IMAAVY - Overview of the Phase 2/3 ENERGY Clinical Trial

SUMMARY

• The company cannot recommend any practices, procedures, or usage of IMAAVY that deviate from the approved labeling.
• ENERGY is a phase 2/3, multicenter, randomized, double-blind, placebo (PBO)-controlled study evaluating the efficacy and safety of IMAAVY vs PBO for the treatment of wAIHA (NCT04119050).^1,2
  • Durable hemoglobin (Hgb) response was achieved by 23.7% of patients in the IMAAVY 30 mg/kg every 4 week (Q4W) group and 21.1% of patients in the IMAAVY 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 at week 24 was 3.4, 1.2, and 0.6 in the IMAAVY 30 mg/kg Q4W, 15 mg/kg Q2W, and PBO groups, respectively.
  • A greater mean percent reduction in average daily dose of prednisone or equivalent from baseline to week 24 was observed with IMAAVY compared to PBO (IMAAVY 30 mg/kg Q4W, 15.1%; 15 mg/kg Q2W, 14.0%; PBO, 3.9%).
  • Most commonly reported (≥10%) treatment-emergent adverse events (TEAEs) occurring in the IMAAVY groups were wAIHA (as reported by the investigators), diarrhea, dizziness, headache, asthenia, peripheral edema, pyrexia, fatigue, and coronavirus disease 2019 (COVID-19).

BACKGROUND

• wAIHA is the most prevalent type of autoimmune hemolytic anemia (AIHA), comprising approximately 60% of cases.³ It is characterized by the presence of autoantibodies (IgG or IgG+ complement component 3d [C3d]⁴) that bind to red blood cell (RBC) antigens and prematurely destroy RBCs through hemolysis.^5,6 These autoantibodies and/or complement fragments on RBCs can be detected by a direct antiglobulin test (DAT), also known as a direct Coombs test.⁶
• wAIHA is termed “warm” due to active antibodies causing hemolysis at body temperature (37°C).³ 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.^6,7
• wAIHA is classified into 2 categories^5,8,9:
  • 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) is currently evaluating the efficacy and safety of IMAAVY vs PBO for the treatment of wAIHA.²

Study Design/Methods

• The study design is shown in Figure: ENERGY Study Design.
• The efficacy analysis population included the full analysis set which was defined as all randomized patients excluding those randomized to receive IMAAVY 30 mg/kg IV Q2W (a regimen which was subsequently discontinued [n=3]).
  • Patients with missing data were treated as not meeting the criteria for the primary endpoint at that visit.
  • Patients who did not achieve durable Hgb response were considered nonresponders.
• The safety analysis population included all randomized patients who received any dose of study treatment, which included the 3 patients who received IMAAVY 30 mg/kg IV Q2W.

Results

Patient Disposition and Baseline Characteristics

• A total of 118 patients were randomized of which 117 patients received any dose of IMAAVY (safety analysis population).
• The efficacy analysis population included 115 patients (IMAAVY 30 mg/kg Q4W, n=38; 15 mg/kg Q2W, n=38; PBO, n=39). For baseline demographics, see Table: Baseline Demographic Characteristics.
• In the IMAAVY 30 mg/kg Q4W, 15 mg/kg Q2W, and PBO groups, 23.7% (9/38), 21.1% (8/38), and 56.4% (22/39) of patients had early escape to the open-label extension (OLE) phase, respectively.
  • Rescue therapy was required by 44.7% (17/38), 26.3% (10/38), and 51.3% (20/39) of patients in the IMAAVY 30 mg/kg Q4W, 15 mg/kg Q2W, and PBO groups, respectively.

Efficacy

Primary Endpoint and Primary Endpoint Related Analyses (Pre-planned)

• Durable Hgb response was achieved by 22.4% (17/76) in the combined IMAAVY group compared to 7.7% (3/39) in the PBO group (P=0.017).
  • Specifically, 23.7% and 21.1% of patients in the IMAAVY 30 mg/kg Q4W (P=0.015) and 15 mg/kg Q2W (P=0.044; not significant) groups achieved durable Hgb response, respectively (see Table: Primary Endpoint: Durable Hgb Response).

• The mean time to first durable Hgb response was 4.7 weeks, 5.0 weeks, and 10.6 weeks in the IMAAVY 30 mg/kg Q4W, 15 mg/kg Q2W, and PBO groups, respectively (see Figure: Time to First Date of Durable Hgb Response).

• The median duration of durable response from the double-blind period including those continuing the same dose into the OLE was 13.3 (interquartile range [IQR]), 10.1-46.1) weeks in the IMAAVY 30 mg/kg Q4W group, 15.1 (IQR, 9.6-22.9) weeks in the 15 mg/kg Q2W group, and 4.9 (IQR, 4.1-15.9) weeks in the PBO group.
• An increase in mean Hgb change from baseline was observed at week 1 (IMAAVY 30 mg/kg Q4W, 1.0 g/dL and 15 mg/kg Q2W, 0.6 g/dL), see Figure: Mean Change in Hemoglobin Over Time.
• Mean absolute Hgb was maintained between 9.8 and 10.7 g/dL post baseline through week 24 in the IMAAVY 30 mg/kg Q4W group.

• Additional prespecified Hgb response related analyses are summarized in Table: Components of Durable Hgb Response.

Post-hoc Analysis: Last Observation Carried Forward (LOCF)

• In an LOCF analysis, the mean hemoglobin level for PBO was below baseline through week 24 (see Figure: Mean Change in Hemoglobin Through Week 24, Last Observation Carried Forward).

Key Secondary Endpoints

• The mean change from baseline at week 24 in FACIT-Fatigue score results are summarized in Table: FACIT-Fatigue Total Score Endpoint Results.
• The least squares (LS) mean change in FACIT-Fatigue score at week 24 was 2.95 (95% confidence interval [CI], 0.84-5.07) and -0.56 (95% CI, -2.57 to 1.46) in patients receiving IMAAVY 30 mg/kg Q4W and PBO, respectively.¹¹
• In the IMAAVY group, improvement in FACIT-Fatigue total score was seen as early as week 2 (see Figure: FACIT-Fatigue Total Score Over Time).

• Corticosteroid dose reduction from baseline to week 24 was observed in the IMAAVY groups (see Table: Corticosteroid Dose Reduction).
  • The mean (SD) absolute prednisone-equivalent daily dose reduction was 3.7 (8.3), 2.5 (6.8), and 0.7 (2.7) mg for IMAAVY 30 mg/kg Q4W, 15 mg/kg Q2W, and PBO groups, respectively.

Hemolytic and Hematologic Markers

• Normalization of indirect bilirubin was reported in 55.3% of patients receiving IMAAVY 30 mg/kg Q4W, 44.7% receiving IMAAVY 15 mg/kg Q2W, and 25.6% receiving PBO.
• Hgb increase of ≥2 g/dL with normalization of indirect bilirubin, lactate dehydrogenase, and haptoglobin was reported in 13.2% of patients receiving IMAAVY 30 mg/kg Q4W, and 2.6% receiving PBO. It was not reported in the IMAAVY 15 mg/kg Q2W group.
• Among patients receiving IMAAVY 30 mg/kg Q4W who achieved durable Hgb response, mean indirect bilirubin levels decreased by week 2 and remained below baseline during the double‑blind phase.

Safety

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

Pharmacodynamics

• IMAAVY resulted in a dose-dependent reduction in total IgG levels.²
  • At week 1, the median reduction in total IgG from baseline was 69% in the IMAAVY 30 mg/kg Q4W group and 60% in the IMAAVY 15 mg/kg Q2W group.
  • Through week 24, the median steady-state predose reduction in total IgG was 33% in the IMAAVY 30 mg/kg Q4W group and 53% in the IMAAVY 15 mg/kg Q2W group.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 31 August 2026.