Janus Biotherapeutics (Janus), a Boston, Massachusetts based autoimmunity therapeutics company dedicated to development of novel, orally available compounds for treating autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s syndrome, psoriasis, and scleroderma, have announced their entry into a collaboration with multinational pharma firm Roche — the world’s largest biotech company and a leader in personalized healthcare. The research partnership will focus on development of a small molecule toll-like receptor (TLR) inhibitor believed to have potential for addressing several autoimmune diseases.
TLRs are a class of proteins that play a key role in the innate immune system, with strong scientific evidence linking aberrant TLR activation and signaling with autoimmune disorder development. Janus will work exclusively with Roche on TLR research and development.
The Challenge: A Significant Unmet Therapeutic Need
According to Janus, approximately 46 million people in the United States suffer from autoimmune rheumatic diseases, with numbers of afflicted expected to swell to 60 million by 2020. These disorders exact a substantial toll on the physical health, emotional well-being, and quality of life of affected patients and are more common causes of activity limitation than heart disease, cancer, or diabetes. Janus cites direct medical costs resulting from autoimmune rheumatic diseases estimated to be in excess of $100 billion dollars annually, not counting additional personal and societal costs from lost productivity that raise the economic burden of these conditions exponentially, and despite frequent dramatic advances in treatments for other serious diseases, progress in developing new therapies for autoimmune rheumatic conditions, has been slow, with the conventional treatment mainstays remaining largely unchanged, and typically characterized by limited effectiveness and need for frequent patient monitoring, and only partially effective at best.
Autoimmune disorders are particularly complex and difficult to treat, with therapies historically consisting primarily of methotrexate, hydroxychloroquine, and steroids — agents that provide some symptomatic relief in some patients but often fail to prevent inflammation-related tissue/joint damage. In addition, these traditional treatments may lose effectiveness over time and are associated with various problematic side effects.
Recently, monoclonal antibodies for the treatment of SLE, RA, and psoriasis have become available, but these agents must be injected, raising issues of patient acceptance and tolerability as well as being associated with potentially serious side effects, with their use generally reserved for patients with moderate-to-severe disease or who have not responded to other treatments. Clearly, there’s an unmet need for new more effective treatments, preferably with oral drug agents, and of a nature that will be beneficial to a significant percentage of patients, especially those with mild-to-moderate and/or early-stage autoimmune disease.
The need for new approaches is particularly pressing in the case of SLE. a severe and disabling systemic and chronic autoimmune disorder of unknown etiology in which various cell types and immunological pathways become dysregulated, allowing the immune system to go awry and dysfunctionally produce antibodies to cells within the body that attack and destroy healthy tissue — causing pain, swelling and inflammation, and damages to joints, skin, blood, heart, brain, kidneys, lungs, bones, and nervous system.
Lupus primarily affects women of childbearing age (ie: between 20 to 40), and women of color are two to three times more likely to develop Lupus than Caucasians. However, men, children, and teenagers and people of all races and ethnic groups can develop Lupus. Typically affecting many parts of the body, including the joints, kidneys, central nervous system, heart, hematological system and others, and can cause severe complications that make aggressive therapies obligatory. Other risk factors include exposure to sunlight, some prescription medications, infection with Epstein-Barr virus, and exposure to certain chemicals.
The Lupus Foundation of America estimates that based on its research at least 1.5 million Americans have lupus, but that the actual number may be as high as 2 million or more, since there have been no large-scale studies to determine the actual number of people in the U.S. living with lupus. More than 16,000 new cases of lupus are reported annually across the country, representing a huge unmet medical need, with only one new treatment having been approved by the FDA in the past 50 years and patients obliged to struggle to draw attention to their disease. As Dr. Abby Abelson, Chair of the Department of Rheumatologic and Immunologic Disease at the Cleveland Clinic comments in a Janus release, “I don’t think there’s a conspiracy here, but [lupus] just hasn’t gotten a lot of funding and it hasn’t gotten a lot of attention from the media.”
Although the monoclonal antibody, Benlysta, is now available, clinical trial results indicate that only 1 in every 11 SLE patients treated will benefit. In light of this, one FDA committee member, Lenore M Buckley, MD, MPH Professor of Medicine (Rheumatology) and of Pediatrics (General Pediatrics); and Professor; Clinical Chief, of the Section of Rheumatology at Yale University School of Medicine observes in the release “There is a need for a drug with even mild efficacy.”
New therapeutic approaches are urgently needed for other related conditions as well.
Toll-like Receptor Antagonism
Janus proposes that realization of the importance of abnormal TLR activation and dendritic cell dysregulation in the development of autoimmune diseases opens up the possibility of an exciting new approach for the treatment of patients with certain of these disorders. The goal of the Janus Biotherapeutics drug development strategy is to develop an agent for blocking aberrant stimulation of TLR 7, 8, and 9, with the resulting downstream damaging proinflammatory activity also reduced or eliminated..
Janus Biotherapeutics say they are well positioned to develop an agent meeting these criteria — the company’s founders and management team being the discoverers, inventors, and developers of several compounds targeting TLR 7, 8, and 9. Janus is currently in the process of developing oral anti-TLR drug candidates for SLE, RA, and possibly psoriasis and Sjogren’s syndrome as well. By blocking unwanted immune activation by these TLRs and thereby reducing downstream levels of a variety of proinflammatory factors, the researchers maintain that an anti-TLR drug should provide improved effectiveness and safety, and in convenient oral medication form should also prove more acceptable to patients, resulting in greater treatment adherence.
“Even if still in a preclinical phase, Janus’ unique triple TLR antagonist has potential therapeutic applications across multiple autoimmune diseases with high unmet medical need,” says Grayson Lipford, Janus’ co-founder and Chief Scientific Officer. “The Janus program will be a part of Roche’s external drug discovery portfolio and benefit from Roche’s know-how in drug development and translational medicine and strong heritage in autoimmune diseases.”
“We are delighted to have found a partner with the capability to fully leverage our team’s world class expertise in TLR biology and chemistry,” observes Joseph Baron, co-founder and CEO of Janus Biotherapeutics. “We hope that this collaboration will ultimately benefit patients with autoimmune diseases and look forward to working with Roche on our shared goal to develop innovative medicines.”
Under the terms of the agreement, Janus will receive an upfront cash payment and R&D funding over a collaboration period. With subsequent achievement of certain predetermined milestones, Roche will have the option to acquire Janus, and in the event that option is exercised, Janus’ shareholders will be eligible to receive an acquisition fee and, potentially, development milestones.
The Lupus Foundation of America
Yale-New Haven Hospital