Phase 2 Bridging Pre-transplant Inflammatory Dampening for Primary Immune Regulatory Disorders (BRIDGE Trial)

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Abstract The Primary Immune Regulatory Disorders (PIRDs) are a group of inborn errors of immunity (IEI) that result from constitutive activation and/or dysregulation of specific immune pathways. There are 130 genes identified to date that are associated with PIRDs. Each PIRD is extremely rare and the PIRDs in general comprise approximately 5% of IEI. Patients with PIRDs often have multiple life-threatening opportunistic infections, autoinflammatory conditions and autoimmune sequelae related to the constant activation of their immune system. Given the rarity of each PIRD and of PIRDs in general there are little if any therapeutic interventions for these patients. Hematopoietic Stem Cell Transplant (HCT) offers a curative option for many patients with PIRDs. The high levels of inflammatory mediators in patients with PIRDs however has made it extremely difficult to have successful outcomes due mostly to graft failure/rejection as well as post-transplant immune complications. Patients with PIRDs therefore have limited therapeutic options and only those that are most severely affected are considered for cures with HCT. The BRIDGE Trial is a Phase 2 clinical trial to improve outcomes of curative therapy with HCT for patients with a PIRD diagnosis. The protocol utilized a biomarker-guided immune suppression prophase to dampen the inflammatory milieu prior to and during a myeloablative conditioning regimen for HCT. For patients with PIRDs that result in perturbations of their IFNγ pathway, a prophase of emapalumab, an IFNγ neutralizing monoclonal antibody will be incorporated prior to and during the conditioning regimen. Patients that have PIRDs that result in dysregulation of other inflammatory pathways will receive a generalized inflammatory suppression prophase with fludarabine and dexamethasone, similar to what is currently being used for patients with hemoglobinopathies undergoing HCT. These targeted inflammatory suppression regimens will provide a more balanced milieu in patients with PIRDs while they receive conditioning and enable more efficient engraftment, balanced immune reconstitution and improved outcomes. This dataset will be pivotal to expand indications for emaplaumab, an orphan drug approved for primary hemophagocytic lymphohistiocytosis (pHLH), to bridging therapy for curative HCT for IFNγ immune dysregulation syndromes. In aims 2 and 3 we take advantage of our expertise in immune reconstitution and biomarker discovery studies to provide in-depth correlative biology. Our focus will center on deep immunophenotyping of reconstituting subsets, identification of soluble biomarkers for immune mediated complications and to identify mechanisms of how a targeted immune suppression prophase helps provide an appropriate immune milieu during conditioning and as the hematopoietic system regenerates after HCT. These studies will provide critical data for continued future clinical trials to provide durable cures to patients with PIRD diagnoses.