Background: Warm autoimmune hemolytic anemia (wAIHA) is characterized by complex immune dysregulation along with red blood cell destruction primarily mediated by immunoglobin G autoantibodies, leading to hemolysis and anemia. Fatigue is a debilitating symptom that significantly impacts the quality of life among patients with wAIHA. Rilzabrutinib, a novel, highly selective, Bruton's tyrosine kinase inhibitor acts via multiple immunomodulatory effects. In the phase 2b LUMINA 2 study (NCT05002777), treatment with rilzabrutinib led to durable hemoglobin (Hb) response, decreased inflammation and hemolysis, and reduced fatigue in previously treated patients with primary wAIHA. Objective: This post hoc analysis assessed the effect of rilzabrutinib on Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score, and its association with Hb response in patients with wAIHA enrolled in the phase 2b LUMINA 2 study. Associations between FACIT-F scores, Hb levels, and inflammatory marker levels were also explored. Methods:In this open-label, single-arm, multicenter study, 22 patients with primary or subset of secondary wAIHA were eligible to receive oral rilzabrutinib 400 mg twice daily for 24 weeks (Part A). Patients with ≥2 g/dL increase in Hb level from baseline by Week 24 were considered Hb responders and continued treatment in Core Part B for up to Week 52. Data obtained after 50 weeks of treatment are reported here. Durable Hb response was defined as Hb level ≥10 g/dL with ≥2 g/dL increase from baseline at 3 consecutive scheduled visits between Weeks 24–50. Fatigue was assessed using the FACIT-F scale (13-item questionnaire; 7-day recall). Individual items on the scale were rated on a 5-point Likert scale (0=Very much, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Not at all; total score 0–52; higher scores=less fatigue). FACIT-F response was defined as ≥3-point increase from baseline (clinically meaningful within-patient improvement). The correlation between changes in Hb levels and FACIT-F scores from baseline was assessed using Spearman's rank correlation coefficient. The association of selected inflammatory biomarkers including interleukin-10 (IL-10), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) with FACIT-F scores was also evaluated. Results: This analysis included 22 patients (median age: 65 years; range: 33-87), with 23% aged ≥75 years. Baseline mean (SD) FACIT-F score was 30.0 (11.1). At Week 24, 14 patients were Hb responders, and 8 were Hb non-responders. Hb responders had a mean (SD) FACIT-F score change from baseline (CFB) of 7.8 (9.6; n=14) vs 3.8 (15.0; n=6) for Hb non-responders. FACIT-F response (≥3-point increase from baseline) was achieved by 64.3% (9/14) of Hb responders vs 25% (2/8) of Hb non-responders. The Hb responders continued to Core Part B (n=14) and demonstrated fatigue improvement through Week 50. The mean (SD) CFB was 7.9 (8.4) at Week 50. The patients with durable response (n=12) showed sustained improvement in FACIT-F scores (mean [SD] CFB at Week 24: 8.8 [10.0]; Week 50: 9.3 [8.1]). The proportion of FACIT-F responders among durable Hb responders increased to 71.4% (10/14) by Week 50. Rilzabrutinib treatment led to progressive reduction in the proportion of patients reporting severe fatigue symptoms across all FACIT-F domains from baseline through Week 50. The most notable improvements were observed in core fatigue symptoms, i.e., feeling fatigued and tired. FACIT-F score changes showed moderate correlation with Hb levels at Week 24 (r=0.486; n=20), but at Week 50, the correlation was weaker (r=0.265; n=14). Moderate-to-strong negative correlation was observed between FACIT-F scores and IL-10, IFN-γ, and TNF-α levels at Week 24 (r=−0.65; –0.663, −0.772; n=10), indicating correlation between reduced fatigue and lower levels of inflammatory biomarkers.Conclusions: Rilzabrutinib treatment was associated with clinically meaningful within-patient improvement in fatigue in wAIHA. The improvement was most pronounced in patients with durable Hb response but was also observed in a few non-responders. Weak-to-moderate correlation of FACIT-F scores with Hb levels and moderate-to-strong negative correlation with inflammatory marker levels suggests that mechanisms other than anemia, particularly chronic inflammation, may contribute to fatigue in wAIHA. These findings support rilzabrutinib's potential to address fatigue in wAIHA via multiple immunomodulatory effects.

Riliprubart is a second-generation, humanized immunoglobulin G4 that inhibits only the activated form of the C1s component of the proximal classical complement pathway. The clinical studies of riliprubart conducted thus far for the treatment of cold agglutinin disease (CAD), a rare autoimmune disease, include a Phase 1 first-in-human study in healthy participants and a Phase 1b single-dose study in 12 adult CAD patients. The objective of this study was to derive a riliprubart dosing regimen for CAD patients using model-informed drug development (MIDD) approaches utilizing available clinical data. A virtual population consisting of 1,000 CAD patients was created by sampling with replacement of the body weight distribution of CAD patients from a clinical database. The 3.5 g IV quarterly (q12w) riliprubart regimen with an additional 3.5 g IV dose on Day 29 is predicted to have a greater than threefold safety margin and >90% efficacy. The observed riliprubart concentration-time profiles from 9 CAD patients were consistently within the popPK simulated 90% prediction interval. Based on the totality of the efficacy, safety, and PK/PD data observed under clinical evaluation, the proposed dose regimen demonstrated suitability for CAD patients.

PurposeTo validate the use of Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire in cold agglutinin disease (CAD) patients using qualitative and quantitative methods and to estimate meaningful within-patient change (MWPC).MethodsQualitative assessment used outcomes from a survey among CAD patients and their caregivers in US. Quantitative assessment used outcomes from two Phase-3 trials in CAD wherein fatigue was evaluated as a key secondary endpoint using the FACIT-Fatigue questionnaire. The reliability, validity, and responsiveness of the FACIT-Fatigue questionnaire were assessed. MWPC was estimated using anchor-based (mean change, receiver operating characteristic [ROC] curves, and logistic regression) and distribution-based methods.ResultsQualitative analyses (n=16) showed that fatigue was the most common and bothersome symptom. All patients reported that FACIT-Fatigue questionnaire captured their experiences of CAD-related fatigue. Quantitative analysis included 55 patients from both studies. Items of FACIT-Fatigue scale were internally consistent (Cronbach’s alpha coefficient: 0.94 at baseline; 0.96 at Week 26). Generally, correlations showed good convergent validity (>0.40). The MWPC estimates ranged from 2.0 to 15.7. Based on more robust ROC and regression-based methods, IQR of MWPC estimates was 4.1–7.3, and individual responder definitions were in range of 5–8 points, where “5” is the lowest recommended MWPC threshold for FACIT-Fatigue in CAD.ConclusionFACIT-Fatigue is a reliable, valid, responsive scale in CAD. The MWPC estimates for FACIT-Fatigue in patients with CAD were consistent with other disease estimates published previously, and “5” can be considered as the lowest recommended threshold for meaningful clinical response in patients with CAD.

Introduction Immune thrombocytopenia (ITP) is characterized by immune dysregulation leading to platelet destruction and impaired platelet production causing thrombocytopenia, increased bleeding risk, and diminished quality of life. Corticosteroids (CS) are often used in front-line, concomitant, and rescue therapy for patients (pts) with ITP; however, long-term or repeated CS use is associated with elevated toxicity. Rilzabrutinib is an oral, reversible, covalent, selective Bruton tyrosine kinase inhibitor that acts through multi-immune modulation. The phase 3 LUNA3 study (NCT04562766, 2020-002063-60) of rilzabrutinib in adult pts with persistent/chronic ITP comprised 3 phases: double-blind (DB), open label (OL), and long-term extension (LTE). Rilzabrutinib demonstrated rapid and durable platelet response; improved physical fatigue and bleeding scores; and favorable safety profile in the DB, OL, and interim analysis of the LTE periods. Reported here are updated results based on longer follow-up from the LUNA3 LTE period, with a special focus on changes in concomitant use of CS from baseline. Methods Pts eligible to enter the LTE had response (platelet count ≥50×109/L or ≥30x109/L and at least doubled from baseline at ≥50% of visits without rescue therapy) during the last 8 weeks of the OL period. In the LTE, pts received oral rilzabrutinib 400 mg bid until loss of response on 2 consecutive visits or for safety reasons. Stable baseline doses of concomitant CS and/or thrombopoietin-receptor agonists (TPO-RA), dose reduction/discontinuation, and rescue therapy were allowed. Results As of April 1, 2025, 69 of 202 (34%) pts who met the predefined response criteria had entered LTE (48 rilzabrutinib pts from DB, including 25 durable platelet responders and 23 non-responders; 21 non-responding placebo pts from DB), and 57 were ongoing in the LTE (41 rilzabrutinib pts, including 23 responders and 18 non-responders from DB; 16 placebo pts from DB). Forty-three (62%) pts had completed ≥12 mo of follow-up in LTE. At baseline, median age of LTE pts was 52 years (range, 18-80), 72% were female. Median duration of ITP was 9.6 years (range, 0.3-42.7), median number of unique prior therapies was 4 (range, 1-9; 26% splenectomized), and 97% of pts had received CS; median baseline platelet count was 18×109/L (range, 2-54×109/L). Median platelet count at LTE entry was 113×109/L (range, 20-877×109/L) and median counts at LTE follow-up visits ranged from 83-168×109/L through 33 mo of LTE. During the first 12 mo of the LTE, pts had platelet counts ≥50×109/L or between 30-50×109/L and at least doubled from baseline for an average of 88% (SD, 24%) of visits. Of pts who received rilzabrutinib monotherapy (n=22, 32%) or rilzabrutinib and concomitant CS and/or TPO-RA (n=47, 68%), median platelet counts at LTE entry were 78×109/L (range, 20-371×109/L) and 115×109/L (range, 28-877×109/L), respectively, and ranged from 78-270×109/L and 90-160×109/L, respectively, through 33 mo of LTE. In the LTE, 14 (20%) pts received rescue medication. Among 34 (49%) pts who entered the LTE on concomitant CS, 10 (29%) discontinued CS use (switched to rilzabrutinib monotherapy), 2 (6%) reduced their CS ≥50% from DB baseline, and 6 (18%) reduced their CS dose to <5 mg (prednisone qd). Median platelet counts before and after CS discontinuation at last available LTE visit were 148×109/L (range, 19-722×109/L) and 178×109/L (range, 3-405×109/L), respectively. Improvements in fatigue scores (ITP-PAQ Item 10) and bleeding symptoms (IBLS) were generally maintained during the LTE. Thirteen (19%) pts had treatment-emergent adverse events (TEAE) that were assessed as related by the investigator; most common were nausea (7%), diarrhea (4%), and upper abdominal pain (3%). Two pts (3%) had grade ≥2 related TEAE of infection; no related grade ≥2 bleeding events, serious adverse events, or deaths occurred. Conclusion Rilzabrutinib continued to demonstrate sustained platelet responses and improvement in all ITP-related symptoms in pts with ITP during the LTE period. Most pts receiving concomitant CS were able to taper or discontinue CS while maintaining platelet responses. Rilzabrutinib continued to demonstrate favorable safety profile in pts with ITP. These LTE findings support rilzabrutinib as an efficacious therapy with durable therapeutic effects and steroid-sparing potential, and underscores further the disease-modifying potential of multi-immune modulation in pts with ITP.

Patients with cold agglutinin disease (CAD) are more vulnerable to infectious agents, thus the COVID-19 pandemic has posed a particular risk to this population. Sutimlimab Phase 3 studies CARDINAL and CADENZA spanned the period before and during the pandemic; investigators were advised to vaccinate enrolled patients without stopping treatment. Of 61 completers from both studies, 47 received ≥1 dose of a COVID-19 vaccine. In the immunogenicity analysis (n = 27) all patients developed an immune response post-COVID-19 vaccination, with detectable immunoglobulin G anti-spike antibodies. Analysis of six patients with booster vaccinations demonstrated increased immune responses pre- to post-booster. COVID-19 vaccines were well tolerated in patients with CAD receiving sutimlimab treatment, and no signs of hemolytic exacerbations were observed post-vaccination.

Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by complement pathway-mediated hemolysis. Riliprubart (SAR445088, BIVV020), a second-generation classical complement inhibitor, is a humanized monoclonal antibody that selectively inhibits only the activated form of C1s. This Phase 1b study evaluated the safety, tolerability, and effect on hemolysis of riliprubart in adult patients with cold agglutinin disease. On day 1, 12 patients received a single IV dose of either 30 mg/kg (n = 6) or 15 mg/kg (n = 6) of riliprubart and were subsequently followed for 15 weeks. Riliprubart was generally well tolerated; there were no treatment-emergent serious adverse events, or treatment-emergent adverse events leading to death or permanent study discontinuation. There were no reports of serious infections, encapsulated bacterial infections including meningococcal infections, hypersensitivity, or thromboembolic events. Rapid improvements in hemoglobin (day 5) and bilirubin (day 1) were observed in both treatment cohorts. Mean hemoglobin levels were maintained at >11.0 g/dL from day 29 and mean levels of bilirubin were normalized by day 29; both responses were maintained throughout the study. Improvements in clinical markers closely correlated with a sustained reduction in the 50% hemolytic complement (CH50) throughout the study. Mean C4 levels, an in vivo marker of treatment activity, increased 1 week after treatment with either dose of riliprubart and were sustained throughout the study. In conclusion, a single IV dose of riliprubart was well tolerated, and led to rapid classical complement inhibition, control of hemolysis, and improvement in anemia, all of which were sustained over 15 weeks. This trial was registered at www.ClinicalTrials.gov as #NCT04269551.

Abstract ID 92096Poster Board 029Introduction: Riliprubart is a humanized immunoglobulin G4 monoclonal antibody that inhibits the active form of C1s, preventing activation of the classical complement pathway (CP), whilst leaving the lectin and the alternative pathways functionally intact. Riliprubart is currently in development for the treatment of complement-mediated diseases, including cold agglutinin disease (CAD).Aim: To determine a dosing regimen for patients with CAD using population pharmacokinetic/pharmacodynamic (popPK/PD) modeling and simulations.Methods: The PKs of riliprubart in healthy subjects was characterized by a two-compartment model with linear elimination and first order absorption. Typical clearance was 2.12 mL/h, and body weight was the primary source of PK variability on peripheral volume of distribution. The riliprubart PK/PD relationship with Wieslab® CP or 50% hemolytic component (CH50) in healthy subjects was adequately described by a direct non-linear effect model.Based on the popPK/PD model developed using data from healthy subjects, riliprubart PK and PD were evaluated in patients with CAD after a single intravenous (IV) dose of 30 or 15 mg/kg. Using a Bayesian approach with pre-defined quality criteria, the PK characteristics of riliprubart in CAD patients was consistent with healthy subjects. Hemoglobin (Hb) response to riliprubart exposure in patients with CAD was adequately described by an indirect PK/PD model, including a zero-order rate constant for Hb production, and a first-order constant for Hb elimination, which is inhibited by riliprubart in the central compartment.The popPK and popPK/PD models were used to simulate a virtual population of 1,000 patients dosed with a quarterly IV regimen, with an additional dose on Day 29, at 3 dose levels: 30 mg/kg, 50 mg/kg and 3.5 g. Evaluation criteria included safety margins and efficacy (as informed by reduction of CH50 values to complement deficient states and >2 g/dL Hb increase from baseline).Results: A quarterly IV regimen with an additional dose on Day 29 for both 50 mg/kg and 3.5 g were projected to achieve the CH50 and Hb efficacy targets for >90% of the population, including patients with extreme low and high body weights.For the flat dose approach, there was a trend in area under the curve at steady state (AUCss) decreasing from extreme low body weights (35–54 kg) to extreme high body weights (130–200 kg); this decrease was ∼2.8-fold. For the body weight-based dose regimen, there was an increase in AUCss with increasing body weight over the same range; this increase was ∼1.2-fold. For 65–105 kg, the exposure between flat and weight-based approaches were comparable. The greatest difference was observed for the low (35–54 kg) and high (130–200 kg) body weights; however, the exposure difference between flat and weight-based approaches were <2-fold at both low and high body weights. The flat dose approach had a greater than 3-fold safety margin in all body weight groups and >90% of patients were predicted to have Ctrough,ss above 300 μg/mL, achieving complement deficient states (based on CH50) leading to improvements of Hb in patients with CAD.Conclusion: Using a popPK/PD modeling and simulation approach to examine the relationship between clinical and PD efficacy markers for riliprubart, a flat quarterly dose of 3.5 g IV with an additional Day 29 dose was proposed to maximize the likelihood of therapeutic benefits for patients with CAD.Funding: This study was funded by Sanofi.

Background Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated. Methods The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 μmol/L on-treatment vs 35.0 μmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD. Interpretation The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs. Funding Sanofi.

Introduction The CADENCE Registry (NCT05791708) is a large international database of patients (pts) with cold agglutinin disease (CAD) or cold agglutinin syndrome (CAS, a cold antibody-driven hemolytic anemia associated with an underlying condition). CADENCE is aimed at understanding the patient demographics, clinical characteristics, treatment patterns, healthcare resource utilization, natural history of disease, long-term clinical outcomes, and impact on patient quality of life. Sutimlimab (SUT) is a humanized monoclonal antibody that selectively inhibits the classical complement pathway by inactivating C1s and is the first approved treatment for CAD. CADENCE includes a SUT cohort with an objective to assess the safety and the effectiveness of SUT in pts with CAD in a real-world setting. Here we report the data from the first interim analysis on the CAD subgroups based on treatment status. Methods Adults ≥18 years of age, diagnosed with CAD or CAS were included. Of 140 pts enrolled at time of analysis (data cutoff: October 6, 2023) 133 pts (7 pts excluded: eligibility criteria unmet) were included in the analysis (CAD, n=112; CAS, n=21). Results The treatment status among CAD pts (based on investigator-reported medications used to treat CAD) at enrollment was treatment-naive (n=50), CAD-SUT ongoing (n=15), other CAD treatment ongoing (n=33), previously on CAD therapy (n=14). The mean (SD) age of pts in the total CAD group and CAD-SUT subgroup at enrollment was 72.0 (10.29) and 74.1 (8.14) years, respectively. The mean (SD) time (months) from diagnosis to first treatment was 32.08 (48.49) in the CAD group and 55.59 (58.26) in the CAD-SUT subgroup. At diagnosis, mean (SD) hemoglobin (Hb) levels were 9.61 (2.22) g/dL and 9.40 (1.88) g/dL, mean (SD) bilirubin levels were 1.95 (0.83) mg/dL and 1.65 (0.37) mg/dL in the CAD group and CAD-SUT subgroup, respectively. At enrollment, Hb was well controlled with mean (SD) levels of 11.25 (1.86) g/dL in the total CAD group and 11.55 (2.02) g/dL in the CAD-SUT subgroup. At enrollment, hemolysis was better controlled in the CAD-SUT subgroup as indicated by the normalization of mean (SD) bilirubin levels (mg/dL) [1.15 (0.94) mg/dL]; compared to 1.64 (0.98) mg/dL in the CAD group. Demographics and clinical characteristics similar to the CAD group were observed in pts with CAS. At enrollment, the FACIT-Fatigue [CAD, 34.93 (12.77); CAD-SUT, 41.83 (11.06)], SF-36 PCS [CAD, 42.89 (10.50); CAD-SUT, 47.86 (8.15)], and SF-36 MCS [ CAD, 48.03 (11.07); CAD-SUT, 50.46 (12.64)] scores were higher in the CAD-SUT subgroup, compared to the CAD group. At enrollment, the proportion of physicians assessing patient response to current treatment as “excellent” or “good” was higher in the CAD-SUT subgroup (91.7%) than the total CAD group (68.5%). Prior to or at enrollment, 55 (49.1%) and 7 (33.3%) pts received any transfusion in the total CAD and total CAS group. The number of pts that received any transfusion in subgroups were: 14 (28.0%) treatment-naive, 9(60.0%) CAD-SUT ongoing, 26 (78.8%) other CAD treatment ongoing, 6 (42.9%) previously on CAD therapy. At enrollment, among the pts receiving ongoing CAD treatment other than SUT (n=33), the most common treatments were rituximab (15.2%), folic acid derivatives (57.6%), direct factor Xa inhibitors (12.1%) and erythropoietin (12.1%). Among all pts with CAD, the most common treatment prior to enrollment was rituximab either as a monotherapy (33%), or in combination with an antineoplastic agent (1.8%). In the subgroup of pts previously on CAD therapy (n=14), 100% had a history of rituximab treatment; about 50% of pts in the CAD-SUT subgroup and the ongoing CAD treatment subgroup and 33.4% of CAS pts had a history of rituximab use. Rituximab monotherapy was the most prescribed treatment as first or second-line therapy in all subgroups. Conclusion In this first interim analysis from the ongoing CADENCE registry, about 50% of enrolled pts with CAD were treatment-naive; among pts with ongoing or history of CAD treatment, the most common treatment prior to enrollment was rituximab, more commonly used as a monotherapy. This initial real-world data on SUT-treated pts is consistent with results from clinical trials, demonstrating the benefit of SUT in managing anemia and hemolysis, and in addressing PROs. Further analyses will provide more insights about the natural history of CAD and CAS and long-term clinical outcomes of SUT.

Background Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B). Methods The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values. Interpretation Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD. Funding Sanofi.

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia characterized by hemolysis from immunoglobulin M (IgM)-induced classical complement pathway activation. Sutimlimab, a first-in-class, humanized, monoclonal antibody selectively inhibits C1s of the C1 complex, thereby preventing classical complement pathway activation; sutimlimab is currently approved for use in the EU, Japan, and USA. The Phase 3 CARDINAL (NCT03347396) and CADENZA (NCT03347422) studies demonstrated that sutimlimab results in sustained improvements in anemia, hemolytic markers, and quality of life in patients with CAD; CARDINAL assessed patients with a recent history of transfusion (≥1 in the last 6 months), while CADENZA investigated patients with no recent history of transfusion (≤1 during the last 12 months, 0 during the last 6 months). Aims: This study assesses if baseline serum markers are associated with response as defined by the primary endpoints of the CARDINAL and CADENZA studies. Methods: All patients who received sutimlimab during Part A (26 weeks) of the CARDINAL (n=22) and CADENZA (n=19) trials were included in this combined analysis. Serum markers collected at baseline were evaluated for predicting responder status. Patients were classified as either responders or non-responders based on whether they met the primary endpoint criteria defined by the clinical trial. For a patient to be a responder in the CARDINAL trial, a hemoglobin (Hb) increase ≥2.0 g/dL from baseline at the treatment assessment timepoint (TAT; defined as the mean value from Weeks 23, 25, and 26) or Hb level ≥12.0 g/dL at TAT was required. For the CADENZA trial, a Hb increase ≥1.5 g/dL from baseline at TAT was required. Other mandatory conditions for both clinical trials for responder status were: no blood transfusion from Week 5 through Week 26, and no treatment for CAD beyond what was permitted per protocol. Descriptive statistics, frequency, or percentage were used to analyze outcomes. Results: Of the 41 patients included in the analysis, 29 (70.7%) were classified as responders (n=13 CARDINAL; n=16 CADENZA). The mean age (standard deviation [SD]) of responders (67.0 [9.9] years) was significantly lower than non-responders (74.3 [7.3] years; p-value=0.0262). No significant differences were noted for ethnicity, race, sex, geographic location, or body mass index. The median (range) reticulocyte count in responders (164.9 [28–301] 109/L) was significantly higher at baseline than in non-responders (102.0 [4–185] 109/L; p-value=0.0055). Significant differences in the median (range) reticulocyte index (semi-quantitative index of the adequacy of bone marrow response to anemia) between responders (4.7 [1–9]) and non-responders (2.6 [1–5]; p-value=0.0091) were also observed. Lower levels of median (range) IgM antibodies were noted in responders (2.37 [0.5–22.4 g/L]) compared with non-responders (6.22 [1.2–12.4] g/L; p-value=0.0080); upper limit of normal for IgM was 3.0 g/L. No significant differences in bilirubin, C4, CAD titer, erythropoietin, ferritin, Functional Assessment of Chronic Illness Therapy – Fatigue, haptoglobin, hemoglobin, lactate dehydrogenase, or total iron-binding capacity were noted at baseline between responders and non-responders. Summary/Conclusion: Post hoc analysis of Phase 3 trial data suggests that predictive serum biomarkers for sutimlimab response in patients with CAD may exist (such as reticulocyte count, reticulocyte index and IgM levels) and should be explored further. Figure:Keywords: Hemoglobin, Complement, Autoimmune hemolytic anemia (AIHA), Hemolysis

Topic: 35. Quality of life and palliative care Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia that is mediated by the classical complement pathway, leading to chronic hemolysis, fatigue, and poor quality of life (QoL). Treatment with sutimlimab – a C1s complement inhibitor – rapidly halted hemolysis, increased hemoglobin levels, and improved fatigue in patients with CAD with no recent history of transfusion (≤1 during the previous 12 months; 0 during the last 6 months) in the randomized, double-blind, placebo-controlled Part A of the Phase 3 CADENZA trial (NCT03347422). Rapid improvements compared with placebo were also observed for patient-reported outcomes (PROs) up to 26 weeks. Aims: To report the long-term effect of sutimlimab treatment on PROs in patients with CAD from Part B, the open-label extension of CADENZA. Methods: All patients who completed Part A were eligible to receive biweekly doses of sutimlimab in Part B (6.5 g if <75 kg or 7.5 g if ≥75 kg body weight), continuing up to 1 year after the last patient finished Part A. PRO endpoints included: incidence of solicited symptomatic anemia (presence/absence of fatigue, weakness, shortness of breath, palpitations, light-headedness, and/or chest pain) and change in these symptoms by visit (improvement, unchanged, or worsened); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score; 12-Item Short Form Health Survey (SF-12) physical and mental component score (PCS, MCS); EuroQol visual analog scale (EQ-VAS); Patient Global Impression of Change (PGIC), and Patient Global Impression of [fatigue] Severity (PGIS). Results: In total, 39 patients entered Part B, and 32 (82.1%) completed. At Part A baseline (BL), 31/39 (79.5%) patients reported at least one solicited symptom of anemia, which decreased to 10/28 (35.7%) in all patients at Week 87 (Figure 1A). The most reported symptoms of anemia were fatigue, weakness, and shortness of breath at both time points. Improvement in at least one solicited symptom of anemia versus BL was observed in 22/28 (78.6%) at Week 87. Improvements in FACIT-Fatigue from BL were seen throughout Part B, with the mean change exceeding the clinically important change (CIC) of 5 points at all Part B visits up to Week 87 (Figure 1B). Improvements in PCS and MCS component scores of the SF-12 versus BL were observed in Part B, with a mean (SE) change from BL at Week 87 of 7.20 (2.06) and 3.93 (1.92) points respectively (n=27 for both). For the PCS, improvements were sustained above the CIC of 3.9 points through 87 weeks. EQ-VAS showed a consistent increase from BL, with mean (SE) change from BL at Week 87 of 15.57 (4.01, n=28) points. PGIC remained positive throughout the treatment period, with 20/28 (71.4%) of patients still reporting improvement from BL at Week 87. PGIS improved from 14/30 (46.7%) patients reporting “none” or “mild” fatigue at BL to 22/28 (78.5%) at Week 87. Summary/Conclusion: Sustained benefits from sutimlimab treatment in CADENZA Part B were observed across several PRO measures for 1 year or more after initiation of sutimlimab. These findings demonstrate that continued inhibition of the classical complement pathway via treatment with sutimlimab results in meaningful long-term benefits to fatigue and patient-reported QoL, in addition to improving symptomatic anemia in patients with CAD. Figure:Keywords: Autoimmune hemolytic anemia (AIHA), Quality of life, Patient reported outcomes

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Sutimlimab (SUT) is a humanized monoclonal antibody approved for patients with cold agglutinin disease (CAD), a rare chronic autoimmune hemolytic anemia. Through selective C1s inhibition, SUT prevents classical complement pathway-mediated hemolysis, characteristic of CAD. In Part A of CADENZA (NCT03347422), a randomized, double-blind, placebo-controlled Phase 3 study, SUT treatment resulted in rapid and sustained improvements in hemoglobin (Hb), hemolytic markers and quality of life (QoL). Aims: To report long-term safety and efficacy findings of SUT treatment in patients (pts) with CAD, from CADENZA Part B, the open-label extension. Methods: In Part A (26 weeks), pts with CAD, without a history of recent blood transfusion, received SUT or placebo (PBO) on Days 0 and 7, then biweekly. Pts completing Part A could enter Part B and receive biweekly SUT for ≥1 year after the last pt completed Part A. Efficacy endpoints included change from baseline (BL) in Hb, hemolytic markers, and FACIT-Fatigue score. The proportion of subjects achieving pre-defined Hb increases and normalized bilirubin was analyzed. Safety data were recorded throughout the study; treatment emergent adverse events (TEAEs) and serious TEAEs (TESAEs). Results: In total, 39 pts completed Part A and entered Part B, and 32 (82.1%) completed Part B. At the end of Part A, in SUT and PBO groups, respectively, mean (SE) Hb was 11.51 (0.40) g/dL and 9.43 (0.40) g/dL (Figure), Hb levels ≥11 g/dL were observed in 73.7% and 20.0% of pts, and change from BL in Hb ≥1.5 g/L was seen in 84.2% and 15.0% of pts (Table). In Part B, improvements in Hb were sustained in the SUT group and the ex-PBO group saw rapid, comparable increases in Hb upon initiation of SUT. At Week 79 (Part B), in the SUT-only and ex-PBO groups, respectively, mean (SE) Hb levels were 11.86 (0.54) g/dL and 11.76 (0.58) g/dL, Hb levels ≥11 g/dL were observed in 76.9% and 66.7% of pts, and change from BL in Hb ≥1.5 g/L was seen in 69.2% and 73.3% of pts (Table). Mean total bilirubin was normalized (≤20.5 μmol/L) at the end of Part A in 88.2% of pts with SUT, versus 22.2% with PBO. In Part B, Week 79, bilirubin normalization was observed in 83.3% and 80.0% of SUT only and ex-PBO pts, respectively (Table). Further efficacy data are shown in the table. Improvements in mean [SE] FACIT-Fatigue scores (BL: 32.96 [1.79]) observed in Part A were sustained in Part B in the SUT-only group (44.31 [2.19] at Week 87); the mean FACIT-Fatigue score increased to comparable levels in the ex-PBO group (41.40 [2.71] at Week 87). In Part B, 36 (92.3%) pts experienced ≥1 TEAE. A total of 11 TESAEs were experienced by 7 (17.9%) pts; one TESAE of hypertension was assessed as related to SUT by the investigator. Thromboembolic events were observed in 2 (5.1%) pts (transient ischemic attack [n=1]; deep vein thrombosis [n=1]); both events occurred in pts with underlying risk factors for thromboembolism and were assessed as non-serious and unrelated to SUT by the Investigator. One TESAE of infection (urinary tract infection Grade ≥3) was reported. No meningococcal infections, serious events of hypersensitivity, anaphylaxis or systemic lupus erythematosus were reported. One pt with a history of tobacco use (received PBO in Part A) experienced a TESAE of squamous cell carcinoma of the lung with fatal outcome. SUT was withdrawn due to this TESAE prior to death. Summary/Conclusion: Long-term SUT treatment was well-tolerated, and was associated with sustained efficacy, with improvements in anemia, hemolysis and QoL. Figure:Keywords: Autoimmune hemolytic anemia (AIHA)

Background:Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia characterized by complement-mediated hemolysis. The classical complement inhibitor sutimlimab, is the first approved pharmacotherapy for treating patients with CAD. The second-generation complement inhibitor SAR445088 (BIVV020) is a humanized monoclonal antibody that selectively inhibits the activated form of C1s (sutimlimab inhibits total C1s). Furthermore, SAR445088 contains mutations that increase FcRn binding, preventing its degradation and allowing it to be recycled back into the system, resulting in reduced drug clearance and a prolonged half-life, which may allow a longer dosing interval than that of sutimlimab. Aims:This Phase 1b open-label study evaluated the safety, tolerability, effect on hemolysis, and pharmacodynamics (PD)/pharmacokinetics (PK) of a single intravenous (IV) dose of SAR445088. The study aimed to assess the impact of SAR445088 on complement-mediated hemolysis to support proof of concept for SAR445088 as a treatment for patients with CAD. Methods:The study design included up to three single-dose cohorts with a maximum of six patients per cohort. SAR445088 was administered on Day 1 with follow-up visits from Day 2 to Day 71; end of study (EOS) visit was on Day 106. The first cohort received a dose of 30 mg/kg IV with decisions about the selection of the dose for the next cohort being based on safety, biomarker activity, and PD. In the second cohort, patients received a lower dose of 15 mg/kg IV; a third, higher-dose cohort was not enrolled. To be enrolled in the study, participants needed to be aged ≥18 years with a confirmed diagnosis of CAD and a hemoglobin level ≤11.0 g/dL at time of screening. The primary endpoint was assessment of safety, with secondary endpoints of hematologic biomarkers and PD/PK. Results:Twelve patients received a single IV dose of SAR445088 (n=6, 30 mg/kg; n=6, 15 mg/kg). Patients enrolled in the study were mainly female (91.7%, n=11) with a median age (range) of 69 (54-80) years, and median (range) hemoglobin at baseline was 9.60 (4.8-10.9) g/dL. There were no treatment-emergent serious adverse events (AEs), discontinuations or deaths reported in the study. Fifty-eight treatment-emergent AEs (TEAEs) were reported in 11 patients (91.7%). There was one reported pre-treatment severe AE (Grade 3) of hemolytic anemia in a patient in the 15 mg/kg IV cohort which began prior to treatment and continued during the treatment period; the remainder of TEAEs were mild or moderate in severity (Grade 1 or 2). The most frequently reported AE was hematuria. No serious infections, meningococcal infections, hypersensitivity, or thromboembolic events were reported. Nine patients (n=4, 30 mg/kg IV cohort; n=5, 15 mg/kg IV cohort) reached an increase of hemoglobin ≥1.5 g/dL from baseline to Day 106 (EOS visit); eight patients (n=4 for both cohorts) reached an increase in hemoglobin >1.0 g/dL from baseline to Day 15 (Figure A). Total mean bilirubin decreased by Day 1 and this was sustained to Day 106 (EOS visit; Figure B).The decrease was more pronounced in the 30 mg/kg IV cohort. Improvements in clinical markers correlated with sustained reductions in CH50 in both treatment cohorts. Reductions in mean percent classical complement pathway (CP) activity were noted 1 hour after a single dose of 30 or 15 mg/kg IV, followed by gradual rebound of CP activity over the 15-week study period. Conclusion:SAR445088 was generally well tolerated; no safety concerns were identified in patients with CAD. A single IV dose of SAR445088 led to classical complement inhibition, control of hemolysis, and improvement in anemia, which was sustained for 15 weeks.

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient's quality of life. CARDINAL was a 2-part, open-label, single -arm, multicenter phase 3 study evaluating the C1s inhibitor, sutimlimab, for treatment of CAD. Part A consisted of the pivotal study phase, with the part B extension phase assessing long-term safety and durability of response including patient-reported outcomes, which is the focus of this report. Altogether, 22 patients continued from part A to part B, majority female (68.2%) with a median age of 71.5 years (range, 55-85). Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale exceeded a predefined, group-level clinically important change of >= 5 points vs baseline, with a mean (standard error [SE]) change of 11.7 (3.7) points at week 135. The 12 -Item Short Form Health Survey physical and mental component scores remained above baseline, with week 123 mean change (SE) exceeding clinically important changes of 3.9 for physical and 2.8 for mental component scores at 4.7 (2.8) and 3.8 (5.7) points, respectively. EuroQol Visual Analogue Scale, scoring patients' self-rated health, also remained above baseline with a change of 17.1 (5.6) points at week 135. Patient Global Impression of (fatigue) Severity improved vs baseline, corroborating FACIT-Fatigue scores. Patient Global Impression of Change indicated a reduction in perceived disease burden. Data from CARDINAL part B support sustained alleviation of CAD disease burden after long-term treatment with sutimlimab over 2 years, returning toward baseline upon treatment cessation. This trial was registered at www.clinicaltrials.gov as #NCT03347396.

Background: Cold agglutinin disease (CAD) is a rare chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab (SUT) is a first-in-class humanized monoclonal antibody that prevents CP activation by selectively inhibiting C1s; both the alternative and lectin pathways remain intact. In the randomized, double-blind, placebo-controlled Part A (26 weeks) of Phase 3 CADENZA, SUT treatment resulted in rapid and sustained improvements in hemoglobin (Hb), hemolytic markers and quality of life (QoL). Aims: To report the long-term safety and efficacy of SUT treatment in patients with CAD from the open-label Part B extension of CADENZA. Methods: In Part A, eligible patients with CAD without a history of recent blood transfusion (≤1 during previous 12 months; 0 during last 6 months), received SUT or placebo (PBO) through intravenous infusions on Days 0 and 7, then biweekly. All patients completing Part A were eligible to enter Part B and receive biweekly SUT for ≥1 year after the last patient completed Part A. Efficacy data up to Week 79 as well as the last available patients' values are reported. Efficacy endpoints included change from baseline (BL) in Hb, hemolytic and pharmacodynamic markers, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, and blood transfusions. Safety data was recorded throughout the study; treatment emergent adverse event (TEAE) and serious TEAE (TESAE). Results: Of the 42 patients enrolled in Part A, 39 completed Part A and entered Part B, with 32 (82.1%) completing Part B; 7 (17.9%) patients discontinued the study prematurely, due to TESAE (n=1), lack of efficacy (n=3), withdrawal of consent (n=2) and withdrawal by sponsor (n=1). SUT treatment rapidly improved Hb levels; mean (SE) Hb at the end of Part A was 11.51 (0.40) g/dL and 9.43 (0.40) g/dL for SUT and PBO groups, respectively. In Part B, improvements in Hb were sustained in the SUT group and the ex-PBO group saw rapid and comparable increases in Hb upon initiation of SUT; at Week 79 mean (SE) Hb levels were 11.86 (0.54) g/dL and 11.76 (0.58) g/dL in the SUT only and ex-PBO groups, respectively (Panel A). Mean total bilirubin was normalized with SUT treatment in Part A and sustained in Part B; similar decreases were observed for patients in the ex-PBO group when they started receiving SUT in Part B (Panel B). Improvements in mean [SE] FACIT-Fatigue scores (BL: 32.96 [1.79]) observed in Part A were sustained in Part B in the SUT only group (44.31 [2.19] at Week 87); the mean FACIT-Fatigue score increased to comparable levels in the ex-PBO group (41.40 [2.71] at Week 87). Improvements in Hb, bilirubin, and FACIT-Fatigue correlated with normalization of C4 and near-complete inhibition of CP activity, that was maintained through the end of treatment. Reductions in mean absolute reticulocyte count and increases in haptoglobin levels observed with SUT treatment in Part A were maintained in Part B, and upon initiation of SUT in Part B, the ex-PBO group reached comparable levels. In Part B, 9 (23.1%) patients received a ≥1 transfusion. Thirty-six (92.3%) patients experienced ≥1 TEAE in Part B. Seven (17.9%) patients experienced a total of 11 TESAEs; one TESAE of hypertension was assessed as related to SUT by the investigator. Thromboembolic events (transient ischemic attack [n=1]; deep vein thrombosis [n=1]) were observed in 2 (5.1%) patients with underlying risk factors for thromboembolism. Both events were assessed as non-serious and unrelated to SUT by the Investigator. One TESAE of infection (urinary tract infection Grade ≥3) was reported. No meningococcal infections, serious events of hypersensitivity, anaphylaxis or systemic lupus erythematosus were reported. One patient with a history of tobacco use (received PBO in Part A) experienced a TESAE of squamous cell carcinoma of the lung with fatal outcome. SUT was withdrawn due to this TESAE prior to the patient's death. Conclusion: Long-term treatment with SUT, an anti-C1s CP inhibitor, maintained mean Hb levels >11 g/dL, achieved sustained normalization of bilirubin and led to clinically meaningful improvements of FACIT-Fatigue scores, while maintaining a favourable safety profile. Improvements in anemia, inhibition of hemolysis and favourable effects on QoL were rapidly achieved and sustained to a similar extent in those patients administered SUT throughout the study and those who switched to SUT treatment in Part B. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Topic: 28. Enzymopathies, membranopathies and other anemias Background: CAD is a rare, chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab (SUT) is a first-in-class, humanized, monoclonal antibody that selectively inhibits C1s, preventing CP activation. Throughout the CADENZA study (NCT03347422), treatment with SUT resulted in sustained improvements in anemia, hemolytic markers, and quality of life (QoL) in patients (pts) with CAD and no recent history of transfusion (≤1 during the previous 12 months; 0 during the last 6 months). Aims: To report results from the follow-up visit 9 weeks after last SUT dose in the Phase 3 CADENZA study. Methods: In CADENZA Part A, eligible pts (n=42) were randomized 1:1 to receive intravenous SUT or placebo on Days 0 and 7, followed by biweekly dosing through Week 25. All pts completing Part A were eligible to enter the Part B open-label extension study and receive biweekly SUT, continuing until 1 year after the last pt had completed Part A. Following the last SUT dose, all pts were assessed at a 9-week follow-up visit (early termination/safety follow-up [ET/SFU]). Efficacy measures included hemoglobin (Hb) levels, hemolytic/pharmacodynamic markers, transfusion requirements and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. Safety endpoints included incidence of adverse events (AEs) and serious AEs occurring during the 9-week follow up period. Descriptive statistics, frequency, or percentage were used to analyze outcomes. Results: Of 39 pts enrolled in Part B, 32 (82%) completed the treatment period and 37 (95%) were assessed during the 9-week follow-up period (6 pts with ET data). Mean (standard error [SE]) Hb was 11.58 (0.33) g/dL (n=39) at the last-available visit on SUT treatment (LV; last non-missing value in Part B) compared with 9.26 (0.15) g/dL (n=39) at baseline (BL); mean Hb at ET/SFU was 9.46 (0.33) g/dL (n=35). Mean (SE) total bilirubin was 17.31 (2.77) µmol/L (n=36) at LV vs 35.04 (1.95) µmol/L (n=35) at BL, and 36.78 (3.09) µmol/L at ET/SFU (n=34). Mean (SE) FACIT-Fatigue score was 41.71 (1.66, n=39) at LV vs 32.96 (1.79, n=39) at BL, and 31.29 (2.28, n=37) at ET/SFU. Absolute reticulocyte count saw sustained reductions during the treatment period; at ET/SFU, values approached BL levels. Decreases in mean lactate dehydrogenase were modest and observed inconsistently during the Part B treatment period. Upon starting SUT treatment, total C4 was consistently increased until cessation of treatment, returning towards BL at ET/SFU. The near-complete inhibition of Wieslab-CP activity observed with SUT treatment was reversed at ET/SFU. Six of nine pts receiving transfusions in Part B received them after the last dose of SUT. During the 9-week post-treatment follow-up period, 16 (41.0%) pts experienced a total of 55 AEs. One event was assessed as related to SUT by the investigator (Grade 2 upper respiratory tract infection). There were no thromboembolic events. Most AEs in the off-treatment period could be attributed to worsening of underlying CAD; fatigue (10 [25.6%]) pts), anemia (7 [17.9%] pts), dyspnea (4 [10.3%] pts), asthenia and hemoglobinuria (3 [7.7%] pts, each) and Raynaud’s phenomenon (1 [2.6%] pts). Summary/Conclusion: After 9 weeks of post-treatment follow-up in the CADENZA trial, mean levels of hemolytic markers, Hb and QoL scores approached pre-SUT values. These results highlight the importance of continuous therapy in pts treated with SUT for CAD. Figure:Keywords: Hemolysis, Complement, Hemoglobin, Autoimmune hemolytic anemia (AIHA)

Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)-mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open-label, single-arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2-year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last-available on-treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on-treatment versus 8.6 g/dL at baseline), bilirubin (16.5 μmol/L on-treatment versus 52.1 μmol/L at baseline), and FACIT-Fatigue scores (40.5 on-treatment versus 32.4 at baseline). In the 9-week follow-up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2-year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017.