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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 (MG), Sjögren’s syndrome, Idiopathic thrombocytopenic purpura (ITP), 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


Nipocalimab (M281), Anti-FcRn Antibody

The presence of pathogenic antibodies which facilitate tissue damage and organ dysfunction is a hallmark of immune-mediated 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 nipocalimab (M281), a fully human IgG1 monoclonal antibody that targets the IgG-binding site of FcRn. Blocking FcRn reduces pathogenic IgG through inhibition of IgG recycling and inhibits the transport of pathogenic IgG across the placenta in pregnancy which is vital for our Hemolytic Disease of the Fetus and Newborn (HDFN) trial.  In pre-clinical models, nipocalimab (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 immune-mediated diseases. A Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of nipocalimab (M281) was initiated in June 2016. In January 2018, Momenta reported positive top-line data showing safety, tolerability, and proof of mechanism for nipocalimab (M281) in a Phase 1 single ascending dose (SAD) and a multiple dose  study of normal human volunteers. You can read more about our Phase 1 study data results here

Novel Autoimmune Drugs M281

Momenta plans to commence two proof of concept studies in the fourth quarter of 2018. These trials are robustly designed to show best in class differentiation for autoimmune and alloimmune disorders. Our primary objective is to help evaluate dosing to achieve safety, tolerability and efficacy of nipocalimab (M281).

Our Trial Indications:

Generalized Myasthenia Gravis (gMG)

Myasthenia Gravis is a chronic autoimmune neuromuscular disease which affects skeletal muscles that are responsible for eye movements, breathing, and moving parts of the body resulting in muscle weakness and fatigue.  In healthy muscles, nerve endings transmit signals that are received by muscle receptors to cause muscle contractions.  In patients with MG, the immune system mistakenly attacks muscle receptors by producing anti-receptor antibodies (most commonly acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies) that can block and destroy these muscle receptors thus preventing the signals from effectively reaching the muscles. Over time, this may lead to symptoms such as limb weakness, drooping eyelids, and double vision as well as difficulties with chewing, swallowing, speech and breathing.   


Hemolytic Disease of the Fetus and Newborn (HDFN)

Hemolytic disease of the fetus and newborn is a rare and potentially life-threatening condition that affects approximately 4,000-8,000 pregnancies each year in the US alone. The disease is caused by antibodies from the mother which target proteins (also called antigens) on the fetal red blood cells (a process known as red cell alloimmunization). The most common antigen is RhD, although other antigens such as Rhc, RhE and Kell may also be involved in the process.

During pregnancy, antibodies can cross the placenta and bind to the antigens on the surface of the fetus’ red blood cells, leading to fetal red blood cell destruction and anemia. Anemia causes less oxygen to be delivered to all the fetal tissues and can lead to organ damage and ultimately lead to fetal heart failure and even fetal death. In additions, sometimes fetuses that have suffered anemia during pregnancy may have significant consequences like cerebral palsy.

Visit our publications page for more information on nipocalimab (M281).

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


Warm Autoimmune Hemolytic Anemia (wAIHA)

wAIHA is a rare autoimmune hemolytic anemia characterized by the destruction of red blood cells due to the presence of pathogenic IgG autoantibodies. Destruction of red blood cells results in severe anemia, leading to weakness and fatigue. As the disease progresses, and without safe and effective treatment, serious complications can develop. Up to 8% of wAIHA patients may die prematurely, with those experiencing active and uncontrolled hemolysis most at risk. Rates as high as 30% have been observed for wAIHA patients with severe disease admitted to an ICU. All suffer from serious complications from the disease and its associated treatments.

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 plans to initiate a Phase 1 study of M230 in healthy volunteers in the first quarter of 2018.  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 $8 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 hsIgG, a robust, controlled sialylation process to generate tetra-Fc-sialylated immunoglobulins with consistent enhanced anti-inflammatory activity. In pre-clinical trials, hsIgG 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 hsIgGproduct 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 in early 2019. The dose-ranging trial will begin with normal volunteers and progress to patients with idiopathic thrombocytopenic purpura, or ITP.

Our Trial Indication:

Immune Thrombocytopenic Purpura (ITP) is an autoimmune syndrome in which abnormal autoantibodies, bind to circulating platelet membranes leading to platelet destruction and subsequent reduction of the number of circulating platelets (thrombocytopenia).  This disease affects children and adults and can be acute or chronic.  Most common symptoms include petechiae, purpura, and epistaxis.  Mortality rates are similar to slightly higher than the age-matched general population; bleeding and infection are the leading causes of mortality in ITP patients.

Visit our publications page for more information on hsIVIg.

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

Last Updated 7/31/2019