Pharmacokinetics

Pharmacokinetics

Investigations into SARM compounds at various stages of preclinical and clinical development are ongoing. These agents could address deleterious muscle wasting phenomena that occur with advanced age and chronic disease. The current study was a randomized, double‐blind, placebo‐controlled investigation of the safety, tolerability, PK and PD of GSK2881078, a novel SARM compound, in single and repeat doses in healthy male and postmenopausal female subjects.

Overall, the dose range of GSK2881078 evaluated was well tolerated among a sample of healthy male and postmenopausal female subjects. AEs occurred in half the study population, with a similar distribution between active treatment and placebo groups. Although SARMs and oral androgens are associated with elevations in liver enzymes, no clinically significant hepatic signals were observed.

There was an approximate dose‐proportional increase in exposures of GSK2881078 in the dose range evaluated in this study. Food did not significantly alter AUC(0–τ) but was associated with a 21% decrease in Cmax. Less than 2% of the GSK2881078 dose was excreted in urine, and CLR was similar in males and females. While trough concentrations were used to assess steady‐state attainment in the study, with an observed t1/2 in humans that was much longer than anticipated, the collection of trough samples only on days 4–8 limited an adequate assessment of steady‐state attainment. With an estimated t1/2 >100 h, steady‐state is expected to be achieved much later than day 8. The long t1/2 probably also accounted for the measurable concentrations in subjects while receiving 0 mg GSK2881078 preceded by an active dosing regimen 5 days earlier in Part A. A washout period longer than 5 days is needed in future studies of this molecule. Given the long t1/2 of GSK2881078 and the objective of emulating steady‐state exposure profiles over the 14‐day course of the study, a loading regimen was devised based on the Part A data, which would elevate plasma exposures rapidly and maintain them over the study period. As a result, direct comparison of PK results to address accumulation of GSK2881078 from day 1 to day 14 is not possible using standard PK approaches but will be addressed in future analyses making use of population PK modelling.

Following repeat dosing, there was an apparent 38% difference in t1/2 between genders for the 0.24 mg BID then 0.24 mg QD treatment, which was probably attributable to tlast occurring much earlier for some of the male subjects. As the quantifiable concentrations with placebo or 0 mg GSK2881078 following single‐dose administration in Part A were included in the analysis for the preceding treatment dose to better characterize GSK2881078 elimination, tlast exceeded the last scheduled sampling time for the corresponding treatment, accounting for the high variability of AUC(0–t) (CVb ranging from 43% to 96%) and the apparent lack of dose proportionality in contrast to Part B, where additional samples permitted improved characterization of the long t1/2.

Consistent with other oral androgens and other SARMs under investigation, GSK2881078 (doses of 0.2 mg BID then 0.08 mg QD and higher) was associated with reductions in HDL, ApoA1, triglycerides and VLDL relative to baseline and placebo in male and female subjects. This was an expected result because androgen receptor agonists are known to affect hepatic metabolism. There were no apparent changes in total cholesterol, LDL or ApoB. The clinical implications of androgen‐associated lipid alterations are not clear.

Reductions in testosterone, DHT, SHBG and FSH were observed relative to baseline and placebo in male subjects, and reductions in SHBG in female subjects receiving GSK2881078. The accompanying decrease in SHBG in both males and females is consistent with hepatic effects observed with other SARMs. Free testosterone did not change in either males or females, consistent with the decrease in SHBG. No clinically meaningful changes were observed in other reproductive hormones. Androgen receptor agonists can act centrally on the hypothalamic–pituitary–gonadal axis, to suppress the signals for gonadal hormonal secretion, LH and FSH. In the present study, neither free testosterone nor LH levels declined, suggesting that the decrease in total testosterone was not due to hypothalamic inhibition. Thus, in men, total testosterone levels can fall, as observed. Effects in the postmenopausal women were minimal. In addition, androgen receptor agonists also suppress production of binding globulins such as SHBG in the liver, leading to lower levels of endogenous sex steroids (testosterone and oestradiol), typically without significant effect on free hormone levels. All hormonal levels were returning to baseline values by the end of the study.

There were no consistent, clinically meaningful changes in adrenal hormones in the male or female subjects. In male and female subjects, TBG was reduced relative to baseline and placebo. As noted, androgen receptor agonists act on the liver to reduce the levels of binding globulins, such as TBG and SHBG. Free hormone levels typically are unaffected, although here, men and women alike showed increases in free T4 at the higher doses. The clinical significance of this is unclear, although there was no evidence of a clinical response to this, such as an increased heart rate. There were no clinically meaningful changes in any other metabolic biomarkers. Monitoring of BNP and troponin showed no evidence of myocardial injury.

Comparison of our results with those from longer duration studies of other SARMs in development reveals modest differences. Our high‐dose male cohort (0.75 mg) yielded approximately similar levels of SHBG and total testosterone suppression as those seen in high‐dose cohorts of enobosarm and LGD‐4033, suggesting similar levels of androgen receptor agonism. Adverse effects were generally not different between SARMs. Of note were elevations in ALT seen with enobosarm, leading to study discontinuation in one subject receiving the highest dose examined, 3 mg QD. One possible differentiating feature of GSK2881078 is the long t1/2 of the compound. GSK2881078 has a terminal t1/2 of 7.5 days, considerably longer than enobosarm or LGD, which may limit peak : trough compound excursion. While daily testosterone concentrations are diurnal, a more static exposure may offer more sustained anabolic stimulation of muscle.

Currently, there are no approved therapies for the prevention or treatment of deleterious muscle wasting, although there is a clinical need for safe anabolic compounds such as SARMs. GSK2881078 has demonstrated clear target engagement shown by significant reductions in SHBG, TBG and HDL. Good safety and tolerability were also demonstrated and are consistent with the broad safety margin shown in preclinical toxicology studies (unpublished data on file, GlaxoSmithKline, King of Prussia, PA, USA). These data, combined with the dose‐proportional plasma levels and predictable biomarker profiles of GSK2881078, provide a pharmacological rationale for further clinical study of this novel SARM for the treatment of muscle wasting.