Pegcetacoplan increased hemoglobin (Hb) levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks of treatment in patients with cold agglutinin disease (CAD) and those with warm antibody autoimmune hemolytic anemia (wAIHA), according to the results of a phase II clinical trial published in Blood.1 The therapy, which inhibits the complement 3 (C3) protein, maintained the improvements in hemolysis and FACIT-fatigue scale scores through 48 weeks of treatment.
“These trial results provide a non-chemotherapy approach to managing CAD,” said study author Morie A. Gertz, MD, chair of general internal medicine at Mayo Clinic in Minnesota. “Current therapy aimed at reducing the monoclonal immunoglobulin M (IgM) protein provides therapy of limited benefit and of limited duration. Complement blockade showed a significant improvement in blood counts in these patients. Since the disease burden is high with significant reduction in activities of daily living and quality of life (QoL), significant improvement of the Hb would be expected to increase daily functionality. This would eliminate the need for transfusions in severely affected patients and improve daily ability in the majority.”
CAD and wAIHA are the two most prevalent types of autoimmune hemolytic anemias, comprising about 25% and 70% of this group of anemias, respectively.2,3 These rare, heterogeneous diseases are characterized by autologous red blood cell (RBC) destruction by autoantibodies and are thought to involve complement activation. In CAD, RBC destruction is due to IgM autoantibodies, called cold agglutinins, that bind to RBCs when the body temperature falls below the core temperature. This results in hemolysis from the deposition of C3b protein. In wAIHA, about 28% to 65% of RBC destruction appears to be due to weak complement activation via immunoglobulin G, which results in RBCs binding with C3b.
Front-line therapy for symptomatic CAD has generally been rituximab, as corticosteroids are only effective at high and unacceptable doses. Some patients also receive rituximab plus chemotherapy agents such as bendamustine and fludarabine, which results in higher efficacy but also toxicity. In 2022, sutimlimab was approved by the U.S. Food and Drug Administration (FDA) to decrease the need for RBC transfusion due to hemolysis in adults with CAD. Sutimlimab is also a complement inhibitor, targeting the C1s complement protein.
For patients with wAIHA, first-line therapy is corticosteroids with adjunctive rituximab added for more severe disease. Second-line therapy is typically rituximab, and third-line options include splenectomy, azathioprine, cyclosporin, and mycophenolate.
The current open-label, prospective phase II study enrolled 13 patients with CAD, regardless of prior therapy history, and 11 patients with wAIHA who relapsed from, did not respond to, or did not tolerate at least one prior treatment. Patients were randomized to receive 270 mg or 360 mg once-daily subcutaneous infusion of pegcetacoplan for 48 weeks. Pegcetacoplan is a C3 inhibitor conjugated to a linear polyethylene glycol molecule to increase its half-life. The molecule binds to C3 with high affinity and C3b, inhibiting the C3 and C5 convertases in the complement pathway. The drug is FDA approved to treat adults with paroxysmal nocturnal hemoglobinuria. An intravitreal injection version of the drug is FDA approved to treat adults with geographic atrophy.
In the CAD cohort, seven and six patients were randomized to receive 270 mg/day and 360 mg/day pegcetacoplan, respectively. Among the patients with wAIHA, five and six patients were randomized to receive 270 mg/day and 360 mg/day pegcetacoplan, respectively. The median compliance was 99.7% in the CAD cohort and 100% in the wAIHA cohort.
In the CAD cohort, median Hb levels increased during the first four weeks and were further maintained, with a median change from baseline (CFB) of 2.4 g/dL at week 8 (1.7 g/dL and 2.4 g/dL in the 270 mg/day and 360 mg/day groups, respectively) and 2.4 g/dL at week 48 (1.8 g/dL and 2.7 g/dL in the 270 mg/day and 360 mg/day groups, respectively).
Also in the CAD cohort, the baseline median FACIT-fatigue scale total score was 26.0 points overall and 30.0 points and 23.5 points in the 270 mg/day and 360 mg/day groups, respectively. At week 8 on study, the self-reported fatigue and its impact on daily activities and function improved, with an increase in median CFB FACIT-fatigue scale total scores of 10.5 points (11.0 and 10.0 points for the 270 mg/day and 360 mg/day groups, respectively). This increase in the FACIT-fatigue scale total score was maintained at week 48, with a median overall CFB of 6.0 points (4.5 points and 9.5 points for the 270 mg/day and 360 mg/day groups, respectively).
In the wAIHA cohort, treatment resulted in increasing median Hb levels until week 8 (median CFB of 2.7 g/dL; 1.5 g/dL in the 270 mg/day group and 2.7 g/dL in the 360 mg/day group), after which Hb levels plateaued. At week 48, the median CFB was 1.7 g/dL (0.2 g/dL in the 270 mg/day group and 1.7 g/dL in the 360 mg/day group).
Four patients in the wAIHA cohort had RBC transfusions, and during the 12 months of study, seven (64.0%) of 11 patients were transfusion-free as compared to six (55.0%) patients in the 12 months before baseline.
Patients with wAIHA showed a reduction in fatigue with a median CFB increase in FACIT-fatigue scale total score of 8.0 points at week 8 (4.5 points and 12.5 points for the 270 mg/day and 360 mg/day groups, respectively). This increase was maintained by the 360 mg/day group but not the 270 mg/day group, with an overall median CFB at week 48 of 4.0 points.
QoL measures improved for both patient groups. In the CAD cohort, the median CFB at week 48 was 1.0 points (1.0 points and 1.0 points for the 270 mg/day and 360 mg/day groups, respectively). In the wAIHA cohort, both dosing groups had an increase in CFB at week 8; this increase in the 360 mg/day group was maintained through to week 48, with median CFB of 2.0 points (0.5 points and 2.0 points for the 270 mg/day group and total wAIHA cohort, respectively).
All 13 patients in the CAD cohort and 10 of 11 patients in the wAIHA cohort experienced at least one treatment-emergent adverse event (TEAE). The most frequently reported TEAEs were diarrhea, headache, hypertension, nausea, and vitamin B12 deficiency. Nine patients in the CAD and eight in the wAIHA cohorts reported at least one AE, with injection site reactions as the most reported TEAE in both cohorts (five in the CAD and six in the wAIHA), but no patient discontinued the study due to these.
One patient in the CAD cohort discontinued pegcetacoplan due to worsening wAIHA and died four weeks after the last dose due to complications from wAIHA, but this was assessed as unrelated to pegcetacoplan by the investigator and sponsor.
“The treatment was also quite tolerable with a very good safety profile,” Dr. Gertz noted.
The limitations of this study are the open-label design, a lack of a comparator, and the relatively small size of the patient cohorts.
While Sobi, the company developing pegcetacopan for CAD and wAIHA, initiated a phase III trial (NCT05096403) specifically for patients with CAD, the company discontinued the trial in early 2024, citing a “decreased medical need in CAD and therefore a limited number of patients eligible for the study.”4
Any conflicts of interest declared by the authors can be found in the original article.
References
- Roman E, Fattizzo B, Shum M, et al. Safety and efficacy of pegcetacoplan treatment for cold agglutinin disease and warm antibody autoimmune hemolytic anemia [published online ahead of print, 2024 November 1]. Blood. doi: 10.1182/blood.2023022549.
- Berentsen S, Hill A, Hill QA, et al. Novel insights into the treatment of complement-mediated hemolytic anemias. Ther Adv Hematol. 2019;10:2040620719873321.
- Barcellini W, Zaninoni A, Giannotta JA, et al. New insights in autoimmune hemolytic anemia: from pathogenesis to therapy stage 1. J Clin Med. 9(12):3859.
- Wexler M. Apellis, Sobi halt development of pegcetacoplan for CAD. Cold Agglutinin Disease. March 7, 2024. Accessed September 12, 2024. https://coldagglutininnews.com/news/experimental-cad-therapy-pegcetacoplan-halted-developers/.
