Equate, a Phase 1b/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of a Novel Targeted Anti-CD6 Therapy, Itolizumab, in Subjects with Newly Diagnosed Acute Graft Versus Host Disease

Background: Acute graft versus host disease (aGVHD) occurs in approximately 50% of patients receiving allogeneic hematopoietic stem cell transplant (HSCT) with standard GVHD prophylaxis regimens and is a significant contributor to morbidity and non-relapse mortality (NRM). There are currently no FDA approved therapies for the initial treatment of newly diagnosed aGVHD. T effector cells (Teff), particularly CD4+ T helper cells, play a central role in the pathogenesis of aGVHD. CD6 is a co-stimulatory receptor, predominantly expressed on CD4+ T helper cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presenting cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation and trafficking and is central to immune mediated inflammation. Previous studies by Soiffer et al. in patients receiving allogeneic bone marrow transplants had shown that depleting CD6+ T cells ex-vivo in donor bone marrow using T-12, an anti-CD6 monoclonal antibody (mAb), as a sole method for GVHD prophylaxis lowered the incidence of acute and chronic GVHD. EQ001 (itolizumab) is a humanized IgG1 mAb that binds to CD6 and blocks the interaction with ALCAM and inhibits both the activity and trafficking of T cells without causing T cell depletion. Itolizumab has s previously been developed and is approved for the treatment of Psoriasis in India. The potential effectiveness of an anti-CD6 mAb targeted approach in treating aGVHD is supported by data from pre-clinical models evaluating the prevention and treatment of GVHD with EQ001. The objective of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of EQ001 in subjects with newly diagnosed aGVHD.

Study Design and Methods: This is a multi-center Phase 1b/2 study (NCT03763318) of EQ001 in subjects with aGVHD. Part A (Phase 1b) of the study is an open-label, multiple ascending dose study of EQ001 in adults with newly diagnosed High Risk (MacMillan Criteria) aGVHD following HSCT. Approximately 24 subjects will be enrolled in successive cohorts of 3 to 6 adult subjects using a standard 3 + 3 dose escalation design. For each cohort, subjects will receive EQ001 administered intravenously (IV) every two weeks for five doses with corticosteroids (CS) tapered over the treatment period. A total of four dose levels will be tested ranging from 0.4 mg/kg to 2.4 mg/kg, and subjects will be followed for an additional 10 months after study treatment is completed. The primary objective of Part A is to evaluate safety and tolerability of EQ001. Secondary objectives include an evaluation of PK, PD (including CD6 receptor occupancy, changes in inflammatory cytokines and novel gut biomarkers [ST2, REG3α], and changes in Teff/T regulatory cells populations), and clinical activity (overall aGVHD response rates on Day 29, durability of the response at Day 57 and up to 1 year, cumulative incidence of NRM, rates of chronic GVHD, and CS dose requirements). Data from Part A will inform the dose selection for Part B (Phase 2) of the study. Enrollment to Part A is ongoing.

Part B is a double-blind, placebo-controlled study in subjects (age ≥12) with newly diagnosed Grade II-IV aGVHD. Approximately 60 subjects will be randomized in a 2:1 ratio to either treatment with EQ001 (n=40) or placebo (n=20) in addition to and within 72 hours of the first dose of CS. EQ001 or placebo will be administered IV every two weeks for five doses, and subjects will be followed for an additional 10 months after the last dose of study treatment. The primary objective of Part B is to evaluate the overall response rate of aGVHD in patients treated with EQ001 versus placebo. Secondary objectives include an evaluation of safety and other clinical endpoints. The primary endpoint is the overall response rate at Day 29 as defined by a complete response, very good partial response or partial response. Additional clinical endpoints include assessment of NRM, chronic GVHD rates, and CS dose requirements.

Conclusion: Inhibiting the CD6-ALCAM pathway with EQ001 represents a unique and promising approach for the treatment of aGVHD following HSCT by inhibiting both the activity and trafficking of T cells. This is the first clinical study to examine the effects of an anti-CD6 therapy for the treatment of patients with newly diagnosed aGVHD.