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nipocalimab
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Nipocalimab - Overview of the Phase 2/3 ENERGY Clinical Trial

Last Updated: 06/25/2026

SUMMARY

  • The company cannot recommend any unapproved practices, procedures, or usage of nipocalimab.
  • ENERGY is a phase 2/3, multicenter, randomized, double-blind, placebo (PBO)-controlled study evaluating the efficacy and safety of nipocalimab vs PBO for the treatment of wAIHA (NCT04119050).1,2
    • Durable hemoglobin (Hgb) response was achieved by 23.7% of patients in the nipocalimab 30 mg/kg every 4 week (Q4W) group and 21.1% of patients in the nipocalimab 15 mg/kg every 2 weeks (Q2W) group compared to 7.7% of patients in the PBO group.
    • The mean change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue total score to week 24 was 3.4, 1.2, and 0.6 in the nipocalimab 30 mg/kg Q4W, 15 mg/kg Q2W, and PBO groups, respectively.3
    • A greater mean percent reduction in average daily dose of prednisone or equivalent from baseline to week 24 was observed with nipocalimab compared to PBO (nipocalimab 30 mg/kg Q4W, 15.1%; 15 mg/kg Q2W, 14.0%; PBO, 3.9%).1
    • The most commonly reported (≥10%) adverse events (AEs) occurring in the combined nipocalimab groups were wAIHA (37.2%), diarrhea (11.5%), and fatigue and pyrexia (both 10.3%).

BACKGROUND

  • wAIHA is the most prevalent type of autoimmune hemolytic anemia (AIHA), comprising approximately 60% of cases.4 It is characterized by the presence of autoantibodies (IgG or IgG+ C3d5) that bind to red blood cell (RBC) antigens and prematurely destroy RBCs through hemolysis.6,7 These autoantibodies and/or complement fragments on RBCs are detected by a direct antiglobulin test (DAT), also known as a direct Coombs test; although some patients with wAIHA may be DAT negative.7
  • wAIHA is termed “warm” due to active antibodies causing hemolysis at body temperature (37°C).4 Clinical symptoms of wAIHA include fatigue, exertional dyspnea, dizziness, jaundice, and darkened urine, whereas laboratory findings include anemia, reticulocytosis, elevated lactate dehydrogenase and unconjugated bilirubin, and reduced haptoglobin.7,8
  • wAIHA is classified into 2 categories6,9,10:
    • Primary wAIHA: no specific etiology identified and occurring in approximately half of the cases
    • Secondary wAIHA: primarily caused by underlying conditions, such as B-cell lymphoma, antiphospholipid syndrome, diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, or chronic lymphocytic leukemia.

CLINICAL DATA

Phase 2/3 Study: ENERGY

A phase 2/3, randomized, PBO-controlled, double-blind, multicenter study (ENERGY) evaluated the efficacy and safety of nipocalimab vs PBO for the treatment of wAIHA over 24 weeks.1

Study Design/Methods

ENERGY Study Design1,2,11,12,a

Abbreviations: AIHA, autoimmune hemolytic anemia; C3d, complement component 3d; DAT, direct antiglobulin test; FACIT, Functional Assessment of Chronic Illness Therapy; Hgb, hemoglobin; Ig, immunoglobulin; IgG, immunoglobulin G; IV, intravenous; LDH, lactate dehydrogenase; LLN, lower limit of normal; OLE, open-label extension; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; R, randomization; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; ULN, upper limit of normal; wAIHA, warm autoimmune hemolytic anemia
aPatients will be followed for 8 weeks after their last dose.
bIf on treatment: stable corticosteroid dose during the screening period or for ≥14 days before randomization, whichever is longer; stable immunosuppressant (azathioprine, mycophenolate mofetil/mycophenolic acid, methotrexate, tacrolimus, cyclosporine, or cyclophosphamide) dose for ≥12 weeks before screening and during the screening period. If any of these drugs were stopped, they must have been stopped for ≥8 weeks before screening.
cStratification factors included primary or versus secondary wAIHA; screening hemoglobin ≤8.5 g/dL or versus >8.5 g/dL; no treatment or corticosteroids at dose ≤20 mg/day of prednisone or equivalent with no immunosuppressants versus immunosuppressants or corticosteroids at >20 mg/day of prednisone or equivalent or no such treatment.
dPatients requiring rescue therapy at or after week 4 or patients with inadequate response at or after week 16 were allowed early escape to OLE.
ePatients on corticosteroids meeting the primary endpoint are required to taper corticosteroids by 10% Q2W.
fPatients who received PBO during the double-blind period will be randomized 1:1 to receive nipocalimab as an intravenous infusion either Q2W or Q4W in OLE. Patients who received nipocalimab during the double-blind period will be assigned to receive nipocalimab as an intravenous infusion either Q2W or Q4W based on the prespecified objective criteria in OLE.
gFor patients receiving them at baseline.

Results

Baseline Demographics


Baseline Demographic Characteristics1
Characteristic
Nipocalimab
PBO
(n=39)
30 mg/kg Q4W
(n=38)
15 mg/kg Q2W
(n=38)
Age, years, mean (range)
56.1 (24-79)
53.1 (18-80)
59.9 (24-86)
Female, %
55
58
51
Primary wAIHA, %
92
87
82
Time since diagnosis of disease, months, median (IQR)
32
(20-60)
44
(21-81)
23
(17-71)
Baseline Hgb, g/dL, mean (SD)
9.2 (1.4)
8.6 (1.3)
9.0 (1.4)
FACIT-Fatigue score, mean (SD)
34.5 (10.7)
35.0 (10.5)
31.1 (12.2)
Current treatment for wAIHA, %
   Any concomitant corticosteroid
74
87
77
   Immunosuppressants or
   corticosteroids at >20 mg/day of
   prednisone or equivalent
45
39
46
Prior treatments for wAIHA, %
   Rituximab
42
55
49
   Transfusions
58
58
59
   Splenectomy
3
16
10
Abbreviations: FACIT, Functional Assessment of Chronic Illness Therapy; Hgb, hemoglobin; IQR, interquartile range; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; SD, standard deviation; wAIHA, warm autoimmune hemolytic anemia.

Efficacy

Primary Endpoint and Primary Endpoint Related Analyses (Pre-planned)
  • Durable Hgb response was achieved by 23.7% and 21.1% of patients in the nipocalimab 30 mg/kg Q4W (P=0.015) and 15 mg/kg Q2W (P=0.044; not significant) groups, respectively compared to 7.7% of patients in the PBO group (see Table: Primary Endpoint: Durable Hemoglobin Response).

Primary Endpoint: Durable Hemoglobin Response1

Nipocalimab
PBO (n=39)
30 mg/kg Q4W
(n=38)
P-value vs PBO
15 mg/kg Q2W
(n=38)
P-value vs PBO
Durable Hgb response, n (%)
9 (23.7)
0.015
8 (21.1)
0.044a
3 (7.7)
Note: One-sided P<0.02499 vs PBO was considered significant.
Abbreviations: Hgb, hemoglobin; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks.
aNot significant.
  • An increase in mean Hgb change from baseline was observed at week 1 and was maintained throughout week 24, see Figure: Mean Change in Hgb Over Time.

Mean Change in Hgb Over Time1

Abbreviations: BL, baseline; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.


Components of Durable Hgb Response1
n (%)
Nipocalimab
PBO (n=39)
30 mg/kg Q4W
(n=38)
Nominal
P-value vs PBO
15 mg/kg Q2W
(n=38)
Nominal
P-value vs PBO
Hgb ≥10 g/dL and increase of ≥2 g/dL for ≥3 consecutive visits by week 24
11 (28.9)
<0.01
9 (23.7)
<0.02499
3 (7.7)
Hgb increase of ≥2 g/dL for ≥3 consecutive visits by week 16
10 (26.3)
<0.02499
9 (23.7)
-
3 (7.7)
Hgb ≥10 g/dL for ≥3 consecutive visits by week 16
21 (55.3)
-
14 (36.8)
-
14 (35.9)
Hgb increase of ≥2 g/dL for ≥1 visit by week 24
23 (60.5)
<0.001
18 (47.4)
<0.001
6 (15.4)
Hgb ≥10 g/dL and increase of ≥2 g/dL for ≥1 visit by week 24
23 (60.5)
<0.001
16 (42.1)
<0.01
6 (15.4)
Note: All P-values are nominal for nipocalimab vs PBO. The endpoint was not controlled for multiple comparisons. Therefore, the P-value is nominal, and statistical significance has not been established.
Abbreviations: Hgb, hemoglobin; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks.
Key Secondary Endpoints

FACIT-Fatigue Total Score Endpoint Results3
Nipocalimab
PBO (n=39)
30 mg/kg Q4W
(n=38)
Nominal P-value vs PBO
15 mg/kg Q2W
(n=38)
Nominal P-value vs PBO
Change from baseline at week 24, mean
3.4
0.007
1.2
0.267
0.6
Note: All P-values are nominal for nipocalimab vs PBO. The endpoint was not controlled for multiple comparisons. Therefore, the P-value is nominal, and statistical significance has not been established.
Abbreviations: FACIT, Functional Assessment of Chronic Illness Therapy; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; SD, standard deviation.

FACIT-Fatigue Total Score Over Time1

Abbreviations: FACIT, Functional Assessment of Chronic Illness Therapy; Hgb, hemoglobin; OLE, open-label extension; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.
aPatients meeting failure criteria (i.e. presence of symptoms and failure to demonstrate ≥1 g/dL Hgb increase) at or after Week 16 were, at the investigator’s discretion, allowed to discontinue double-blinded treatment and early escape to the OLE.


Corticosteroid Dose Reduction1
Nipocalimab
PBO (n=28)
30 mg/kg Q4W
(n=26)
Nominal P-value vs PBO
15 mg/kg Q2W
(n=32)
Nominal P-value vs PBO
Mean (SD) percent reduction in average daily dose of corticosteroids at week 24, %
-15.1
(28.24)
0.039
-14.0
(30.42)
0.055
-3.9 (16.33)
Note: All P-values are nominal for nipocalimab vs PBO. The endpoint was not controlled for multiple comparisons. Therefore, the P-value is nominal, and statistical significance has not been established.
Abbreviations: PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; SD, standard deviation.

Safety

  • Overall, TEAEs were comparable between PBO and nipocalimab groups. For a summary of adverse events, see Table: Summary of AEs

Summary of AEs1
AE, n (%)
Nipocalimab
PBO
(n=39)
30 mg/kg Q4W (n=38)
15 mg/kg Q2W (n=37)a
TEAEs
35 (92.1)
30 (81.1)
35 (89.7)
SAEs
8 (21.1)
6 (16.2)
14 (35.9)
AEs leading to treatment discontinuation
2 (5.3)
5 (13.5)
1 (2.6)
AEs of interest
   Grade ≥3 infections
2 (5.3)
3 (8.1)
5 (12.8)
   MACE
0
2 (5.4)b
0
   VTE (DVT and/or PE)
1 (2.6)
0
0
   Hypoalbuminemia (albumin <20 g/L)
0
0
0
Death
0
2 (5.4)
0
Abbreviations: AE, adverse event; DVT, deep vein thrombosis; MACE, major adverse cardiovascular event; PBO, placebo; PE, pulmonary embolism; Q2W, every 2 weeks; Q4W, every 4 weeks; SAE, serious adverse event; TEAE, treatment-emergent adverse event; VTE, venous thromboembolism;.
aOne patient was randomized to nipocalimab 15 mg/kg Q2W, but did not receive nipocalimab.
bTwo cases of MACE occurred in patients with complex medical histories in the nipocalimab 15 mg/kg Q2W group, later leading to death (causes of death were not related to study treatment).

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) was conducted on 11 June 2026.

References

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1 Fattizzo B, Murakhovskaya I, Ueda Y, et al. Nipocalimab for warm autoimmune hemolytic anemia: results from the phase 2/3 randomized double-blind ENERGY study. Oral presentation presented at: European Hematology Association (EHA) Congress; June 11-14, 2026; Stockholm, Sweden.  
2 Janssen Research & Development, LLC. Efficacy and safety of M281 in adults with warm autoimmune hemolytic anemia (ENERGY). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 June 5]. Available from: https://clinicaltrials.gov/study/NCT04119050 NLM Identifier NCT04119050.  
3 Murakhovskaya I, Fattizzo B, Ueda Y, et al. Assessment of nipocalimab effects on fatigue in warm autoimmune hemolytic anemia: results from the double-blind phase 2/3 ENERGY trial. Oral presentation presented at: European Hematology Association (EHA) Congress; June 11–14, 2026; Stockholm, Sweden.  
4 Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282(6281):2023-2027.  
5 Toapanta FR, Ross TM. Complement-mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity. Immunol Res. 2006;36(1-3):197-210.  
6 Sudulagunta SR, Kumbhat M, Sodalagunta MB, et al. Warm autoimmune hemolytic anemia: clinical profile and management. J Hematol. 2017;6(1):12-20.  
7 Kalfa TA. Warm antibody autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2016;2016(1):690-697.  
8 Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: new insights based on a single‐center experience with 60 patients. Am J Hematol. 2014;89(9):E150-E155.  
9 Alonso HC, Manuel AV, Amir CG, et al. Warm autoimmune hemolytic anemia: experience from a single referral center in Mexico City. Blood Res. 2017;52(1):44-49.  
10 Tranekær S, Hansen DL, Frederiksen H. Epidemiology of secondary warm autoimmune haemolytic anaemia - a systematic review and meta-analysis. J Clin Med. 2021;10(6):1244.  
11 Murakhovskaya I, Fattizzo B, Cueto D, et al. Study design of a phase 2/3, randomised, double-blind, placebo-controlled study to assess the efficacy and safety of nipocalimab, an FcRn antagonist, in warm autoimmune haemolytic anaemia (wAIHA). Poster presented at: European Hematology Association (EHA); June 9-17, 2021; Virtual.  
12 Murakhovskaya I, Fattizzo B, Ebrahim T, et al. ENERGY trial in warm autoimmune hemolytic anemia (wAIHA): Design of a phase 2/3 randomized, double-blind, placebo-controlled study to assess the efficacy and safety of nipocalimab, an FcRN blocker. Poster presented at: 43rd Annual Congress of the French Society of Hematology (SFH); March 29-31, 2023; Paris.  

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