Other possible Indications for vamorolone*

Glucocorticoids are front-line therapy for hundreds of inflammatory disorders, including asthma, myasthenia gravis, inflammatory bowel disease, multiple sclerosis, lupus, among many others. They were discovered in the late 1940’s, and the remarkable benefit to a handful of arthritis patients led to the fastest Nobel Prize ever awarded. The discovery and initial clinical use in four arthritis patients led to the Nobel Prize in Physiology or Medicine in 1950 to Drs. Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”. Quoting from the 1950 Award Ceremony Speech:

“In the April of 1949, Hench, Kendall, Slocumb and Polley published their experiences in respect of the dramatic effects of cortisone in cases of chronic rheumatoid arthritis. A rapid improvement set in, pains and tenderness in the joints abated or disappeared, mobility increased, so that patients who had previously been complete invalids could walk about freely, and their general condition was also favourably affected. Similar results were obtained with a preparation from the anterior lobe of the pituitary, the so-called ACTH (Adreno-Cortico-Tropic Hormone), which, as the name indicates, stimulates the adrenal cortex to increased activity. Unfortunately if the improvement is to last, further supplies of the remedy are necessary, and during the process more or less serious secondary effects in the form of fullness of the face, the growth of hair on the face in women, nervous symptoms, etc., often develop in consequence of disturbances in the endocrine balance. Cortisone also has a good effect in cases of acute rheumatic fever, and this applies as well to some other illnesses, probably also to burns.”
(http://www.nobelprize.org/nobel_prizes/medicine/laureates/1950/press.html)

The Nobel Prize was awarded in substantial part for the dramatic effect of cortisol on reversing joint inflammation of four arthritis patients, reported in 1949, with the award in 1950 – cited by the Nobel Committee as the fastest Nobel ever awarded. But even at that time, the extensive side effects were noted, including many experienced by DMD patients treated with steroids, namely “Unfortunately if the improvement is to last, further supplies of the remedy are necessary, and during the process more or less serious secondary effects in the form of fullness of the face, the growth of hair on the face in women, nervous symptoms, etc., often develop in consequence of disturbances in the endocrine balance.”  Yet, 65 years later, the chemistry is utilized for 90 million prescriptions per year in the US, with the same side effect profiles.

The remarkable benefit of glucocorticoids is likely a consequence of their complex mechanisms of action, with multiple subactivities such as transactivation, transrepression, physiochemical membrane properties (and effects on protein signaling), and cross-reaction to other steroid hormone receptors (such as mineralocorticoid receptor). It is likely that certain subactivities can be particularly beneficial in some inflammatory disorders, while others can be detrimental. In effect, it is the summation of the range of subactivities that may dictate the efficacy/side-effect balance in any particular disease state.

In some inflammatory diseases, certain side effects limit the efficacy (and prescription) of glucocorticoids. While the Nobel Prize was awarded for efficacy in arthritis, the bone side effects, leading to weak bones in older individuals, worsening age-related bone fragility, limit prescription despite clear efficacy on the joints.

Preclinical studies have been done to investigate the possible benefit of vamorolone in the following conditions:

  • Becker muscular dystrophy.  Becker muscular dystrophy (BMD) is allelic to Duchenne muscular dystrophy (BMD) (e.g. both show gene mutations of the same DMD gene), but whereas those affected with DMD show little or no dystrophin in their skeletal muscle, those affected with BMD show residual dystrophin (present, but abnormal dystrophin). The residual dystrophin protein in BMD muscle is able to mitigate the clinical picture of typical DMD, with a broad range of symptoms from slightly milder than DMD to asymptomatic. Individuals with Becker muscular dystrophy show variable levels of dystrophin in their muscle. The variable levels of dystrophin in BMD muscle has been correlated with inflammation of the muscle, where inflammation-associated microRNAs directly bind to the dystrophin mRNA and inhibit dystrophin protein production (Fiorillo et al. 2015). In mouse models of muscle inflammatory disease, dystrophin levels are decreased by these microRNAs, and this may contribute to muscle weakness (Kinder et al. 2020).

    A mouse model of Becker muscular dystrophy has been developed that faithfully recapitulates features of the human disease (Heier et al. 2023). Treatment of these BMD mice with vamorolone or prednisolone decreased inflammation-associated microRNAs, and increased dystrophin levels in muscle (McCormack et al. 2023).

    This pre-clinical research suggests that vamorolone may benefit Becker muscular dystrophy patients in two ways; first, by anti-inflammatory effects (shared with DMD); second by increasing dystrophin levels.

    A double-blind, placebo-controlled clinical trial assessing vamorolone in the treatment of BMD is currently enrolling in the USA and Italy (NCT05166109). This trial is partly funded by the FDA orphan drug grant program.

  • Pre-clinical models of inflammatory disease and vamorolone treatment
    • Asthma. Glucocorticoids are standard of care in asthma, both through inhalers and systemic treatment. However, glucocorticoids do not treat the lung fibrosis seen in asthma, and this fibrosis leads to long-term loss of lung function. The NIH awarded a STTR grant to ReveraGen to develop vamorolone for asthma patients. Initial animal studies have been published (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646769/).
    • Inflammatory bowel disease. Steroids are standard of care, but chronic prescription is again limited by side effect profiles. The side effects are particularly problematic in pediatric IBD patients. NIH has awarded a STTR grant to ReveraGen, collaboratively with Children’s National Medical Center, to complete pre-clinical studies of vamorolone in animal models of IBD. https://www.ncbi.nlm.nih.gov/pubmed/27261270
    • Rheumatoid Arthritis. Rheumatoid arthritis is a chronic disease characterized by inflammation of the lining of the synovial joints resulting in long-term joint damage. Glucocorticoids are standard of care, but chronic treatment leads to side effects that eventually limit prescription. The NIH has awarded a STTR to ReveraGen to develop vamorolone for rheumatoid arthritis.
    • Multiple sclerosis. Multiple sclerosis is a chronic inflammatory disorder where the myelin coating many nerve processes is attacked. Glucocorticoids are standard of care, but chronic treatment leads to side effects that eventually limit prescription. A commonly used mouse model of multiple sclerosis, Murine Experimental Autoimmune Encephalomyelitis, has been tested with vamorolone, and the drug has shown benefit (http://www.ncbi.nlm.nih.gov/pubmed/25392236). The NIH has awarded a STTR to ReveraGen to develop vamorolone for multiple sclerosis.
    • ANCA-associated vasculitis (AAV). ANCA-associated vasculitis diseases include heterogenous groups of autoimmune conditions characterized by small vessel inflammation in various organs. Glucocorticoids are effective at rapidly inducing remission and preventing relapse, but their long-term use has reportedly shown substantial physical and emotional adverse effects in adults. NIH has awarded a SBIR grant to ReveraGen, collaboratively with the University of Pennsylvania, to develop clinical studies with vamorolone for use in AAV.
    • Juvenile Dermatomyositis (JDM). Juvenile Dermatomyositis is a pediatric inflammatory myopathy characterized by muscle weakness and distinct skin rashes commonly localized to the eyelids and over the joints and extremities. A main goal of JDM treatment is to reduce inflammation which may prevent future disability. Fast acting and effective corticosteroids are often used first, but side effects limit their long-term use. NIH has awarded a SBIR grant to ReveraGen, collaboratively with Northwestern University, to develop clinical studies with vamorolone for use in JDM.
    • Calpain3 Deficiency (LGMD2A). Calpain 3 Deficiency (LGMD2A) is the most common autosomal genetic diseases resulting from mutations in the CAPN3 gene which encodes for dependent proteases required for proper skeletal muscle function. While there are no specific treatments to date, glucocorticoids have been used to manage symptoms and improve quality of life. Safety concerns limit their long-term use. Eventually, impaired contractibility of muscle fibers and chronic inflammation associated with defective NF-kB inflammatory pathways lead to muscle atrophy and eventual cell death.
    • Limb Girdle Muscular Dystrophy Type 2B (LGMD2B). Limb Girdle Muscular Dystrophy Type 2B belong to a class of autosomal neuromuscular disorders characterized by distinct weakness of the pelvic and shoulder muscles. Mutations of the DYSF gene result in deficiencies of the dysferlin protein, which is crucial to muscle membrane repair. Vamorolone may be a likely candidate for this disease as it has shown to exhibit membrane stabilizing properties.
      https://www.ncbi.nlm.nih.gov/pubmed/30166241

*There are many other possible indications for vamorolone; the above are a list of possible examples with supportive preclinical data.