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Other 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, physicochemical 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 dramatic 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.

ReveraGen is identifying those disorders where the side effects of glucocorticoids outweigh benefit, and developing vamorolone in these new indications. A summary of these follows:

  • 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.
  • Sickle cell anemia. Sickle cell disease is a relatively common disorder in persons of African descent, due to the protection that the heterozygous state confers against malaria. In the homozygous state, patients show sickling of red blood cells, leading to a chronic inflammatory state that can present as ‘sickle cell crises’ of acute pain and ischemia. Glucocorticoids have been used to reduce the inflammatory state, but side effect profiles prevent routine prescription. The NIH has awarded a STTR to ReveraGen to develop vamorolone for sickle cell disease.
  • 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 (see http://www.ncbi.nlm.nih.gov/pubmed/25392236). The NIH has awarded a STTR to ReveraGen to develop vamorolone for multiple sclerosis.
  • Cystic fibrosis. Gene mutations in the CFTR gene lead to a chronic inflammatory state in patient airways, with excessive mucous production, and growth of bacteria in lungs that must be periodically treated with high dose antibiotics. The antibiotics lead to changes in the microbiome, and emergence of resistant strains. Vamorolone may be able to reduce the inflammation and reduce mucous production in CF airways. 
  • 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. Glucocorticoids are often not prescribed as the side effects outweigh the benefits. Vamorolone may show promise in BMD, and it is expected that a clinical program in BMD will soon follow the DMD clinical program.