Long-term data show sustained benefit of sutimlimab for CAD

The final 2-year (part B) results of the phase III CARDINAL study continued to demonstrate the favourable risk-benefit profile of sutimlimab, a first-in-class selective anti-C1s classical complement pathway (CP) inhibitor, for the management of cold agglutinin disease (CAD), a rare chronic, autoimmune haemolytic anaemia characterized by classical CP-mediated haemolysis.

“[The] interim follow-up [has] demonstrated that sutimlimab resulted in sustained improvements in haemolytic markers and quality of life (QoL),” said Dr Alexander Röth from University Hospital Essen, Germany. “[In part B, sutimlimab] continued to inhibit haemolysis and improve anaemia and QoL.”

There was rapid and sustained increase in mean haemoglobin from baseline to week 1 (1.35 g/dL). From week 5 through 131, haemoglobin levels of >11 g/dL continued to be stable and durable. [EHA 2022, abstract S285]

Bilirubin also rapidly dropped within a week and normalized from week 3 through 131 with occasional excursions. “[This is important] as bilirubin is a really exclusive, good parameter for haemolytic activity in CAD, [which] is associated with increased risk of thromboembolic events and mortality,” Röth noted. [Res Pract Thromb Haemost 2020;4:628-635; Blood Advances 2019;3:2980-2985; Eur J Haematol 2022;00:1-11]

Additional markers

Week 131 also saw improvements in additional haemolytic markers, such as haptoglobin levels, which normalized from 0.21 to 0.38 g/L. “[This is] a really sensitive marker for haemolytic activity,” said Röth.

Lactate dehydrogenase also dropped from 453 to 303 U/L, as did the mean absolute reticulocyte count (from 143 to 81 x 10⁹/L). Other key symptomatic CAD effects that dropped throughout part B were fatigue (from 73 percent to ≤41 percent), weakness (from 64 percent to ≤33 percent), and shortness of breath (from 59 percent to ≤21 percent).

Fatigue, safety

After completing the 26-week part A of CARDINAL, 22 patients (mean age 72 years, 68 percent female) went on to participate in the safety extension phase (part B). They received IV sutimlimab at days 0 and 7 and then Q2W thereafter. They were dosed according to weight (6.5 g [<75 kg] and 7.5 g [≥75 kg]). Fifteen patients remained transfusion-independent throughout part B.

The improvements in FACIT*-Fatigue scores were clinically meaningful. “Patients started with a really bad [baseline] FACIT-Fatigue score of 32.4, which was comparable to scores associated with … cancer,” Röth pointed out. “At the beginning of [part B], there was a dramatic improvement in the FACIT-Fatigue score of 7 points within the first week, [which] was consistent with a clinically meaningful change (≥5).”

All 22 patients reported treatment-emergent adverse events (TEAEs), but only half were considered drug-related. Three patients withdrew from the study owing to AEs. “Sutimlimab was generally well tolerated with no relevant complications … The type and frequency of TEAEs [were] consistent with an older and medically complex population,” said Röth.

Of the serious infections that occurred in seven patients, one was a case of sepsis due to Streptococcus pneumoniae, while another was Klebsiella pneumoniae that ended up fatally 14 days following receipt of the last sutimlimab dose. “[This patient was hospitalized] for worsening general conditions and acrocyanosis,” noted Röth.

There were no meningococcal infections reported nor were there any cases of systemic lupus erythematosus, serious hypersensitivity, or anaphylaxis during the study.

“The reductions in classical CP activity … correlated nicely with near-complete inhibition of CP activity pathway,” said Röth. “[Overall,] this study has demonstrated that sutimlimab is an effective and well-tolerated long-term therapy for the management of chronic CAD through continued upstream inhibition of the classical CP.”

These findings support those reported in part A of CARDINAL, as well as in CADENZA, which evaluated CAD patients without a history of recent blood transfusion. [NEJM 2021;384:1323-1334; Haematologica 2022;107:7; EHA 2021;324699:S291]