The European Medicines Agency (EMA) has officially granted orphan drug designation to pegtarazimod (RLS-0071) for the treatment of patients suffering from graft-versus-host disease (GVHD). This decision follows promising data from the ongoing phase 2 AURORA trial (NCT06343792), which includes multiple cohorts of hospitalized patients experiencing steroid-refractory acute GVHD.
David Marek, chief executive officer of ReAlta, expressed optimism regarding the EMA’s decision, stating, “Receiving EMA orphan drug designation represents a significant new regulatory milestone in our efforts to address the urgent unmet need in acute GVHD.” He highlighted the positive feedback received from the EMA based on the initial cohort data from the ongoing phase 2 trial, which aims to provide a much-needed therapeutic option for patients in Europe.
In August 2024, the U.S. Food and Drug Administration (FDA) similarly granted orphan drug and fast track designations to pegtarazimod for the same indication. Pegtarazimod is a 15-amino-acid peptide designed to modulate both humoral and cellular inflammation. It works by selectively inhibiting complement activation at C1, myeloperoxidase activity, and the formation of neutrophil extracellular traps.
Findings from a related study published in 2024 illustrated the drug’s mechanism of action. Healthy participants who inhaled low doses of lipopolysaccharide experienced a reduction in neutrophils in their sputum by approximately 50% compared to those who received a placebo (P = .04). This reduction also extended to key neutrophil effectors, such as myeloperoxidase, neutrophil elastase, and IL-1β, highlighting the agent’s potential in addressing the inflammatory processes associated with GVHD.
Ongoing Clinical Trials and Patient Eligibility
The AURORA trial is an open-label, prospective, dose-escalation study enrolling patients globally, including in the United States, Germany, and Spain. Eligible participants are adults or adolescents over the age of 12 who are hospitalized for the treatment of steroid-refractory acute GVHD, classified as grade II to IV, following allogeneic hematopoietic stem cell transplantation (HSCT).
Participants must have an expected hospital stay of at least one week from when RLS-0071 treatment begins and should weigh between 40 kg and 140 kg at screening. Additionally, they cannot plan to undergo further GVHD treatment or adjust prophylactic GVHD medications during the treatment period. The study has established specific criteria for neutrophil recovery, requiring a blood neutrophil count above 500/mL without growth factor support for at least three consecutive measurements.
Patients enrolled in the trial will receive pegtarazimod for either 7 or 14 days, depending on their assigned dose group. The various dosing regimens include 10 mg/kg administered every 8 hours for 7 days, or 40 mg/kg for the same duration, among other combinations involving concurrent ruxolitinib.
Projected Outcomes and Future Directions
The primary endpoints of the trial focus on the incidence of treatment-related adverse effects and treatment-emergent serious adverse effects, as well as the overall response rate. Secondary endpoints will assess various factors including refractoriness to RLS-0071, overall corticosteroid use, survival rates, and hospital length of stay.
Kenji Cunnion, MD, MPH, chief medical officer of ReAlta, emphasized the targeted nature of pegtarazimod’s intervention, stating, “Our targeted intervention addresses the specific pathways driving tissue damage, including the inhibition of extracellular myeloperoxidase, NETosis, and neutrophil elastase, while preserving beneficial immune function.” He added that the encouraging preclinical and clinical data underscore pegtarazimod’s potential to effectively manage the neutrophil-driven disease processes particularly associated with lower gastrointestinal acute GVHD, which has historically been challenging to treat and carries a high mortality rate.
Data from additional cohorts of the phase 2 trial are anticipated in 2026, as researchers work towards developing effective interventions for patients suffering from this serious condition. The ongoing research and regulatory recognitions affirm the growing understanding of GVHD and the potential of innovative treatments to improve patient outcomes.