ANX1502 found safe in Phase 1 trial with healthy volunteers

Experimental oral treatment for CAD well tolerated with no serious side effects

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Twice-daily dosing of ANX1502, Annexon Biosciences’ experimental oral therapy for autoimmune conditions such as cold agglutinin disease (CAD), reached the desired levels in the blood of healthy volunteers who took part in a Phase 1 clinical trial.

Taken by mouth as a liquid suspension, ANX1502 was well tolerated, with no reports of serious side effects. Its pharmacokinetics, or its movement into, through, and out of the body, also supported the use of twice-daily dosing in a future proof-of-concept study.

“We are excited to have reached an important step in the clinical development of ANX1502, our first-in-kind small molecule complement inhibitor that we believe can have meaningful impact on a range of autoimmune conditions,” Ted Yednock, PhD, Annexon’s chief innovation officer, said in a company press release. “Based on these data, we look forward to advancing a tablet formulation of ANX1502 into a proof-of-concept study in patients with CAD.”

Initially planned for 2023, the proof-of-concept trial is now expected to launch this year.

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CAD is caused by self-reactive antibodies called cold agglutinins, which bind to red blood cells at low temperatures, making them a target for destruction by elements of the immune system, including the complement system.

The complement system is a domino-like chain of proteins that work together in a tightly regulated manner to protect the body against infection and clear away damaged cells. In CAD, however, it becomes overly active.

When cold agglutinins bind to red blood cells, they set off the activation of a complement enzyme called C1s. This leads to the cleavage of the complement C4 and C2 proteins, further continuing the chain reaction until it triggers hemolysis, or the breakdown of red blood cells.

ANX1502 is a prodrug, which is an inactive compound that can be converted in the body to produce an active compound, in this case, ANX1439. A small molecule, it prevents C1s from splitting both C4 and C2, thereby stopping the chain reaction. This is expected to control hemolysis and ease the resulting symptoms.

Evaluating ANX1502 in up to 84 healthy adults

The Phase 1 trial (NCT05521269) was designed to evaluate ANX1502’s safety, tolerability, pharmacokinetics, and pharmacodynamics (effects on the body) in up to 84 healthy adults enrolled at a single site in the Netherlands.

Participants received either a single dose of ANX1502, ranging from 25 to 1,050 mg, multiple ascending doses from 200 to 525 mg twice daily for 14 days, or a matching placebo.

Results showed that ANX1502 reached the desired levels in the blood in both the single and multiple ascending dose groups. Moreover, measures of pharmacokinetics varied in a dose-dependent manner.

Single doses of 525 to 1,025 mg of ANX1502 resulted in a decrease of the blood levels of C4d in participants who initially had higher-than-median C4d levels. As C4d is a fragment of C4 generated during its split, it can be used as a biomarker, with a decrease in C4d levels indicating absence of C4 cleavage.

Across all doses tested, ANX1502 was generally well tolerated, with only mild or moderate adverse events reported. The most frequent side effects were gastrointestinal problems, including nausea, vomiting, and diarrhea.

There were no reports of serious adverse events or significant clinical or lab abnormalities.

“We’re very encouraged by the results from our Phase 1 [single and multiple ascending dose study] showing that ANX1502 was well tolerated and achieved target drug levels with supportive impact on a key biomarker in healthy volunteers,” Yednock said.

After it completes the proof-of-concept study in people with CAD, Annexon plans to continue testing ANX1502 in serious complement-mediated autoimmune diseases. Its goal is to provide patients effective treatment with convenient dosing for long-term use.