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Duchenne Muscular Dystrophy and Disease Progression

Duchenne muscular dystrophy is a progressive disease, with weakness typically first evident in early childhood, and then progressive loss of skeletal muscle. However, gene mutations in the DMD gene are present from conception, and this leads to loss of the dystrophin protein in muscle in all muscle from fetal life onwards (including skeletal muscle, heart muscle, and smooth muscle in gut and blood vessels; as well as some neurons).

If the dystrophin protein is missing in a DMD patient from fetal life, why does it take so many years to see disability? Muscles seem to be able to function relatively well for some years without dystrophin. It seems that skeletal muscle has increasing challenges dealing with dystrophin-deficiency as that patient ages. Since the identification of the dystrophin gene and protein, one question was answered (What initiates the disease?) but then a second question was posed (What causes the progression of the disease?).

The question of cause/effect in dystrophin-deficiency in skeletal muscle became even more important as pet owners began bringing in their cats and dogs with muscular dystrophy, and these were found to have dystrophin gene mutations and loss of dystrophin in their muscle. Cats missing dystrophin show muscles that are too large, and do not show the progressive weakness seen in DMD. Mice missing dystrophin also show over-growth of muscle, without much evidence of the progressive weakness in DMD, while dogs show some muscles with remarkably over-growth and others with muscle wasting even though all are missing dystrophin.

All these observations suggest that there are changes in muscle in DMD as a function of age, where muscle can compensate for many years, but then loses this ability to compensate. This seems to correlate with a ‘switch’ from successful muscle regeneration, to unsuccessful regeneration in DMD muscle.

This paradox led to studies of muscle throughout the age range in DMD (fetal, newborns, childhood), where it was found that fetal muscle showed very little abnormal (other than missing dystrophin), while newborn muscle showed activation of NFkB cascades (‘cell danger’ signals), and muscles from patients with obvious weakness showed TGFbeta cascade associated with fibrosis (scar tissue formation). It was also found that asynchronous regeneration (pockets of muscle that undergo degeneration/regeneration) may lead to these TGFbeta cascades and scar tissue formation.

These studies led to the initiation of the vamorolone drug development program. The model is that NFkB cell danger signals initiate soon after birth, and these signals help the muscle regenerate and compensate for dystrophin deficiency. Over time, these cell danger signals transition to scar tissue formation (fibrosis in muscle), and this in turn makes it challenging for the muscle to regenerate effectively. It is then that muscle loss and weakness ensues, leading to patient disability.

Prednisone and deflazacort inhibit NFkB cell danger pathways. Perhaps these drugs slow down the transition from NFkB to fibrosis? If so, can we find a novel steroidal drug that loses side effects of corticosteroids, and significantly slow the transition to fibrosis and muscle loss? These disease models became the basis for the vamorolone development program.

The hypothesis that vamorolone may retain efficacy (improved muscle function in DMD) via effective inhibition of inflammation pathways, while reducing safety concerns seen with corticosteroid drugs, has been borne out in clinical trials of vamorolone in DMD. A series of clinical studies in 2 groups of DMD boys (one group of 48 boys, and a second group of 121 boys) have been published. The first group of 48 boys participated in a series of open-label trials covering 2.5 years of treatment, and a broad range of doses of vamorolone was tested (0.25, 0.75, 2.0, and 6.0 mg/kg/day – a 24-fold range).  Four publications have described this robust set of dose-ranging studies:

These studies suggested efficacy and safety of vamorolone, and the data were utilized to design a robust randomized double-blind, placebo- and prednisone-controlled clinical trial in 121 DMD boys. This study was successful in showing that vamorolone retained the efficacy (improved motor function) of prednisone, while reducing some safety concerns, such as stunting of growth.