A randomized, double-blind, placebo-controlled multicenter phase 3 study (CASCADE) is ongoing to evaluate the efficacy and safety of pegcetacoplan in patients with primary cold agglutinin disease (CAD).

The primary outcome measure is response defined as hemoglobin (Hb) level increase of 1.5 g/dL or higher from baseline which is maintained from week 16 through week 24 in absence of blood transfusion from week 5 through week 24.

In addition, researchers will evaluate change from baseline to week 24 in Hb level, markers of hemolysis (lactate dehydrogenase, haptoglobin level, indirect bilirubin level, and absolute reticulocyte counts), Functional Assessment of Cancer Therapy-Anemia/Fatigue Scale Score, 12-item short form survey, and 5-level EuroQol 5-dimensions questionnaire. Transfusion avoidance and the number of packed red blood cell transfusions, both assessed from week 5 to week 24, are also secondary endpoints.

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This study follows previous observations supporting the efficacy and safety of pegcetacoplan in CAD. A phase 2, open-label, prospective pilot study (NCT03226678) was conducted on individuals diagnosed with warm autoimmune hemolytic anemia (n=12) or CAD (n=13).

“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 authors explained.

The CASCADE study will enroll 57 patients aged 18 or more years diagnosed with primary CAD. Additional inclusion criteria include Hb level of 9 g/dL or less, documented bone marrow biopsy result within 1 year of screening, and to either have or agree to receive vaccination against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Patient enrollment will occur in the US, Europe, and Japan.

Patients who received other anti-complement therapies (approved or investigational) within 5 half-lives prior to randomization, rituximab monotherapy within 12 weeks prior to randomization, or rituximab combination therapies within 16 weeks prior to randomization are excluded from the study. Additional exclusion criteria are a history of an aggressive lymphoma or presence of a lymphoma requiring therapy, having received an organ transplant, and diagnosis of cold agglutinin syndrome secondary to Mycoplasma pneumoniae, Epstein- Barr virus, or other infection.


Jilma B, Roman E, Ueda Y, et al. Trial in progress: randomized, double-blind, placebo-controlled multicenter phase 3 study to evaluate the efficacy and safety of pegcetacoplan in patients with cold agglutinin disease (CASCADE). Blood. 2022;140(Supplement 1):5326-5327. doi:10.1182/blood-2022-155989