Male hypogonadism can be a result of failure of the testes (primary gonadal failure) or due to failure of stimulation by the pituitary (secondary hypogonadism). Primary hypogonadism, failure of the testes can be congenital (inherited), such as Klinefelter’s syndrome, in which men are born with an extra X sex chromosome (XXY), or acquired during life due to a variety of causes, including failure of the testes to descend into the scrotum, inflammation due to infections such as mumps, chemotherapy or radiotherapy affecting the testes, and following removal of the testes for testicular tumours. Secondary hypogonadism usually results from a benign tumour of the pituitary gland that causes hypopituitarism. Secondary hypogonadism may occasionally be congenital, such as in Kallmann’s syndrome, which is a rare genetic condition where there is loss of development of the nerves that supply the pituitary to stimulate the release of the gonadotrophins.
The estimates for prevalence vary dramatically between studies based on study designs and inclusion criteria. Clear-cut hypogonadism in young men occurs in approximately one per cent. of the population, however, as testosterone falls with aging and in the obese, some studies suggest a prevalence of 12 per cent. for under 60 year olds, 20 per cent. for those in their 60s, 30 per cent. in their 70s and 50 per cent. in their 80s12. The classical hypogonadism market in Europe and US is primarily driven by topical formulations, which the company currently estimate to be of a value of over $5 billion in 2015.
Treatment for hypogonadism is Testosterone Replacement Therapy. The options currently available for the replacement of testosterone are intramuscular injections, generally every two or three weeks; testosterone patches worn either on the body, rotated between the buttocks, arms, back or abdomen, or on the scrotum, used daily; and testosterone gels that are applied daily to the shoulders, upper arms or abdomen.
There is some controversy over the risks and benefits in replacing testosterone in older men (including the potential for cardiovascular disease)13 and Diurnal is focused on developing testosterone replacement for men with clearly-defined hypogonadism according to current clinical guidelines.
Diurnal is developing a native oral testosterone replacement treatment for patients suffering from hypogonadism. The challenge for oral testosterone therapy has been the considerable metabolism both in the intestinal wall and during the first hepatic pass which reduces bioavailability by up to 98 per cent. and can cause liver toxicity as testosterone is rapidly removed by the liver. Attempts have been made to use crystalline form but this has resulted in a low level serum concentration.
The only currently available oral forms are either alkylated or esterified and are therapies that present well-documented significant pharmacokinetic variability14.
Diurnal has successfully completed in vivo pre-clinical studies of its novel formulation and has initiated a proof of concept study in human hypogonadal patients in Q4,2016. Diurnal has been granted patents in key territories worldwide in respect of this lipid-based formulation of native testosterone for oral delivery and characterised by a combination of ethanol and benzyl alcohol which enhances both the solubility and bioavailability of native testosterone.
12 Article by S.M Harman, E.J Metter, J.D Tobin, J. Pearson, M.R. Blackman entitled ‘Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging’ published in The Journal of Clinical Endocrinology & Metabolism (2001) 86(2): 724-731.
13 FDA Drug Safety Communication entitled ‘FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use’, 3 March 2015, an update to the FDA Drug Safety Communication entitled ‘FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products’, 31 January 2014.
14 Article by E. Nieschlag and H.M. Behre entitled ‘Testosterone Therapy’ (1997).
No current products exist that replicate the natural physiological rhythm of testosterone.