Complement-directed therapy for cold agglutinin disease: sutimlimab

ABSTRACT

Introduction

Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia defined as a distinct, low-grade lymphoproliferative disorder and characterized by the presence of immunoglobulin M (IgM) antibodies that recognize the ‘I’ antigen on red blood cell membranes. Hemolysis in CAD is mediated by activation of the classical complement pathway by IgM–antigen complexes. Sutimlimab directly targets classical complement pathway activation and has been shown to be generally well tolerated with rapid and sustained effects on hemoglobin levels, hemolytic markers, and fatigue in patients with CAD.

Areas covered

This review will outline the drug profile of sutimlimab and summarize the key efficacy and safety data focusing on the Phase 3 studies that formed the basis of the approval of sutimlimab in patients with CAD in the US, the EU, and Japan.

Expert opinion

Sutimlimab provides patients with an approved therapeutic option that can be used as part of a holistic approach to CAD management. The beneficial effects of sutimlimab go beyond rapid inhibition of hemolysis and include sustained meaningful improvements in fatigue and quality-of-life measures. Further, real-world evidence of the effectiveness and safety of sutimlimab in CAD and cold agglutinin syndrome will be assessed via the CADENCE registry.

KEYWORDS:

• Cold agglutinin disease
• Complement C1s
• Complement-directed therapies
• Hemolysis
• Quality of life
• Sutimlimab

1. Introduction

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA) with autoantibodies produced by a distinct low-grade clonal B-cell lymphoid proliferation in the absence of underlying disease [1–4]. Lymphoproliferative disorders are a group of heterogeneous diseases characterized by unregulated and excessive production of lymphocytes (i.e. B-cells, T-cells, or natural killer cells), which may be caused by iatrogenic or acquired genetic mutations [5]. CAD falls within the category of small B-cell lymphoid neoplasms, which is the preferred terminology for low-grade B-cell lymphomas as they may not be indolent. However, CAD does not fulfill the criteria of a B-cell lymphoma and is instead described as a B-cell lymphoid proliferation. CAD is distinct from lymphoplasmacytic lymphoma and unlike lymphoplasmacytic lymphoma or marginal zone lymphoma it does not transform into large cell lymphoma (Table 1) [1,2,6,7]. CAD is distinguishable from cold agglutinin syndrome (CAS), which is characterized by the presence of cold agglutinin antibodies secondary to underlying conditions such as malignancy or infection [8]. Primary CAD accounts for about 15–25% of AIHAs and has a prevalence of 16/1,000,000 in Europe [3,9–11].

Table 1. Characteristics of CAD-associated lymphoproliferative disease compared to lymphoplasmacytic lymphoma and secondary bone marrow infiltration by marginal zone lymphoma [7].

	Small lymphocytes	Plasma cells	CD20	IgK	IgM	CD27	CD5	Ig somatic mutation rate	MYD88 L265P mutation
Lymphoplasmacytic lymphoma	++	+	+	+	+	+	±	+++	+++
Bone marrow involvement, marginal zone lymphoma	+	+	+		+	_	_	+	+
CAD-associated lymphoid neoplasia	++	++	+	++		+	+	+

Ig, immunoglobulin

Autoantibodies in CAD are produced by the clonal population of B-cells in the bone marrow and are characterized by higher activity at a low thermal amplitude for binding to the ‘I’ antigen on red blood cells in adults, coining their name cold agglutinins [3,12–14]. Most cold agglutinins bind to red blood cell antigens at an optimum temperature of ≤4°C; however, they may show activity at higher temperatures of 28°C to 30°C and even at temperatures approaching 37°C [12]. Any of these temperatures may be reached in the peripheral parts of the body such as fingertips, toes, nose, and ears, thus mediating the pathogenicity of the autoantibodies [12,15,16]. Individual antigen specificity, thermal amplitude, and clonality of cold agglutinins vary between patients [14], resulting in marked clinical heterogeneity in the CAD patient population [10,13,17]. In CAD patients, the majority of cold agglutinins are of the immunoglobulin M (IgM) class, however, immunoglobulin G (IgG) and immunoglobulin A (IgA) have been noted [3,12,15]. Both IgM and IgG–antigen complexes on red blood cells can be potent activators of the classical complement pathway [3,4,10,14].

Cold agglutinin–antigen complexes on red blood cells bind complement protein C1q generating the C1 complex, resulting in classical complement pathway activation and production of C3a and C3b [3,14]. C3b is deposited on the red blood cells and acts as a powerful opsonin causing predominantly extravascular hemolysis in the liver. It also causes, to a lesser extent, intravascular hemolysis via the terminal complement cascade and formation of the membrane attack complex. Both C3a, from proximal complement activation and C5a from terminal complement activation contribute to a systemic inflammatory state in CAD (Figure 1) [4,11,14,18]. Complement-mediated symptoms include hemolysis, anemia, fatigue, dyspnea, jaundice, hemoglobinuria, and an increased risk of thromboembolic events [4,9,10,17,22,23]. Beyond activating the classical complement system, IgM bound to the surface of red blood cells can cause agglutination of red blood cells, leading to agglutination-mediated circulatory symptoms in 40–90% of patients with CAD [10,14]. Circulatory symptoms in CAD are often first observed in the exposed, peripheral vasculature [16].

Figure 1. The role of the complement pathway in CAD and mechanism of action of sutimlimab [3,10,18–21].

C, complement protein; Ig, immunoglobulin; MAC, membrane attack complex; MBL, mannose-binding lectin; RBC, red blood cell

The current diagnostic criteria for CAD include presence of chronic hemolysis, a positive polyspecific direct antiglobulin test (DAT) (Coombs Test), a monospecific DAT strongly positive for C3d (and negative or weakly positive with IgG), a cold agglutinin titer of 1:64 or greater at 4°C, and an absence of underlying clinical disease (infection, overt malignancy, autoimmune disease, or primary immunodeficiency) [4,9]. However, there are many symptoms associated with CAD that are not measured by the standard diagnostic tests including inflammation, fatigue, and risk of thrombosis.

CAD is associated with diverse symptoms, which can negatively affect quality of life [10,15,23,24]. Clinical heterogeneity of symptoms may be related to the predominant type of hemolysis (intravascular and/or extravascular), the thermal amplitude and efficiency in activating complement (rather than the autoantibody titer), and the efficacy of the generation of reticulocytes in response [25].

All patients with CAD have chronic hemolysis with or without anemia [17]. Any trigger of complement activation can exacerbate hemolysis, overwhelming the natural complement inhibitory proteins on red blood cells and increasing the amount of intravascular hemolysis [4]. Hemolytic anemia can be present with minimal to no circulatory symptoms, and vice versa [26]. In a cohort of 232 patients with CAD from Norway, Italy, the United Kingdom, Finland, and Denmark, more than 69% of patients were found to experience chronic hemolysis with no or mild vascular symptoms, while less than 10% of patients presented with circulatory symptoms with compensated hemolysis [13]. Most patients with CAD have mild circulatory symptoms (e.g. acrocyanosis), but in up to 20% of patients these mild symptoms progress and can lead to Raynaud’s phenomenon, ulcerations, and gangrene [26]. Fatigue is a frequently reported symptom, with more than 90% of patients experiencing fatigue due to CAD and more than half reporting their symptoms as severe or moderate [27,28]. Fatigue experienced by patients with CAD is multifactorial with contributions by classical complement pathway activation and chronic inflammation, in addition to being the result of chronic anemia [27,28]. CAD has been shown to be associated with a significantly increased risk of thromboembolism, both venous and arterial, compared with matched controls [29–32]. Chronic complement activation in CAD may promote thrombus formation independently of hemolysis via increased platelet aggregation, tissue factor expression, or procoagulant extracellular vesicle release [32]. Patients with CAD also have an increased mortality risk [29,33]. Ongoing hemolysis, anemia, and complement activation are all believed to contribute to an increased risk for thromboembolic events and mortality in CAD [25,32].

CAD symptoms, particularly fatigue, place a profound burden on patients, with multiple negative impacts on everyday life, affecting psychological and physical well-being and reducing quality of life [28,34]. It has been found that patients with CAD are 60% more likely to have medically attended anxiety or depression than matched comparisons [8].

Clinical symptoms of CAD are often underestimated and use of active treatment is often delayed or not employed at all [4]. Moreover, CAD is associated with high healthcare utilization and costs, including high rates of hospital admission, length of hospital stay, emergency room admissions, outpatient visits, and transfusions [23,35–37]. Until recently, there was no approved treatment for patients with CAD, and treatment approaches and responses remain inconsistent, with many patients found to relapse despite multiple lines of therapy [23].

Current unapproved therapeutic approaches to CAD are often associated with inadequate efficacy, delayed or transient response, and safety issues [4,9,11,14,23,38]. In addition, some therapies may impair patients’ response to vaccines (and COVID-19 vaccination) due to their immunosuppressive effect [14,39]. There has been a substantial unmet need for an approved, non-cytotoxic pharmacotherapy with a fast onset of action, high response rates, long duration of response, and a favorable safety and tolerability profile [4,11,38].

This article aims to provide a concise review of the pharmacology, clinical efficacy, and tolerability of sutimlimab, a humanized monoclonal antibody that selectively inhibits complement component C1s, including a critical appraisal of the most important and up-to-date information and an expert view on the role of the sutimlimab in clinical practice.

2. Overview of the therapeutic landscape

2.1. Treatment goals

For patients with CAD with symptoms related to anemia, the treatment goal has been to increase hemoglobin levels [9]. Additional goals of treatment may be to achieve long-term control of the lymphoproliferative disorder because this can be associated with hematologic remission [9]. All treatments should aim to reduce the risk of thromboembolic events and mortality and improve quality of life, although little evaluation of treatment effects on these goals has been done in the past [9].

For patients without relevant symptoms, it has been recommended to watch and wait [9]. However, approximately 70% of patients will require pharmacologic treatment eventually [15]. Chronic symptomatic anemia is the most common reason cited for treatment [15]. The results of the Stanford Healthcare Study suggested that 72% of patients with CAD had at least one severe anemia event within the first year of follow-up [23]. Acrocyanosis, although a common manifestation of CAD, it is not usually the driving indication for therapeutic management [9].

2.2. Recommended treatments

Currently recommended pharmacological treatments include the use of therapies that are not approved for CAD such as rituximab, a monoclonal antibody targeting CD20 on B-cells [9]. Rituximab has been used to treat CAD since the late 1990s; it is the most well-documented therapy for CAD and can be used first-line in symptomatic CAD as monotherapy or in combination with bendamustine [9,15].

Repeat treatment with rituximab monotherapy or combination treatment with rituximab and bendamustine, if not given as first-line, is recommended as second-line therapy [9]. Addition of fludarabine to rituximab therapy has been found to improve overall response rate and duration of response but can have more serious side effects, such as severe neutropenia [15]. Thus, rituximab–fludarabine combination may be considered as a second-line option in otherwise fit, elderly patients [9]. One of the main considerations for B-cell-directed therapy is the length of time it takes to see a response in hemoglobin levels [40].

For third-line options, it is recommended that patients are included in clinical trials if possible [9]. Recent clinical trials have focused on the complement inhibitors eculizumab and sutimlimab. Eculizumab is a monoclonal anti-C5 antibody and was the first complement inhibitor used for the treatment of severe CAD with primarily intravascular hemolysis [9]. Based on activity on the terminal portion of complement activation, eculizumab was shown to have benefit in reducing intravascular hemolysis but had no effect on extravascular hemolysis [41].

In emergency situations, as rescue therapy, blood transfusions with a blood warmer can be given to CAD patients, depending on hemoglobin levels [9]. The issues with compatibility during blood typing and cross matching are not the same as they are for warm AIHA [42]. Plasma exchange is also a potential emergency therapy for reducing the level of IgM in the plasma for transient benefit [9]; and use of terminal complement inhibitors such as eculizumab has been reported in situations of life-threatening cold agglutinin-mediated intravascular hemolysis [9].

2.3. Potential treatments

Other treatments with potential benefits for CAD include bortezomib, a reversible inhibitor against chymotrypsin-like activity of the 26S proteasome, which has been investigated in patients with relapsed CAD [9,43]; and pegcetacoplan (APL-2) is a pegylated compstatin analog, which is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and is being investigated in AIHA including CAD [9,44]. There is also some evidence suggesting that Bruton’s tyrosine kinase inhibition using ibrutinib could be an effective treatment for CAD or CAS-related acrocyanosis [45].

3. Introduction to sutimlimab

3.1. Sutimlimab mechanism of action

Sutimlimab is a humanized monoclonal IgG4 antibody which selectively targets complement component C1s, inhibiting the formation of the C1 complex and classical complement pathway activation (Figure 1) [18–20,46]. Binding of C1q to a cold-agglutinin–antigen-complex on the red blood cell surface initiates the classical complement cascade in CAD [4]. Sutimlimab inhibits classical complement pathway activation at this initial stage by targeting the C1-component C1s, a serine protease that cleaves C4 and C2 [20]. It does not affect the lectin and alternative pathways [20].

4. Clinical efficacy of sutimlimab

4.1. Overview of sutimlimab clinical development

Early-phase studies of sutimlimab included a Phase 1 study (NCT02502903) to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of sutimlimab in controlling anemia and hemolysis in patients with CAD (Figure 2) [19,20]. The study consisted of four sub-parts: a single ascending dose study (Part A) and a multiple ascending dose study (Part B), both in normal human volunteers; a multiple dose study (Part C) in patients with a complement-mediated disorder; and lastly a multiple dose study in patients with CAD previously treated within the scope of a clinical trial or named patient program (Part E). Data from this first-in-human trial showed the pharmacokinetics and pharmacodynamics were predictable and consistent in healthy volunteers [19]. In patients with CAD, sutimlimab was found to provide complement blockade and resolution of hemolysis, with an overall median increase in hemoglobin of 3.9 g/dL [19]. These clinically meaningful increases in hemoglobin levels resulted in all patients remaining transfusion-independent during sutimlimab treatment [19].

Figure 2. An overview of the clinical trial program for sutimlimab in CAD [19,20,46–51].

An open-label extension of the Phase 1 study was then conducted to evaluate the safety and efficacy of continuous long-term maintenance treatment with sutimlimab in patients with CAD [47,48]. In patients with CAD transitioning from the Phase 1 trial to the Phase 1b extension, re-exposure to sutimlimab following a period of discontinuation was safe, rapidly halted hemolysis, and increased hemoglobin levels [47]. Continued treatment with sutimlimab appeared safe and was found to effectively inhibit hemolysis [47].

Late-phase development of sutimlimab consisted of two Phase 3 clinical trials, CARDINAL and CADENZA, both completed in 2021 (Figure 2, Table 2) [46,49–51]. These studies also included important assessments of patient-reported outcomes, including changes in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short-Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change (PGIC), and Patient Global Impression of [fatigue] Severity (PGIS) scores.

Table 2. Summary of the Phase 3 CARDINAL and CADENZA studies [46,49–51].

Study name (ID), Phase, and participant number	Study design and eligibility criteria	Interventions		Endpoints	Sources
		Part A	Part B
CARDINAL Phase 3 (NCT03347396) n=24	Open-label, single-arm, multicenter study Key eligibility criteria: Baseline Hgb ≤10 g/dL Active hemolysis: total bilirubin above normal ≥1 blood transfusion within 6 months of enrollment No treatment with rituximab within 3 months or combination therapies within 6 months CAS excluded	All patients treated within one group: Intravenous, weight-based dosing at Days 0 and 7 and then biweekly thereafter <75 kg: 6.5 g; ≥75 kg: 7.5 g Treatment period: 26 weeks	Biweekly sutimlimab administration continued from Part A for up to 177 weeks Treatment period: up to 2 years after the last patient completed Part A Followed by post-treatment follow-up period: 9 weeks	Primary endpoint: Composite responder analysis (at the TAT):^a An increase from baseline in Hgb level ≥ 2 g/dL or a Hgb level ≥ 12 g/dL at the TAT AND No blood transfusion required Weeks 5 to 26 AND No treatment for CAD beyond what was permitted per protocol Secondary endpoints: Key disease-related markers Mean change from baseline in: Anemia (Hgb) Hemolysis (eg, total bilirubin, LDH) Quality of life (fatigue, as measured by FACIT-Fatigue) Transfusion use after the first 5 weeks	[46,49]
CADENZA Phase 3 (NCT03347422) n=42	Randomized, double-blind, placebo-controlled study Key eligibility criteria: Baseline Hgb ≤10 g/dL Bilirubin level above the normal reference range Exclusion of patients with a history of blood transfusion within CAS excluded	Patients randomized 1:1 into two treatment groups: Intravenous weight-based dosing of 6.5 g sutimlimab (<75 kg body weight) or 7.5 g sutimlimab (>75 kg body weight) on Days 0 and 7, followed by biweekly administration thereafter 6.5 g placebo (<75 kg body weight) or 7.5 g placebo (>75 kg body weight) on Days 0 and 7, followed by biweekly administration thereafter Treatment period: 26 weeks	To maintain blinding: crossover dose at Week 26 to allow placebo patients to receive a loading dose at the start of sutimlimab dosing throughout Part B All patients received biweekly sutimlimab from Week 27 for up to 177 weeks Treatment period: up to 1 year after the last patient completed Part A Followed by post-treatment follow-up period: 9 weeks	Primary endpoint: Composite responder analysis (at the TAT)^a An increase from baseline in Hgb level ≥ 1.5 g/dL at the TAT AND No blood transfusion required Weeks 5 to 26 AND No use of protocol-prohibited CAD medication from Weeks 5 to 26 Secondary endpoints: key disease-related markers Mean change from baseline in anemia at TAT (Hgb) Mean change from baseline in hemolysis at TAT (e.g., bilirubin, LDH) Mean change from baseline in quality of life at TAT (measured by Incidence of solicited symptomatic anemia at end of treatment	[50,51]

FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; Hgb, hemoglobin; LDH, lactate dehydrogenase; TAT, treatment assessment timepoint

^aDefined as the average of Weeks 23, 25, and 26

4.2. CARDINAL

CARDINAL (NCT03347396) was a two-part, open-label, single-arm, multicenter Phase 3 study to assess the efficacy and safety of sutimlimab in patients with CAD and a recent history of transfusion (Figure 2) [46]. The study consisted of a 26-week treatment period (Part A) and an extension period (Part B) for 2 years after the last patient completed Part A [46].

Patients enrolled in the CARDINAL study were ≥18 years of age with a confirmed CAD diagnosis, evidence of active hemolysis (screening hemoglobin ≤10 g/dL), and a history of recent transfusion in the prior 6 months. Sutimlimab was given intravenously on Days 0 and 7, followed by biweekly dosing for 26 weeks (Part A) and continuing for 2 years (Part B). The dose was based on weight, with patients weighing <75 kg receiving a 6.5 g dose and patients ≥75 kg receiving a 7.5 g dose. Patients included in the trial had to have been vaccinated against encapsulated bacterial pathogens within 5 years before enrollment [46].

The composite primary endpoint was a normalization of the hemoglobin level to ≥12 g/dL or an increase from baseline in hemoglobulin level ≥2 g/dL, without the need for blood transfusion between Week 5 and the end of Part A, or treatments for CAD prohibited by the protocol. Key secondary endpoints included the mean change from baseline to hemoglobin level; hemolysis, determined by bilirubin level and lactate dehydrogenase (LDH) level; quality of life, assessed using the FACIT-Fatigue score at the time of treatment assessment; and the number of blood transfusions received after the first 5 weeks of treatment [46].

A total of 24 patients were enrolled in Part A of the CARDINAL study and received ≥1 dose of sutimlimab. The baseline characteristics were consistent with those expected for a population with CAD. Most patients were female (62%), with a mean age of 71 years (Table 3) [46,52]. The mean number of transfusions during the prior year was 4.8 and the mean baseline hemoglobin level and mean FACIT-Fatigue score were 8.6 g/dL and 32.5, respectively. Ninety-two percent of patients (22 out of 24) completed Part A of the study and continued into Part B.

Table 3. Summary of the key patient demographics and baseline characteristics [46,51–53].

Parameter	CARDINAL [46,52]	CADENZA [51,53]
	Part A	Part A
	Sutimlimab (n=24)	Placebo group (n=20)	Sutimlimab group (n=22)
Age, years, mean (SD)	71.0 (8.0)	68.2 (10.1)	65.3 (10.9)
Female, n (%)	15 (62.5	16 (80.0)	17 (77.3)
Patients with transfusions in the prior year (CARDINAL, mean [SD]; CADENZA, n [%])	4.8 (6.2)	0 (0)	3 (13.6)
Patients with disabling circulatory symptoms, n (%)	2 (8.3)	0 (0)	3 (13.6)
Acrocyanosis, n (%)	3 (12.5)	4 (20.0)	9 (40.9)
Raynaud’s phenomenon, n (%)	1 (4.2)	3 (15.0)	5 (22.7)
Patients with ≥1 prior CAD therapy(s) within the last 5 years, n (%)	15 (62.5	15 (75.0)	16 (72.7)
Patients with a history of ≥1 thromboembolic event within the last year, n (%)	8 (33.3)	0 (0)	0 (0)
Baseline Hgb, g/dL, mean (SD)	8.6 (1.6)	9.3 (1.0)	9.2 (1.1)
Baseline total bilirubin, µmol/L, mean (SD)	51.0 (23.0)	35.8 (12)	41.2 (27)
Baseline PROs^a
FACIT-Fatigue score, mean (SD)	32.5 (10.6)	33.0 (10.9)	31.7 (12.8)
EQ-VAS (CARDINAL, mean [range]; CADENZA, mean [SD])	62.0 (25.0–80.0)	66.0 (18.8)	61.2 (19.5)
SF-12 physical component Score (CARDINAL, mean [range]; CADENZA, mean [SD])	38.69 (19.9–52.2)	39.0 (7.7)	43.4 (6.0)
SF-12 mental component score (CARDINAL, mean [range]; CADENZA, mean [SD])	49.83 (33.9–63.2)	49.8 (10.0)	43.9 (10.4)
	Sutimlimab (n=6)	Placebo group (n=15)	Sutimlimab group (n=17)
PGIS, patients (%) reporting each category
None	1 (16.7	2 (13.3)	3 (17.6)
Mild	1 (16.7)	4 (26.7)	6 (35.3)
Moderate	2 (33.3)	7 (46.7)	6 (35.3)
Severe	2 (33.3)	2 (13.3)	2 (11.8)
Very severe	0 (0)	0 (0)	0 (0)

CAD, cold agglutinin disease; EQ-VAS, EuroQol visual analogue scale; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; Hgb, hemoglobin; PGIS, Patient Global Impression of [fatigue] Severity; PRO, patient-reported outcome; SD, standard deviation; SF-12, 12-Item Short Form Health Survey

^aFACIT-Fatigue score range is 0 (worst fatigue) to 52 (no fatigue); EQ-VAS scale (0–100): worst health (0) to best health (100); SF-12 scores range from 0 to 100 (higher scores representing better self-reported health)

A total of 13 of the 24 patients (54%) enrolled in the study met the prespecified criteria for the primary endpoint (Table 4) [46,51,54]. Six of the 11 patients who did not meet the primary endpoint had evidence of a response, whereas three did not, and two patients discontinued the study for reasons that were unrelated to treatment with sutimlimab [46].

Table 4. Summary of the key efficacy results of the phase 3 CARDINAL and CADENZA studies at week 26 [46,51,54].

Parameter/Statistic	CARDINAL [46]	CADENZA [51,54]
	Part A	Part A
	Sutimlimab (n=24)	Placebo group (n=20)	Sutimlimab group (n=22)	Treatment effect
Responder^a, n (%; 95% CI)	13 (54)	3 (15; 3.2, 37.9)	16 (73; 49.8, 89.3)
Odds ratio (95% CI)				15.94 (2.88, 88.04)
P value				<0.001
Hgb, mean change from BL g/dL (LS mean (95% CI of LS mean)	2.60 (0.74, 4.46)	0.09 (−0.5, 0.68)	2.66 (2.09, 3.22)	2.56 (1.75, 3.38)
P value				<0.001
Mean number of transfusions (Week 5 to 26)	0.9	0.5 (1.1)	0.5 (0.2)	NC
Total bilirubin, mean, µmol/L	15.48 (0.76 x ULN)	33.95	12.12
Mean change from BL (LS mean)	−38.18	−1.83	−22.13	NC
Number of patients normalized (%)	13 (54.2)	4 (22.2)	15 (88.2)
FACIT-Fatigue Scale, mean score	44.26	33.66	43.15
Mean change from BL (LS mean)	10.85	1.91	10.83	8.93
95% CI of LS mean	(8.0, 13.7)	(−1.65, 5.46)	(7.45, 14.22)	(4, 13.85)
P value				<0.001

BL, baseline; CI, confidence interval; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; Hgb, hemoglobin; LS, least squares; NC, not calculated; ULN, upper limit of normal

^aA responder was defined as a patient with an increase from baseline in hemoglobin level ≥1.5 g/dL at the treatment assessment time point (mean value from Weeks 23, 25, and 26), no blood transfusion from Week 5 through Week 26, and no treatment for CAD beyond what was permitted per protocol from Week 5 through Week 26

The results of the pivotal Part A showed a significant 2.6 g/dL mean increase in hemoglobin level at the time of treatment assessment (Weeks 23, 25, and 26). The mean hemoglobin level was maintained at >11 g/dL in patients from Week 3 through to the end of the study period, and normalization of mean bilirubin levels was seen by Week 3 (Figure 3) [46,51]. The LDH level decreased to less than 1.5 times the upper limit of the normal range for the duration of treatment in 14 patients, and 17 of 24 patients (71%) did not receive a transfusion from Week 5 through to Week 26. Clinically meaningful reductions in fatigue were observed by the first week (mean score on the FACIT-Fatigue scale at baseline, 32.5; mean score at the time of treatment assessment, 44.3 [with a higher score indicating less fatigue]) and were maintained throughout the study. Functional assay for complement activation confirmed that sutimlimab rapidly inhibited the classic complement pathway and that inhibition of the classical complement pathway coincided with the increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue [46].

Figure 3. Effect of sutimlimab on A. hemoglobin levels and B. bilirubin levels from baseline to week 26 [46,51].

Figure adapted from Röth A, Barcellini W, D’Sa S, et al. Sutimlimab in Cold Agglutinin Disease. N Engl J Med. 8 April 2021;384(14):1323–1334 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; and reprinted from Röth A, Berentsen S, Barcellini W, et al. Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial. Blood. 1 September 2022;140(9):980–991 with permission from Elsevier.

One-year interim results of Part B of the CARDINAL study demonstrated continued inhibition of the classical complement pathway with sutimlimab and sustained treatment effects in CAD [55]. This was further supported by data from the 2-year follow-up of the long-term extension of the CARDINAL study which demonstrated continued inhibition of hemolysis, durable and stable hemoglobin levels maintained at >11 g/dL, normalization of mean total bilirubin, and sustained improvements in FACIT-Fatigue scores for up to 2 years [56]. Additionally, sutimlimab demonstrated reductions in the key symptomatic effects of CAD such as fatigue, weakness, and shortness of breath throughout Part B [56].

Results of patient-reported outcomes from the CARDINAL study showed that substantial improvements were observed in all 13 FACIT-Fatigue component domains from baseline to the end of Week 26 (Table 4). Increases in SF-12 scores (physical component score [PCS] and mental component score [MCS]) were also clinically meaningful, with a mean change from baseline of 5.37 and 4.47, respectively (Table 5) [52,53,57]; and were associated with a reduction in classical complement pathway activity and increased total C4 [52,53]. These changes were found to coincide with the increases in hemoglobin and normalization of bilirubin with sutimlimab treatment and suggested that classical complement activation and hemolysis may be drivers of fatigue and poor quality of life in CAD [52]. Improvements were also seen in EQ-5D-5 L index and VAS scores after initiation of sutimlimab, with a mean change from a baseline of 16.8, with the greatest improvements seen in the ‘usual activities’ domain. PGIC and PGIS ratings were also both improved at Week 26 (Table 5) [52].

Table 5. Summary of the change in patient-reported outcomes in the Phase 3 CARDINAL and CADENZA studies^a at week 26 [52,53,57].

Parameter/Statistic	CARDINAL [52]	CADENZA [53,57]
	Part A	Part A
	Sutimlimab (n=16)	Placebo group (n=18)	Sutimlimab group (n=18)
SF-12 physical component scores Mean (range [CARDINAL]) or LS mean (SE [CADENZA]) score change from BL	5.37 (−7, 16.0)	1.57 (1.44)	5.54 (1.44)
SF-12 mental component score Mean (range [CARDINAL]) or LS mean (SE [CADENZA]) score change from BL	4.47 (−1.8, 33.2)	−0.48 (2.25)	5.65 (2.25)
EQ-VAS score Mean (range [CARDINAL]) or LS mean (SE [CADENZA]) score change from BL	16.8 (−10.0, 45.0)	2.54 (3.77)	13.29 (3.77)
	Sutimlimab (n=17)	Placebo group (n=19)	Sutimlimab group (n=18)
PGIS, patients (%) reporting each category
None	2 (11.8)	2 (10.5)	6 (33.3)
Mild/moderate	11 (64.7)/4 (23.5)	11 (57.9)	11 (61.1)
Severe	0 (0)	6 (31.6)	1 (5.6)
Very severe	0 (0)	0	0

BL, baseline; EQ-VAS, EuroQol visual analogue scale; LS, least squares; PGIS, Patient Global Impression of [fatigue] Severity

^aA higher score represents improved quality of life

In addition, an ad hoc analysis of the data from patients from Part A of the CARDINAL study investigated the interplay between complement-mediated inflammation and fatigue by assessing the changes in inflammatory cytokines and their relation to fatigue [58]. Sutimlimab treatment resulted in rapid and durable decreases in proinflammatory cytokine interleukin (IL)-6 and regulatory cytokine IL-10 levels compared with baseline, with effects seen as early as Week 1. Decreased complement-mediated inflammation demonstrated by IL-6 and IL-10 changes occurred concurrently with FACIT-Fatigue score improvement over time, suggesting that complement-mediated inflammation likely contributes to the manifestation of fatigue in patients with CAD [58].

4.3. CADENZA

CADENZA (NCT03347422) was a two-part Phase 3 randomized, double-blind, placebo-controlled study, which assessed the safety and efficacy of sutimlimab in patients with CAD and no recent history of transfusion (Figure 2) [51]. The study consisted of a 26-week treatment period (Part A) and an open-label extension period (Part B) for a minimum of 1 year after the last patient completed Part A [51].

Patients eligible to enroll in the study had a confirmed CAD diagnosis, hemoglobin ≤10 g/dL, a bilirubin level above the normal reference range, and a ferritin level above the lower limit of normal. Patients were excluded if they had a history of blood transfusion within 6 months of screening, or ≥ 1 transfusion within the past year. Enrolled patients were randomized 1:1 to receive 26 weeks of either sutimlimab or placebo by a permuted block randomization. Sutimlimab (6.5 g for patients weighing <75 kg and 7.5 g for those with body weight ≥75 kg) or placebo was given by intravenous infusion on Days 0 and 7, followed by biweekly dosing through to Week 25 in Part A and continuing until 1 year in Part B. Documented vaccination against encapsulated bacteria within 5 years of enrollment was required [51].

The primary endpoint was a composite of hemoglobin increase from baseline of ≥1.5 g/dL at the treatment assessment time-point (average of Weeks 23, 25, and 26), absence of blood transfusions from Week 5 to Week 26, and avoidance of treatments for CAD prohibited by the protocol from Week 5 to Week 26. Key secondary endpoints included mean change from baseline hemoglobin, bilirubin, and LDH levels at the treatment assessment timepoint and FACIT-Fatigue scores. Additional efficacy endpoints were reticulocyte count, haptoglobin levels, and the number of patients achieving mean increases in hemoglobin levels (of ≥1 g/dL, ≥1.5 g/dL, ≥2 g/dL, and ≥3 g/dL) [51].

Forty-two of 66 screened patients were randomized to receive sutimlimab (n = 22) or placebo (n = 20). Thirty-nine patients (19 [86.4%] in the sutimlimab arm and 20 [100%] in the placebo arm) completed Part A of the study and continued into Part B. In Part A, baseline characteristics were typical of a CAD patient population with 78.6% women, and a median age of 66 years (Table 3) [51]. The mean hemoglobin levels were 9.3 g/dL and 9.2 g/dL, and the mean FACIT-Fatigue scores were 33.0 and 31.7, in the placebo and the sutimlimab arms, respectively. Sixteen (73%) of the patients treated with sutimlimab met the prespecified criteria for the composite primary endpoint and achieved the protocol-defined responder criteria compared with three (15%) patients who received placebo (Table 4) [46,51,54]. The odds of achieving the response criteria defined in the composite primary endpoint were significantly greater for patients who received 26 weeks of sutimlimab treatment than those receiving placebo (odds ratio 15.9; 95% CI: 2.9, 88.0; p < 0.001). Sixteen patients (73%) treated with sutimlimab compared with three patients (15%) who received placebo had increases in hemoglobin levels ≥1.5 g/dL from baseline at the treatment assessment timepoint, and hemoglobin levels were increased ≥2.0 g/dL from baseline in all 16 (100%) sutimlimab-treated patients compared with two patients (10.0%) on placebo. Eighteen patients (82%) in the sutimlimab arm and 16 patients (80%) in the placebo arm did not receive blood transfusions from Week 5 to Week 26 [51]. The majority of patients did not require the use of protocol-prohibited CAD treatments from Week 5 to Week 26 [51].

The three patients in the sutimlimab arm who did not meet the response criteria did not achieve the required ≥1.5 g/dL increase in hemoglobin from baseline to treatment assessment timepoint, and a blood transfusion was given to one patient. An additional three patients in the sutimlimab arm discontinued early due to treatment-emergent adverse events (TEAEs) and were excluded from the primary endpoint [51].

The mean hemoglobin level was maintained at ≥11 g/dL from Week 3 to the treatment assessment timepoint in the sutimlimab group, and sutimlimab led to rapid and sustained control of hemolysis. Within 1 to 3 weeks of sutimlimab, the mean total bilirubin was normalized and was maintained at levels below the upper limit of normal to Week 26 (Figure 3). Similar results were seen for LDH levels at the treatment assessment timepoint, with normalization in 11 (58%) patients in the sutimlimab arm and six (30%) patients in the placebo arm. The reticulocyte count was found to decrease as the hemoglobin level increased in patients treated with sutimlimab, and an increase in haptoglobin level coincided with a decrease in bilirubin level. These changes in the additional markers of hemolysis were not observed in the placebo arm [51].

By Week 1 the FACIT-Fatigue score had improved by ~ 5 points from baseline in the sutimlimab arm, compared with no change in the placebo arm, indicating a clinically meaningful improvement (Table 4) [51]. The least-squares mean change in FACIT-Fatigue from baseline to treatment assessment timepoint was 10.8 points in the sutimlimab arm compared with 1.9 points in the placebo arm (p < 0.001) [53]. Clinically important changes were also observed in component scores of SF-12 with a least-squares mean change from baseline to Week 26 of 5.54 versus 1.57 (p = 0.064) for physical (PCS) and 5.65 versus −0.48 (p = 0.065) in mental (MCS) scores (Table 5). Furthermore, most patients in the sutimlimab arm (73.7%) responded as ”improved” on the PGIC, although patient-perceived fatigue severity (PGIS) had worsened in 6.7% of patients in the sutimlimab arm and in 46.7% of patients in the placebo arm. Overall, these results showed that as well as improving hematological parameters, treatment with sutimlimab allowed significant patient-reported benefits versus placebo [53].

Of the 39 patients that completed Part A of the CADENZA study, 32 (82%) completed Part B [59]. Improvements in hemoglobin levels in patients previously treated with sutimlimab were sustained, and for those previously treated with placebo, rapid and comparable increases in hemoglobin were observed following initiation of sutimlimab. The normalization of mean total bilirubin with sutimlimab was sustained until last visit in Part B, and similar decreases were observed in those patients previously treated with placebo when they started sutimlimab treatment. Decreases in LDH levels and mean absolute reticulocyte and increases in haptoglobuin were maintained and those previously treated with placebo who had begun treatment with sutimlimab reached comparable levels. Similarly, improvements in mean FACIT-Fatigue scores were sustained in Part B in those previously treated with sutimlimab and rapidly reached comparable levels in those previously treated with placebo following initiation of sutimlimab [59]. The mean (SE) change from baseline in FACIT-Fatigue score was 8.0 points (2.8, n = 18) in patients who switched to sutimlimab treatment in Part B (13 weeks after sutimlimab initiation), and mean improvements were sustained above the clinically important change threshold for over 1 year from completion of Part A. Clinically meaningful improvements were also seen in the physical (PCS) and mental (MCS) SF-12 component score and EQ VAS was consistently increased from baseline in all patients. PGIC and PGIS also showed positive improvements throughout the treatment period up to Week 87 [60].

4.4. CADENCE

The real-world efficacy of sutimlimab in patients with CAD is planned to be investigated in the CADENCE registry [61]. The CADENCE registry aims to develop a large, international database of patients with CAD or CAS in order to collect prospective longitudinal data to increase understanding of patient and clinical characteristics, complications, and long-term clinical and patient-reported outcomes with treatment for CAD and CAS as well as gathering information about health-resource utilization. The estimated total number of subjects to be enrolled in the study is 400, and patients will be followed for up to 6 years [61].

5. Safety of sutimlimab

Sutimlimab has demonstrated an acceptable safety profile across the trials in patients with CAD [19,20,46,47,51]. Sutimlimab treatment was generally well tolerated, with adverse events consistent with an older and medically complex patient population. The most common adverse reactions reported in the CARDINAL and CADENZA studies included headache, hypertension, urinary tract infection, upper respiratory tract infection, nasopharyngitis, nausea, abdominal pain, infusion-related reactions, and acrocyanosis [46,54,60]. A summary of the safety data from 66 patients who participated in the CARDINAL and CADENZA studies is shown in Table 6. As well as recording TEAEs and treatment-emergent serious adverse events (TESAEs), key safety outcomes in the CARDINAL and CADENZA studies included assessment of hemolytic breakthrough, and infections of grade 3 or higher, changes observed autoimmune panel parameters, as well as other clinical laboratory evaluations [46,51].

Table 6. Summary of the safety data for sutimlimab from the phase 3 CARDINAL and CADENZA studies [46,51,56,59].

AE	CARDINAL		CADENZA
	Part A [46]	Part B [56]	Part A [51]		Part B^a [59]
	Sutimlimab (n=24)	Sutimlimab (n=22)	Placebo group (n=20)	Sutimlimab group (n=22)	Sutimlimab (n=39)
TEAEs, n	124	380	90	146	395
Patients with ≥1 TEAE, n (%)	22 (92)	22 (100)	20 (100)	21 (96)	36 (92)
Patients with ≥1 related TEAE, -n (%)	9 (37)	11 (50)	4 (20	8 (36)	16 (41)
Patients with ≥1 TEAE grade 3 or higher, n (%)	-	-	3 (15)	5 (23)	-
Patients with ≥1 TEAE infection grade 3 or higher, n (%)	-	-	1 (5)	2 (9)	-
TESAEs, n	16	37	3	4	11
Patients with ≥1 TESAE, n (%)	7 (29)	12 (55)	1 (5)	3 (14)	7 (18)
Patients with ≥1 related TESAE, -n (%)	0	2 (9)	0	1 (5)	1 (3)
Patients with ≥1 TESAE infection, n (%)	2 (8)	7 (32)	1 (5)	1 (5)	1 (3)
Total number of TESAE thromboembolic events, n	-	2	0	1	2
Patients with ≥1 TESAE thromboembolic event, n (%)	-	-	0	1 (5)	-
Patients who discontinued treatment and/or study owing to a TEAE, n (%)	1 (4)	3 (14)	0	3 (14)	1 (3)
Deaths, n (%)	1 (4)	2 (9)^b	0	0	1 (3)

AE, adverse event; TEAE, treatment-emergent adverse event; TESAE, treatment-emergent serious adverse event

^aOf 42 patients enrolled in Part A, 39 completed Part A and continued into Part B

^bBoth events with a fatal outcome were considered not related to sutimlimab by the investigator

In Part A of the CARDINAL study, ≥1 TEAE occurred during the treatment period in 22 of 24 patients (92%), and seven of 24 patients (29%) had ≥1 TESAE, which were deemed by the investigators not to be related to sutimlimab treatment. There were nine patients who experienced 13 mild-to-moderate adverse events that were considered by the investigator to be related to sutimlimab [46]. In Part A of the CADENZA study, it was found that 21 of 22 patients in the sutimlimab arm (96%) and 20 of 20 (100%) of patients in the placebo arm experienced ≥1 TEAE. The majority of TEAEs were considered not to be related to sutimlimab by the investigator. However, there were eight patients that experienced 28 TEAEs that were considered to be related to sutimlimab treatment, and four patients in the placebo group experienced seven TEAEs that were considered to be related to placebo administration by the investigator [51]. In the sutimlimab group, symptoms of headache, hypertension, rhinitis, Raynaud’s phenomenon, and acrocyanosis were more frequently reported than in the placebo group, with a difference of ≥3 patients between the groups. Three patients in the sutimlimab arm discontinued the study due to adverse events, while no patients in the placebo arm discontinued [46,51].

The long-term safety of sutimlimab was evaluated in the extension phase (Part B) of CARDINAL for 2 years and CADENZA for 1 year following the last patient out from Part A in each study [56,59]. In Part B of the CARDINAL study, 22 of 22 patients (100%) had ≥1 TEAE and 11 patients (50%) had ≥1 TEAE that was considered to be related to sutimlimab by the investigator [56]. In addition, 12 patients experienced ≥1 TESAE, with two patients experiencing ≥1 TESAEs related to sutimlimab and seven patients experiencing TESAEs of infection. There were no meningococcal infections identified. One patient had a fatal outcome 14 days following the last dose of sutimlimab after a TESAE of Klebsiella pneumoniae. Another patient died during the follow-up period after completion of the treatment phase in the study. Both deaths were considered not related to sutimlimab by the investigator. Three patients (13.6%) discontinued the study due to adverse events and two patients had TEAE of thromboembolic events. In Part B of the CADENZA study, 36 of 39 patients (92%) experienced ≥1 TEAE, and 16 patients (41%) experienced ≥1 TEAE that was considered to be related to sutimlimab by the investigator [59]. In total, there were 11 TESAEs in seven patients, with one TESAE of hypertension being assessed as related to sutimlimab by the investigator. There were two non-serious thromboembolic events observed in two patients with underlying risk factors for thromboembolism, and one patient had a serious TEAE of urinary tract infection. There was a fatal outcome in one patient with a history of tobacco use who experienced a TESAE of squamous cell carcinoma of the lung. Sutimlimab was withdrawn due to this event prior to the patient’s death [56,59].

It is recommended that patients with complement deficiencies be vaccinated for encapsulated bacteria to reduce the risk of encapsulated bacterial infections. Therefore, vaccination was a requirement for patients entering the sutimlimab clinical trial program. Patients receiving sutimlimab should be monitored for signs and symptoms of infection, infusion-related reactions, autoimmune disease, or recurrent hemolysis if treatment is interrupted [62]. No patients were found to develop systemic lupus erythematous or other autoimmune disorders or worsening of preexisting autoimmune disorders, and no serious hypersensitivity reactions or anaphylaxis were reported in either study [56,59].

Based on the results of the CARDINAL and CADENZA studies, sutimlimab has been approved in the US, the EU, and Japan for the treatment of CAD, and has received the FDA’s Breakthrough Therapy and Orphan Drug designations for CAD and the Orphan Drug designation in the EU for CAD [51,54,62–64]. There are currently no other therapies approved for the treatment of CAD, and a comparison of the recommended unapproved treatments for CAD versus sutimlimab is shown in Table 7 [13,40,41,46,51,65–69]. This includes a description of the clinical study design, efficacy, time to response, duration of therapy and level of toxicity associated with the treatments. It should be noted that sutimlimab has no effect on circulatory symptoms such as Raynaud’s phenomenon and acrocyanosis, as these are not complement-mediated symptoms [69]. These symptoms were reported as adverse events in patients treated with sutimlimab in both Phase 3 studies, CARDINAL and CADENZA, which is not unexpected due to the mechanism of action of sutimlimab [51,55]. Circulatory symptoms of CAD are often managed with thermal protection alone, but for patients who have severe circulatory symptoms with compensated hemolysis, sutimlimab monotherapy may not be suitable [9,69].

Table 7. Comparison of sutimlimab versus other unapproved therapies used for treatment of CAD including study design, efficacy, time to response, duration of response, and toxicity [13,40,41,43,46,51,65–68,69].

Drug(s) studied	Study design	Courses of therapy, n	OR, %	CR, %	Hgb increase, g/dL	Time to response	Response duration	Toxicity	Source
Complement-directed therapies
Sutimlimab	Open-label, single-arm (CARDINAL: Part A) (n=24)	-	54^a	-	2.6^d	As early as 1 week	Sustained (as long as treatment is continued)	Low	[46]
Sutimlimab	Randomized, double-blind, placebo-controlled (CADENZA: Part A) (n=42)	-	73^b	-	2.7^e	As early as 1 week	Sustained (as long as treatment is continued)	Low	[51]
Eculizumab	Prospective, bicentric, nonrandomized (DECADE) (n=13)	-	54^c	-	0.8^f	-	Maintained (as long as treatment is continued)	Low	[41]
B-cell-directed therapies
Rituximab	Prospective, nonrandomized (n=27)	37	54	4	4.0^g	1.5 months (median)	11 months (median, observed)	Low	[65]
Rituximab	Prospective, nonrandomized (n=20)	20	45	5	3.1^g	3 months (median)	6.5 months (median, observed)	Low	[66]
Bendamustine + rituximab	Prospective, nonrandomized (n=45)	45	71	40	4.0^g	1.9 months (median)	>32 months (median, observed)	Relatively low, manageable	[67]
Bendamustine + rituximab	Follow-up, part of larger study (n=45)	45	78	53	Not re-evaluated	24 months (maximum)	>88 months (median, estimated)	Long-term: low	[13]
Fludarabine + rituximab	Prospective, nonrandomized (n=29	29	76	21	3.1^g	4 months (median)	>66 months (median, estimated)	Significant	[68]
Bortezomib	Prospective, nonrandomized (GIMEMA) (n=19)	19	32	16	2.9^g	-	16 months (median, observed)	Low	[43]

CR, complete response; Hgb, hemoglobin; OR, overall response

^aThe composite primary endpoint was a normalization of hemoglobin level to ≥12 g/dL or an increase from baseline in hemoglobulin level ≥2 g/dL, without the need for blood transfusion between Week 5 and the end of Part A, or treatments for CAD prohibited by the protocol

^bThe primary endpoint was a composite of hemoglobin increase from baseline of ≥1.5 g/dL at the treatment assessment time-point (average of Weeks 23, 25, and 26), absence of blood transfusions from Week 5 to Week 26, and avoidance of treatments for CAD prohibited by the protocol from Week 5 to Week 26

^cResponder defined by a drop in the lactate dehydrogenase level ≥250 U/L

^dLeast squares mean change from baseline

^eMean change from baseline

^fMedian change from baseline

^gMedian increase among responders

Table adapted with permission of Elsevier, from Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137(10):1295–303; permission conveyed through Copyright Clearance Center, Inc.

The safety of sutimlimab will continue to be assessed in the CADENCE registry, which will include a cohort study to assess the safety and the effectiveness of sutimlimab in patients with CAD in a real-world setting, with at least 3 years’ follow-up [61].

6. Conclusion

Sutimlimab is the first approved treatment for CAD. Data from Phase 3 clinical trials demonstrate that sutimlimab treatment is generally well tolerated and results in rapid and sustained efficacy in patients with CAD (with and without a history of red blood cell transfusion), with markedly increased hemoglobin, rapidly inhibited hemolysis, and meaningfully improved quality of life and patient-reported outcomes. The evidence suggests that sutimlimab has the potential to be an important advancement in the treatment of CAD.

7. Expert opinion

Chronic complement activation has important effects beyond hemolysis, which must be considered as we manage patients with CAD. For example, the results of the ad hoc analysis of the Phase 3 CARDINAL study suggested that complement-mediated inflammation likely contributes to fatigue in patients with CAD, which is supported by improved FACIT-Fatigue scores following sutimlimab-mediated inhibition of the complement pathway [52,53,58]. Furthermore, the role of complement in reducing the risk of thromboembolism is supported by one study in CAD and several studies in PNH that demonstrated the benefit of complement inhibition in decreasing both hemolysis and thromboembolisms [32,70,71].

It has been demonstrated that the level at which the complement pathway is inhibited has implications for the efficacy and safety of complement inhibitors as treatments for CAD. Eculizumab, a C5 inhibitor which targets the terminal complement activation, has been found to be an effective treatment for PNH but is less efficacious for CAD. This difference in efficacy is based on the ability of eculizumab to only mitigate intravascular hemolysis and not the chronic extravascular hemolysis in CAD, as inhibition at C5 does not address the extravascular hemolysis mediated by C3b [12,14,72]. Pegcetacoplan, which inhibits the complement pathway at the C3 level, has been shown to have efficacy in PNH as well as AIHA, including CAD [12,14,72]. The complement blockade induced by C3 inhibition, which does not allow complete activation of either the lectin or alternative pathways, may pose a greater risk of severe infection than inhibition at the C1 level. C1 inhibition with sutimlimab targets only the classical complement pathway, leaving the alternative and lectin pathways intact to generate complement components if needed [12,14,72].

Corticosteroids continue to be used at very high doses for long periods of time for the treatment of CAD, despite a lack of efficacy and recommendations by the international consensus group that they not be utilized [9,11,13,73]. Rituximab monotherapy while relatively nontoxic has been shown to have lower response rates in CAD than in other AIHAs [73]. Time to response in CAD ranges from 1 to 8 months, which falls short of the rapid improvements many patients need [74]. Based on this, more immunosuppressive treatments are often required to achieve efficacy, which can limit their use [12,72,73]. The combination of rituximab with fludarabine or bendamustine increased efficacy in CAD compared with rituximab monotherapy but also presented greater side effects, with some grade 3–4 hematological toxicity demonstrated with rituximab plus fludarabine [67,68]. Combination B-cell directed therapy with bendamustine plus rituximab has been shown to have a median time to response of 1.9 months and a median time to best response of 7.0 months [67]. In contrast, in the CARDINAL and CADENZA studies, C1s inhibition with sutimlimab increased mean hemoglobin levels within the first week [46,51]. Additional concerns regarding B-cell targeted therapies include their association with an impaired response to COVID-19 and other vaccinations [75]. Conversely, COVID-19 vaccination response was found to be adequate in patients being treated with sutimlimab [76].

In CAD, complement inhibition therapy with sutimlimab can also provide rapid clinical response when used in patients who have been refractory to treatment, in those who have lost response to prior therapy, or in emergency situations [9,77]. Considerations of evaluating classical complement pathway targeted therapy use in alleviating anemia and systemic inflammatory symptoms as a bridge while also initiating B-cell-directed therapy to attempt to irradicate the B-cell clone and effect a durable remission have been raised. However, evidence for the use of a combination of complement inhibition and immunosuppressive therapy in CAD is currently lacking [78].

Clinical data available to date support the positive benefit–risk profile of sutimlimab in both transfusion-dependent and ‘milder’ forms of CAD, with rapid and sustained effects on hemolysis and meaningful improvements in fatigue and quality-of-life measures [56,59]. There are preliminary data to suggest that C1 inhibition may also provide an efficacious acute-management tool in CAS [72]. Patients with CAS will be included in the CADENCE sutimlimab cohort study [61]. This international CAD registry will contribute to increased understanding of CAD and CAS and allow observation of findings that may not be seen in a short clinical trial.

As we look to the future, an increased understanding of disease characteristics or predictors of response may support clinicians in their management of CAD. The clinical phenotypic variations seen in CAD may, in fact, inform the best algorithm for clinical management. For example, patients who have hemolysis, thrombosis, or other signs of chronic complement activation may be better managed with regimens that include classical complement pathway inhibition plus or minus B-cell-directed therapy. In contrast, patients who have mainly acrocyanotic symptoms, which are IgM-mediated, may benefit more from aggressive B-cell-directed therapy, as control of acrocyanosis may not be achieved with complement-based therapy.

Looking ahead, it is likely that, as we continue to evaluate and understand the pathophysiology of CAD, the clinical practice of managing CAD will evolve to a more holistic approach. We will hopefully have the tools to monitor and evaluate not only laboratory parameters and the physical impact of the disease but also the functional, cognitive, and emotional health effects CAD has on the patient. Ultimately, the choice of therapy in CAD must be individualized to address the underlying pathophysiology of the symptoms of CAD patients but also to address the patients’ goals of treatment [72].

Article highlights

• Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia recognized as a low-grade lymphoproliferative disorder without any underlying or associated disease, which causes hemolysis and anemia via complement activation and acrocyanosis via immunoglobulin M (IgM) mediated agglutination of red blood cells

• CAD symptoms can have a profound negative impact on everyday life and current unapproved treatment options for CAD are associated with inconsistent and delayed responses and safety issues

• Sutimlimab is a humanized monoclonal antibody that selectively targets complement factor C1s, resulting in inhibition of the classical complement pathway

• Two Phase 3 trials, CARDINAL and CADENZA, demonstrated that treatment with sutimlimab results in a rapid and sustained treatment effect in most patients with CAD, halting hemolysis, markedly increasing hemoglobin levels, reducing fatigue, and improving quality of life, with an acceptable safety profile

• The CADENCE registry will assess the safety and effectiveness of sutimlimab in patients with CAD in a real-world setting

• Currently, sutimlimab is approved in the US, the EU, and Japan for the treatment of CAD and has the potential to be an important advancement as part of a holistic approach to CAD management

Declaration of interest

CM Broome has received honoraria from Sanofi,Alexion, Incyte, Argenx and Dianthus.Theauthors have no other relevant affiliations or financial involvementwith any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials discussed inthe manuscript apart from those disclosed.

Abbreviations

AE	=	adverse events
AIHA	=	autoimmune hemolytic anemia
BL	=	baseline
BTK	=	Bruton’s tyrosine kinase
C	=	complement protein
CAD	=	cold agglutinin disease
CAS	=	cold agglutinin syndrome
CI	=	confidence interval
CR	=	complete response
DAT	=	direct antiglobulin test
EQ-VAS	=	EuroQol visual analogue scale
FACIT-Fatigue	=	Functional Assessment of Chronic Illness Therapy-Fatigue
Hgb	=	hemoglobin
Ig	=	immunoglobulin
IgA	=	immunoglobulin A
IgG	=	immunoglobulin G
IgM	=	immunoglobulin M
IL	=	interleukin
LDH	=	lactate dehydrogenase
LS	=	least squares
MAC	=	membrane attack complex
MAD	=	multiple ascending dose
MBL	=	mannose-binding lectin
MCS	=	mental component score
NC	=	not calculated
NPP	=	named patient program
OR	=	overall response
PCS	=	physical component score
PD	=	pharmacodynamic
PGIC	=	Patient Global Impression of Change
PGIS	=	Patient Global Impression of [fatigue] Severity
PNH	=	paroxysmal nocturnal hemoglobinuria
PRO	=	patient-reported outcomes
RBC	=	red blood cell
SAD	=	single ascending dose
SD	=	standard deviation
ST-12	=	12-Item Short Form Health Survey
TAT	=	treatment assessment timepoint
TEAE	=	treatment-emergent adverse event
TESAE	=	treatment-emergent serious adverse event
ULN	=	upper limit of normal

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Medical writing support in line with Good Publication Practice guidelines was provided by Emily Foster of Lucid Group Communications Ltd. This support was funded by Sanofi in line with Good Publication Practice guidelines.

Additional information

Funding

Sanofi funded the medical writing support for this manuscript only.