PARIS, August 24 (Benin News) –
Scientists have announced that they have entered phase 2 clinical trials with a pill containing a compound that, in mice, not only prevents symptoms of lupus, but also reverses signs of organ damage caused by the disease and prevents the death. The researchers will present their findings at the fall meeting of the American Chemical Society (ACS).
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 therapies must be injected, others have serious side effects, and many are not very effective.
“Few new therapies have been successful, but we believe our compound could be an effective treatment for lupus,” says Dr. Alaric Dyckman. This disease affects 5 million people worldwide, according to the Lupus Foundation of America. Symptoms include skin rashes, extreme fatigue, pain, inflammation, and organ damage, such as the kidneys and heart, which can lead to death.
Lupus develops when the immune system attacks body tissues. Several 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 they detect viral RNA or mistakenly identify the virus. a person’s own RNA as a threat.
“Genetic data and evaluations of injectable treatments have suggested that TLR7 and 8 may 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. In 2010, together with other scientists from Bristol Myers Squibb (BMS), he set out to develop such compounds.
These new options would be welcome, they note, because many patients do not fully respond to current medications. The two approved treatments, developed specifically for lupus, reduce the activity of specific components of the immune system: AstraZeneca’s anifrolumab blocks an interferon protein receptor, while GlaxoSmithKline’s belimumab reduces the survival of white blood cells known as the name “B cells”.
Other treatments include steroids and other systemic immunosuppressants, antimalarials, anti-inflammatories, and blood thinners. However, anifrolumab and belimumab must be given by injection or infusion, Dyckman points out, while steroids and systemic immunosuppressants are associated with safety concerns and were not originally designed to treat the disease. lupus.
BMS researchers began searching for a suitable alternative by sifting through the company’s collection of compounds for molecules that might block TLR7/8 signaling. The team modified the structures of early hits to reduce interaction with other receptors, improve potency and allow for oral dosing. The resulting compound, afimethoran, binds to target TLRs, inhibiting their function to achieve beneficial activity. Like anifrolumab, it interferes with interferon, and like belimumab, it controls damage caused by overactive B cells. It also inhibits the production of several pro-inflammatory cytokines that cause much of the tissue damage in lupus.
“With afimethoran, we were not only able to prevent the development of lupus symptoms in mice before disease onset, but we were able to reverse the symptoms and prevent the death of animals that were within days or weeks of succumb to the disease,” says Dyckman. We had not observed this reversal with other mechanisms we had tested, so we were particularly excited about this finding. Dr. Dyckman believes that the combined effects of afimethoran give it the potential to control lupus as well as, or better than, existing treatments, and do so by mouth, rather than by injection or infusion.
The team also found that afimetoran combined well with corticosteroid treatments in mice. This means patients could use lower doses of steroids, a mainstay of lupus treatment. Lower doses would be beneficial as steroids have side effects, such as weight gain, bone thinning, high blood pressure and diabetes, as well as an increased risk of infection.
Phase 1 clinical trials of afimethorphan have been completed to assess safety in healthy people and shed light on how the compound behaves in the body. Trials have shown that a low oral dose, given once daily, can almost completely block TLR7/8 signaling. And now a phase 2 trial is underway to test its effectiveness in lupus patients. According to Dyckman, due to its mode of action, it could also be effective in other autoimmune disorders, such as psoriasis or arthritis.
BMS is testing other compounds for lupus, such as deucravacitinib, an orally-administered selective tyrosine kinase 2 (TYK2) inhibitor, which is entering phase 3 studies. Other companies are also making progress. Merck, for example, is evaluating its own oral TLR7/8 blocker, enpatoran, in phase 2 trials.
The fact that there is so much research going on doesn’t worry Dyckman because, despite intense efforts to develop new therapies over the past decades, few have been successful. So it’s important to get a lot of shots on goal,” he said. Furthermore, lupus is such a heterogeneous disease that no single approach is likely to provide relief to all patients.