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. BMD is caused by gene mutations in the dystrophin (DMD) gene, but the types of mutations lead to a milder disease than is seen in DMD boys. BMD is quite variable, with some patients showing disease only slightly milder than DMD, whereas others show retention of muscle strength through older age. Inflammation has been shown to regulate dystrophin in BMD, but glucocorticoids are often not prescribed as the side effects outweigh the benefits. Vamorolone may show promise in BMD. A Phase 2 pilot study assessing vamorolone in the treatment of BMD is currently enrolling in the USA (NCT05166109). https://www.ncbi.nlm.nih.gov/pubmed/26321630
• Becker muscular dystrophy.  While Duchenne muscular dystrophy patients show absence or near absence of dystrophin in their muscle, there are many other patients that show present but abnormal dystrophin due to mutations in the DMD Some of these patients with abnormal dystrophin show a muscular dystrophy phenotype that is milder than typical DMD, but the range of severity is quite great (from just slightly milder than typical DMD, to asymptomatic at older age). Becker muscular dystrophy patients typically show inflammation in their muscle, and corticosteroids are prescribed in about 20% of more severe Becker dystrophy patients, but corticosteroids are not considered standard of care due to the severe side effect profiles associated with corticosteroids, and the often milder symptoms in many Becker muscular dystrophy patients (https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32564389/).
• Pre-clinical models and vamorolone treatment
  Vamorolone is being tested in a double-blind, placebo-controlled trial of Becker muscular dystrophy patients (https://clinicaltrials.gov/ct2/show/NCT05166109).
• 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.