Safety and efficacy of classical complement pathway inhibition with sutimlimab in chronic immune thrombocytopenia

Abstract

Chronic/refractory immune thrombocytopenia (ITP) is a rare and pathophysiologically heterogeneous disorder with variable responsiveness to available treatments. Sutimlimab, a first-in-class humanized monoclonal anti-C1s IgG4 antibody, selectively inhibits the classical pathway. This phase 1 study (NCT03275454) assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of biweekly sutimlimab in patients with chronic/refractory ITP with an inadequate response to ≥2 therapies (platelet count ≤ 30 × 109/L). Twelve patients (median age 42 years) received sutimlimab for a median of 20.5 weeks followed by a median 2-week washout period (part A). In part B, 7 of the 12 eligible patients received sutimlimab retreatment for a median of 113 weeks. In part A, the mean (standard deviation) platelet count increased from 25 × 109/L (17) to 54 × 109/L (60) 24 hours after starting sutimlimab, maintaining ≥50 × 109/L throughout part A. Five patients (42%) achieved durable platelet count responses (≥50 × 109/L in ≥50% of follow-up visits) and 4 achieved complete response (platelet count ≥100 × 109/L). The mean platelet count returned to baseline during washout and increased upon retreatment in part B. The mean platelet count improvements accompanied the rapid inhibition of the classical pathway. There were 74 treatment-emergent adverse events in part A (n = 10) and 70 in part B (n = 6). Five serious adverse events were observed; 1 event (migraine) was assessed by the investigator as related to sutimlimab. These results demonstrated that in some patients with ITP, autoantibodies activate the classical complement pathway, accelerating platelet destruction or impairing platelet production and contributing to treatment failure. Thus, C1s inhibition may be a safe and beneficial therapeutic approach for patients with chronic/refractory ITP.

Graphical abstract

Figure 1.

Study design. ∗Platelet counts were assessed in part A on days 0 (4 and 8 hours after the first dose), 4, 11, 14, 28, 42, 56, 70, 84, 98, 112, 126, 134, 140, and 154; weekly throughout the washout period; and in part B at 4 and 8 hours after the first dose, on day 4, and then every 2 weeks before each sutimlimab dose. Additional platelet monitoring was performed as needed for safety monitoring or at the discretion of the investigator. If the patient’s platelet count exceeded 450 × 10⁹/L, their next dose of sutimlimab was withheld and dosing resumed when the platelet count was <150 × 10⁹/L. Dosing of concomitant ITP medications could be reduced at any time in patients with elevated platelet counts. ^¶Patients entering part B received an additional loading dose if >17 days had elapsed since the last dose received in part A. ^¤Dosing may be delayed due to high platelet levels; an additional loading dose was considered if resumption of sutimlimab treatment occurred more than 17 days after the last dose. ^¥Blood samples for PK and PD analysis were taken before every sutimlimab dose and at 0.5, 1, 4, 8, and 24 hours after the first and last dose in part A. Blood was sampled weekly during washout, every 4 doses during part B, and 9 weeks after dose completion (last sample not shown on diagram). ^øDuring part A, clinic visits with full assessments occurred on days 0, 1, 4, 7, 11, 14 and then every 2 weeks through to the end-of-treatment visit (day 147; week 21) and the end-of-washout visit (day 196). During part B, clinic visits were on days 0 and 4 and every 2 weeks thereafter, with end-of-treatment and end-of-study visits occurring 1 week and a maximum of 9 weeks after dose completion, respectively. A-EOS, part A end of study; A-EOT, part A end of treatment; ITP, immune thrombocytopenia; IV, intravenous; LPI, last patient in; PD, pharmacodynamic; PK, pharmacokinetic.

Figure 2.

Patient disposition.^aTwo patients received a maximum dose of 5.5 g sutimlimab in accordance with versions 1 and 2 of the protocol and completed part A only; 1 patient received doses of 5.5 g and 6.5 g, and 2 patients received doses of 5.5 g and 7.5 g. ^bFour patients discontinued part A due to reasons unrelated to sutimlimab; 3 discontinued due to the need for rescue therapy or unresponsiveness as per the investigator’s decision, and 1 discontinued due to reasons unknown. ^cOnly patients with evidence of treatment efficacy in part A were eligible for part B. One durable responder from part A did not enroll in part B because part B was not included in the study protocol at that time. ^dThree patients discontinued due to reasons unrelated to sutimlimab: 2 discontinued due to the need for rescue therapy or unresponsiveness as per the investigator’s decision, and 1 patient chose to withdraw (the participant required rescue therapy for severe thrombocytopenia and then withdrew consent at the early terminated visit).

Figure 3.

Mean platelet count from baseline to end-of-study treatment with sutimlimab. The value at part A baseline is the average of all platelet counts during the screening period, including day 0 before dosing. The value at part B baseline is the average of all platelet counts during the screening period in part B. N numbers at each point vary according to data availability. In part A, data were available for 5 to 12 patients at each time point, except as follows: n = 4 on days 70, 84, and 154 and n = 1 on day 196. In part B, data were available for 5 to 7 patients at each time point, except as follows: n = 4 for doses 15 to 49, 51, and 53; n = 3 for doses 52, 54, and 55; n = 2 for doses 56 and 57; and n = 1 for doses 58 to 61. OS, end of study; EOT, end of treatment; SEM, standard error of the mean. ^aFor patients enrolled in protocol version 3 or higher, the washout period starts on day 147 and ends on day 196.

Figure 4.

Effect of sutimlimab treatment on classical complement pathway activity. Changes in (A) CH50 vs platelet count, (B) total C4 levels, and (C) C1q levels from baseline to the end-of-study treatment with sutimlimab. CAE, complement activity enzyme; EOS, end of study; EOT, end of treatment; SEM, standard error of the mean. ^aFor patients enrolled in protocol version 3 or higher, the washout period starts on day 147 and ends on day 196. The value at part A baseline is the average of all platelet counts during the screening period, including day 0 before dosing. The value at part B baseline is the average of all platelet counts during the screening period in part B.

Figure 4.

Effect of sutimlimab treatment on classical complement pathway activity. Changes in (A) CH50 vs platelet count, (B) total C4 levels, and (C) C1q levels from baseline to the end-of-study treatment with sutimlimab. CAE, complement activity enzyme; EOS, end of study; EOT, end of treatment; SEM, standard error of the mean. ^aFor patients enrolled in protocol version 3 or higher, the washout period starts on day 147 and ends on day 196. The value at part A baseline is the average of all platelet counts during the screening period, including day 0 before dosing. The value at part B baseline is the average of all platelet counts during the screening period in part B.