BioSpace Speaks with R&D Leaders for World Lupus Day
Courtesy of Lupus News Today
May 10th is World Lupus Day, a day that honors and brings awareness to the millions of people suffering from lupus worldwide. On this occasion, BioSpace spoke with several companies making inroads in research and development for the disease.
What is Lupus?
Lupus is a chronic, inflammatory autoimmune disease that spans four types: systemic, cutaneous, drug-induced and neonatal. Typically, when people refer to “lupus” they are referring to systemic lupus erythematosus (SLE). SLE is a form of lupus in which the immune system can attack any and all systems of the body.
The symptoms of SLE can vary widely with each patient but generally include fatigue, muscle and joint pain, headaches, low-grade fevers, cognitive symptoms and sensitivity to sunlight. However, because SLE can potentially impact any organ or bodily system, the symptoms can include more severe organ and tissue damage that can be life-threatening.
The Lupus Foundation of America estimates that 1.5 million people in the U.S. have some form of lupus. SLE accounts for 70% of all lupus cases with a major organ such as the kidneys, lungs, brain or liver being impacted in 50% of patients.
The Current Treatment Landscape
Depending on disease severity, there may be several treatment options for lupus. Patients may take anti-inflammatories, antimalarials and steroids to help treat flares of the disease or daily symptoms. Additionally, some patients may take biologics to help keep the immune system working properly or immunosuppressives to help prevent it from attacking the body.
Although some treatments like plaquenil, prednisone and aspirin were approved to treat SLE by the U.S. Food and Drug Administration many decades ago, it wasn’t until 2011 that the FDA greenlit the first targeted therapy for the disease, Benlysta (belimumab), developed by Human Genome Sciences and GlaxoSmithKline. Later, in July 2021, the FDA approved AstraZeneca’s Saphnelo (anifrolumab) as the second targeted therapy to treat adults with systemic lupus erythematosus. Earlier in 2021, Aurinia Pharmaceuticals secured FDA approval for Lupkynis for the treatment of lupus nephritis (LN).
The lack of lupus-specific therapeutics doesn’t always stem from a lack of interest and effort, though. Two issues facing researchers and drug developers are the lack of consistency in defining disease modification in lupus and the heterogeneity of the disease.
Two patients with lupus may present with different symptoms and severity of disease. While one patient may only have skin rashes, the other may progress to kidney failure. Putting these very different patients together in the same clinical trial may make it difficult to interpret clinical outcomes because some patients do not present with much of a baseline for comparison at the end of treatment.
In April, GSK-backed researchers made an effort to resolve this issue by introducing a standardized definition of disease modification in SLE and LN, the first step toward encouraging researchers and drug developers to think about how they measure objective clinical outcomes. This work may help to better drive R&D in the space.
Several companies are working diligently on lupus therapeutics no matter the barriers.
Equillium is Targeting Underlying Lupus Pathophysiology
Equillium is currently conducting Phase Ib studies of its candidate itolizumab which is intended to treat both SLE and LN. Itolizumab is a first-in-class monoclonal antibody targeting the CD6-ALCAM signaling pathway.
Itolizumab binds to CD6, a co-stimulatory receptor for ALCAM, which is expressed on autoreactive T-cells. Through modulation of the receptor, the therapeutic can inhibit the co-stimulatory signaling which ultimately helps to stop the proliferation and secretion of proinflammatory cells. By targeting CD6, itolizumab can alleviate inflammatory states in patients without suppressing the entire immune system. Equillium anticipates sharing Phase Ib results in mid-2022. A molecule that targets both the activity and the trafficking of inflammatory mechanisms helps to target underlying lupus pathophysiology.
“Our approach to treating autoimmune and inflammatory diseases is one where we really believe in novel mechanisms,” Equillium CSO Stephen Connelly, Ph.D. told BioSpace. “We’re still using drugs that were developed 50 years ago. I don’t have many things that I own that are 50 years old that I use and find utility in. Autoimmune and inflammatory diseases are lacking in innovation, so at Equillium we are setting out to try to solve that.”
Biogen Provides Updates to Lupus Program
Nathalie Franchimont, Ph.D., SVP and head of the multiple sclerosis and immunology development unit at Biogen, provided updates on her company’s lupus programs to BioSpace via email.
Biogen’s lupus candidate, BIIB059, is a humanized monoclonal antibody that is currently in Phase II clinical trials for patients with cutaneous lupus erythematosus (CLE) and SLE. Franchimont explained that the therapeutic binds to blood dendritic cell antigen 2 (BDCA2), a protein that is uniquely expressed on plasmacytoid dendritic cells (pDCs). By binding BDCA2, the production of inflammatory mediators such as Type-1 interferons (IFN-1s) and other cytokines and chemokines are inhibited. The inhibiting of these cells could decrease inflammation and reduce tissue damage in lupus patients.
In Phase II studies, BIIB059 met its primary endpoints, demonstrating statistically significant reduction of disease activity in people with CLE and SLE. Both joint and skin manifestations and activity were reduced. Phase III studies, Topaz-1 and Topaz 2 are underway with an estimated study completion date in late 2025.
Vera Takes a Two-Pronged Approach
Vera Therapeutics is investigating a drug called atacicept in patients with LN. Atacicept is a recombinant fusion protein that contains the soluble TACI receptor which binds to cytokines BLyS and APRIL, which promote B-cell survival and autoantibody production. By inhibiting these cytokines, autoantibodies that cause SLE disease manifestations can be reduced.
“There’s evidence in animal models that targeting APRIL and BLyS has a more profound effect on limiting the production of disease-causing autoantibodies. We also have some clinical evidence. There’s a Phase II study done of atacicept in systemic lupus that, while it missed its primary endpoint in all comers, did show efficacy in those with active disease,” Vera Founder and CEO Marshall Fordyce, M.D., said in an interview with BioSpace. “That got my attention as a drug developer, and I thought the results showed that the mechanism worked.”
Vera has decided to take atacicept into the realm of LN and with FDA feedback, the company got the green light to pursue the drug in a Phase III clinical trial which is anticipated to begin later this year.
Kyverna is Investigating CAR-T Therapies
Newcomer Kyverna is looking to make its mark in lupus therapeutics by utilizing an anti-CD19 CAR-T cell therapy. With this approach, the company hopes to create a therapeutic that provides an optimal and long-lasting response.
Anti-CD19 CAR-T cell therapy genetically modifies a patient’s own T-cells to deplete B cells, which are drivers of autoimmunity. Not only would the therapeutic help to eliminate disease manifestations, but it also provides benefits when compared with other immunotherapies that may cause long-term side effects.
“It could be a single therapy that has potential for a really long duration of effect in the order of years [and] perhaps even [be]curative,” James Chung, M.D., Ph.D., chief medical officer at Kyverna told BioSpace.
Kyverna plans to enter clinical trials later this year. Having already communicated with the FDA, the company is engaging with potential investigators and clinical trial sites.
How Can Patients Get Involved?
There are lots of ways for lupus patients to get involved with research and clinical development efforts. Patients are encouraged to participate in clinical trials, patient advisory boards and patient advocacy by the Lupus Research Alliance (LRA).
“Scientists cannot achieve success without the active participation of individuals living with lupus. No matter how great a discovery in the laboratory is, translating the discovery into a new medication for individuals living with lupus takes testing – and patient participation in the research process. I would tell people living with lupus just that – that we cannot accelerate lupus research without their participation,” Caroline Donovan, director of patient engagement at the Lupus Therapeutics, part of LRA, told BioSpace.
Donovan also emphasized that individuals of color are essential to helping to reduce lupus health disparities and achieve health equity.
Beyond participating in clinical trials, patients can also take part in patient advisory boards where they can help to make lupus clinical trials more patient-centric. The LRA is also planning to expand its Patient Advocates in Lupus (PALS) pilot program which aims to mitigate barriers to participation in lupus clinical research.
The LRA is also working hard to support the next great discovery in lupus therapeutics and bring personalized care to patients.
“The Lupus Research Alliance and our clinical affiliate Lupus Therapeutics support upcoming therapeutics in a wide range of ways, from funding basic and translational science to clinical trials,” said Andrea O’Neill, executive director of the LRA. “Lupus Research Alliance has invested more than $220 million that has identified at least fifteen unique disease pathways in lupus and enabled the discovery, validation and/or testing of more than a dozen different therapies for this extraordinarily complex disease that affects each person differently and warrants personalized treatment.”
O’Neill also noted that Lupus Therapeutics is currently working with the lupus research industry on a number of clinical research trials that are in Phase II and Phase III studies throughout 57 academic centers across North America.