Full copy can be found at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111291/
DISCUSSION
LGD-4033 was safe and well tolerated over the range of doses that were evaluated over a 3-week period. Even during this short treatment period, there was clear evidence of the compound’s androgenic activity, as reflected in the increase in LBM, and significant suppression of testosterone, sex hormone–binding globulin, and HDL cholesterol levels. In spite of demonstrable androgenic activity, serum prostate-specific antigen did not change significantly. The study also revealed other attractive PK attributes of the drug—including a prolonged circulating half-life, dose-proportional systemic exposure, and robust relationships between the dose and outcomes. The gains in LBM were similar to those reported with another SARM (17), although the treatment duration in the latter trial was substantially longer (12 weeks).
The study had many features of a good trial design; subject allocation by randomization, concealed randomization, blinding, and independent appraisal of safety data by a Data and Safety Monitoring Board. By virtue of being an ascending-dose study, the study also had some inherent constraints. The doses of study medication were administered sequentially in ascending order rather than in random order. The sample size, although substantially larger than in most phase I ascending-dose studies, was not based on considerations of effect sizes, as the study’s primary aim was to establish safety and tolerability rather than efficacy. Similarly, the 3-week study duration was not designed to demonstrate maximal effects on skeletal muscle mass and muscle strength which were not the primary outcomes of the trial. In light of these inherent constraints, it is particularly remarkable that significant dose-dependent gains in LBM were evident in this short duration, indicating this SARM’s substantial androgenic–anabolic activity on the skeletal muscle.
Several attractive PK features of this SARM are noteworthy. Its prolonged elimination half-life renders it amenable to once daily or even a less frequent dosing regimen. Daily administration of the drug was associated with dose-proportional increase in systemic exposure resulting in predictable accumulation upon multiple dosing. There was a robust relationship between the dose and the plasma concentrations. The mean area-under-the-curves (AUC) in men receiving the 0.3- and 1.0-mg dose were above the drug AUC estimated to be efficacious in monkeys, and all three doses produced AUCs that exceeded the AUC estimated to be efficacious in orchidectomized rats.
In a manner typical of all oral androgens (25,26,27), the oral administration of LGD-4033 was associated with significant suppression of HDL cholesterol at the 1.0-mg dose. Triglyceride levels also decreased, but LDL cholesterol did not change. Neither the mechanism nor the clinical significance of the HDL suppression with orally administered androgens is well understood (25). HDL cholesterol has been negatively associated with the risk of coronary artery disease in epidemiological studies (25,28); however, pharmacologically induced changes in HDL cholesterol have not been necessarily associated with changes in cardiovascular risk. In animal models, the degree of anti-atherogenic effect of HDL cholesterol is determined more by the mechanism of HDL modification than by the changes in HDL levels (28,29). Thus, the increases in HDL cholesterol due to overproduction of apoA1, but not due to inhibition of HDL catabolism, have been found to be atheroprotective (28,29,30,31,32). The HDL lowering effect of oral androgens has been attributed to the upregulation of scavenger receptor B1 and the hepatic lipase, both of which are involved in HDL catabolism (32,33). Neither the hyperexpression of scavenger receptor B1 nor that of hepatic lipase has been associated with acceleration of atherogenesis, even though increased expression of each is associated with reduced HDL cholesterol (28,29,30,31). Thus, clinical significance of the HDL decrease associated with oral androgens remains unclear. Long-term studies are needed to clarify the effects of long-term SARM administration on cardiovascular risk. In the interim, the initial trials are likely to be conducted for acute or subacute indications, such as cancer cachexia and functional limitations associated with acute illness or hip fracture, where the short-term changes in HDL cholesterol may not be clinically important.
Exogenous androgens would be expected to lower endogenous testosterone levels. However, LGD-4033 has been shown to increase bone mineral density, periosteal bone formation, and femur bending strength in preclinical models. Other SARMs have also been shown to maintain measures of sexual function in the orchiectomized rodent model (18).
The mechanisms by which androgens increase muscle mass remain incompletely understood. Testosterone administration induces hypertrophy of both type I and type II muscle fibers (34). Muscle fiber hypertrophy can result from either increased muscle protein synthesis or decreased muscle protein degradation. Our studies did not reveal a significant difference in fractional muscle protein synthesis between the placebo and the active drug groups at the 0.3-mg dose. These studies were conducted in the fasted state when the fractional muscle protein synthesis is low; however, testosterone trials that have reported an increase in FSR have also been conducted in the fasted state as have trials that failed to show improvements in FSR (35). Previous human and animal studies have shown inhibition of muscle proteolysis and muscle protein degradation pathways during testosterone administration, as potential mechanisms for increased muscle mass (36,37). Testosterone also increases the number of satellite cells (38) by promoting the proliferation of satellite cells and the differentiation of muscle progenitor cells (39,40). Those mechanisms were not investigated in this study.
The past decade has witnessed the emergence of a number of nonsteroidal SARMs from several pharmaceutical companies. Currently, SARMs are being developed as a new class of function-promoting anabolic therapies to treat the loss of muscle mass and function associated with aging and illness, cancer cachexia, osteoporosis, and other conditions associated with muscle loss. This 3-week phase I study, by demonstrating the safety and tolerability of LGD-4033 and significant gains in muscle mass and strength, paves the way for longer term efficacy trials in one or more populations of older individuals for which SARMs may be indicated. Short-term indications for grievous conditions, such as cancer cachexia or functional limitations following an acute illness or hip fracture, might provide a more attractive risk:benefit profile for initial trials of SARMs than long-term indications such as aging-associated sarcopenia.
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FUNDING
DISCUSSION
LGD-4033 was safe and well tolerated over the range of doses that were evaluated over a 3-week period. Even during this short treatment period, there was clear evidence of the compound’s androgenic activity, as reflected in the increase in LBM, and significant suppression of testosterone, sex hormone–binding globulin, and HDL cholesterol levels. In spite of demonstrable androgenic activity, serum prostate-specific antigen did not change significantly. The study also revealed other attractive PK attributes of the drug—including a prolonged circulating half-life, dose-proportional systemic exposure, and robust relationships between the dose and outcomes. The gains in LBM were similar to those reported with another SARM (17), although the treatment duration in the latter trial was substantially longer (12 weeks).
The study had many features of a good trial design; subject allocation by randomization, concealed randomization, blinding, and independent appraisal of safety data by a Data and Safety Monitoring Board. By virtue of being an ascending-dose study, the study also had some inherent constraints. The doses of study medication were administered sequentially in ascending order rather than in random order. The sample size, although substantially larger than in most phase I ascending-dose studies, was not based on considerations of effect sizes, as the study’s primary aim was to establish safety and tolerability rather than efficacy. Similarly, the 3-week study duration was not designed to demonstrate maximal effects on skeletal muscle mass and muscle strength which were not the primary outcomes of the trial. In light of these inherent constraints, it is particularly remarkable that significant dose-dependent gains in LBM were evident in this short duration, indicating this SARM’s substantial androgenic–anabolic activity on the skeletal muscle.
Several attractive PK features of this SARM are noteworthy. Its prolonged elimination half-life renders it amenable to once daily or even a less frequent dosing regimen. Daily administration of the drug was associated with dose-proportional increase in systemic exposure resulting in predictable accumulation upon multiple dosing. There was a robust relationship between the dose and the plasma concentrations. The mean area-under-the-curves (AUC) in men receiving the 0.3- and 1.0-mg dose were above the drug AUC estimated to be efficacious in monkeys, and all three doses produced AUCs that exceeded the AUC estimated to be efficacious in orchidectomized rats.
In a manner typical of all oral androgens (25,26,27), the oral administration of LGD-4033 was associated with significant suppression of HDL cholesterol at the 1.0-mg dose. Triglyceride levels also decreased, but LDL cholesterol did not change. Neither the mechanism nor the clinical significance of the HDL suppression with orally administered androgens is well understood (25). HDL cholesterol has been negatively associated with the risk of coronary artery disease in epidemiological studies (25,28); however, pharmacologically induced changes in HDL cholesterol have not been necessarily associated with changes in cardiovascular risk. In animal models, the degree of anti-atherogenic effect of HDL cholesterol is determined more by the mechanism of HDL modification than by the changes in HDL levels (28,29). Thus, the increases in HDL cholesterol due to overproduction of apoA1, but not due to inhibition of HDL catabolism, have been found to be atheroprotective (28,29,30,31,32). The HDL lowering effect of oral androgens has been attributed to the upregulation of scavenger receptor B1 and the hepatic lipase, both of which are involved in HDL catabolism (32,33). Neither the hyperexpression of scavenger receptor B1 nor that of hepatic lipase has been associated with acceleration of atherogenesis, even though increased expression of each is associated with reduced HDL cholesterol (28,29,30,31). Thus, clinical significance of the HDL decrease associated with oral androgens remains unclear. Long-term studies are needed to clarify the effects of long-term SARM administration on cardiovascular risk. In the interim, the initial trials are likely to be conducted for acute or subacute indications, such as cancer cachexia and functional limitations associated with acute illness or hip fracture, where the short-term changes in HDL cholesterol may not be clinically important.
Exogenous androgens would be expected to lower endogenous testosterone levels. However, LGD-4033 has been shown to increase bone mineral density, periosteal bone formation, and femur bending strength in preclinical models. Other SARMs have also been shown to maintain measures of sexual function in the orchiectomized rodent model (18).
The mechanisms by which androgens increase muscle mass remain incompletely understood. Testosterone administration induces hypertrophy of both type I and type II muscle fibers (34). Muscle fiber hypertrophy can result from either increased muscle protein synthesis or decreased muscle protein degradation. Our studies did not reveal a significant difference in fractional muscle protein synthesis between the placebo and the active drug groups at the 0.3-mg dose. These studies were conducted in the fasted state when the fractional muscle protein synthesis is low; however, testosterone trials that have reported an increase in FSR have also been conducted in the fasted state as have trials that failed to show improvements in FSR (35). Previous human and animal studies have shown inhibition of muscle proteolysis and muscle protein degradation pathways during testosterone administration, as potential mechanisms for increased muscle mass (36,37). Testosterone also increases the number of satellite cells (38) by promoting the proliferation of satellite cells and the differentiation of muscle progenitor cells (39,40). Those mechanisms were not investigated in this study.
The past decade has witnessed the emergence of a number of nonsteroidal SARMs from several pharmaceutical companies. Currently, SARMs are being developed as a new class of function-promoting anabolic therapies to treat the loss of muscle mass and function associated with aging and illness, cancer cachexia, osteoporosis, and other conditions associated with muscle loss. This 3-week phase I study, by demonstrating the safety and tolerability of LGD-4033 and significant gains in muscle mass and strength, paves the way for longer term efficacy trials in one or more populations of older individuals for which SARMs may be indicated. Short-term indications for grievous conditions, such as cancer cachexia or functional limitations following an acute illness or hip fracture, might provide a more attractive risk:benefit profile for initial trials of SARMs than long-term indications such as aging-associated sarcopenia.
Go to:
FUNDING
