Rare diseases suffer from a myriad of challenges, including misdiagnosis, no diagnosis, or lack of appropriate treatments. The NIH estimates that ~10,000 rare diseases are affecting ~ 30 million individuals in the U.S. The Global Genes organization suggests that worldwide at least 400 million people are living with rare disorders.

A subset of such conditions includes 80–90 types of rare autoimmune diseases. While some, such as myasthenia gravis or Guillain-Barré syndrome, have more widespread name recognition, many others fly below the public radar.

As with many rare diseases, critical treatments are often lacking. The good news is that a number of companies are working in this arena with candidates in clinical trials. This can be a win-win scenario as patients with few treatment options can benefit from new drugs while at the same time such research may enhance knowledge of fundamental molecular pathways driving more widespread disorders.

Companies that develop therapeutics for rare autoimmune diseases are utilizing a number of strategies. For example, drugs to treat sarcoidosis, (in which damaging granulomas form throughout the body) are being developed that target tRNA synthetase domains involved in both normal cellular responses as well as autoimmune conditions.

Another strategy recycles an approved drug given Orphan Disease Designation to treat a rare B-cell driven disease that causes skin and lung fibrosis. Additionally, other candidates are targeting the melanocortin system, a group of widely expressed small protein hormones involved in processes such as energy homeostasis, pigmentation, and inflammation. In this case, receptor agonists are being tested that restore pigmentation in vitiligo and halt the damaging inflammation in ocular disorders such as uveitis.

tRNA synthetase therapeutics

Amino-acyl tRNA synthetases are enzymes that catalyze the attachment of amino acids to their specific tRNA partners. The resulting tRNAs are escorted into the ribosomal machinery where they enter into the protein synthesis pathway. However, tRNA synthetases are much more than simple connectors. According to Sanjay S. Shukla, MD, MS, president and CEO of aTyr Pharma, tRNA synthetases evolved to include novel domains that may more broadly play critical roles to cellular responses involved in disease states, in particular, cellular stress, and tissue homeostasis.

Sanjay S. Shukla, MD
Sanjay S. Shukla, MD

“aTyr’s platform and approach is centered around leveraging the extracellular function of these domains by identifying the target receptor or signaling pathway impacted by a domain, identifying disease areas that are implicated by those targets and pathways, and then creating engineered protein therapies around those domains,” he says.

The company’s lead product is efzofitimod for the treatment of interstitial lung disease (ILD), a group of immune-mediated disorders that cause inflammation and fibrosis of the lungs. This includes pulmonary sarcoidosis and systemic sclerosis (SSc or scleroderma)-related ILD.

“Based on its mechanism of action, we believe efzofitimod has potential in ILD beyond sarcoidosis and SSc-ILD, including other connective tissue disease-related ILD, such as those that result from other forms of autoimmune conditions (e.g., rheumatoid arthritis-ILD), and chronic hypersensitivity pneumonitis,” explains Shukla, adding that one of the big challenges with sarcoidosis is the lack of approved, effective, and safe treatments, especially for the more than 20% of patients who develop lung fibrosis.

“First-line therapy is typically oral corticosteroids, which can help manage symptoms such as cough and shortness of breath, but often come with side effects and toxicity, as they are not meant to be taken long term. Second- and third-line treatments are mostly off-label, and also come with toxicity. There are no disease-modifying treatments available.”

heart granulomas
Cardiac sarcoidosis is a rare condition which affects a small number of people who suffer from a condition called sarcoidosis, an inflammatory condition that can affect multiple organs. The disease tends to affect younger people, generally between 25 and 45 years old. Sarcoidosis is characterized by the presence of granulomas. These are ball-like collections of inflammatory cells that cluster around and react to a foreign substance. The inflammation associated with granulomas can damage virtually every part of the heart, including the electrical system, muscle, valves, arteries, and the pericardium. [OGphoto/Getty Images]

The company is currently conducting a Phase III study of efzofitimod in patients with pulmonary sarcoidosis and a Phase II study for patients with SSc-ILD.

“This is a really exciting area of emerging immunobiology that leverages our innate biology, which is why we refer to it as ‘evolutionary intelligence.’ We look forward to advancing tRNA synthetase biology to the extent that it may lead to the rise of a new class of medicines,” he predicts.

Targeting B cells

GSK has its sights on treatment of SSc-ILD. Their strategy, however, is targeted B-lymphocyte stimulator (BlyS) inhibition using belimumab to patients affected by B cell-mediated immune conditions. The drug, a fully humanized monoclonal antibody, prohibits the prolonged survival of B cells induced by increased BlyS and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

Research indicates that B cells play an important role in the pathogenesis of SSc and SSc-ILD,” reports Roger A. Levy, MD, global medical expert, immunology, and specialty medicine. “Further, BlyS levels are increased and correlate with the extent of skin and lung fibrosis. B cells are dependent on BlyS for survival, therefore, inhibition of BlyS with belimumab, will lead to a reduction in B cells and potentially address the underlying disease dysfunction.”

The FDA has already approved the belimumab (Benlysta) for the treatment of active systemic lupus erythematosus (SLE) and lupus nephritis. Last year, they granted Orphan Drug Designation to belimumab for the treatment of SSc. Such status provides benefits including assistance in the drug development process, tax credits, exemptions from certain FDA fees and seven years for exclusive marketing.

GSK is currently conducting Phase II/III clinical trials evaluating the efficacy and safety of belimumab compared to standard of care in adults with SSc-ILD.

According to Levy, “GSK has taken an important step to fully elucidate the potential benefits of targeted B-lymphocyte stimulator modulation with belimumab in B-cell mediated immune diseases beyond SLE.”

Melanocortin analog for vitiligo

Vitiligo is an autoimmune disorder resulting in loss of skin pigment. The condition, affecting ~ 0.5 to 2% of the world’s population, occurs when pigment-producing melanocytes are destroyed. Loss of skin color often first appears on the hands and face then spreads to other body parts.

“While the disease affects all races and sexes equally, it is particularly problematic in individuals of color,” explains Philippe Wolgen, MD, CEO, CLINUVEL. “There is currently no clinically meaningful, safe systemic treatment option, although there is an approved cream for topical use. However, a systemic disease needs a systemic solution. We are focusing on the therapeutic potential of melanocortins, a group of small peptide hormones derived from the cleavage of the larger proopiomelanocortin (POMC) protein.”

In particular, the company has developed a 13 amino acid analog of alpha-melanocyte stimulating hormone (alpha-MSH), a naturally occurring peptide that stimulates melanogenesis. The compound, SCENESSE® (afamelanotide), plays a role in regulating (that is, stimulating) pigmentation similar to alpha-MSH.

Philippe Wolgen MD
Philippe Wolgen, MD

“Although the drug was developed more than 20 years ago, our program had to wait until the FDA was ready to recognize vitiligo as a disease,” notes Wolgen. “Things changed in 2020 when Dr. Kendell Marcus, an exceptionally shining light and visionary, became director for FDA’s Division of Dermatology and Dentistry. She orchestrated a change in FDA policy to recognize vitiligo as a disease entity affecting darker populations most. This opened the doors for further clinical trials of SCENESSE since insurance companies showed they were prepared to pay for vitiligo drugs.”

Wolgen points out that the innovative drug is currently in Phase III trials in concert with the use of special ultraviolet light exposure in dermatology offices. “Narrow band ultraviolet UV-B treatment (the 311-nanometer wavelength) is currently standard of care. When used with SCENESSE, we have seen dramatic improvements in patients. We can’t really blind this study because it is visually obvious when repigmentation starts.”

SCENESSE is already approved in the U.S., Europe, and Australia for treatment of erythropoietic protoporphyria, a rare metabolic disorder causing phototoxicity. Aside from their vitiligo program, clinical trials also are underway for treatment of xeroderma pigmentosum, a rare disfiguring disease caused by defective DNA repair mechanisms and leading to frequent skin cancers.

Quelling uveitis inflammation

Another rare autoimmune disease, uveitis, affects ~ 38 individuals per 100,000. Similar to other autoimmune disorders, this inflammatory disease of the eye often presents in younger patients (< 40 years of age) and may lead to blindness. While 60% of uveitis patients are affected primarily in the eyes, the other 40% have concurrent autoimmune conditions such as multiple sclerosis.

Palatin Technologies also is developing therapeutics based on the melanocortin system and is focusing on inflammatory and autoimmune diseases, with emphasis on ocular disorders. Carl Spana, PhD, CEO reports, “The melanocortin system has five related receptors, MCR1-5. These mediate many processes including inflammation and immune responses. We are developing highly selective melanocortin agonists that target one or a combination of these receptors.”

Spana cites the example of MCR1. “In almost every case where you see an ocular nurse cell or corneal endothelial cell, for example, activation of MCR1 helps these cells survive whatever stress they are under. We select candidates based on their receptor profile, ability to activate the endogenous receptors involved in the stress response, and their pharmacokinetics. Thus, receptor-selective melanocortin agonists can help prevent and reverse inflammation, as for example, in noninfectious uveitis.”

According to Spana, agonists fit the bill in seeking longer lasting effects. “One of the advantages we have is that most agonists have a prolonged effect as compared to an antagonist or enzyme inhibitor because you are activating an endogenous effect.”

In addition to ocular diseases, the company also has melanocortin agonist programs in clinical trials for ulcerative colitis and diabetic nephropathy, among others.

Although it remains an uphill battle, treatments for rare autoimmune diseases are progressing steadily along with an enhanced understanding of how the immune system misfires to cause cell, tissue, and organ damage. Greater mechanistic knowledge, financial backing for orphan diseases, and creative therapeutic strategies should help create more effective treatment and prevention strategies.

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