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Novel Drugs for Autoimmune Indications

Autoimmune diseases result from a dysfunction of the immune system in which the body attacks its own organs, tissues, and cells. To date, physicians and scientists have identified more than 80 clinically distinct autoimmune diseases1. Several are well known, including rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and systemic lupus erythematosus; others are less familiar, including myasthenia gravis, Sjögren’s syndrome, dermatomyositis, and pemphigus. Collectively, these diseases, as a category, affect 50 million Americans1. Additionally, autoimmune diseases are reported to be on the rise in the U.S. and around the world, making this poorly understood category of disease a public health crisis at levels comparable to heart disease and cancer.

Many autoimmune diseases are characterized by the formation of autoantibodies that bind self-antigens to form immune complexes (ICs). These ICs can recruit and activate immune cells leading to tissue inflammation and damage, and thereby presenting a common pathological mechanism across multiple autoimmune diseases. However, few therapeutic agents exist that interfere directly with these autoantibodies or IC-immune cell activation processes. Today, intravenous immunoglobulin (IVIg) and plasmapharesis represent the most targeted approaches to treat autoantibody-driven disease. These therapies are far from optimal for patients and are restricted in use for those patients whose disease is difficult to control.

Momenta is pioneering improved therapeutics for patients with autoimmune diseases, and in particular, those with autoantibody-driven disease. We are applying our complex systems analysis platform to identify potential improvements we can design into presently marketed complex mixture drugs. By evaluating their interaction with biologic systems, we can obtain an enhanced understanding of their function to identify biological activities we can exploit. This is the approach behind our research efforts to utilize the sialylation of intravenous immunoglobulin, or IVIg, and our program to develop a recombinant Fc version of IVIg.

1 NIH Autoimmune Diseases Coordinating Committee 2013


M281, Anti-FcRn Antibody

The presence of pathogenic autoantibodies which facilitate tissue damage and organ dysfunction is a hallmark of autoimmune diseases. In clinical settings, therapeutic plasmapheresis and immunoabsorption are often used to remove autoantibodies and other blood components contributing to disease. The clinical benefit of these procedures suggest that the removal of autoantibodies may lead to improvement of symptoms in some autoimmune indications. Removal of autoantibodies may be addressable by targeting FcRn, the neonatal Fc receptor which recycles immunoglobulin G (IgG) into circulation maintaining the long half-life of IgG.

Using proprietary antibody engineering technology we have developed a product referred to as M281, a fully human IgG1 monoclonal antibody that targets the IgG-binding site of FcRn. In pre-clinical models, M281 potently antagonizes FcRn binding of IgGs and rapidly diminishes circulating levels of IgG antibodies. The antibody has been seen to effectively improve disease in preclinical animal models of autoantibody-driven disease. A Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of M281 was initiated in June 2016. In January 2018, Momenta reported positive top-line data showing safety, tolerability, and proof of mechanism for M281 in a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study of normal human volunteers. We plan to initiate two proof-of-concept studies in the fourth quarter of 2018.

Novel Autoimmune Drugs M281

Visit our publications page for more information on M281.

Interested in collaborating on this program? Visit our collaborations page for contact information.

M230 (CSL730) Recombinant Fc Multimer in Collaboration with CSL Behring

Antigen-autoantibody immune complexes (ICs) are a common pathogenic hallmark of many autoimmune diseases. The multiple Fc domains of ICs aggregate Fcγ receptors (FcγRs), triggering cellular activation processes that play critical roles in inflammation and tissue damage. The rational engineering of therapeutics that broadly antagonize FcγRs has been hampered by a limited understanding of the molecular determinants directing FcγR activation.

Through the engineering and characterization of Fc structures, we were able to derive novel insights into FcγR modulation and have generated a unique recombinant trivalent human IgG1 Fc multimer, referred to as M230, with optimal physiochemical and biological properties. Pre-clinical studies with M230 have shown enhanced potency and efficacy over intravenous immunoglobulin in animal models of autoimmune disease.

In January 2017, we entered into an exclusive research collaboration and worldwide license agreement with CSL, a leading global biotherapeutics company, to develop and commercialize M230.  As part of the agreement, we received a $50 million upfront license fee from CSL and are eligible to receive future milestone and royalty payments. 

In September 2017, Momenta announced that it opted into a 50% cost and profit sharing arrangement for all products developed under the CSL agreement, including M230. Under the agreement Momenta will fund 50% of global research and development and U.S. commercialization and manufacturing costs in exchange for 50% of U.S. profits. Royalties remain payable to Momenta for territories outside the U.S. and milestones are reduced.  In addition to advancing M230, CSL and Momenta are collaborating to develop additional recombinant Fc multimer proteins that may originate from Momenta's or CSL's research.

CSL's Phase 1 study of M230 in healthy volunteers is ongoing, and is  anticipated to be completed in 2019. M230 has the potential to be developed as a first-in-class therapeutic for patients with immune-complex driven diseases.

Novel Autoimmune Drugs M230

Visit our publications page for more information on M230.

Interested in collaborating on this program? Visit our collaborations page for contact information.

M254, Hyper-sialylated IVIg (hsIVIg)

Intravenous immunoglobulin (IVIg) is a therapeutic blood product prepared from the pooled plasma of 3,000 to 60,000 healthy donors per batch. IVIg has been used for more than 30 years for the treatment of a variety of acute and chronic autoimmune and systemic inflammatory diseases. The global market for IVIg exceeds $6 billion, with the majority of products currently approved being for use in treatment of autoimmune disease.

Despite the beneficial therapeutic effects of IVIg in inflammatory diseases, consistent therapeutic efficacy and the challenges of administration remain major limitations for patients and physicians using IVIg. This has stimulated our desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency.

The identification of the important anti-inflammatory role of Fc-sialylation has presented us an opportunity to create more potent immunoglobulin therapies. Using proprietary sialylation technology, a method to add sialic acid to protein, we have developed hsIVIg, a robust, controlled sialylation process to generate tetra-Fc-sialylated immunoglobulins with consistent enhanced anti-inflammatory activity. In pre-clinical trials, hsIVIg has been shown to be at least 10× more potent than the parent IVIg product in a variety of animal models of autoimmune disease. We believe our hsIVIg product has the potential to be developed as a high-potency alternative to IVIg. We have completed the IND-enabling toxicology study and plan to initiate a Phase I/II proof–of-concept clinical trial by late 2018 or early 2019.  The dose-ranging trial will begin with normal volunteers and progress to patients with idiopathic thrombocytopenic purpura, or ITP.

Visit our publications page for more information on hsIVIg.

Interested in collaborating on this program? Visit our collaborations page for contact information.

Last Updated 1/26/2018