments for rare disorders.

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