Concomitant Use of Sutimlimab and COVID-19 Vaccines in Patients with Cold Agglutinin Disease from the Phase 3 Cardinal and Cadenza Studies

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia, characterized by chronic hemolysis mediated by the classical complement pathway (CP). The ongoing COVID-19 pandemic has posed additional challenges in treating patients with CAD. Anti-CD20 therapies (used off-label in CAD) increase the risk of serious COVID-19 infection and reduce COVID-19 vaccine responses. Sutimlimab (SUT), approved by the FDA, PMDA and EMA for patients with CAD, is a first-in-class humanized monoclonal antibody which selectively targets C1s in the CP, addressing the underlying mechanism of hemolysis in CAD. The Phase 3 CARDINAL and CADENZA studies spanned the period before and during the pandemic, and investigators were advised to vaccinate enrolled patients without stopping SUT treatment. However, the impact of SUT on immune response to COVID‐19 vaccination remains unknown. Aims: To explore concomitant use of COVID-19 vaccines and SUT in patients with CAD. Methods: Post hoc analysis from the open-label extension (OLE) of the CADENZA and CARDINAL studies. Immunogenicity to COVID-19 vaccines was analyzed in a subset of patients fully vaccinated (2 doses) against COVID-19, and in those receiving a booster, who had consented to the use of stored samples (collected no later than 6 months after vaccination). Anti-SARS-CoV-2 Spike (EUROIMMUN Anti-SARS-CoV-2 ELISA) and anti-SARS-CoV-2 Nucleocapsid (Abbott Architect i2000 SR) IgG titers were measured. Data on tolerability to COVID-19 vaccine were collected through adverse event (AE) reports. Results: Of 61 completers from both studies, 47 received ≥1 dose of a COVID-19 vaccine; 14 received none; 11 had an additional booster. The mean inter-dose interval between first and second dose in fully vaccinated patients (n=37) was 38 days, and the mean time from second dose to booster was 165 days (range 85─208; n=11). The mean (SD) time from any vaccine dose to next SUT dose was 7.78 (4.03) days, and from last SUT dose to any vaccine dose, 8.85 (9.67) days (n=86 for both). Only 1/47 patients missed a SUT dose following the first vaccination, and 1 patient missed a SUT dose following booster administration. Both times were at the investigator’s discretion. No patients missed a SUT dose after the second COVID vaccination dose. Ten AEs were reported in 8 patients during the 7 days after any vaccine dose, but none more than once, and there were no serious AEs. No COVID-19 cases were reported during the OLE. The immunogenicity analysis comprised 27 patients; all developed an immune response post-vaccination, with detectable IgG anti-Spike antibodies. The mean time between last dose and serum collection was 65 days (range: 25–137). A further analysis of 6 patients with booster vaccinations demonstrated increased immune responses pre- to post-booster (mean [95% CI] log10 titer change: 1.82 [0.79–2.85]) (Figure), with significantly greater titer levels versus post second dose (p=0.0054). To rule out previous asymptomatic COVID-19 infection, anti-nucleocapsid SARS-Cov-2 IgG antibodies were assayed and were negative in all cases. Anemia and hemolysis markers were measured after vaccination; no indications of hemolytic exacerbation were observed. Summary/Conclusion: COVID-19 vaccination response was not impaired in patients receiving SUT for the treatment of CAD, and there was no need to modify the SUT dosing schedule. COVID-19 vaccines were well tolerated, and there were no signs of increased hemolytic marker activity following COVID-19 vaccination in patients receiving SUT.Keywords: COVID-19, Complement, Autoimmune hemolytic anemia (AIHA)