A pill that treats lupus and reverses its damage is in phase 2 trials

Albert Roy is currently Executive Director of Lupus Therapeutics of the Lupus Research Alliance and will become President and CEO of the Alliance in September 2022. He described the effects of SLE on Medical News Today:

“Up to 90% of people with lupus will have inflammation or swelling of the joint lining, causing stiffness and pain, most commonly in the hands and wrists. Most people with SLE have unexplained fevers .

Fatigue from lupus, Roy noted, can be “severe enough to have a significant impact on patients’ quality of life, including reducing their ability to function at home or at work.”

“About half of people with lupus have a red ‘malar’ rash that can appear on the cheeks and butterfly-shaped bridge of the nose or other parts of the body, and can be painful or itchy. Because many people with lupus are photosensitive, rashes often first develop or worsen after exposure to sunlight.
— Albert Roy, CEO of Lupus Therapeutics

Lupus can also lead to cardiovascular disease, kidney disease, and stroke.

“Specifically,” Roy said, “people with lupus are at increased risk for atherosclerosis — the deposition of fats and cholesterol [plaque] along the wall of the arterial wall. In some people, inflammation can occur in the heart itself (myocarditis and endocarditis) or in the membrane around it. Endocarditis can damage heart valves, which can lead to heart murmurs.

“When the disease affects the kidneys, it is called lupus nephritis, and patients usually need intensive drug treatment to prevent permanent damage. Lupus can also attack the brain or central nervous system, which can cause seizures or a stroke,” he continued.

To add to the challenge of treating lupus symptoms, Roy said, “there is no single test to definitively diagnose lupus, and it could take months or even years to be sure.”

Diagnose lupus

“Typically, your doctor will perform a complete history and physical examination, including blood tests. The doctor may also perform skin and kidney biopsies (removal of tissue samples which are then examined under a microscope) to establish a diagnosis.
— Albert Roy, CEO of Lupus Therapeutics

Other common types of lupus, Roy said, are:

• Cutaneous lupus, which causes a rash or lesion on the skin, usually when exposed to sunlight
• Drug-induced lupus, similar to SLE, which is caused by an overreaction to certain medications. Symptoms usually go away once the drug is stopped.
• Neonatal lupus, which occurs when an infant acquires autoantibodies from their mother with SLE.

Afimetoran inhibits the function of the cellular proteins TLR7 and TLR8.

TLR7 and TLR8 trigger the immune system, usually in response to foreign RNA. However, in people with lupus, they activate the immune system when they mistake the individual’s own RNA for a threat, causing a range of lupus symptoms.

“It is well documented,” says Roy, “that aberrant activation of TLR7/8 is potentially pathogenic and linked to the progression of certain autoimmune diseases such as lupus. Previous efforts to develop TLR7/8 inhibitors have been largely unsuccessful due to the challenge of producing a small molecule inhibitor for these difficult targets.

Dr. Alaric Dyckman, director of Bristol Myers Squibb, recalled an important finding from their research.

“The first remarkable discovery was the identification of small molecules that could bind directly to TLR7 and TLR8 and inhibit their function, confirming that they are valid drug targets for this modality,” he said. MNT.

BMS identified the molecules by screening the company’s huge collection of compounds for anything that might block TLRs 7 and 8.

Dr. Dyckman described the BMS collection:

“The Compound Collection is a physical inventory of a large number of purified samples that have been preserved for many years and are carefully stored for continued use. The samples in the collection come from materials prepared in-house, as well as from samples purchased from external sources For the TLR screening, 1.25 million samples from this collection were tested for their inhibitory capacity in cell-based assays.

Inhibition of TLRs 7 and 8 should pose no new problems, Dr. Dyckman believes:

“TLR7 and TLR8 function as part of the innate immune system, providing surveillance against pathogens. They are not alone in this role, and a range of other proteins in the body perform similar and overlapping protective functions. This redundancy supports the idea that a TLR7 and TLR8 inhibitor could be administered without undue concern for broad immunosuppression.

“For mouse models of lupus, we were able to show that not only could we prevent the development of lupus-like symptoms in animals receiving our compound treatment before disease onset, [but] we could [also] actually reversing symptoms in animals that had established disease, preventing the lethality associated with these very challenging models,” Dr. Dyckman said.

“Such a reversal had not been demonstrated with other mechanisms that we had assessed in animal models of the disease prior to this work,” he added.

The researchers also found that afimetoran worked well with corticosteroid treatments in in vitro studies and in mice. This is important because doctors often prescribe such steroids to treat inflammatory symptoms of lupus.

“In Phase 1 human clinical trials,” said Dr. Dyckman, “we were very pleased to find that across a range of single and repeat doses, afimetoran was well tolerated.”

With a single 24-hour dose, he said, “afimetoran, once daily, was able to almost completely block signaling via TLR7 or TLR8 with very low doses.”

BMS will continue to monitor safety during phase 2 trials.

“The Lupus Research Alliance and Lupus Therapeutics,” Roy said, “are proud to partner with BMS, Amgen, Lilly, UCB, Biogen and Vera Therapeutics to advance and evaluate their novel therapeutic approaches.”