APL-2, being developed by Apellis, is an experimental therapy for people with cold agglutinin disease (CAD) and other blood disorders.

How APL-2 works

CAD is caused by the body producing autoantibodies that mistakenly bind to red blood cells (RBCs) when exposed to cold temperatures. This causes the RBCs to clump together and triggers the complement pathway, which is part of the immune system, to destroy them, leading to anemia.

APL-2 is a synthetic peptide (a small protein) that binds and blocks the C3 and C3b proteins of the complement system. The complement system consists of three parts: the classical, alternative, and lectin pathways. C3 and C3b are involved in all three pathways, so blocking them inhibits the entire complement pathway. This raises concerns because blocking the whole complement system may increase the risk of infections. However, no significant infections have been reported to date in trials in which ALP-2 was administered systemically.

APL-2 in clinical trials

A multicenter and open-label Phase 2 clinical trial (NCT03226678), called the PLAUDIT study, is ongoing at multiple sites across the U.S. The study is assessing the safety, tolerability, efficacy, and pharmacokinetics (absorption, distribution, metabolism, and excretion) of APL-2 in patients with CAD or warm type autoimmune hemolytic anemia (wAIHA).

People with either disease have been randomly assigned to either 270 mg per day or 360 mg per day of APL-2 treatment for up to 12 months via subcutaneous (under the skin) injection to identify the optimal dose.

Of the 12 enrolled CAD patients, an interim data analysis of five patients treated for at least 56 days showed that their mean hemoglobin levels (the protein in RBCs that carries oxygen) increased from 8.7 g per dL at baseline (study start) to 12.1 g per dL. Two of the five had reached day 168, with a mean hemoglobin level of 12.6 g per dL. The mean absolute reticulocyte count (ARC) decreased from 137.5 X 10⁹ per L at baseline to 46.6 X 10⁹ per L, and increased slightly to 70.8 X 10⁹ per L (n=2) on day 168. Reticulocytes are immature RBCs, and CAD patients have a higher than normal reticulocyte count to compensate for the reduced number of mature RBCs. The mean bilirubin decreased from 1.9 mg per dL at baseline to 0.5 mg per dL. Bilirubin is produced when RBCs are broken down and is subsequently excreted. Bilirubin levels can be higher than normal in CAD patients, because bilirubin builds up at a higher rate than it can be expelled. The mean LD, a measure of liver function, decreased from 487.8 U per L at baseline to 173.4 U per L, and was at 143.5 U per L on day 168.

A later interim data analysis of 10 patients given APL-2 for at least 168 days reported a mean hemoglobin level of 11.2 g per dL, a mean ARC of 64 X 10⁹ per L, a mean bilirubin level of 0.4 mg per dL, and a mean LDH of 183 U per L. The mean functional assessment of chronic illness therapy (FACIT) fatigue score rose from 29.4 at baseline to 39.1. An increase of three or more points is considered to be clinically significant, and indicates better self-assessments of life quality and well-being.

These data suggest that APL-2 treatment provides a sustained clinical benefit for CAD patients. The study is expected to conclude in December 2019.

Additional information

Apellis is planning to open a Phase 3 clinical trial of APL-2 in people with CAD in early 2020.


Last updated: Aug. 19, 2019


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