Robust Engraftment with Mgta-456, a CD34+ Expanded Cell Therapy Product in Patients with Inherited Metabolic Disorders (IMD): Preliminary Phase 2 Trial Results

Background Mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD) are fatal IMDs affecting the central nervous system treatable through allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of a non-carrier HLA matched related donor, cord blood (CB) is the preferred source of cells in IMDs due to rapid availability and flexibility in matching. However, prolonged neutropenia and high graft failure rates present a challenge, particularly with reduced intensity conditioning regimens. MGTA-456 is produced from a single CB unit using an aryl hydrocarbon receptor antagonist in a 15-day expansion culture of CD34 + cells. In previous phase 1/2 studies, hematologic malignancy patients treated with myeloablative conditioning and MGTA-456, with median 324-fold CD34+ expansion, showed 100% engraftment with a 9 day reduction in time to neutrophil recovery. As higher CD34 + doses have been correlated with improved engraftment in IMD transplant patients, we hypothesize MGTA-456 may reduce duration of neutropenia and risk of graft failure and more rapidly correct the metabolic deficiency in IMD patients. Patients and Methods A Phase 2, open-label trial (NCT03406962) initiated in Feb 2018 is enrolling up to 12 patients 2 x4 days) and busulfan (total exposure 21,000 to 22,000 μM/min/L −1 x4 days). Immunoprophylaxis consists of cyclosporin and methylprednisolone. Results Five patients have been treated per protocol to date (Figure 1). MGTA-456 contained a median 561-fold expansion of CD34 + cells after culture with a median infused CD34 + cell dose of 110 × 10 6 cells/kg and median total nucleated cell dose of 26.4 × 10 7 (Figure 2). The median duration of neutropenia was 1 day (range 0-9), in contrast to a median of 8 days for a historical cohort (Figure 3). Myeloid chimerism was ≥98% donor by day +14 in evaluable patients. Two patients developed autoimmune cytopenia, a known complication in IMD patients after HSCT, unrelated to MGTA-456. Time to discharge after transplant was a median of 19.5 days at time of reporting. Preliminary data from MPS1 patients demonstrated normalization of blood alpha-L-iduronidase enzyme activity and decreased urinary glycosoaminoglycan levels after transplant. Conclusions Treatment of IMD patients with MGTA-456 showed early and robust engraftment in all patients with marked reduction in days of neutropenia compared to a historical cohort. These preliminary data, in combination with the previous hematologic malignancy patients treated, suggest MGTA-456 substantially enhances engraftment and rate of neutrophil recovery.