Safety and Efficacy of the Glucagon-like Peptide 2 (GLP-2) Analog Apraglutide in Patients with Steroid-Refractory Gastrointestinal Acute Graft-Versus-Host Disease (aGvHD) in Combination with Best Available Therapy: Results from a Multicenter, Randomized, Single-Blind, Proof-of-Concept, Phase 2 Stargaze Trial

Introduction: Acute graft-versus-host disease (aGvHD) is a severe and life-threatening condition that often develops after allogeneic hematopoietic cell transplantation (alloHCT). Approximately 50% of patients (pts) who receive systemic glucocorticoids (GCs) as first-line treatment do not achieve an adequate and durable response and become steroid refractory (SR). Among pts with grade II–IV aGvHD, ~70% have gastrointestinal (GI) involvement, a key driver of morbidity and mortality. GI aGvHD is often steroid-refractory, and despite recent improvements with the availability of ruxolitinib (RUX) as second-line therapy, an unmet need remains for non-immunosuppressive treatments. Preclinical studies have suggested that glucagon-like peptide 2 (GLP-2) analogs protect and regenerate Paneth cells and intestinal stem cells and thus have the potential to improve clinical outcomes in GI aGvHD (Norona J, et al. Blood 2020). The aims of STARGAZE, the first prospective trial of a GLP-2 analog in SR GI aGvHD, are to assess the safety, tolerability, and preliminary efficacy of the GLP-2 analog apraglutide (APRA) in combination with best available therapy in pts with SR lower-GI aGvHD.

Methods: In the STARGAZE phase 2 trial (NCT05415410), pts received APRA subcutaneously, once weekly, until Week 7 (up to Week 12 if no lower-GI aGvHD complete response [CR] at Week 8, plus optional treatment up to Week 25), with a follow-up period of up to 2 years after the first dose of APRA. APRA was initiated within 5 days of starting RUX as second-line therapy in pts with an inadequate response to GCs. Eligible pts (aged ≥12 years with grade II–IV SR aGvHD and stage 1–4 lower-GI aGvHD) weighing ≥50 kg were randomized 1:1 to high- or low-dose APRA arms; pts weighing 40.0–49.9 kg received a fixed dose of APRA. The primary endpoints assessed safety and tolerability of APRA. Secondary endpoints included all-organ and lower-GI overall response rates (ORRs) and CR rates on Days 28, 56, and 91. Durable overall response was assessed from Day 28 to Day 56 and from Day 56 to Day 91. Specific values in this prespecified interim analysis may be subject to change in the final analysis.

Results: This fully recruited study enrolled 31 pts (high-dose APRA: n=15; low-dose APRA: n=15; fixed dose: n=1); baseline and disease characteristics were well balanced across arms. Twenty-seven (87.1%) pts had grade III–IV aGvHD and 20 (64.5%) pts had lower-GI stage 3–4 aGvHD. APRA was well tolerated, with an acceptable safety profile; most adverse events were non-serious and assessed as not related to APRA treatment, including in the 11 pts who had fatal events. On Days 28, 56, and 91, all-organ ORRs were 58.1%, 51.6%, and 45.2%, respectively, with CR rates of 25.8%, 29.0%, and 29.0%, respectively. Lower-GI ORRs were 54.8%, 51.6%, and 48.4%, respectively, with CR rates of 29.0%, 29.0%, and 32.3%, respectively. Durable overall response from Day 28 to Day 56 was 45.2% for both all-organ and lower-GI ORRs. Durable overall response from Day 56 to Day 91 was 41.9% for the all-organ ORR and 45.2% for the lower-GI ORR.

Conclusions: The results of STARGAZE, the first prospective trial of a GLP-2 analog in SR lower-GI aGvHD, show that APRA was well tolerated and efficacious when added to RUX in the second-line setting. The majority of pts receiving APRA plus RUX had an overall response (all-organ and/or lower-GI response) at Days 28 and 56. Notably, durable overall responses were observed from Day 28 to Day 56 and from Day 56 to Day 91. The outcomes, based on the novel regenerative mechanism of action of APRA, are encouraging in this severely ill population.