Source: American Chemical Society Lupus is an autoimmune disease that attacks organs and can be fatal. There is no cure, so current treatments aim to limit damage and improve symptoms. Some of these treatments must be given by injection, some have serious side effects, and many are not very effective. But today, scientists report that they have begun phase 2 clinical trials of a pill containing a compound that, in mice, not only prevents lupus-like symptoms but also reverses signs of organ damage caused by the disease and prevents death. The researchers will present their results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2022 is a hybrid virtual and in-person meeting from August 21-25, with on-demand access available from August 26 through September 26. 9. The meeting includes nearly 11,000 presentations on a wide range of science topics. “Few new treatments have been successful, but we believe our compound could be an effective treatment for lupus,” says Alaric Dyckman, Ph.D. The disease affects 5 million people worldwide, according to the Lupus Foundation of America. Symptoms include rashes, extreme fatigue, pain, inflammation and deterioration of organs such as the kidneys and heart, which can lead to death. Lupus develops when the immune system attacks the body’s tissues. Years ago, researchers began to suspect that this process involved toll-like receptors (TLRs) 7 and 8, which are cellular proteins that activate the immune system when it detects viral RNA or misidentifies a person’s RNA as a threat. “Genetic data and evaluations of injectable therapies suggest that TLR7 and 8 could be drug targets for lupus. What was missing was the ability to directly block these receptors with small molecules that could be taken orally,” says Dyckman. So in 2010, he and other scientists at Bristol Myers Squibb (BMS) set out to develop such compounds. New options would be welcome, as many patients do not fully respond to current drugs. The two approved treatments developed specifically for lupus reduce the activity of specific components of the immune system: AstraZeneca’s anifrolumab blocks a receptor for the protein interferon, while GlaxoSmithKline’s belimumab reduces the survival of white blood cells known as B cells. Other treatments include steroids and other general immunosuppressants, antimalarials, anti-inflammatories and anticoagulants. However, anifrolumab and belimumab must be given by injection or infusion, Dyckman notes, while steroids and general immunosuppressants are associated with safety concerns and were not originally designed to treat lupus. BMS researchers began zeroing in on a suitable alternative by screening the company’s compound collection for molecules that could block TLR7/8 signaling. The team modified the structures of the original hits to reduce interaction with other receptors, improve potency and allow for oral administration. The resulting compound, “afimetoran”, binds to target TLRs, inhibiting their function to achieve a beneficial effect. Like anifrolumab, it interferes with interferon, and like belimumab, it controls damage from overactive B cells. It also inhibits the production of multiple pro-inflammatory cytokines that cause a lot of tissue damage in lupus. “With afimetoran, not only could we prevent the development of lupus-like symptoms in mice before the onset of disease, but we could actually reverse the symptoms and prevent death in animals that were days or weeks away from succumbing in the disease,” says Dyckman. . “We had not seen this reversal with other mechanisms we had evaluated, so we were particularly excited by this finding.” BMS researchers began zeroing in on a suitable alternative by screening the company’s compound collection for molecules that could block TLR7/8 signaling. Image is public domain Dyckman says he believes the combined effects of afimetoran allow it to control lupus as well as or better than existing treatments, and it does so by oral administration, as opposed to requiring an injection or infusion. The team also found that afimetoran combined well with corticosteroid treatments in mice. This means patients may be able to use lower doses of steroids, which are the mainstay of lupus treatment. Lower doses would be beneficial because steroids have side effects such as weight gain, thinning bones, high blood pressure and diabetes, as well as an increased risk of infection. See also Phase 1 clinical trials of afimetoran have been completed to assess safety in healthy humans and shed light on how the compound behaves in the body. Tests showed that a low once-daily oral dose could almost completely block signaling through TLR7/8. And now, a phase 2 trial to test its effectiveness in lupus patients is underway. Because of its mode of action, Dyckman says, it may also work in other autoimmune disorders, such as psoriasis or arthritis. BMS is testing other anti-lupus compounds, such as deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor that is in phase 3 studies. Other companies are also making progress. Merck, for example, is evaluating its own oral TLR7/8 inhibitor, enpatoran, in phase 2 trials. But the packed field isn’t about Diekman. Despite intensive efforts to develop new treatments in recent decades, few have succeeded. “So it’s important to get a lot of shots on goal,” he says. “Also, lupus is such a heterogeneous disease that it is unlikely that any single approach will provide relief for all patients out there.” Funding: The researchers acknowledge support and funding from Bristol Myers Squibb.
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Author: Katie Cottingham Credit: American Chemical SocietyCommunication: Katie Cottingham – American Chemical SocietyImage: Image in the public domain Original research: Findings will be presented at ACS Fall 2022
