In a first-in-human trial, sutimlimab rapidly halted hemolysis, corrected anemia, precluded the need for transfusion, and caused no serious adverse effects in patients with cold agglutinin disease.
Sutimlimab also “induced clinically meaningful increases in hemoglobin levels, even in patients with multiple previous lines of therapy,” according to investigators.
The European Medicines Agency and the U.S. Food and Drug Administration (FDA) awarded sutimlimab orphan drug status based on these results. The FDA also granted sutimlimab breakthrough therapy designation.
Sutimlimab is a humanized anti-C1s IgG4 monoclonal antibody that blocks the classical complement pathway–specific protease C1s and prevents further hemolysis in patients with cold agglutinin disease.
Cold agglutinin disease is a rare, acquired chronic autoimmune hemolytic condition that destroys red blood cells. It leads to chronic anemia, severe fatigue, and potentially fatal thrombotic events. No drug has yet been approved to treat cold agglutinin disease.
The phase 1 trial of sutimlimab (formerly BIVV009 and TNT009) in cold agglutinin disease was conducted at the Medical University of Vienna in Austria and reported in Blood.
The study (NCT02502903) involved 10 patients, ages 56 to 76, who were previously treated with multiple lines of therapy, including two patients who failed treatment with eculizumab.
Of the 10 patients, eight were female, eight were Caucasian, one was Asian, and one was Hispanic. Patients had cold agglutinin disease for a median of 5 years (range, 1 – 20).
At baseline, the median hemoglobin level was 7.8 g/dL, the median number of reticulocytes was 133 x 109/L, the median bilirubin was 2.0 mg/dL, and the median haptoglobin was less than 12 mg/dL.
The patients received an initial dose of 10 mg/kg intravenous sutimlimab as a test dose to allow rapid wash-out of the drug if unforeseen adverse effects occurred with the first infusion.
One to 4 days later, they received the full dose of 60 mg/kg, followed by three additional weekly doses.
Investigators observed the patients for 49 to 53 days.
Within the first week, patients’ median hemoglobin levels increased by 1.6 g/dL (P=0.007), and the median best response was an increase of 3.9 g/dL (P=0.005) after 6 weeks.
Seven patients had increased hemoglobin levels by more than 2 g/dL, and this included those who recently failed to respond or relapsed after rituximab, rituximab plus bendamustine, or eculizumab.
In five patients, hemoglobin increased by 4 g/dL or more. In four patients, it completely normalized to 12 g/dL.
In the first 24 hours after sutimlimab infusion, reticulocyte counts increased by a median of 41% and then gradually declined as hemoglobin levels rose.
In four patients, haptoglobin levels normalized within 1 to 2 weeks. In eight patients who had abnormal bilirubin levels at baseline, sutimlimab decreased the median bilirubin levels by 61%, normalizing levels in most patients within 24 hours of the first infusion (P=0.007).
When sutimlimab was washed out, bilirubin levels increased again, which demonstrated the recurrence of hemolysis.
Approximately 3 to 4 weeks after the last dose of sutimlimab, hemolysis and anemia recurred in all responders.
When patients were re-exposed to sutimlimab, rapid and complete inhibition of hemolysis occurred once again.
None of the patients required packed red blood cell transfusions during treatment.
The investigators reported that all infusions were well tolerated without premedication and without relevant drug-related adverse effects.
They reported few adverse events during the trial. All were mild or moderate in severity, and most were considered unrelated or unlikely related to sutimlimab.
Two adverse events—one mild purpural rash on both hands and one case of moderate hair loss (each occurring in one patient)—were possibly related to sutimlimab.
While the investigators considered the safety data encouraging, they recommended interpreting the data “cautiously in light of the limited duration of the trial.”
“Provided that safety results remain positive, sutimlimab could become the first approved treatment for cold agglutinin disease,” said corresponding author Bernd Jilma, MD, of the Medical University of Vienna in Austria.
“The drug clearly addresses an unmet medical need, as we have seen rapid, strong responses in patients for whom multiple prior therapies have failed.”
This study was funded by True North Therapeutics, Inc, now part of Bioverativ, a Sanofi company.
Some of the authors disclosed financial relationships, including employment, with True North Therapeutics and Bioverativ.
A phase 3 trial of sutimlimab is underway with top-line results due in 2019.