Anti-inflammatory drug pegtarazimod (RLS-0071) demonstrates clinical improvement in lower gastrointestinal acute graft-versus-host disease (aGvHD) and target engagement of key inflammatory marker myeloperoxidase (MPO) Free

Introduction: Acute graft versus host disease (aGvHD) remains a common complication for patients receiving allogeneic hematopoietic transplantation with approximately 60% of patients developing aGvHD of grades II – IV. The most severe form of aGvHD involves the intestines leading to pain, diarrhea, malabsorption, and malnutrition. Acute intestinal GVHD that is refractory to corticosteroids has an unfavorable prognosis with less than 50% of patients surviving 1 year after diagnosis.

The pathogenesis of GvHD is complex with alloreactive donor-derived T-cells recognizing the recipient's body as foreign leading to inflammation and tissue damage. In the case of aGvHD, recent work suggests that much of the pathogenesis is driven by the conditioning regimen causing loss of intestinal barrier integrity followed by neutrophil recruitment, activation, toxic myeloperoxidase (MPO) release and NETosis. Gastrointestinal (GI) damage due to neutrophil-mediated inflammation is the primary contributor to mortality in aGvHD patients. Pegtarazimod is a dual acting anti-inflammatory drug that inhibits the classical pathway of complement and neutrophil effectors, MPO and NETosis. In multiple mouse models of aGvHD, pegtarazimod decreased GI tissue damage and significantly improved survival. Given these findings, pegtarazimod is currently being evaluated in a Phase 2 open-label clinical trial (AURORA; Clinical.Trials.gov ID:NCT06343792) for patients with aGvHD.

Methods: In the AURORA trial, patients hospitalized with steroid-refractory aGvHD after allogeneic hematopoietic stem cell transplantation received pegtarazimod simultaneously with ruxolitinib, currently the only authorized product for the treatment of aGvHD. Pegtarazimod was administered intravenously at a dose of 10mg/kg, every 8 hours for 7 days. Safety and tolerability of pegtarazimod was assessed along with preliminary efficacy as evaluated by clinical response in the lower GI, skin, and liver characterized as Grade II, III, or IV as per the Mount Sinai Acute GVHD International Consortium (MAGIC) guidelines. In addition, plasma levels of MPO were evaluated as a pharmacodynamic (PD) measurement of drug activity in a qualified assay.

Results: Pegtarazimod was administered to 6 patients and was generally well tolerated. No clear safety signals were identified. Clinical MAGIC Stage improvement was shown for 6 of 6 participants over 7 days of treatment. Improvement in lower GI MAGIC Stage occurred for 4 of 5 participants over 7 days of treatment with pegtarazimod, with improvements of 1, 2 or 3 Stage levels. In addition to the clinical responses, pegtarazimod treatment over 7 days decreased median plasma MPO levels by 68% (P = 0.02). After discontinuation of pegtarazimod, three of 5 participants showed subsequent increase in MPO levels that correlated with worsening in Lower GI Stage. Two participants that maintained stable MPO levels after discontinuation of pegtarazimod remained clinically stable for lower GI Stage.

Conclusions: Pegtarazimod was generally well tolerated and was associated with improvement in clinical GVHD grades in patients with steroid-refractory aGvHD in only 7 days. Lower GI clinical improvement strongly correlated with decreases in plasma MPO level linking the mechanisms of action of RLS-0071 on neutrophils with the lower GI clinical responses. These preliminary data are encouraging for pegtarazimod in the population of steroid-refractory aGvHD with lower intestinal tract involvement.