CASCADE trial seeks to enroll up to 57 patients in US, Europe, Japan

Pegcetacoplan had 'consistent, meaningful, and prolonged effects' in pilot study

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Enrollment is underway in a Phase 3 clinical trial testing the investigational therapy pegcetacoplan in adults with primary cold agglutinin disease (CAD), according to a corporate update from the treatment’s developer, Apellis Pharmaceuticals.

The trial, called CASCADE (NCT05096403), is enrolling up to 57 patients, 18 and older, in at least one U.S. site, with additional sites in the U.S., Europe, and Japan also expected to be involved. The first patient was dosed last year. The trial’s goal is to evaluate the therapy’s safety and effectiveness against a placebo.

In CAD, antibodies known as cold agglutinins bind to red blood cells in cold temperatures, activating the complement pathway — a branch of the immune system — that helps to target and destroy these cells (a process called hemolysis).

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Pegcetacoplan designed to block activity of C3 complement protein

Pegcetacoplan, previously known as APL-2, is designed to limit the activation of the body’s complement system by blocking the activity of the C3 complement protein. C3 attaches to the surface of red blood cells, tagging them for destruction.

Its systemic formulation, administered as an under-the-skin injection via an infusion pump, is being co-developed by Swedish Orphan Biovitrum (Sobi) following a collaboration agreement between both companies.

The agreement made Sobi the lead responsible for the Phase 3 CASCADE trial and granted the company commercialization rights to systemic pegcetacoplan outside the U.S. Apellis retains rights in the U.S. and global rights for the therapy’s eye-targeting formulation.

Data from a pilot Phase 2 trial (NCT03226678), involving 13 CAD patients and 11 people with a related disorder called warm antibody autoimmune hemolytic anemia, showed that pegcetacoplan safely reduced hemolysis and increased hemoglobin levels. Hemoglobin is the protein red blood cells use to carry oxygen through the body.

These promising findings supported the launch of the three-part Phase 3 CASCADE trial.

“Pegcetacoplan produced consistent, meaningful, and prolonged effects on most relevant clinical efficacy measures along with an acceptable safety profile in patients with CAD, supporting further clinical development of pegcetacoplan in this indication,” the researchers wrote in an abstract to a recent conference presentation.

In part A, participants will be randomly assigned to receive pegcetacoplan (1,080 mg) or a placebo, twice weekly for 24 weeks, or nearly six months. Those completing the six-month placebo-controlled period are eligible to enter part B of the study, in which all will receive pegcetacoplan, at the same dosing, for six months.

After an evaluation, maintenance treatment may continue in part C for up to a year, which would mean a total of two years’ treatment for those who were originally assigned the therapy.

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Trial aims to assess hemoglobin response to pegcetacoplan

The trial’s main goal is to assess response to the investigational therapy, defined as an increase in hemoglobin of at least 1.5 grams per deciliter (g/dL) since the study’s start (baseline). The increase must be maintained from week 16 through week 24 and without the need for blood transfusions between weeks five and 24.

Secondary goals include changes during part A in hemoglobin levels, need for blood transfusions, levels of hemolysis markers, and fatigue and other anemia-related symptoms, as measured by the Functional Assessment of Cancer Therapy-Anemia/Fatigue Scale Score.

Changes in health-related quality of life will also be assessed, using the 12-item short form survey and the five level EuroQol five dimensions questionnaire, as well as safety measures.

Pegcetacoplan, sold as Empaveli in the U.S. and Aspaveli in Europe, is approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria, another blood disorder. Its eye-targeted injection formulation, sold under the brand name Syfovre, is also approved in the U.S. for geographic atrophy, an age-related eye disorder.