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First-line treatment with itolizumab failed to demonstrate a meaningful difference in day-29 objective response rate (ORR) and complete response (CR) rate vs placebo in patients with acute graft-vs-host disease (aGVHD), failing to meet the primary and a key secondary end point of the phase 3 EQUATOR trial (NCT05263999). However, statistically significant and clinically meaningful improvements in day-99 CR rate, duration of CR, and failure-free survival (FFS) were seen.1
The day-29 CR rate in the intention-to-treat (ITT) population was 43.0% in the itolizumab arm (n = 79) vs 48.1% in the placebo arm (n = 79). The day-29 ORRs in the ITT population of patients who received itolizumab and placebo, respectively, were 62.0% (very good partial response [VGPR], 10.1%; partial response [PR], 8.9%) and 54.4% (VGPR, 1.3%; PR, 5.1%).
Itolizumab also demonstrated a favorable safety profile and did not raise the risk of clinical sequelae, including infection or sepsis. Additionally, the rates of steroid tapering and primary disease relapse/chronic GVHD were comparable between arms.
“While we did not observe improvements in day 29 outcomes, itolizumab demonstrated compelling clinical results in several important longer-term outcomes, conferring potential patient benefit where there are no approved therapies,” Bruce Steel, chief executive officer at Equillium, stated in a news release. “Based on these data and prior FDA guidance, we have filed for breakthrough therapy designation and have been granted a meeting to discuss the potential for accelerated approval of itolizumab for first-line treatment of aGVHD, a rare disease where one-year mortality exceeds 40% and itolizumab has already received orphan drug and fast track designations. We expect feedback from the FDA during May and, if positive, we would plan to submit a biologics license application during the first half of 2026.”
Itolizumab is a first-in-class anti-CD6 monoclonal antibody that selectively targets the CD6-ALCAM signaling pathway to downregulate pathogenic T effector cells while preserving T regulatory cells.
EQUATOR is a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial comparing the efficacy and safety of intravenous itolizumab vs placebo as frontline therapy in 158 adult and adolescent patients with grade III to IV aGVHD, or grade II aGVHD with lower gastrointestinal involvement.1,2 Patients were randomly assigned 1:1 to receive itolizumab or placebo in combination with high doses of corticosteroids, which is the current standard of care.1
The primary study end point is day-29 CR rate. Key secondary end points include day-29 ORR, the rate of durable CR from day 29 through day 99, day-99 CR rate, duration of CR, FFS, and overall survival (OS).
Efficacy was evaluated in the ITT (itolizumab, n = 79; placebo, n = 79) and modified ITT (mITT; itolizumab, n = 78; placebo, n = 77) populations.
Eligible patients received itolizumab within 3 days of the first administration of high-dose corticosteroids with a treatment period spanning days 1 to 99, and a follow-up period spanning days 100 to 365. The administration schedule was such that patients received 2 mg/kg of methylprednisolone or an equivalent on day 1, plus either 1.6 mg/kg of itolizumab followed by 6 doses of 0.8 mg/kg of the agent once every 2 weeks (n = 79), or placebo for 7 doses every other week (n = 79).
Additional results indicated that the durable CR rate at day 99 in the ITT population was 29.1% in the itolizumab arm vs 16.5% in the placebo arm. The durable CR rates at day 99 among patients who achieved CR at day 29 in the ITT population were 67.6% and 34.2% in the itolizumab and placebo arms, respectively (P = .005). The day-99 CR rates in the mITT population were 44.9% and 28.6% in the itolizumab and placebo arms, respectively (P =.035).
The median duration of CR in the mITT population was 336 days in the itolizumab arm vs 72 days in the placebo arm (P =.017).
The estimated 365-day FFS rates in the mITT population were 39.5% and 22.9% in the itolizumab and placebo arms, respectively. The median number of days patients were failure free was 154 vs 70 in the itolizumab and placebo arms, respectively (P =.043). The estimated 365-day OS rate in the mITT population was 66.7% in the itolizumab arm vs 49.6% in the placebo arm; a total of 19 and 25 deaths had occurred, respectively.
Regarding safety, the most common treatment-emergent serious adverse effects (TESAEs) in the itolizumab (n = 78) and placebo (n = 77) arms, respectively, were sepsis (5.1%; 18.2%), respiratory failure (3.8%; 5.2%), pneumonia (3.8%; 3.9%), and septic shock (2.6%; 5.2%).
Any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.7% and 96.1% of patients in the itolizumab and placebo arms, respectively. TEAEs leading to drug discontinuation occurred in 12.8% and 3.9% of patients in the itolizumab and placebo arms, respectively.
TESAEs occurred in 57.7% and 61.0% of patients in the itolizumab and placebo arms, respectively. Infections and infestations that were characterized as TESAEs occurred in 28.2% and 37.7% of patients in the itolizumab and placebo arms, respectively. Treatment-related TESAEs occurred in 6.4% and 3.9% of patients in the itolizumab and placebo arms, respectively. TEAEs leading to death occurred in 23.1% and 32.5% of patients in the itolizumab and placebo arms, respectively. There were no treatment-related TEAEs that led to death.
The EQUATOR study is ongoing with 30 patients in the follow-up period per protocol.
“The longer-term outcomes are important,” John Koreth, MBBS, DPhil, professor of medicine, Dana-Farber Cancer Institute, Harvard Medical School, added. “There are no approvals in first-line therapy for aGVHD, and no drug candidates have been able to demonstrate efficacy beyond four weeks. To demonstrate statistical significance in prespecified end points of duration of complete response and failure-free survival, compared to standard of care therapy, is clinically meaningful.”
References
Equillium announces results of the phase 3 EQUATOR study of itolizumab in first-line treatment of patients with acute graft-versus-host disease. News release. Equillium. March 27, 2025. Accessed March 27, 2025. https://www.equilliumbio.com/investors/press-releases/news-details/2025/Equillium-Announces-Results-of-the-Phase-3-EQUATOR-Study-of-Itolizumab-in-First-Line-Treatment-of-Patients-with-Acute-Graft-Versus-Host-Disease/default.aspx
A study of itolizumab in combination with corticosteroids for the first-line treatment of acute graft versus host disease (EQUATOR). ClinicalTrials.gov. Updated March 25, 2025. Accessed March 27, 2025. https://clinicaltrials.gov/study/NCT05263999