Complement-directed therapy for cold agglutinin disease: sutimlimab

Figures & data

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

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

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

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

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)

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

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.

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

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

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.

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