summary: A newly developed pill to treat lupus, affimateran, not only prevents lupus-like symptoms in mice, it also reverses signs of organ damage caused by the disease and prevents death. The drug is now undergoing phase 2 clinical trials to assess its effectiveness in lupus patients.
Source: American Chemical Society
Lupus is an autoimmune disease that attacks the organs and can be fatal. There is no cure, so current treatments aim to limit the damage and reduce symptoms. Some of these treatments have to be injected, some have serious side effects, and many are not very effective.
But today, scientists report that they have begun a phase 2 clinical trial with a pill containing a compound that not only prevented lupus-like symptoms in mice, but also signs of organ damage caused by the disease. also reverses and prevents death.
The researchers will present their results at the American Chemical Society (ACS) fall meeting. ACS Fall 2022 is a hybrid meeting being held virtually and in person August 21-25, with on-demand access available August 26-Sept. 9. The meeting has about 11,000 presentations on a wide range of science topics.
“Some new treatments have been successful, but we believe our compound may be an effective treatment for lupus,” says Alaric Dieckmann, Ph.D. According to the Lupus Foundation of America, the disease affects 5 million people worldwide. Symptoms include rashes, extreme fatigue, pain, swelling 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 they detect or mistakenly detect viral RNA. identify a person’s own RNA as a threat.
“Genetic data and evaluation of injectable therapies suggested that TLRs 7 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 Dickman. 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 respond fully to current medications. Two approved treatments developed specifically for lupus reduce the activity of specific immune system components: AstraZeneca’s anifrolumab blocks a receptor for the protein interferon, while GlaxoSmithKline’s belimumab blocks white blood cells known as B cells. diminishes its existence.
Other treatments include steroids and other general immune suppressants, antimalarial, anti-inflammatory, and anticoagulant.
However, anifrolumab and belimumab must be given by injection or infusion, notes Diekman, while steroids and general immune suppressants are associated with safety concerns and were not originally designed to treat lupus.
The BMS researchers began to zero in on a suitable alternative by examining the company’s compound collection for molecules that could block TLR7/8 signaling. The team modified the structures of the initial hit to reduce interactions with other receptors, improving potency and enabling oral dosing.
The resulting compound, “affimatoran”, binds to target TLRs, inhibiting their operation to elicit beneficial activity. Like anifrolumab, it interferes with interferon, and like belimumab, it controls the damage caused by overactive B cells. It also inhibits the production of several proinflammatory cytokines that cause a lot of tissue damage in lupus.
“With Afimatoran, we can not only prevent the development of lupus-like symptoms in mice before the onset of their disease, but we can actually reverse symptoms and prevent death in animals that succumb to the disease.” were days or weeks away,” Diekman says.
“We didn’t see that reversal with the other mechanisms we evaluated, so we were particularly excited about that finding.”
Diekman says he believes afimatron’s combined effects give it its ability to control lupus as well as do this better than existing treatments, either through oral delivery, as needed by injection or infusion. is opposite to.
The team also found that afimatron combined well with corticosteroid treatment in rats. This means patients may be able to use lower doses of steroids, a mainstay of lupus treatment.
Low doses would be beneficial because steroids have side effects, such as weight gain, thinning of the bones, high blood pressure and diabetes, as well as an increased risk of infection.
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Phase 1 clinical trials of afimatron have been completed to evaluate safety in healthy people and shed light on the compound’s behavior in the body.
Trials showed that a low, once-daily oral dose could almost completely block signaling through TLR7/8. And now, a phase 2 trial is underway to test its effectiveness in lupus patients. Because of its mode of action, Diekman says, it may also work in other autoimmune disorders, such as psoriasis or arthritis.
BMS is testing other compounds against lupus, such as ducravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor that is moving into phase 3 studies. Other companies are also making progress. For example, Merck is evaluating its own oral TLR7/8 inhibitor, enpatoran, in phase 2 trials.
But the crowded field doesn’t worry Dieckmann. Despite intense efforts to develop new treatments over the past several decades, only a few have been successful.
“So it’s important to get a lot of shots on target,” he says. “Furthermore, lupus is such a heterogeneous disease that it is unlikely that any single approach will provide relief for all patients.”
Financing: The researchers acknowledge support and funding from Bristol Myers Squibb.
About this neuropharmacology research news
Author: Katie Cottingham
Source: American Chemical Society
contact: Katie Cottingham – American Chemical Society
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Basic Research: Conclusion ACS Fall 2022 . will be presented in
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