This is a prospective, phase II/III, randomized clinical study to compare the efficacy and safety of BEGEDINA® (Begelomab) versus "conventional treatment" for treating steroid-resistant acute graft versus host disease (GvHD). Despite prophylactic treatment, GvHD still develops in up to 30% of allogeneic hemopoietic stem cell transplant (HSCT) recipients. GvHD is a life-threatening and complex immunological disease that may be acute or chronic. Acute GvHD affects mainly the skin, liver and gastrointestinal (GI) tissues with long-term survival directly related to the severity of skin, liver and gut involvement. First line treatment for patients with acute GvHD (Grade II or higher) is the immunosuppressive corticosteroid methylprednisolone. Although effective in over 50% of patients, durable responses are observed in only a third of patients and it also confers a risk of severe infection. Steroid-resistant acute GvHD is associated with a high rate of morbidity and mortality, primarily from infections and/or multi-organ failure. Despite this, there are no authorized treatments for non-responders and GvHD remains largely an untreatable disease with limited survival and thus a great unmet therapeutic need. BEGEDINA® (Begelomab) is a murine immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and is produced by biotechnological means and is a new potential therapeutic approach. BEGEDINA® has been shown to bind to CD26 which is present on a subset of CD4+ T helper lymphocytes leading to down-regulation of CD26 signaling and inhibition of immune response and thus therapeutic improvements. BEGEDINA has been investigated in two completed clinical studies: a pilot study and a dose-finding study and so far showing promising efficacy, safety and tolerability.

The primary objective for this study is therefore to determine the efficacy of BEGEDINA® versus conventional therapy in steroid-resistant acute GvHD. To satisfy this objective, two co primary hypothesis will be tested. The first is that the overall response rate consisting of the Complete Responders and the Partial Responders (CR+PR) at Study Day 28 will be higher in the BEGEDINA® treated subjects. The second is that the incidence of transplant-related mortality (TRM) at 6 months will be reduced in those subjects treated with BEGEDINA® versus those treated with conventional therapy. Additional secondary efficacy endpoints will also be assessed as a measure of effectiveness. In addition, some pharmacokinetics assessments will be performed. Adverse events (AEs) will be coded using MedDRA and the frequency, causality and intensity of AEs will be compared to conventional therapies. Further safety analysis will also include laboratory findings, vital signs, immunogenicity and other assessments. Finally, some exploratory analysis will also be performed.

This will be a prospective, multicenter, randomized, open-label, phase II/III clinical study in which subjects will be randomly assigned in a 1:1 ratio to receive BEGEDINA® treatment or the best conventional treatment available in their territory as no second line therapy is currently approved. It is planned to enroll 184 male or female adult subjects with an upper age limit of 65 years with steroid-resistant acute GvHD. BEGEDINA® will be administered at a dose of 2.7 mg/m2/day for 5 consecutive days from Study Day 1 through to Study Day 5, and on Study Days 10, 14, 17, 21, 24, and 28. Thus, the expected duration for each subject will be approximately 12 months. The final statistical analysis plan (SAP) will be finalized prior to database lock. Baseline characteristics of the subject sample will be described using summary statistics. All statistical tests will be conducted at a 2-sided significance level of 5% unless specifically specified. Multiple Imputation methods will be used as the primary method for accounting for missing data.