Many drug makers are investing in new science and hope to develop new therapeutics that address autoimmune disease. BioSpace has captured some key efforts.
A healthy immune system defends the body against disease and other conditions. However, if the immune system malfunctions, it can attack healthy cells, tissues and organs. Autoimmune disease impacts different parts of the body, weakening functionality. It may be life-threatening.
Researchers are aware of more than 80 diseases that occur when the immune system attacks the body’s own organs, tissues and cells. The more common autoimmune diseases include type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease.
Autoimmune diseases affect more than 24 million people in the U.S. On top of this, another 8 million carry auto-antibodies, blood molecules that indicate a person’s chance of developing an autoimmune disease. The cause of many of the diseases is unknown.
Many drug makers are investing in new science and hope to develop new therapeutics that address autoimmune disease. BioSpace has captured some key efforts.
Inflammatory Overreaction
Researchers at Australia’s Baker Institute and the University of Melbourne are jointly working to develop a new anti-inflammatory drug that could lessen the damage from heart attacks, extend the viability of transplanted organs, help treat autoimmune diseases, such as multiple sclerosis, and possibly reduce fatal complications from viruses, such as COVID-19.
In late 2020, the effort received $200,000 in seed funding from the Baker Department of Cardiometabolic Health at the University of Melbourne’s medical school. Scientists will be testing a drug class targeting the C-reactive protein (CRP) marker of acute inflammation in the body. The protein may be involved in such conditions, and a CRP test may be used to find or monitor conditions that cause inflammation. These include inflammatory bowel disease, lupus or rheumatoid arthritis.
Investigators are developing a therapeutic that directly targets the body’s inflammatory overreaction, when the immune system begins to indiscriminately attack individual organs or the whole body. They have characterized a protein molecule and better understand its structure and pro-inflammatory function.
Next, they plan on identifying potential therapeutic candidates. They’ll use software that searches available drugs, as well as drug-like compounds. Each will be computationally docked into surface pockets of the CRP structure. Then they will test the more promising compounds to find the optimum candidate. Early data is enabling the scientists to narrow groups of drug-like compounds that may work best, but these must be optimized to block the CRP effectively.
Monoclonal Antibodies
Scientists at Charité, University Medicine Berlin, have been able to use daratumumab to successfully treat two female patients who have systemic lupus erythematosus. The human monoclonal antibody targets specific immune plasma cells. The researchers regulated the abnormal immunological memory processes found in these patients. Treatment-induced sustainable clinical responses and reduced systemic inflammation.
Daratumumab already is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus. The cells secrete auto-antibodies, but do not respond to standard immunosuppression.
Daratumumab induced substantial clinical responses in the patients. The clinical responses were sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. The patients’ symptoms included inflammation of the heart and kidneys and antibody-induced anemia. A once-weekly administration of daratumumab for four weeks led to a rapid and significant improvement in symptoms. Scientists documented a significant depletion of long-lived plasma cells, a reduction of interferon type I activity, and a down-regulation of T-cell transcripts associated with chronic inflammation.
Bioelectronic Platform
In late October, SetPoint Medical received Breakthrough Device Designation from the FDA for the use of its novel bioelectronic device by patients with rheumatoid arthritis (RA) who have an incomplete response to, or are intolerant to multiple biologic drugs. The company is developing its platform for the treatment of chronic, inflammation-mediated autoimmune diseases, and is initially focused on the treatment of RA.
SetPoint Medical received FDA Investigational Device Exemption (IDE) approval for a multicenter, double-blind, randomized, sham-controlled pivotal trial that will enroll up to 250 patients at 40 clinical trial sites in the U.S. The trial is to examine the safety and effectiveness of the bioelectronic platform in patients with moderate-to-severe RA who are incomplete responders, or who cannot tolerate biologic or targeted synthetic disease-modifying anti-rheumatic drugs.
There are approximately 1.5 million Americans diagnosed with RA, many of whom do not respond to biological and targeted agents. Or they lose therapeutic response, or are intolerant to these agents. SetPoint’s investigational platform stimulates the vagus nerve to activate the endogenous inflammatory reflex and reduce inflammation.
Antigen-Specific Drugs
In September, Anokion, developing drugs for treating autoimmune disease by restoring normal immune tolerance, expanded an exclusive global collaboration agreement with Bristol Myers Squibb on developing therapeutics for autoimmune diseases to include Anokion’s lead antigen-specific drug candidate, KAN-101, for treating celiac disease.
Under the terms of the amended agreement, originally executed in 2016 with Bristol Myers’ Celgene, an undisclosed fee was paid to Anokion to include KAN-101 for the treatment of celiac disease in the exclusive global collaboration. Anokion is responsible for preclinical activities and Phase I clinical development of partnered programs, and Bristol Myers Squibb will fund subsequent trials and commercial activities at clinical proof-of-concept.
KAN-101 is in a randomized, double-blind, placebo-controlled Phase I study, Assessment of KAN-101 in Celiac Disease. The study is designed to evaluate its safety and tolerability in patients with celiac disease who are on a gluten-free diet.
Small Molecule Inhibitors
In October, NMD Pharma A/S reported that the first subject has been dosed in a Phase I/IIa clinical trial of NMD670, the company’s lead program in development to treat the symptoms of myasthenia gravis, an autoimmune neuromuscular disease that leads to varying degrees of skeletal muscle weakness.
NMD670 is a first-in-class small-molecule inhibitor of the muscle-specific chloride ion channel, the ClC-1 ion channel. NMD Pharma has demonstrated that inhibiting ClC-1 strengthens neuromuscular transmission and ultimately skeletal muscle function.
The Phase I/IIa clinical trial is a randomized, double-blind, placebo-controlled, single and multiple dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of NMD670 in 79 male and female healthy subjects and patients with myasthenia gravis. The primary outcome includes safety and tolerability endpoints. The secondary outcome involves pharmacokinetic endpoints.
Receptor Inhibitors
Also in September, the FDA accepted a new drug application (NDA) from ChemoCentryx seeking approval for its investigational candidate, avacopan, for treating anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis), a rare autoimmune disease.
The FDA has set an action date of July 7, 2021. In ANCA-associated vasculitis, over-activation of the complement pathway further activates neutrophils, leading to inflammation and destruction of small blood vessels. Avacopan is an orally-administered selective complement 5a receptor inhibitor.
The NDA was based on data from the Phase III ADVOCATE study that compared the efficacy of avacopan in combination with Roche’s RHHBY Rituxan (rituximab) or cyclophosphamide.
Patients treated with avacopan achieved both primary endpoints of clinical remission at 26 and 52 weeks. Clinical remission was statistically superior in the avacopan arm compared to SOC at 52 weeks.
In November, the European Medicines Agency agreed to review the Marketing Authorization Application for avacopan for the treatment of patients with ANCA-associated vasculitis.
Oral, Small Molecules
In September, Corbus Pharmaceuticals Holdings announced topline results from its 52-week Phase III RESOLVE-1 study of lenabasum in patients with diffuse cutaneous systemic sclerosis (SSc), a rare life-threatening multi-system autoimmune disease for which there are no FDA-approved treatments.
SSc, a form of scleroderma, is a chronic, rare, debilitating condition affecting approximately 200,000 people in North America, the European Union and Japan. The condition affects the skin and internal organs and is driven by inflammation and fibrosis, which can lead to severe damage and failure of several multiple body organs.
For the primary endpoint, the median American College of Rheumatology Combined Response Index for Systemic Sclerosis (ACR CRISS) scores at week 52 were 0.887 in the placebo arm and 0.888 in the lenabasum 20 mg twice daily arm. ACR CRISS is a composite endpoint that reflects the probability of patient improvement. The maximum achievable ACR CRISS score is 1.0.
RESOLVE-1 is the first 52-week, randomized, placebo-controlled Phase III trial that tested the efficacy and safety of lenabasum in 365 patients with diffuse cutaneous SSc in a multinational, double-blind, randomized, placebo-controlled study, with dosing of lenabasum at 20 mg twice daily, lenabasum at 5 mg twice daily, or placebo twice daily for 52 weeks. The majority of enrolled patients -- 84% -- were receiving background immunosuppressive drugs, reflecting recent trends in clinical practice.
Lenabasum has received Orphan Drug designation and Fast Track designation for the treatment of SSc from the FDA, and Orphan Designation for the treatment of SSc from the European Medicines Agency.
Meanwhile, Horizon Therapeutics is to initiate an exploratory clinical trial of SSc, a subtype of systemic sclerosis that causes fibrosis over large areas of the skin and often involves internal organ damage, especially to the lungs, kidneys and gastrointestinal tract. The company will use its Tepezza (teprotumumab-trbw), an insulin-like growth factor type-1 receptor inhibitor that’s already approved for treating thyroid eye disease.
Lead Pharma is collaborating with Roche, hoping to lead the way in the development of oral small molecules for immune-mediated diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases.
In this single target research collaboration, Lead Pharma and Roche will work together in research activities up to the selection of a pre-clinical candidate, after which Roche will be responsible for further development and global commercialization.
Under the terms of the agreement, Lead Pharma will receive an upfront payment of $13 million, and will be eligible to receive research funding and pre-clinical milestone payments; total potential payments including research, development, regulatory and sales milestones may add up to an aggregate of about $250 million, plus royalties on worldwide sales.
Anti-CD40L Antibody
In early November, Novus Therapeutics announced that the first subject has been enrolled in the Phase IIa clinical trial evaluating AT-1501, the company’s lead product candidate, in adults with amyotrophic lateral sclerosis (ALS). AT-1501 blocks the activation of the CD40L pathway, which has been shown to improve muscle function, slow disease progression, and improve survival in a pre-clinical animal model of ALS. AT-1501 previously received Orphan Drug Designation from the FDA for treatment of ALS.
AT-1501 is a humanized IgG1 anti-CD40L antibody with high affinity for CD40L, a well-validated target with broad therapeutic potential. The CD40/CD40L pathway is key in generating pro-inflammatory responses in autoimmune disease, allograft transplant rejection and neuroinflammation. In a Phase I safety study of healthy volunteers and adults with ALS, AT-1501 was well tolerated at all doses tested.
The company has received $108 million in private placement funding led by BVF Partners. The money will help move AT-1501 through four Phase II trials in renal transplantation, islet cell transplantation, autoimmune nephritis, and ALS.
Warm Autoimmune Hemolytic Anemia
In October, Johnson & Johnson successfully completed its acquisition of Momenta Pharmaceuticals, which develops therapies for immune-mediated diseases, in an all-cash transaction for approximately $6.5 billion.
Momenta is developing treatments for diseases driven by autoantibodies, which are antibodies produced by the immune system that initiate many rare autoimmune disorders. The company’s lead drug candidate, nipocalimab, is in a pivotal Phase III clinical trial testing it in warm autoimmune hemolytic anemia (AIHA), which is the most common form of autoimmune hemolytic anemia. It is defined by the presence of autoantibodies that attach to and destroy red blood cells at temperatures equal to or greater than normal body temperature.
Often, the autoantibody involved is immunoglobulin G, according to the National Organization for Rare Disorders. The company’s nipocalimab is an antibody designed to block the neonatal Fc receptor system FcRn, which recycles immunoglobulin G. Nipocalimab is designed to reduce the levels of immunoglobulin G in the bloodstream.
In November, Rigel Pharmaceuticals reached an agreement with the FDA on the final design of its FORWARD study, a pivotal Phase III clinical trial of fostamatinib disodium hexahydrate (fostamatinib) in AIHA. The FDA agreed to Rigel’s proposed durable response measure for the primary efficacy endpoint as well as the inclusion of additional secondary endpoints.
The Phase III clinical trial is a randomized, double-blind, placebo-controlled study of approximately 90 patients with primary or secondary warm AIHA who have failed at least one prior treatment. The primary efficacy endpoint for the trial is a durable response defined as a hemoglobin level ≥ 10 g/dl with an increase from baseline of ≥ 2 g/dl on three consecutive available visits during the 24-week treatment period, with the response not being attributed to rescue therapy.
This endpoint allows for missed visits due to the COVID-19 pandemic without impacting a durable outcome. As of November 5, the trial had enrolled 57 of the 90 patients targeted for enrollment and currently has more than 90 clinical trial sites established across 22 countries.
New Immune System Cell
Scientists at Trinity College Dublin have identified a new cell in the immune system with unusual properties. Their research, published in the Journal of Experimental Medicine, may facilitate new therapeutics for treating some autoimmune diseases.
The authors wrote, “T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR–mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs.
“They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1β and IL-23. Hybrid αβ-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation.
“These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system,” the authors stated.
In an autoimmune disease model, the scientists found that the hybrid T cells can trigger the inflammatory cascade that mediates tissue damage in autoimmunity. Essentially, ways to inhibit these highly activated immune cells in susceptible individuals may open up new approaches for treating autoimmune diseases, including multiple sclerosis, according to the researchers.
Partnership Effort
A research partnership between The Indiana University School of Medicine and Eli Lilly focuses on the development of potential molecules for treating autoimmune diseases. The partnership also involves collaboration with the Indiana Clinical and Translational Sciences Institute (CTSI), which is known for its research analytics.
The project will also be aided by the Regenstrief Institute, involved in digital health data. By plugging Lilly’s deep amount of data into IU’s analytics and informatics, the partnership will create more meaningful data.
Extending Collaboration
In November, Cue Biopharma extended the term of the research program under its existing 2017 research collaboration and license agreement with Merck toward developing a clinical candidate for the treatment of type 1 diabetes and an undisclosed autoimmune disease.
Cue Biopharma entered into an exclusive patent license and research collaboration agreement with Merck in November 2017 to develop biologics for the treatment of selected autoimmune diseases. Under the terms of the extension, Cue Biopharma will receive additional financial research support to develop preclinical biologics with the objective of identifying clinical candidates.
The company’s CUE-300 framework can target a range of addressable autoimmune diseases by selectively modulating disease-associated T cells so that healthy cells are protected from immune attack, without compromising the immune system.
Current therapies for treating autoimmune diseases rely on global inhibition or dampening of immune responses, which often reduce a patient’s ability to mount normal immune responses to bacteria, viruses, and cancer. CUE-300 Series Immuno-STATs may offer autoimmune patients therapeutic benefits without compromising their immune systems.
Patient Recruitment
Beyond Celiac, a patient advocacy and research-driven celiac disease organization, is partnering with Anokion’s Kanyos Bio to recruit patients for the ACeD (Assessment of KAN-101 in Celiac Disease) Study. Currently, in a Phase I clinical trial, KAN-101, the company’s lead antigen-specific drug candidate, for the treatment of celiac disease, has the potential to induce immune tolerance to gluten. Patient dosing already has begun.
Anokion’s Phase I clinical trial of KAN-101 is a randomized, double-blind, placebo-controlled, first-in-human study designed to evaluate the safety and tolerability of KAN-101 in patients with celiac disease on a gluten-free diet. Celiac disease patients will receive a single dose of KAN-101 across four single-ascending dose cohorts, or three doses of either KAN-101 or placebo across three multiple-ascending dose cohorts.
