Indications

Indications

Muscle-wasting disorders

SARMs could be used in diseases where steroidal androgens have been proposed as therapeutics. The initial focus of SARM clinical development was their use for muscle wasting conditions. However, the use of SARMs is now expanding to other diseases such as breast cancer.

Adults over 40 years of age lose about 1% muscle mass each year. With life expectancy increasing around the globe, the number of people with compromised muscle mass and accordingly deficits in physical function has increased in the last decade. Age-related muscle wasting or sarcopenia and muscle wasting due to cancer, also called cancer cachexia, are two serious muscle wasting disorders with no treatment options. Sarcopenia is a major cause of frailty and carries with it an increase in physical disability as well as morbidity and mortality. The demographic that is widely affected by cancer is adults over 60 years of age. This age-group, already at higher risk to be deficient in muscle due to age-related decline, is then at high risk to lose additional muscle due as their cancer progresses and they receive anti-cancer therapy. Advanced cancer patients lose up to 1.5 kg of lean mass per year. Studies have also demonstrated that muscle mass directly correlates with survival in cancer patients. Androgens are important for building and maintaining skeletal muscle, and due to their anabolic effects on muscle are considered front-runners in the potential treatment of cancer cachexia and sarcopenia. SARMs are particularly relevant in this regard due to their tissue-selectivity and potential to provide therapeutic increases in muscle mass with reduced side-effects.

With wide-spread use of corticosteroids to combat inflammation and allergies, even children are susceptible to corticosteroid-induced muscle wasting. Although non-steroidal SGRMs that spare muscle and bone, but have significant anti-inflammatory effects, have been preclinically developed and tested, they have not successfully entered clinical trials, making steroidal corticosteroids the only available option for a number of indications. SARMs have been shown to be effective in ameliorating multiple preclinical models of muscle wasting including glucocorticoid mediated muscle atrophy.

Osteoporosis
The ability of SARMs to increase both muscle and bone strength in animal models suggests that they may provide a unique dual approach to osteoporosis therapy. Currently osteoporosis is primarily treated with anti-resorptive agents that prevent further breakdown of bone by the body. Anti-resorptive agents potentially prevent further bone turn-over, but will be unable to increase bone mass. In preclinical models, AR agonists such as DHT and SARMs have prevented bone loss in both castrated male rats and ovariectomized female rats. They also increased cortical and trabecular bone mineral density above baseline in these experimental conditions. SARMs have been shown not only to prevent loss of bone (i.e., treatment begins at time of surgery) in ovariectomized and castrated rats, but also to increase bone strength.

Duchenne muscular dystrophy (DMD)

DMD is a genetic disorder that arises due to mutations in the cytoskeletal protein dystrophin. The dystrophin gene is located in the X chromosome and a number of its mutations cause truncated proteins that manifest clinically in the form of muscular dystrophy. Boys with DMD suffer from progressive muscle wasting and weakness and will become wheel-chair-bound often before reaching puberty. Boys with DMD suffer from cardiac and respiratory failures due to weakness in the heart and lung muscles, respectively, resulting in premature death. Recently, therapies to correct mutations using exon-skipping strategies have been developed with one of these molecules receiving approval from the Food and Drug Administration (FDA). Although corticosteroids are the standard of care to combat inflammation in DMD, with the exception of the novel exon skipping drug there are currently no disease-modifying therapeutic agents, available to treat DMD. Regrettably prolonged use of corticosteroids results in undesirable side-effects such as muscle wasting.