This shows a pack of pink pills

Lupus pill shows promise in mice; clinical trials underway

To summarize: Afimetoran, a newly developed pill for lupus, not only prevented lupus-like symptoms in mice, but also reversed signs of organ damage caused by the disease and prevented death. The drug is currently undergoing Phase 2 clinical trials to evaluate its effectiveness in lupus patients.

resource: 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 injected, some have serious side effects, and many are not very effective.

But today, scientists report that they have begun phase 2 clinical trials with a pill containing a compound that not only prevents lupus-like symptoms in mice, but also reverses signs of disease-induced organ damage and prevents die.

The researchers will present their findings at the fall meeting of the American Chemical Society (ACS). The ACS Fall 2022 meeting is a hybrid conference that will be held virtually in person August 21-25, with on-demand access August 26-September. 9. The conference featured nearly 11,000 presentations on a wide range of scientific topics.

“Few new treatments have been successful, but we believe our compounds may be an effective treatment for lupus,” said Dr. Alaric Dyckman. According to the Lupus Foundation of America, the disease affects 5 million people worldwide. Symptoms include rash, extreme fatigue, pain, inflammation, and degeneration of organs such as the kidneys and heart, which can lead to death.

Lupus develops when the immune system attacks body tissues. Years ago, researchers began to suspect that this process involves toll-like receptors (TLRs) 7 and 8, which are cellular proteins that activate the immune system when they detect viral RNA or mistakenly identify a person’s own RNA as a threat.

“Evaluation of genetic data and injectable treatments suggest that TLR7 and 8 may be drug targets for lupus. What’s missing is the ability to directly block these receptors with small molecules that can be taken orally,” Dyckman said. So in 2010, he and other scientists at Bristol-Myers Squibb (BMS) set out to develop such compounds.

New options will be welcome, as many patients do not fully respond to current drugs. Two approved therapies developed specifically for lupus reduce the activity of specific components of the immune system: AstraZeneca’s anifrolumab blocks receptors for proteins called interferon, while GlaxoSmithKline’s belimumab reduces the activity of cells called B cells viability of white blood cells.

Other treatments include steroids and other general immunosuppressants, antimalarial drugs, anti-inflammatory drugs, and anticoagulants.

However, Dyckman noted that anifrolumab and belimumab must be administered by injection or infusion, while steroids and general immunosuppressants have been linked to safety concerns and were not originally designed to treat lupus.

BMS researchers set out to find suitable alternatives by screening the company’s collection of compounds for molecules that could block TLR7/8 signaling. The team modified the structure of the initial hit to reduce interactions with other receptors, improve potency and enable oral administration.

The resulting compound “afimetoran” binds to target TLRs, inhibiting their operation for 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 multiple pro-inflammatory cytokines that cause massive tissue damage in lupus.

“Using afimetoran, not only can we prevent the development of lupus-like symptoms in mice before they develop disease, but we can actually reverse the symptoms and prevent the death of animals that die from the disease days or weeks later,” Dyckman said.

“We didn’t see a reversal with other mechanisms we’ve evaluated, so we’re particularly excited about this finding.”

BMS researchers set out to find suitable alternatives by screening the company’s collection of compounds for molecules that could block TLR7/8 signaling.Image is in the public domain

Dyckman said he believes the combined effects of afimetoran make it possible to control lupus as well or better than existing treatments, and to control lupus by oral administration, rather than requiring injections or infusions.

The team also found that afemetoline combined well with corticosteroid treatment in mice. This means that patients may be able to use lower doses of steroids, 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, and an increased risk of infection.

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Phase 1 clinical trials of afimetoran have been completed to assess safety in healthy humans and to elucidate the compound’s behavior in vivo.

Trials have shown that low-dose oral once-daily doses almost completely block signaling through TLR7/8. Now, a phase 2 trial testing its effectiveness in lupus patients is underway. Because of its mode of action, it may also play a role in other autoimmune diseases, such as psoriasis or arthritis, Dyckman said.

BMS is testing other lupus-targeting compounds, such as deucravicitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor that is entering Phase 3 studies. Other companies are also making progress. For example, Merck is evaluating its own oral TLR7/8 blocker, enpatoran, in a phase 2 trial.

But the crowded field doesn’t care about Dyckman. Despite tremendous efforts to develop new treatments over the past few decades, few have succeeded.

“So it’s important to get a lot of shots,” he said. “Furthermore, lupus is a heterogeneous disease, and it is unlikely that any single approach will provide relief for all patients.”

funds: The researchers thank Bristol-Myers Squibb for support and funding.

About this Neuropharmacology Research News

author: Katie Cottingham
resource: American Chemical Society
touch: Katie Cottingham – American Chemical Society
picture: Image is in the public domain

Original research: Findings to be presented at ACS Fall 2022

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