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

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Scientists are working on new treatments to prevent the symptoms of lupus and reverse its effects. VICTOR TORRES/Stocksy
  • Lupus is an incurable, life-altering autoimmune disorder that can lead to death in extreme cases.
  • The best that doctors can do for people with lupus is to try to address and control their symptoms and try to prevent permanent damage to the body.
  • At a recent meeting, Bristol-Meyers-Squibb presented research outlining a new pill that can treat lupus and reverse the damage it causes.

Lupus is a chronic autoimmune disease that attacks healthy tissue. It can cause bouts of fatigue, joint pain or swelling, skin rashes, headaches, sensitivity to light, and chest pain when breathing deeply. In extreme cases, it can be fatal when it causes damage to internal organs.

There is no cure for lupus. Doctors implement a variety of therapies aimed at lessening its symptoms and reducing the damage it can cause.

At the American Chemical Society’s Fall 2022 meeting on August 21, 2022, Bristol-Meyers-Squibb (BMS) presented the results of promising research on a pill that BMS hopes to directly treat systemic lupus erythematosus (THEM). SLE is the most common form of lupus.

The new pill is called afimetoran and has reduced lupus-like symptoms, reversed organ damage and prevented deaths in mice.

BMS has begun phase 2 human clinical trials of afimethoran. Phase 2 trials test a drug’s effectiveness and side effects.

Albert Roy He 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 to Today’s medical news:

“Up to 90% of people with lupus will have inflammation or swelling in the lining of their joints, leading to stiffness and pain, most often in the hands and wrists. Most people with SLE experience unexplained fevers.”

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Lupus fatigue, Roy noted, can be “severe enough to significantly affect patients’ quality of life, including diminished ability to function at home or at work.”

“About half of people with lupus experience a red ‘malar’ rash that can appear on the cheeks and the bridge of the nose in a butterfly shape or on other parts of the body, and can be painful or itchy. Because many people with lupus are photosensitive, rashes often develop or worsen after being in the sun.”
— 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 of atherosclerosis — the deposition of fats and cholesterol [plaque] along the lining of the arterial wall. In some people, the inflammation can occur in the heart itself (myocarditis Y endocarditis) or the membrane that surrounds 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 generally require intensive drug treatment to prevent permanent damage. Lupus can also attack the brain or central nervous system, which can cause seizures or strokes,” he continued.

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

lupus diagnosis

“Usually your doctor will perform a complete medical history and physical exam, including blood tests. The doctor may also perform skin and kidney biopsies (remove tissue samples that are then examined under a microscope) to make a diagnosis.”
— Albert Roy, CEO of Lupus Therapeutics

The 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 a baby acquires autoantibodies from its mother with SLE.
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Afimetoran inhibits the function of the cellular proteins TLR7 and TLR8.

TLR7 and TLR8 activate 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 variety of lupus symptoms.

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

Dr Alaric Dyckmandirector of Bristol Myers Squibb, recalled an important finding of his research.

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

BMS identified the molecules by screening the company’s massive collection of compounds for any that might block TLR 7 and 8.

Dr. Dyckman described the BMS collection:

“The Composite Collection is a physical inventory of a large number of purified samples that have been curated for many years and carefully stored for continued use. The samples in the collection come from materials prepared internally, as well as samples acquired from external sources. For the TLR screen, 1.25 million samples from this collection were tested for their inhibitory capacity in cellular assays.”

Inhibition of TLR 7 and 8 should not pose any new problems, Dr. Dyckman said:

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

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“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] it actually reverses symptoms in animals that had established disease, preventing the lethality associated with these very challenging models,” said Dr. Dyckman.

“A reversal like this had not been demonstrated with other mechanisms that we had tested in animal models of disease prior to this work,” he added.

The researchers also found that afimethoran worked well in conjunction with corticosteroid treatments in in vitro studies and in mice. This is important because doctors often prescribe this type of steroid to treat the inflammatory symptoms of lupus.

“In phase 1 human clinical trials,” said Dr. Dyckman, “we were very pleased to find that, at a variety of single and repeat dose levels, afimetoran was well tolerated.”

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

BMS will continue to monitor safety during phase 2 trials.

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