The collaboration will centre on selective androgen receptor modulators (SARMs), which can be used to treat age-related muscle loss (sarcopenia) as well as other musculoskeletal conditions. GTx already has one SARM in clinical development, namely Ostarine. A proof-of-concept Phase II study of the drug began in May last year including patients suffering from cancer-related muscle loss. In order for androgens to perform their physiologic functions, they must interact with and activate their hormone receptors. Once a hormone binds with its receptor, a series of cellular events are activated, resulting in androgenic tissue effects. Although drugs such as steroids have been used for over 50 years to stimulate these receptors, they are not specific to any particular tissue type. By activating the receptors in unwanted places, steroid use can cause unwanted side effects. For example, testosterone therapy has been linked to the stimulation of prostate cancer, acne. It also not entirely suitable for treating women since it can lead to the abnormal development of male sexual characteristics (virilisation). GTx believes they can circumvent this problem through its SARM molecules. The nonsteroidal small molecules either stimulate or block hormone receptors depending on the type of tissue in which the receptor is found. Thus, they may be able to replace confer many of the benefits of testosterone without the unwanted side effects. Since they are small molecules, they can also be dosed orally. So far, the first-in-class Ostarine has demonstrated the ability to build lean body mass (muscle) and may also have the potential to improve physical performance. Merck is clearly convinced by GTx's research: "By selectively targeting the androgen receptor, SARMs offer a promising alternative to androgen therapy with the potential advantages of oral dosing, tissue selectivity and improved safety and tolerability," said Dr Alan Ezekowitz, senior vice president and franchise head, Bone, Respiratory, Immunology, and Endocrine, Merck Research Laboratories. As part of the deal with Merck, the two companies will pool their SARM programmes. Merck will be responsible for all future costs associated with ongoing development and, if approved, commercialization of Ostarine and other investigational SARMs resulting from the collaboration. The pharma giant has agreed to pay an upfront payment of $40m plus $15 million in research reimbursements to be paid over the initial three years of the collaboration. In addition, Merck will make an equity investment of $30m in GTx GTx will also be eligible to receive up to $422m in future milestone payments associated with the development and approval of a drug candidate if multiple indications receive regulatory approval. Additional milestones may be received for the development and approval of other collaboration drug candidates. GTx will then receive royalties on any resulting worldwide sales. The Tennessee-based biopharmaceutical firm also has with a second molecule called prostarine in preclinical development as a treatment for benign prostatic hyperplasia (BPH). The rest of its pipeline is filled with a selective oestrogen receptor modulator (dubbed SERM due to the American spelling of estrogen) called toremifene, which is marketed under the name Fareston as a breast cancer treatment and is in clinical trials under the name Acapodene for the prevention of prostate cancer and as a therapy to ameliorate the side effects of androgen deprivation therapy. A number of other companies are also investigating the clinical benefits of androgen receptor modulators. For example, Ligand Pharmaceuticals has an androgen receptor modulator called LGD-3303 in preclinical test. As part of a deal with Ligand, Tap Pharmaceutical Prodcuts is also developing a SARM called LGD2941. That drug is currently in Phase I clinical trials. Bioenvision had a SERM molecule trilostane approved as a breast or prostate cancer drug, where it was marketed under the name Modrenal or Modrefen respectively. The firm was also developing non-steroidal inhibitors of 17(beta), an enzyme involved in the production of androgens and estrogen. However, what has happened to this programme following Genzyme's acquisition of the company last month is unclear. Meanwhile, Acadia Pharmaceuticals' drug, ACP-105 is currently in preclinical development as a treatment for testosterone deficiency.