Overview: Afimetoran, a newly developed pill to treat lupus, not only prevents lupus-like symptoms in mice, it also repairs 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 organs and can be fatal. There is no cure, so current treatments are designed to limit damage and relieve symptoms. Some of these therapies need to be injected, 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 not only prevents lupus-like symptoms in mice, 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 meeting held virtually and in person from August 21 to 25, with on-demand access available from August 26 to September 26. 9. The meeting includes nearly 11,000 presentations on a wide range of scientific topics.
“Few new therapies have succeeded, but we believe our compound could be an effective treatment for lupus,” says Alaric Dyckman, Ph.D. According to the Lupus Foundation of America, the disease affects 5 million people worldwide. Symptoms include skin 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 tissues of the body. Years ago, researchers began to suspect that this process involved toll-like receptors (TLRs) 7 and 8, cellular proteins that activate the immune system when they detect viral RNA or mistakenly identify a person’s own RNA as a threat.
“Genetic data and evaluations of injectable treatments suggested that TLR7 and 8 could be drug targets for lupus. What was lacking was the ability to directly block these receptors with small molecules that could be taken orally,” says Dyckman. So in 2010, he started. and other scientists at Bristol Myers Squibb (BMS) are developing such compounds.
New options would be welcome, as many patients do not respond fully to current medications. The two approved therapies 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 immune suppressants, antimalarials, anti-inflammatories and anticoagulants.
However, anifrolumab and belimumab must be given by injection or infusion, Dyckman notes, while steroids and general immune suppressants are linked to safety concerns and were not originally designed to treat lupus.
The BMS researchers began the search for a suitable alternative by screening the company’s curated library for molecules that could block TLR7/8 signaling. The team modified the structures of the first hits to reduce interaction with other receptors, improve potency and allow for oral dosing.
The resulting compound, “afimetoran”, binds to the target TLRs and inhibits their action to achieve beneficial activity. 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, we were not only able to prevent the development of lupus-like symptoms in mice before their disease started, but we were also able to reverse the symptoms and prevent death in animals that were days or weeks away from succumbing to the disease,” says Dyckman. .
“We hadn’t seen that reversal with other mechanisms that we had evaluated, so we were particularly excited about that finding.”
Dyckman says he believes the combined effects of afimetoran have the potential to control lupus as well as or better than existing treatments and do it by oral administration as opposed to requiring injection or infusion.
The team also found that afimetoran went well with corticosteroid treatments in mice. That means patients may be able to take lower doses of steroids, a 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.
Phase 1 clinical trials with afimetoran to evaluate safety in healthy humans and shed light on the compound’s behavior in the body have been completed.
The studies showed that a low once-daily oral dose could almost completely block signaling via TLR7/8. And now a phase 2 trial is underway to test its effectiveness in lupus patients. Because of its mechanism of action, Dyckman says, it may also work in other autoimmune diseases, such as psoriasis or arthritis.
BMS is testing other compounds against lupus, such as deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor that is entering Phase 3 trials. Other companies are also making progress. For example, Merck is evaluating its own oral TLR7/8 blocker, enpatoran, in Phase 2 trials.
But the busy field does not interest Dyckman. Despite intensive efforts to develop new therapies in recent decades, few have succeeded.
“So it’s important to get a lot of shots on target,” he says. “In addition, lupus is such a heterogeneous disease that a single approach is unlikely to provide relief for all the patients out there.”
Financing: The researchers acknowledge support and funding from Bristol Myers Squibb.
About this research news on neuropharmacology
Author: Katie Cottingham
Source: American Chemical Society
Contact: Katie Cottingham – American Chemical Society
Image: The image is in the public domain
Original research: The findings will be presented at ACS Fall 2022