Although first-line itolizumab treatment did not improve complete or overall response rates at Day 29 of treatment for patients with acute graft-versus-host disease (GVHD; a serious complication that may affect people who have had a stem cell transplant using cells from a donor), the agent did achieve statistical significance across other trial end points, according to topline data from the phase 3 EQUATOR study press release from Equillium, Inc.
Consequently, the company has filed for Breakthrough Therapy designation with the U.S. Food and Drug Application (FDA) and is planning on requesting a meeting to discuss the potential for the investigative agent's Accelerated Approval. Feedback on these requests is expected during May 2025, the release notes.
“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, CEO at Equillium, said in the 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 acute GVHD, 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.”
Glossary:
Breakthrough Therapy Designation: an FDA designation that expedites drug development.
Accelerated Approval: a program which allows for faster approval of drugs for serious conditions that fill an unmet medical need.
Orphan Drug Designation: a designation in which pharmaceutical agents are developed to treat certain rare medical conditions.
Fast Track Designation: a program that allows for faster approval of drugs for serious conditions that fill an unmet medical need.
Biologics license application: request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.
Complete response rate: the disappearance of all signs of cancer in the body.
Overall response rate: the proportion of patients who have a partial or complete response to therapy.
Sepsis: life-threatening complication of an infection.
Overall survival: the average length of time patients are alive after the start of treatment.
Several long-term benefits were observed with itolizumab, including a significant and meaningful improvement in complete response at Day 99, the duration of complete response and failure-free survival. Moreover, the investigative treatment had a tolerable safety and tolerability profile and did not increase the risk of infection or sepsis, both of which are primary drivers of high mortality associated with acute GVHD.
At Day 29, the complete response rate in the intent-to-treat population — the primary trial end point — was 43% in the itolizumab group and 48.1% in the placebo group. The overall response rate — a key secondary end point — was 62% with itolizumab and 54.4% with placebo. Among responders, very good partial response rates were 10.1% and 1.3%, while partial response rates were 8.9% and 5.1%, respectively.
The duration of complete response was significantly longer in patients receiving itolizumab, with a median of 336 days versus 72 days in the placebo group. Failure-free survival also favored itolizumab, with a median of 154 days versus 70 days in the placebo group. Additionally, by Day 99, the complete response rate was significantly higher in the itolizumab group (44.9%) compared with placebo (28.6%).
A positive trend in overall survival was observed, with fewer deaths in the itolizumab group (24.4%) compared with placebo (32.5%). Moreover, rates of steroid tapering, primary disease relapse and chronic GVHD were similar between both treatment arms.
The safety profile of itolizumab was consistent with previous studies and showed no increased risk of clinical complications such as infection or sepsis. Treatment-emergent side effects occurred in 98.7% of itolizumab-treated patients and 96.1% of those on placebo. Serious side effects were reported in 57.7% and 61% of patients, respectively, with infection-related serious treatment-emergent side effects occurring in 28.2% of itolizumab-treated patients versus 37.7% in the placebo group. Sepsis was less frequent with itolizumab at 5.1% versus 18.2%, and no treatment-related deaths were reported in either group.
More Information on the Trial and Its Safety
GVHD is a serious complication that can occur following allogeneic stem cell transplants, resulting when the donor's immune cells attack the recipient's body. It can cause symptoms such as skin rash, itching, nausea, diarrhea, jaundice and eye irritation. GVHD is the leading cause of non-relapse mortality in patients with cancer who have received transplant and limits who can receive a transplant. It can lead to severe complications, with one-year survival rates as low as 40%. Currently, there are no approved treatments for first-line acute GVHD.
To address the unmet needs which arise from GVHD, researchers are investigating the clinical-stage, first-in-class anti-CD6 monoclonal antibody itolizumab, which helps regulate the immune system. By blocking this pathway, itolizumab reduces harmful immune cells while preserving beneficial ones that keep the immune system balanced. This approach may help control immuno-inflammatory diseases caused by an overactive immune response, according to the press release.
The EQUATOR trial is a randomized, double-blind, placebo-controlled multicenter study, and is comparing the efficacy and safety of intravenous itolizumab versus placebo with high doses of corticosteroids, the current standard of care, in the first-line setting. In total, 158 adult and adolescent patients with acute GVHD are enrolled.
Per the study protocol, patients received itolizumab within three days of the first administration of high-dose corticosteroids. The treatment period spanned Days 1 to 99, followed by a follow-up period from Days 100 to 365. All subjects received 2 milligrams per kilogram (mg/kg) of methylprednisolone or an equivalent dose on Day 1 and were randomized into two treatment groups. Group A (79 patients) received an initial dose of itolizumab at 1.6 mg/kg, followed by six doses of 0.8 mg/kg every two weeks in combination with systemic corticosteroids. Group B (79 patients) received a placebo administered every other week for seven doses, along with systemic corticosteroids.
“The longer-term outcomes are important,” Dr. John Koreth, a professor of medicine at both Dana-Farber Cancer Institute and Harvard Medical School, in Boston, concluded in the release. “There are no approvals in first-line therapy for acute GVHD, and no drug candidates have been able to demonstrate efficacy beyond four weeks. To demonstrate statistical significance in pre-specified endpoints of duration of complete response and failure-free survival, compared to standard of care therapy, is clinically meaningful.”
The trial remains ongoing, and all patients have completed dosing, with 30 patients remaining in the follow-up period per protocol.
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