ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.
Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.
“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (), indicating a substantial improvement in their quality of life, Dr. Röth said.
Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.
Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.
Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.
Dr. Röth presented results of the phase 3, open-label. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.
Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.
A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.
The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.
Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.
The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.
The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.
Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.
As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.
All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.
All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.
The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.
In a press briefing the day before the presentation, moderator, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”
“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”
Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.
The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.
SOURCE: Röth A et al. ASH 2019,