Hyper-Sialylated IgG M254, an Innovative Therapeutic Candidate, Evaluated in Healthy Volunteers and in Patients with Immune Thrombocytopenia Purpura: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics
Authors: Arroyo Santiago , Tiessen Renger G , Denney William S , Jin Jim , van Iersel Mattheus Paulus (Thijs) , Zeitz Heidi , Manning Anthony M , Schipperus Martin R. , Bussel James B. 
Published: November 2019

Background: Intravenous immunoglobulin (IVIg), a therapeutic blood product prepared from pooled plasma of 3,000-60,000 healthy donors, is the treatment of choice for immunodeficiency syndromes. It has also been used to treat many acute and chronic autoimmune and systemic inflammatory diseases. The precise mechanism of action of IVIg is not well-understood, but occasional long-term effects presumably reflect immunomodulatory and anti-inflammatory properties. Although clinically useful, IVIg has several limitations including variable efficacy, infusion-related side effects, which may be due to prolonged infusion times and the large volumes needed, high cost, and supply shortages. IVIg alternatives could leverage the broad biological activities of IVIg and provide more consistent and potent anti-inflammatory activity with increased ease of administration.
M254, a novel hyper-sialylated IgG investigational product derived from commercially available IVIg, is hypothesized to have greater potency than IVIg. M254 is designed based on scientific evidence demonstrating the relevance of glycosylation on immunoglobulin function, especially the anti-inflammatory activity of IVIg, which has been shown to be dependent on Fc-sialyation. Preclinical data suggests that M254 has up to a ~10 fold enhancement of activity in four independent in vivo model systems: collagen antibody-induced arthritis and pemphigoid skin blistering models, K/BxN- sera induced arthritis model, and an immune thrombocytopenia (ITP) mouse model. These preclinical findings along with demonstrating platelet count increases, support the clinical evaluation of M254 in healthy volunteers and in patients with ITP.
Study Design and Methods: This first-in-human, phase 1/2 clinical study has 4 parts (NCT03866577). Part A enrolled 25 healthy volunteers; subsequent parts of the study will enroll patients with ITP. The study design is provided in Figure 1.
Part A assessed safety, tolerability, and PK of M254 after administration of a single ascending dose in healthy volunteers (n=25). Part B will assess safety, tolerability, and PK of M254 after administration of a single ascending dose followed by 1000 mg/kg IVIg administration in patients with ITP (n=10) with an exploratory evaluation of platelet response with M254 compared to IVIg. This exploratory platelet response evaluation allows a model-based, informed dose selection for Part C, which will be a 2 arm, crossover design comparing the platelet response of M254 with IVIg in patients with ITP (n=20). Part C will have 2 cohorts: high dose of M254 in Cohort 1 and low dose of M254 in Cohort 2. In combination with Part B, Part C will allow a model-based estimate of the M254 dose which is equivalent to IVIg. Using the totality of the data and dose ranging enables high confidence in the M254 dose while requiring a minimum number of patients with ITP. Part D will be a multiple dose study of M254 for the evaluation of safety, tolerability, PK, and PD platelet response in patients with ITP.
For Part B, C, and D, adult patients with ITP (with or without splenectomy) for > 3 months, platelet count between 15 and 50 x 109/L, receiving stable maintenance immunosuppressive therapy, and no history of other clotting disorders may be eligible. Key exclusion criteria include history of arterial or venous thrombosis and having ≥ 2 risk factors for thrombosis or clotting disorders, known history of non-responsive to IVIg, evidence of HCV, HBV, and HIV infection, and newly diagnosed ITP patients who are naïve to anti-ITP treatments.
Trial Progress: Part A (healthy volunteers) has been completed. In Part A, ascending doses of M254 from 3mg/kg to 250mg/kg were administered and were determined to be well tolerated. There was a single subject at 250 mg/kg that experienced a short lasting moderate systemic infusion reaction with chills, headache, nausea, vomiting and fever. No skin reactions, no pruritus and no changes in C3, C4 or white blood cells subsets in the extra blood sample taken during the reaction. This is not an unexpected even as infusion reactions often occur with IVIg. The protocol allowed for a seamless transition from evaluating M254 in healthy volunteers to patients with ITP. We have now initiated Part B of the study.
Figure 1

Disclosures
Arroyo: Momenta Pharmaceuticals: Employment. Tiessen:PRA Health Sciences: Employment. Denney:Human Predictions: Employment. Jin:Momenta Pharmaceuticals: Employment. van Iersel:PRA Health Sciences: Employment. Zeitz:Momenta Pharmaceuticals: Employment. Manning:Momenta Pharmaceuticals: Employment. Schipperus:Momenta Pharmaceuticals: Consultancy. Bussel:argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 3S Bio: Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.