FDA Rejects Breakthrough Designation, Approval for Itolizumab in Acute GVHD

Although the FDA highlighted a lack of improved 29-day responses with itolizumab attained on study, they indicated an openness to evaluating longer term outcomes backed by independent data to support end point validity.

The FDA has declined breakthrough therapy designation and support for an accelerated approval pathway for itolizumab (Alzumab) as a first-line treatment for patients 12 years or older with acute graft-versus-host disease (GVHD), according to a news release from the drug’s developer, Equillium.¹

The decision was based on data from the phase 3 EQUATOR trial (NCT05263999) wherein itolizumab was assessed vs placebo in grade 3 to 4 acute GVHD, or grade 2 GVHD with lower gastrointestinal involvement, in combination with corticosterioids.² FDA feedback came from a Type D meeting held between the agency and the developers. Although the FDA highlighted a lack of improved 29-day responses with itolizumab attained on study, they indicated an openness to evaluating longer term outcomes backed by independent data to support end point validity.

"We are clearly disappointed with the FDA feedback that focused almost exclusively on day 29 outcomes," Bruce Steel, chief executive officer at Equillium, said in the news release on the FDA decision.¹ "While itolizumab did not demonstrate improvements by day 29, we believe the very favorable safety profile and totality of longer-term data were clinically compelling and suggest itolizumab may confer a meaningful benefit for patients [with] this severe orphan disease where mortality rates remain very high. Based on this feedback we plan to accelerate closure of the [phase 3] EQUATOR study. We are very grateful to all of the patients, clinical sites, and our partners who helped us conduct this important study."

Investigators of the phase 3 multi-center study randomly assigned patients with acute GVHD 1:1 to receive either itolizumab or a placebo comparator, with a target enrollment of 200 patients.² Itolizumab was given intravenously at an initial dose of 1.6 mg/kg within 3 days of the first administration of high-dose corticosteroids, followed by 6 doses at 0.8 mg/kg of itolizumab biweekly with concurrent systemic corticosteroid use.³ Placebo was administered 7 times as biweekly doses in combination with systemic corticosteroids. Both arms received 2 mg/kg of methylprednisolone or equivalent on day 1.

The primary end point of the study was 29-day complete response (CR) rate. Key secondary end points included overall response rate at day 29 and rate of durable CR from day 29 to 99. Additional secondary end points included 99-day CR rate, duration of CR, failure-free survival, and overall survival.

Patients with clinically diagnosed grade 3 to 4 acute GVHD or grade 2 GVHD with lower gastrointestinal involvement were eligible for study enrollment if they were 12 years and older and more than 40 kg; had an initial allogenic hematopoietic stem cell transplantation (HSCT); evidence of myeloid engraftment; and if they began systemic corticosteroids within 72 hours of study drug administration and 2 mg/kg of methylprednisolone or equivalent on day 1.

Ineligibility criteria for enrollment included evidence of morphological relapsed, progressive, persistent, or untreated malignancy; an unplanned donor lymphocyte infusion for persistent or recurrent malignancy following HSCT; evidence of persistent disease requiring treatment or chronic GVHD/overlap syndrome; immunosuppressant use other than corticosteroids; and use of any systemic corticosteroid of more than 0.5 mg/kg per day of methylprednisolone or equivalent for indications other than acute GVHD within 7 days of acute GVHD onset.

“We will continue to evaluate options to advance or partner itolizumab for future clinical development that will likely be needed to support approval, as well as explore options with the rest of our novel therapeutic candidates directed towards immuno-inflammatory diseases," Steel concluded.¹

References

1. Equillium announces feedback from the U.S. Food and Drug Administration. News release. Equillium, Inc. April 24, 2025. Accessed April 25, 2025. https://tinyurl.com/mw2d9rmj
2. A study of itolizumab in combination with corticosteroids for the first-line treatment of acute graft versus host disease (EQUATOR). ClinicalTrials.gov. Updated March 12, 2025. Accessed April 25, 2025. https://tinyurl.com/4ayj8p5j
3. The EQUATOR study. Equillium, Inc. Accessed April 25, 2025. https://tinyurl.com/4z8vmsmu