The results of promising research from a drug company will provide hope to the more than 5m people worldwide (90% of whom are women) suffering from the chronic and incurable autoimmune disease, lupus, that attacks healthy tissue.
Lupus causes fatigue, pain, or swelling in the joints, skin rashes, headaches, sensitivity to light, and chest pain while breathing in deeply, and in extreme cases, is fatal when it causes damage to internal organs.
Physicians generally deploy an array of therapies aimed at lessening its symptoms and reducing the damage it can cause, but at the American Chemical Society’s recent meeting on 21 August 2022, Bristol Myers Squibb (BMS) presented results of research regarding a pill the company hopes will treat treat systemic lupus erythematosus (SLE). SLE is the most common form of lupus.
The new pill, called afimetoran, reduced lupus-like symptoms, reversed organ damage, and prevented fatalities in mice, and the company has since begun phase two human clinical trials of the drug to test its effectiveness and side effects.
Albert Roy, executive director of Lupus Therapeutics of the Lupus Research Alliance, who becomes president and CEO of the Alliance in September, described the effects of SLE to Medical News Today:
“Up to 90% of people with lupus will have inflammation or swelling of the joint lining, causing stiffness and pain, most often in the hands and wrists. Most people with SLE experience unexplained fevers.”
Fatigue from lupus can be “severe enough to significantly impact patients’ quality of life, including lessening their ability to function at home or at work.”
“About half of people with lupus experience a red ‘malar’ rash that may appear across the cheeks and bridge of the nose in the shape of a butterfly or on other parts of the body, and can be painful or itchy. Because many people with lupus are photosensitive, skin rashes often first develop or worsen after being out in the sun.”
Lupus can also lead to cardiovascular disease, kidney disease and stroke.
“Specifically,” said Roy, “people with lupus are at an increased risk for atherosclerosis – the deposition of fats and cholesterol (plaque) along the lining of the arterial wall. In some people, inflammation can occur in the heart itself (myocarditis and endocarditis) or the membrane that surrounds it. Endocarditis can damage heart valves, which can result in heart murmurs.”
He said when the disease affects the kidneys, it’s called lupus nephritis, and patients generally require intensive drug treatment to prevent permanent damage. Lupus also may attack the brain or central nervous system, which can cause seizures or stroke.
Adding to the challenge of addressing lupus’ symptoms, said Roy, is that there is no single test to definitively diagnose lupus, and it could take months or even years to be sure.
The Lupus Foundation of America reports that an estimated 1.5m people in the country have a form of lupus, and there are around 16 000 new cases each year.
There are four different types of lupus: neonatal, cutaneous, drug-induced and systemic, which accounts for 70% of all lupus cases.
A major tissue or organ in the body – such as the heart, brain, kidneys, and lungs – will be affected in half of all systemic lupus cases.
About 10%–15% of people with lupus may die prematurely from lupus complications. However, most people can expect to live a “normal lifespan” due to the improvements in diagnosis and disease management that are available.
Coping with lupus can be challenging due to the number of areas of the body that are affected by the disease. People with lupus frequently cite pain, lifestyle changes, and the emotional problems that result from the disease as the most difficult elements of living with lupus.
While lupus can be an on-going source of discomfort, its outlook is generally positive. With appropriate treatment and frequent clinical follow-up, lupus organisations estimate that 80% to 90% of people with lupus will have a normal life expectancy.
The effects of lupus depend on the severity of the disease. Some people who have severe flare-ups could be at greater risk of their lupus being life-threatening.
How afimetoran works against lupus
Afimetoran inhibits the function of cellular proteins TLR7 and TLR8, both of which 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 as a threat, causing a range of lupus symptoms.
“It is well-documented,” said Roy, “that aberrant activation of TLR7/8 is potentially pathogenic and linked to the progression of certain autoimmune diseases such as lupus. Prior efforts to develop inhibitors of TLR7/8 have been largely unsuccessful because of the challenge of producing a small-molecule inhibitor for these difficult targets.”
Dr Alaric Dyckman, director at Bristol Myers Squibb, recalled an important finding from their research.
“The first remarkable finding was the identification of small molecules that could bind directly to TLR7 and TLR8 and inhibit their function, confirming these as valid drug targets for this modality,” he told MNT.
BMS identified the molecules by screening the company’s massive collection of compounds for any that might block TLR 7 and 8.
“The compound collection is a physical inventory of numerous purified samples that has been curated over many years and carefully stored for ongoing use. The samples come from internally prepared materials, as well as samples purchased from external sources. For the TLR screen, 1.25m samples from this collection were tested for their inhibitory ability in cellular assays.”
Inhibiting TLR 7 and 8 should not pose new problems, said Dyckman:
“TLR7 and TLR8 function as part of the innate immune system, providing surveillance against pathogens. They are not alone in that role, and a range 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.”
Testing afimetoran in mice
“For mouse models of lupus, we showed that not only could we prevent the development of lupus-like symptoms in the animals receiving our compound treatment before disease onset, (but) could (also) actually reverse the symptoms in animals that had established disease, preventing the lethality that is associated with these very challenging models.
“Reversal such as this had not been demonstrated with other mechanisms that we had evaluated in the animal models of disease prior to this work,” he added.
The researchers also found that afimetoran worked well alongside corticosteroid treatments in in vitro studies and in mice. This is important because physicians often prescribe such steroids to address lupus’ inflammatory symptoms.
Next steps for afimetoran
“In phase one human clinical trials,” said Dyckman, “we were pleased to find that across a range of single and repeated dose levels, afimetoran was well tolerated.
“With a 24-hour single dose, afimetoran, once-daily, was able to almost completely block signalling through TLR7 or TLR8 with very low doses.”
BMS will continue monitoring safety during the phase two trials.
See more from MedicalBrief archives:
Collaborative lupus research uncovers two new findings
UK releases first guideline on care and treatment of adults with lupus