Highlights from

ASH 2019

61st Annual Meeting & Exposition of the American Society of Hematology

Orlando, Florida (USA) 7 - 10 December 2019

Pivotal phase 3 trial in cold agglutinin disease: sutimlimab can stop haemolysis

In a phase 3 clinical trial, patients with cold agglutinin disease (CAD) treated with sutimlimab demonstrated improved haemoglobin levels, required fewer blood transfusions, and felt significantly less fatigued [1].

Sutimlimab is a first-in-class humanised monoclonal antibody that selectively inhibits the C1 complex of the classical complement pathway. Since C1 complement pathway overactivation is thought to drive CAD pathogenesis, the rationale was to evaluate whether sutimlimab could modify key disease outcomes such as haemolytic anaemia. There are currently no approved treatments for CAD.

Dr Alexander Röth (University of Duisburg-Essen, Germany) presented Part A of the open-label, single-arm, multicentre CARDINAL study, in which 22 CAD patients (average age of 71 years) received intravenous sutimlimab on days 0 and 7, followed by biweekly infusions for 26 weeks. Part B is the ongoing extension phase.

The primary endpoint for efficacy was a composite endpoint of increased haemoglobin ≥2 g/dL or an average haemoglobin level ≥12 g/dL, in combination with no need for transfusions between weeks 5-26. Secondary efficacy endpoints were a change from baseline of (1) haemolytic markers, e.g. bilirubin, and (2) quality of life as measured by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale.

The prespecified primary endpoint was met by 13 patients (54.2%), who showed a mean haemoglobin increase of 2.6 g/dL (standard error 0.4). In total, 20 of the 22 patients (82.2%) achieved a mean haemoglobin increase of at least 1 g/dL. Researchers noted a “rapid and sustained” haemoglobin response, as demonstrated by a 1.2 g/dL increase by week 1 and 2.3 g/dL increase by week 3. Further, mean total haemoglobin 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 normalisation of mean total bilirubin, which is a marker of extravascular haemolysis in CAD. Patients’ FACIT-F scores improved significantly within the first week of treatment and peaked at week 5, with stable improvements noted through week 26.

Almost all patients (92%) experienced at least one adverse event during the course of the study, and 29% experienced a serious adverse event. However, most of these events were deemed to be unrelated to sutimlimab by the overseeing committee. In total, 2 patients (8.3%) experienced serious adverse events involving infection; none of which were assessed by the investigator as related to sutimlimab. No patient discontinued sutimlimab due to infection and there were no meningococcal infections identified. All sutimlimab-related adverse events were considered non-serious and included swelling, hypertension, and runny nose. All patients who completed Part A of the trial elected to continue to participate in Part B that will assess longer term outcomes of sutimlimab.

“This drug appears to stop the haemolysis process,” Dr Röth said. “Haemolysis causes anaemia, increases risk for thrombosis and causes fatigue, so the central drive is to stop the haemolysis. Treatment with sutimlimab stops haemolysis almost completely, which is very important. In some ways, this is a cure for the haemolysis of the disease, because we are stopping the whole process; this is a dramatic breakthrough.”

Keywords: Autoimmune Haemolytic Anaemia; Haemolysis; sutimlimab; CARDINAL

Top image: @ iStockPhoto: ustas7777777

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