Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder in which a somatic mutation in PIGA leads to reduced or absent expression of glycosylphosphatidylinositol-anchored complement regulatory proteins. PNH presents with the central manifestations of complement-mediated hemolytic anemia, bone marrow failure, and thrombosis. The introduction of terminal complement inhibitors that block complement protein 5 (C5) has revolutionized the management of PNH by reducing the risk for thrombosis, extending survival to be similar to that of healthy controls, and improving quality of life. C5 inhibitors approved by the US Food and Drug Administration (FDA) include eculizumab (administered intravenously every 2 weeks), ravulizumab (administered intravenously every 8 weeks), and, most recently, crovalimab (administered subcutaneously every 4 weeks). Given the chronic nature and life-threatening complications of PNH, longterm efficacy and safety data of treatment approaches are invaluable. The most extensive experience has been gained with eculizumab, and now 6-year data with ravulizumab point to its durable control of terminal complement activity and intravascular hemolysis. Although terminal complement inhibitors effectively control intravascular hemolysis, approximately 30% of patients receiving C5 inhibitors develop clinically significant extravascular hemolysis with ongoing transfusion requirements or symptomatic anemia. Upstream complement inhibitors that inhibit components of the alternative complement system have been developed with the goal of addressing both intravascular and extravascular hemolysis. The C3 inhibitor pegcetacoplan (administered subcutaneously twice weekly) and the factor B inhibitor iptacopan (administered orally twice daily), both used as single agents, have demonstrated effective control of hemolysis with increased hemoglobin and transfusion avoidance in both C5 inhibitor-naive and C5 inhibitor-experienced patients with clinically significant extravascular hemolysis. The factor D inhibitor danicopan (administered orally 3 times a day) is used as an add-on to ravulizumab or eculizumab and offers a combination approach by targeting both terminal complement and the alternative pathway. Breakthrough hemolysis in the event of a strong complement trigger is possible on any complement inhibitor, but these breakthrough events could be more severe with alternative pathway inhibitor monotherapy. Rates of breakthrough hemolysis and whether they differ between the alternative pathway inhibitors remain to be determined in the real-world setting.

INTRODUCTION:Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, non-malignant hematologic disease characterized by complement-mediated hemolysis (with or without hemoglobinuria), fatigue, increased susceptibility to thrombosis, and bone marrow dysfunction. The development of complement inhibitors has transformed outcomes for patients with PNH, but patients may still experience pharmacodynamic breakthrough hemolysis (BTH), which can be caused by exposure to a complement amplifying condition (CAC), such as vaccination, infection, or surgery. MATERIALS AND METHODS:A 13-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on how to classify pharmacodynamic BTH in patients with complement-inhibitor treated PNH. Physicians reviewed literature, rated the appropriateness of over 400 scenarios, and discussed the ratings at an in-person meeting. RESULTS:After the meeting, the panel agreed on 77% of scenarios. Here, we present the group's agreed-upon recommendations on how to manage BTH caused by a CAC, as well as provide a severity classification system for BTH and strategies to mitigate risk of BTH in special circumstances (e.g. vaccination, planned or unplanned surgery, and pregnancy). DISCUSSION:In general, as severity of BTH increased, experts agreed more interventions to manage the BTH were appropriate. These recommendations are based on clinical experience and opinion. Without clear data from randomized trials to guide the management of BTH, expert opinion can be useful to support patient care.

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.

Patients with cold agglutinin disease (CAD) experience fatigue and poor quality of life. However, previous CAD-related studies have not explored patient-reported outcomes such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Sutimlimab, a C1s complement inhibitor, has been shown to halt haemolysis in CAD. Here, we present 26-weeks’ patient-reported data from CARDINAL Part A (ClinicalTrials.gov, NCT03347396), which assessed efficacy and safety of sutimlimab in patients with CAD and recent history of transfusion. Aside from measuring changes in haemolytic markers, FACIT-Fatigue was measured at the treatment assessment timepoint (TAT; average of weeks 23, 25, and 26). Exploratory endpoints included the change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) and the 12-Item Short Form Health Survey (SF-12) at TAT, and Patient Global Impression of Change (PGIC), and Patient Global Impression of (fatigue) Severity (PGIS) at week 26. Mean (range) FACIT-Fatigue scores increased from 32.5 (14.0–47.0) at baseline (a score indicative of severe fatigue) to 44.3 (28.0–51.0) at TAT. Considerable improvements were reported for EQ-5D-5L at TAT, SF-12 scores at TAT, and PGIC and PGIS scores at week 26. Sutimlimab treatment resulted in sustained improvements in symptoms of fatigue and overall quality of life in patients with CAD. NCT03347396. Registered 20 November, 2017.

What is this summary about? Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, serious blood disease, characterized by uncontrolled activation of the complement system that causes hemolysis (destruction of red blood cells). The complement component 5 (C5) inhibitor eculizumab was the first approved treatment for PNH. The PEGASUS trial compared eculizumab with pegcetacoplan, a new complement component 3 (C3) inhibitor. Because C3 is activated before C5, blocking C3 would also block C5; thus, a C3 inhibitor might prevent hemolysis more completely than a C5 inhibitor in patients with PNH. During the first 16 weeks of PEGASUS, patients received either pegcetacoplan or eculizumab; results were published separately. This summary describes results of the following 32 weeks of PEGASUS, during which all patients received pegcetacoplan to evaluate if pegcetacoplan continued to be effective and safe for up to 48 weeks. What were the results? Pegcetacoplan continued to be effective in participants who received it throughout the study and improved symptoms in participants who switched from eculizumab. The most common adverse events (side effects) were skin irritation at the injection site, hemolysis, nasopharyngitis (runny nose and sore throat), and diarrhea. Adverse events were serious and related to pegcetacoplan in 4 of 77 (5%) patients; all patients recovered from these events. What do the results mean? Pegcetacoplan improved symptoms and was well tolerated for up to 48 weeks by most patients in PEGASUS, suggesting that adult patients with PNH may benefit from long-term pegcetacoplan treatment.

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.

Background: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired, hematologic disorder characterized by chronic complement-mediated hemolysis and associated with a mutation in the PIG-A gene, thrombosis, and immune-mediated marrow failure. The Global PNH Patient Registry, initiated in 2021, is the first patient-driven and patient-focused PNH registry. The Aplastic Anemia and MDS International Foundation leads The Global PNH Patient Registry with input from patients and caregivers along with hematologists and researchers. All data are provided by individuals with PNH or their caregivers. The goals are to: 1) enhance the understanding of PNH, 2) identify gaps and improve the care of patients with PNH, and 3) empower and unite the PNH community. Methods: Individuals with a self-reported PNH diagnosis are eligible to participate. The Global PNH Patient Registry is hosted on the National Organization for Rare Disorders' IAMRARE® platform - a web-based, secure portal for obtaining consent and entering patient-reported data. Study participants need to be able to read English, have a computer or mobile device, and have access to the internet. The study was reviewed and approved by North Star Review Board (IRB #NB100005). Study participants provide information on demographics, diagnosis, history of procedures, medications and supplements, current symptoms, health care utilization and quality of life. After the initial survey completion, participants are notified every 6 months to update information. This analysis includes the initial completion of each survey entered between April 2021 and April 2024. The data was analyzed to provide counts, percentages and mean values. Quality of life was measured by using select PROMIS® measures that were scored and transformed to standardized t-score values using the PROMIS Scoring Manuals (www.healthmeasures.net). Results: 173 people consented to participate and completed at least one survey in. The Global PNH Patient Registry participants are 99% adults with 60% aged 18 to 50 and 39% aged 50 and older. 65% of participants are female and 11% affiliate with the LGBTQ+ community. 15% are Hispanic, 12% are Asian, 6 % are Black or African American and 77% are White. 69% of participants live in the United States. The average age of symptom onset and diagnosis was 34 and 36 respectively. 43% reported having been diagnosed within 6 months of symptoms and 31% reported 2 or more years to receive a diagnosis. Receipt of a flow cytometry test, the definitive diagnostic tool, was reported by 67% of participants. Co-morbid conditions were reported by 55% of participants with aplastic anemia being the most commonly reported (38%). Fatigue was the most reported symptom with 64% indicating that they experience it “Often” or “Almost Always”. The next were lower back pain (39%), “brain fog” (38%), bruising easily (37%) and joint pain (36%). Most participants have a PNH-related care visit at least once a month with 61% reporting 7 or more in the past 6 months. Medication use was reported by 92% of participants, with 68% reporting having ever taken a complement inhibitor. PROMIS quality of life instruments that measured emotional support, depression and pain interference had average scores that were comparable to the general population. The instruments measuring fatigue, anxiety and participation in social activities had average scores indicating mild impairment and the average scores for physical function indicated moderate impairment compared to the general population (median: 34, 10th percentile 23, 90th percentile 42). At the individual level, more than half of individuals had scores indicating impairment with 35% of individuals had scores indicating severe impairment of physical function. Conclusions: The Global PNH Patient Registry highlights the power and potential of patient-reported data to provide meaningful insights on the natural history of PNH in a clinically and demographically diverse population. Plans include expanding recruitment and retention efforts, translating the registry into Spanish, examining the longitudinal data, and developing processes to broaden the use of the data within the community. Considering the evolving landscape of anti-complement therapeutic options available for patients, we believe this registry will be invaluable for monitoring the experience of individuals living with PNH in an increasingly complex field.

Cold agglutinin disease is a very rare haemolytic anaemia characterized by antibody-mediated haemolysis, complement activation, thrombosis and poor quality of life. In recent years, our understanding of the complement system and its role in disease has increased dramatically. However, because there is an increased risk of infection with inhibiting complement at the complement 5 and complement 3 levels, blocking the classical complement pathway is being explored instead as a way to strategically inhibit the complement system while minimizing the infection risks. Sutimlimab is a humanized immunoglobulin G4 antibody developed to inhibit the classical complement pathway. Its role and efficacy in treating patients with cold agglutinin disease will be the focus of this paper.

What is this summary about? This plain language summary is about a phase 3 clinical trial called PEGASUS. The PEGASUS trial studied adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder usually acquired in adulthood without a known cause. Patients with PNH have defects in the complement system, which is part of the immune defense system. This complement defect results in the destruction of red blood cells; this is called hemolysis. Hemolysis then causes anemia. People with anemia do not have enough red blood cells to carry oxygen around the body, which can cause fatigue (extreme tiredness), shortness of breath, or headache. Anemia can be measured by the level or amount of hemoglobin in the blood. Hemolysis can be measured by the amount of hemoglobin, lactate dehydrogenase (LDH), and reticulocytes in the blood. Hemoglobin and LDH are proteins inside red blood cells. In patients with PNH, hemolysis causes hemoglobin levels to go down and LDH levels go up. Reticulocytes are immature red blood cells; their level goes up during hemolysis to replace destroyed red blood cells. Eculizumab is the current standard of care for patients with PNH. Eculizumab is a medicine that blocks or inhibits the complement component 5 (C5). Pegcetacoplan is a new medicine, the first that inhibits the complement component C3. The PEGASUS study compared the new medicine pegcetacoplan with eculizumab in adults with PNH who remained anemic even after being treated with eculizumab for at least 3 months. In PEGASUS, 41 participants received pegcetacoplan and 39 people received eculizumab for 16 weeks. What were the results? The trial results showed that pegcetacoplan decreased signs of hemolysis compared to eculizumab. Participants treated with pegcetacoplan for 16 weeks had increased blood levels of hemoglobin, and decreased levels of LDH and reticulocytes; also, 85% of them no longer needed a blood transfusion compared with 15% of those treated with eculizumab. A patient survey showed that 73% of patients who received pegcetacoplan had decreased fatigue. None of the participants treated with eculizumab had decreased fatigue. Most participants in both treatment groups had side effects. However, no serious infections or thrombosis (blood clots) occurred with either treatment group. Episodes of hemolysis during treatment, called breakthrough hemolysis, happened in 10% of pegcetacoplan- and 23% of eculizumab-treated participants. What do the results mean? Pegcetacoplan reduced the level of hemolysis in adults with PNH better than eculizumab did. Pegcetacoplan was well tolerated by most patients in this study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening, acquired disease in which blood cells lacking complement regulatory proteins are destroyed because of uncontrolled complement activity. Since 2007, terminal complement inhibitors have revolutionized the treatment of this disease. However, patients treated with these inhibitors can still experience anemia because of C3-mediated extravascular hemolysis and clinically relevant levels of breakthrough or residual intravascular hemolysis. Proximal complement inhibitors, which are only just beginning to emerge, have the potential to address this problem by targeting components of the pathway upstream of C5, thereby protecting patients against both intra- and extravascular hemolysis. In this review, we describe different biomarkers that can be used to monitor complement pathway blockade and discuss key laboratory assessments for evaluating treatment efficacy. We also consider how these assessments are affected by each class of inhibitor and highlight how evolving treatment goals may influence the relative importance of these assessments.

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

Immune thrombocytopenia (ITP) is a disorder characterized by low platelets due to increased clearance and decreased platelet production. While ITP has been characterized as an acquired disorder of the adaptive immune system, the resulting platelet autoantibodies provide ancillary links to the innate immune system via antibody interaction with the complement system. Most autoantibodies in patients with ITP are of the IgG1 subclass, which can be potent activators of the classical complement pathway. Antibody-coated platelets can initiate complement activation via the classical pathway leading to both direct platelet destruction and enhanced clearance of C3b-coated platelets by complement receptors. Similar autoantibody interactions with bone marrow megakaryocytes can also result in complement injury and ineffective thrombopoiesis. The development of novel therapeutic complement inhibitors has revived interest in the role of complement in autoantibody-mediated disorders, such as ITP. A recent early-phase clinical trial of a classical complement pathway inhibitor has demonstrated efficacy in a subset of ITP patients refractory to conventional immune modulation. In this review, we will analyse the role of complement in refractory ITP.

Pegcetacoplan is the newest inhibitor of the complement system to be approved by the FDA and EMA for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). The cyclic peptide inhibitor of C3 was evaluated in several clinical trials in PHN leading to its approval. The focus of this paper will review the efficacy and safety of Pegcetacoplan (PEG), and considerations for use in patients with PNH.

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)

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