Sutimlimab demonstrates ‘rapid, sustained’ responses in cold agglutinin disease
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ORLANDO — Sutimlimab, a first-in-class selective inhibitor of the complement pathway, induced rapid improvement in hemoglobin levels and reduced the need for transfusions among patients with cold agglutinin disease, according to results of the phase 3 CARDINAL study.
Cold agglutinin disease (CAD) — driven by the classical complement pathway — is a rare autoimmune hemolytic anemia that increases risk for thromboembolism and early mortality.
“There are no approved treatments for cold agglutinin disease, and treatment has been limited to a watch-and-wait strategy,” Alexander Röth, MD, physician in the department of hematology at University of Duisburg-Essen, told Healio. “If patients got severally anemic, they would receive a transfusion. However, we are restrictive with the use of transfusions, so there has been a high unmet need and a high burden for patients with this disease. The disease has been largely ignored because there are no available treatments.”
Sutimlimab (BIVV009, Sanofi) is a first-in-class humanized monoclonal antibody that selectively inhibits the C1 complex of the classical complement pathway, which activates hemolysis among patients with CAD.
“Cold agglutin disease is a complement-mediated disease,” Röth said. “There is an underlying lymphoproliferative disease that produces pathological immunoglobulin M [IgM], which binds to a certain antigen on the red blood cells. When IgM binds, it activates the classical complement pathway, and with this activation it leads to opsonization of the red blood cells with certain complement factors, which are recognized in the liver and then destroyed. Patients suffer from hemolysis, anemia and, due to the hemolysis, they are at risk for thrombosis. They have significantly reduced quality of life due to fatigue and other symptoms.”
This research would not have been possible without increased interest in the complement system, Röth told Healio.
“We have started to invest in the complement system, and it’s an ongoing movement to think the complement system could be relevant,” he said. “It has been ignored for decades and we never thought this could play a role.”
Röth and colleagues assessed the safety and efficacy of sutimlimab among 24 patients (mean age, 71.3 years; range, 55-85; 62.5% women) with CAD who had a recent history of transfusion (mean transfusions within 6 months prior to enrollment, 3.2; range, 1-19), hemoglobin of 10 g/dL or lower at study screening (mean baseline hemoglobin, 8.6 g/dL; range, 4.9-11.1) and a total bilirubin level above normal. Most patients (62.5%) had failed prior therapies.
The open-label, single-arm, multicenter CARDINAL study included a 26-week treatment phase (Part A) — results of which Röth and colleagues presented at the meeting — as well as an ongoing extension phase (Part B).
Patients received IV sutimlimab on days 0 and 7, followed by biweekly infusions, at a dose of 6.5 g for patients weighing less than 75 kg, and 7.5 g for those weighing 75 kg or more.
A composite of an increase in hemoglobin of at least 2 g/dL or an average hemoglobin level of at least 12 g/dL in combination with transfusion avoidance from weeks 5 to 26 served as the primary efficacy endpoint. Secondary efficacy endpoints included change from baseline in hemolytic markers such as bilirubin and quality of life, as measured by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale.
Twenty-two patients completed Part A of the study, all of whom enrolled in Part B.
Overall, 13 patients (54.2%) achieved the prespecified primary endpoint.
At treatment assessment, researchers estimated a mean hemoglobin increase of 2.6 g/dL (standard error [SE], 0.4), with 20 patients (82.2%) achieving a mean hemoglobin increase of at least 1 g/dL. Researchers noted a “rapid and sustained” hemoglobin response, they wrote, as demonstrated by a 1.2 g/dL increase by week 1 and 2.3 g/dL increase by week 3. Further, mean hemoglobin exceeded 11 g/dL by week 3, showing sustained responses. Seventeen patients (70.8%) did not require transfusions from weeks 5 to 26.
By week 3, researchers also observed normalization of mean total bilirubin, which is a marker of extravascular hemolysis in CAD, Röth said during a press conference.
Patients’ FACIT-F scores improved within the first week of treatment and peaked at week 5, with stable improvements noted through week 26. At treatment assessment, the mean FACIT-F score increase was 11 points (SE, 1.4).
“At baseline, patients had really poor quality of life, with FACIT-F scores for fatigue of 32, which is comparable to patients with end-stage cancer,” Röth told Healio. “With treatment, we see a dramatic increase of seven points within 1 week, which is enormous. We would consider an increase of three points to be significant.”
Researchers noted that improvement in these study efficacy measures corresponded with rapid normalization of complement C4 and near-total inhibition of complement pathway activity.
“This drug appears to stop the hemolysis process,” Röth said. “Hemolysis causes anemia, increases risk for thrombosis and causes fatigue, so the central drive is to stop the hemolysis. Treatment with sutimlimab stops hemolysis almost completely, which is very important. In some ways, this is a cure for the hemolysis of the disease, because we are stopping the whole process; this is a dramatic breakthrough.”
Twenty-two (91.7%) patients experienced at least one treatment-emergent adverse event. Seven patients (29.2%) experienced a serious event, but none of these was deemed related to treatment with sutimlimab. One patient with hepatic cancer died, but this also was deemed unrelated to the study.
Although patients experienced serious infections during the trial, there were no cases of meningococcal infections. Researchers also noted no patients experienced thromboembolisms, corresponding with decreases in mean D-dimer and thrombin-antithrombin III complex thrombotic markers.
“We expected to see adverse events as this was an elderly population with a complex medical background,” Röth told Healio. “But, otherwise, based on the treatment, there were no relevant side effects. In my opinion, it’s a really clean drug. The only downside is that it’s a biweekly treatment. However, the patients know the outcomes they are getting, and the compliance was around 100%. This shows you as a physician what you are achieving. This was really rewarding to do the trial based on all of the positive feedback from the patients.” – by Alexandra Todak
Reference:
Röth A, et al. Abstract LBA-2. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Röth reports research funding or honoraria from and consultant roles with Alexion, Bioverativ, Novartis and Roche. Please see the abstract for all other authors’ relevant financial disclosures.
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Robert Brodsky, MD
Researchers presented data showing that the experimental drug sutimlimab is effective against cold agglutinin disease, which is a rare autoimmune hemolytic anemia. Currently, there are no FDA-approved drugs for this indication. In the study, patients who received sutimlimab for 26 weeks had markedly improved hemoglobin levels, required fewer blood transfusions and felt significantly less fatigued. The results indicate the potential to offer a targeted therapy for cold agglutinin disease.
These are very exciting data. These patients are very difficult to treat. Right now, we usually use rituximab (Rituxan; Genentech, Biogen) first line, but only half of those patients respond and usually a response lasts for only about 6 months or so. This is a welcome addition to our treatment options.
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