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87

Journal of Gerontology: MEDICAL SCIENCES

Cite journal as: J Gerontol A Biol Sci Med Sci. 2013 January;68(1):87–95

doi:10.1093/gerona/gls078

© The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America.

All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Advance Access publication March 28, 2012

Journal of Gerontology: MEDICAL SCIENCES © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America.

Cite journal as: J Gerontol A Biol Sci Med Sci All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

doi:10.1093/gerona/gls078

1

AS men and women grow old, they lose muscle mass,

muscle strength , and leg power ( 1 , 2 , 3 , 4 , 5 , 6 ), mostly

due to the preferential loss of type II muscle fi bers ( 5 ).

Sarcopenia, the age-associated loss of muscle mass and

strength, increases the risk of falls, fractures, physical disability,

and poor quality of life ( 1 , 3 , 6 , 7 ). Similarly, the

course of many illnesses, such as chronic obstructive lung

disease, end - stage renal disease, and some types of cancer,

is punctuated by the loss of muscle mass and physical function,

which contributes to mobility limitation and disability

( 7 , 8 ). Thus, there is an unmet need for anabolic therapies

that improve physical function and reduce the burden of

disability in persons experiencing functional limitations

due to aging or illness. Among the various candidate function -

promoting anabolic therapies that are in development,

androgens are the farthest along in development.

Testosterone administration increases muscle mass and

strength ( 9 , 10 , 11 , 12 , 13 , 14 , 15 ), but concerns regarding its

potential adverse effects on the prostate have restrained

enthusiasm for its use as an anabolic therapy and have

motivated efforts to develop selective androgen receptor

modulators (SARMs), a new class of androgen receptor

The Safety, Pharmacokinetics, and Effects of

LGD-4033, a Novel Nonsteroidal Oral, Selective

Androgen Receptor Modulator, in Healthy Young Men

Shehzad Basaria , 1 Lauren Collins , 1 , * E. Lichar Dillon , 2 , * Katie Orwoll , 1 Thomas W. Storer , 1

Renee Miciek , 1 Jagadish Ulloor , 1 Anqi Zhang , 1 Richard Eder , 1 Heather Zientek , 3 Gilad Gordon , 3

Syed Kazmi , 3 Melinda Sheffi eld-Moore , 2 , * and Shalender Bhasin 1

1 Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Massachusetts .

2 Department of Medicine, University of Texas Medical Branch, Galveston .

3 Ligand Pharmaceuticals , San Diego, California .

* These authors contributed equally and are joint second authors.

Address correspondence to Shalender Bhasin, MD, Section of Endocrinology, Boston University School of Medicine, Boston, MA 02118.

Email: Bhasin@bu.edu

Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of

selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a

novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affi nity and selectivity.

Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered

daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.

Methods. In this placebo-controlled study, 76 healthy men (21 – 50 years) were randomized to placebo or 0.1, 0.3, or

1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specifi c antigen, electrocardiogram,

hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.

Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was

similar between active and placebo groups. Hemoglobin, prostate-specifi c antigen, aspartate aminotransferase, alanine

aminotransferase, or QT intervals did not change signifi cantly at any dose. LGD-4033 had a long elimination half-life and

dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent

suppression of total testosterone, sex hormone – binding globulin, high density lipoprotein cholesterol, and triglyceride

levels. Follicle-stimulating hormone and free testosterone showed signifi cant suppression at 1.0-mg dose only. Lean body

mass increased dose dependently, but fat mass did not change signifi cantly. Hormone levels and lipids returned to baseline

after treatment discontinuation.

Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profi le, and increased lean body mass even during

this short period without change in prostate-specifi c antigen. Longer randomized trials should evaluate its effi cacy

in improving physical function and health outcomes in select populations.

Key Words: Selective androgen receptor modulators — SARMs — Sarcopenia — Function promoting anabolic therapies —

Cachexia .

Received December 8 , 2011 ; Accepted February 2 , 2012

Decision Editor: Luigi Ferrucci, MD, PhD

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288 BASARIA ET AL.

ligands that are tissue selective ( 8 , 16 , 17 , 18 , 19 ). The last

decade has witnessed substantial pharmaceutical efforts to

develop nonsteroidal SARMs to treat muscle wasting and

functional limitations associated with acute and chronic illness

and aging ( 8 , 16 , 17 , 18 , 19 ). LGD-4033 is a novel nonsteroidal,

oral SARM that binds to androgen receptor with

high affi nity (Ki of ~ 1 nM) and selectivity. In animal models,

LGD-4033 has demonstrated anabolic activity in the muscle,

anti-resorptive and anabolic activity in bone, and robust

selectivity for muscle versus prostate.

Here we report the results of a randomized, double-blind,

placebo-controlled, ascending-dose study, which evaluated

the safety, tolerability, and pharmacokinetics (PK) of LGD-

4033 in healthy men. We also evaluated the effects of graded

doses of LGD-4033 on lean body mass (LBM), muscle

strength , and physical function. LGD-4033 doses of 0.1,

0.3, and 1.0 mg were selected for multiple dosing over 21

days because a previous phase I single ascending-dose study

had established the safety of up to 22 mg LGD-4033. We also

tested the hypothesis that the LGD-4033 increases muscle

mass by stimulating fractional synthetic rate (FSR) of mixed -

muscle proteins, measured using continuous steady state

infusion of labeled phenylalanine in men randomized to either

placebo or 0.3-mg daily dose of LGD-4033. This dose was

selected for FSR study because preclinical data suggested

that this dose was the most likely to increase LBM.

Study Design

This was a double-blind, placebo-controlled, multiple

once-daily dose escalation study of LGD-4033 in healthy

men, approved by Boston University ’ s Institutional Review

Board. All subjects provided written, informed consent.

Subjects

Nonsmoking, healthy men, 21 – 50 years, with body mass

index between 18 and 32 kg/m 2 , who were capable of

providing informed consent, were eligible. We excluded

subjects who had an active disease, prostate-specifi c antigen

>3 ng/mL, aspartate aminotransferase or ALT >1.5 times the

upper limit of normal, hematocrit <37% or >48%, creatinine

>2.0 mg/dL, and (HDL) cholesterol <40 mg/dL ; had used

anabolic steroids, recombinant human growth hormone,

dehydroepiandrosterone , and androstenedione during the

past year ; or were using any recreational drug.

Study Intervention

Three dose levels — 0.1, 0.3 , and 1.0 mg — were evaluated

against placebo. Each dose of LGD-4033 or placebo

was administered daily orally with 8 ounces of water

after an overnight fast. A total of 20 doses were administered

over 21 days; no dose was given on day 2 to allow

PK sampling for 48 hours after the fi rst dose. The 21-day

treatment period was followed by a 5-week observation

period.

Randomization

The subjects were randomized to the active drug or

placebo group based on protocol-defi ned randomization

schema: six active and two placebo in 0.1-mg cohort; 10 – 12

active and 10 – 12 placebo in 0.3-mg and 1.0-mg cohorts.

A protocol amendment after the completion of 1.0-mg

cohort added 12 active and six placebo subjects in the

0.1-mg cohort. Randomization lists, generated by the

biostatistician, were sent directly to Investigational Drug

Service.

The subjects were initially assigned to either placebo or

0.1 mg LGD-4033 daily. At the completion of each dose

level, the safety data were reviewed by a Safety Panel and

separately by a Data and Safety Monitoring Board, which

determined whether the dose could be escalated to a higher

level, based on prespecifi ed safety criteria. Dose escalation

proceeded only if an acceptable safety profi le with no clinically

signifi cant and/or unexpected toxicity was observed at

the lower dose.

Blinding

The study was a double-blind trial with concealed randomization.

The subjects and study personnel were unaware

of the intervention. Only the biostatistician and Investigational

Drug Service were aware of the subject ’ s group

allocation. The Investigational Drug Service maintained the

randomization code and dispensed the study medication

based on the randomization list.

Outcomes

The primary aim was to assess the safety and tolerability

of escalating doses of LGD-4033 following repeated oncedaily

oral administration for 21 days. Secondary aims included

the determination of the PK and pharmacodynamics of

LGD-4033 and its effects on mixed - muscle FSR. Additionally,

we investigated the effects of 21 days of treatment with

LGD-4033 on LBM measured by dual - energy x-ray absorptiometry,

maximal voluntary strength measured by one repetition

maximum method, and physical function, assessed

by the stair-climbing power, recognizing that a 21-day duration

may not be suffi ciently long to fully elucidate the

anabolic effects of the SARM on LBM, muscle strength,

and physical function.

Schedule of Events

LGD-4033 concentrations were measured using a validated

liquid chromatographic – tandem mass spectrometry

method in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6, 8,

10, 12, 24, 28, 32, and 48 hours after the fi rst dose. Oncedaily

dosing recommenced on day 3 for 20 days , and on day

21, venous blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10,

12, 24, 28, 32, 48, 72, 96, 120 , and 168 hours after day 21

dosing.

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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 89

3

Luteinizing hormone, follicle-stimulating hormone,

adrenocorticotropic hormone, cortisol, total and free testosterone,

sex hormone – binding globulin levels, and plasma

lipids were measured periodically throughout the 21-day

intervention period and 7 and 35 days after drug cessation.

LBM and fat mass were measured at baseline and on days

20 and 28. Leg press strength and stair-climbing power and

speed were assessed at baseline and between days 23 and 25.

M ethods

Body composition was assessed using dual-energy x-ray

absorptiometry (Hologic 4500) scanner, calibrated using a

soft tissue phantom before each scan. To measure the leg

press strength ( 15 , 20 , 21 ), subjects underwent whole-body

warm up, followed by one set of 5 – 10 repetitions using

40 % – 60% of the estimated maximum. Following appropriate

rest periods between attempts, subjects lifted progressively

heavier weights until the subject could not complete the lift.

The last successfully completed lift was recorded as the one

repetition maximum .

The 12-step stair-climb test required subjects to ascend a

staircase with step rise of 17 cm as fast as possible with time

recorded by activation of switchmats on the 8th and 12th

stair ( 15 , 20 , 21 ). The test – retest reliability is 0.85 and coeffi

cients of variation 2%. After familiarization, two trials

were given with the best time taken as the stair-climb score.

Power was calculated from the time elapsed, body weight,

and vertical distance.

Fractional Protein Synthesis Rates

On days 1 and 20, at 7 am , an 18-gauge catheter was

inserted into the forearm vein of each arm, one for blood

sampling and one for tracer infusion. Baseline blood samples

were drawn for analysis of amino acid enrichments from

one arm, heated with a heating pad. At 8 am , a primed

(2.0 μ mol / kg) constant infusion (0.06 μ mol / kg / min utes ) of

l -[ring- 13 C 6 ] phenylalanine was started and maintained for

6 hours. Venous blood was obtained at 0, 60, 120, 150, 165,

180, 195, 210, 240, 300, 330, 345, and 360 min utes during

the infusion. Two muscle biopsies (100 – 300 mg) were taken

at 180 and 360 min utes from vastus lateralis, ~ 10 to 15 cm

above the knee, using a 5-mm Bergstrom biopsy needle, and

snap frozen in liquid nitrogen for storage in a − 80 ° C freezer

until analysis.

Phenylalanine enrichments in arterialized venous blood

was determined after deproteinization with sulfosalicylic acid,

extraction with cation exchange chromatography (Dowex AG

50W-8X, 100 – 200 mesh H+ form; BioRad Laboratories,

Richmond, CA), derivatization using tert -butyldimethylsilyl,

followed by gas chromatography – mass spectrometry in

electron impact mode (GC HP 5890, MSD HP 5989, Hewlett

Packard, Palo Alto, CA ; 22 ).

Muscle samples were weighed and the proteins precipitated

with 800 μ l of 10% sulfosalicylic acid. Intracellular

phenylalanine enrichment was determined by extraction

with cation exchange chromatography (Dowex AG 50W-8X,

200 – 400 mesh H+ form; BioRad Laboratories, Inc.), tert -

butyldimethylsilyl derivatization, and gas chromatography –

mass spectrometry in electron impact mode ( 22 ). The

remaining pellet containing bound mixed-muscle proteins

was repeatedly washed, dried at 50°C overnight , and hydrolyzed

in 3 mL of 6 N HCL at 110 ° C for 24 hours. Amino

acids in the hydrolysate were extracted and derivatized and

analyzed by monitoring the ions 238 and 240 ( 22 ).

Mixed - muscle FSR was calculated by measuring the

incorporation of l -[ring- 13 C 6 ]-phenylalanine into protein

using the precursor – product model:

= − × × P2 P1 M FSR [(E E ) /(E t)]60 100,

where E P1 and E P2 are enrichments of bound l -[ring- 13 C 6 ]-

phenylalanine in the fi rst and second muscle biopsies, t is the

time between biopsies, and E M is the mean l -[ring- 13 C 6 ]-

phenylalanine enrichment in muscle intracellular pool ( 22 ).

Hormone Assays

Total testosterone was measured using liquid chromatography

– tandem mass spectrometry ( 23 ) , and free testosterone

was calculated using a published law-of-mass-action

equation ( 24). Serum luteinizing hormone, follicle-stimulating

hormone , and sex hormone – binding globulin were measured

using two site - directed immunofl uorometric assays

( 9 , 21 ).

Statistical Analyses

Safety parameters were listed and summarized by study

intervention, dose, and time point. Adverse events were

tabulated by System Organ Class and Preferred Term based

on MedDRA dictionary version 12.

Plasma drug concentration – time data were analyzed using

noncompartmental methods. PK parameters were summarized

by dose group , and selected PK parameters were

analyzed using comparative statistics. Dose proportionality

of PK parameters was assessed by linear regression.

Pharmacodynamic assessments were summarized for each

dose and time point. Changes from baseline in hormone levels,

lipids, and FSR were analyzed using repeated measures

analyses of variance, with a dose factor and time-in-treatment

factor and baseline value as covariate. A similar approach

was used to analyze change from baseline in LBM, one repetition

maximum strength , and stair-climbing power.

For dual-energy x-ray absorptiometry , muscle strength,

and stair-climbing power, a trend analysis of change from

baseline was applied using a mixed-model analysis of repeated

measures and adjusted for baseline value. Two postbaseline

measures up to day 28 were utilized in repeated

measure model. This analysis was performed on evaluable

subjects who had baseline measures and at least one

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490 BASARIA ET AL.

post-baseline measure. Placebo subjects from the three cohorts

were pooled for analysis. This resulted in sample sizes

of 30 men for dual-energy x-ray absorptiometry analysis

and 29 men for muscle strength analysis in the placebo

group, 17 in the 0.1-mg, 10 in the 0.3-mg, and 11 in the 1.0-mg

dose groups.

R esults

Flow of Subjects

A total of 389 subjects were screened in person, 131 were

eligible , and 76 were randomized (CONSORT diagram,

Supplementary Appendix Figure 1 ). Eight subjects were

either lost to follow-up or discontinued and 68 subjects

completed the trial.

Subjects

The participants were young (mean age 37 years), lean

( body mass index 25.8 kg/m 2 ) , and had normal testosterone,

luteinizing hormone , and follicle-stimulating hormone

levels ( Table 1 ). The groups were similar in their baseline

characteristics.

Compliance

The compliance, assessed by drug logs and by counting

the unused tablets, was 100%, among men who were included

in the effi cacy analysis.

Safety Data

LGD-4033 was safe and well tolerated at all doses. The

frequency of adverse events was similar between the placebo

and any dose group. Headache, pain related to muscle

biopsy, and dry mouth were the most common events and

did not show dose relationship ( Supplementary Appendix

Table 1 ). More upper respiratory tract infections were

observed in LGD-4033 1.0 - mg group , but these events were

not considered drug related. No drug-related severe or serious

adverse events occurred. One cellulitis (in placebo group)

and one gastroenteritis (0.3 mg group) were severe but were

not considered study drug related. There was no study discontinuation

due to adverse events. There were no clinically

signifi cant changes in liver enzymes, hematocrit, prostatespecifi

c antigen , or electrocardiogram at any dose.

Pharmacokinetics

LGD-4033 displayed a prolonged elimination half-life

(24 – 36 hours) and linear PK ( Figure 1 ). There was a dose -

proportional increase in LGD-4033 concentrations on

days 1 and 21. Serum LGD-4033 concentrations were nearly

threefold higher on day 21 than on day 1, refl ecting accumulation

upon multiple dosing. The mean areas under the

drug concentration curve on day 21 were 19, 85 , and 238 ng

24 hour/mL, respectively, in men receiving 0.1, 0.3, and 1.0 mg

LGD-4033 daily.

Hormone Levels

There was a dose-dependent suppression of total testosterone

and sex hormone – binding globulin levels from

baseline to day 21 ( Figure 2 ). Free testosterone suppression

was noted at the 1.0-mg dose only. The suppression of

total testosterone was greater than that of free testosterone.

Serum luteinizing hormone levels did not show any

meaningful changes from baseline, whereas the folliclestimulating

hormone levels were suppressed only in the

1.0-mg dose group ( Figure 2D and E ). Upon discontinuation

of LGD-4033, the hormone levels returned to baseline

by day 56.

Table 1. Baseline Characteristics of the Subjects

Placebo/LGD Dose Group Placebo

LGD-4033 Doses

0.1 mg 0.3 mg 1 mg All Subjects

N 33 18 11 14 76

Age (years) 36.0 (9.4) 37.0 (10.4) 35.6 (8.4) 40.9 (8.7) 37.1 (9.4)

Body weight (kg) 81.5 (13.6) 78.2 (13.9) 80.5 (13.5) 84.6 (10.2) 81.2 (13.0)

Height (cm) 176.8 (6.4) 178.0 (9.6) 175.3 (7.3) 176.8 (6.9) 176.9 (7.4)

Body mass index (kg/m 2 ) 25.9 (3.4) 24.6 (3.0) 26.2 (3.5) 27.0 (2.7) 25.8 (3.3)

TESTO (ng/dL) 549 (136) 564 (153) 543 (111) 551 (144) 552 (136)

FT (ng/dL) 11.39 (3.11) 11.4 (3.1) 11.4 (3.4) 11.36 (3.3) 11.2 (3.1)

Sex hormone – binding globulin (nmol/L) 34.1 (11.7) 37.5 (21.6) 34.0 (8.6) 36.4 (11.1) 35.3 (14.1)

Luteinizing hormone (U/L) 3.9 (1.9) 3.6 (1.5) 3.0 (0.7) 3.7 (1.1) 3.7 (1.5)

Follicle-stimulating hormone (U/L) 4.0 (3.4) 3.1 (2.1) 4.1 (2.0) 4.1 (2.2) 3.8 (2.7)

prostate-specifi c antigen (ng/mL) 0.8 (0.5) 1.3 (1.6) 0.7 (0.2) 0.8 (0.5) 0.9 (0.9)

Lean body mass (kg) 60.6 (9.1) 58.9 (7.6) 60.6 (8.7) 63.9 (4.7) 60.7 (8.1)

Fat mass (kg) 16.4 (7.5) 13.3 (7.5) 15.7 (5.5) 17.2 (6.5) 15.7 (7.0)

Leg press strength (N) 1440.6 (381.0) 1364.8 (298.8) 1535.0 (287.1) 1476.1 (247.6) 1441.3 (326.8)

Stair-climbing power (W) 659.3 (123.1) 614.2 (125.3) 678.7 (98.4) 665.9 (136.8) 651.8 (122.2)

Notes : The subjects assigned to the placebo group in each of the three cohorts were pooled for the purpose of analyses. Data are mean ± ( SD ). The number of

subjects in each group is shown in row 2. FT= free testosterone; TESTO = testosterone.

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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 91

5

Plasma Lipids

Total and low density lipoprotein (LDL) cholesterol did

not change signifi cantly from baseline at any dose ( Table 2 ).

HDL cholesterol decreased from baseline at doses ≥ 0.3 mg;

HDL cholesterol returned to baseline after treatment discontinuation

( Table 2 ). Triglyceride levels decreased from

baseline across all doses.

Body Composition

LBM increased dose dependently ( p for trend = .04 ;

Figure 3A ). The increase in LBM averaged 1.21 kg at the

1.0 - mg dose ( p = .047 vs placebo). The increase in LBM

was correlated with the dose. Fat mass ( Figure 3B ) did not

change signifi cantly. The increase in appendicular skeletal

muscle mass in the 0.3 - and 1.0 - mg groups was not signifi -

cantly differently from that in the placebo group (change

from baseline − 0.2, 0.04, 0.47 , and 0.37 kg for the placebo,

0.1, 0.3, and 1.0-mg groups, p for trend = .078).

L4033-2: Day 1 PK

0.1

1

10

100

0 10 20 30 40 50

Time (h)

Plasma Conc. (ng/mL)

Cohort 1- 0.1 mg (n=6)

Cohort 2- 0.3 mg (n=11)

Cohort 3- 1 mg (n=14)

L4033-2: Day 21 PK

0.1

1

10

100

0 30 60 90 120 150 180

Time (h)

Plasma Conc. (ng/mL)

Cohort 1- 0.1 mg (n=5)

Cohort 2- 0.3 mg (n=10)

Cohort 3- 1 mg (n=11)

Muscle Performance and Physical Function

The increase in strength averaged 68.3 N at the 1.0-mg

dose, but this change was not signifi cantly different from

that in the placebo group ( Figure 3C ). Stair - climbing speed

and power revealed a trend toward dose-related improvement,

but these changes did not achieve statistical signifi cance.

Fractional Mixed - Muscle Protein Synthesis Rates

Plasma phenylalanine concentrations did not change signifi

cantly from 180 to 360 min utes indicating achievement

of a steady state. Baseline FSR averaged ~ 6% / h , consistent

with published literature. The change in FSR from baseline,

measured in the fasted state, did not differ signifi cantly

between 0.3-mg dose and the placebo groups (0.033 ± 0.016

vs 0.031 ± 0.011, p = .99; Supplementary Appendix Table 2 ).

D iscussion

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 refl ected in the

increase in LBM, and signifi cant suppression of testosterone,

sex hormone – binding globulin , and HDL cholesterol levels.

In spite of demonstrable androgenic activity, serum prostatespecifi

c antigen did not change signifi cantly. 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 ascendingdose

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 effi cacy. 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

signifi cant 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 doseproportional

increase in systemic exposure resulting in

Figure 1. Pharmacokinetics of LGD-4033 in Healthy Men. Legend.LGD-4033

concentrations were measured in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6,

8, 10, 12, 24, 28, 32, and 48 hours after the fi rst dose (upper panel). Once-daily

dosing recommenced on day 3. On day 21, venous blood was collected at 0, 0.5,

1, 2, 3, 4, 6, 8, 10, 12, 24, 28, 32, 48, 72, 96, 120, and 168 hours after day 21

dosing (lower panel).

L4033-2: Day 1 PK

Time (h)

Plasma Conc. (ng/mL)

Cohort 1- mg (n=6)

Cohort 2- (n=11)

3- 1 mg (n=14)

L4033-2: Day 21 PK

Time (h)

Plasma Conc. (ng/mL)

Cohort 1- mg (n=5)

2- 0.3 mg (n=10)

3- 1 mg (n=11)

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692 BASARIA ET AL.

A B

C D

E F

Figure 2. (A) The effects of LGD-4033 selective androgen receptor modulator on serum total testosterone levels. Change from baseline in serum total testosterone

levels are shown. The data are mean ± standard error of the mean ( SEM ) , n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in

the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( B ) Change in the free testosterone levels from baseline. Change from

baseline in serum free testosterone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and

14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( C ) Change in sex hormone – binding globulin levels from baseline.

Change from baseline in serum sex hormone – binding globulin levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose,

11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( D ) Change in luteinizing hormone

(U/L) levels from baseline. Change from baseline in serum luteinizing hormone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the

0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( E ) Change in follicle -

stimulating hormone (U/L) levels from baseline. Change from baseline in serum follicle-stimulating hormone levels is shown. The data are mean ± SEM, n = 33

in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment

period. ( F ) Change in prostate - specifi c antigen (ng/mL) levels from baseline. Change from baseline in prostate-specifi c antigen levels is shown. The data are mean ±

SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the

21-day treatment period.

A B

C D

E F

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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 93

7

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 effi cacious in monkeys, and all three

doses produced AUCs that exceeded the AUC estimated to

be effi cacious in orchidectomized rats.

In a manner typical of all oral androgens ( 25 , 26 , 27 ), the

oral administration of LGD-4033 was associated with signifi

cant 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 signifi -

cance 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 modifi cation 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

Table 2. The Effects of LGD-4033 Selective Androgen Receptor

Modulator on Plasma Lipids

Treatment Group *

Mean ( SD )

Baseline

Mean ( SE ) Change From

Baseline

Day 21 Day 56

Total cholesterol (mg/dL)

Placebo 163.4 (28.1) − 1.6 (2.9) 5.2 (4.2)

0.1 mg 163.3 (33.5) − 10.8 (3.6) 0.4 (5.5)

0.3 mg 168.6 (16.6) − 18.0 (4.8) 6.4 (5.0)

1 mg 175.1 (33.5) − 14.3 (8.1) 0.3 (4.4)

HDL cholesterol (mg/dL)

Placebo 52.5 (11.8) − 1.7 (1.2) 0.4 (1.8)

0.1 mg 56.1 (17.3) − 1.0 (2.6) 3.5 (2.3)

0.3 mg 50.3 (8.0) − 10.4 (1.4) 0.6 (1.7)

1 mg 49.2 (11.7) − 19.4 (2.1) − 1.1 (3.2)

LDL cholesterol (mg/dL)

Placebo 92.4 (26.2) 0.9 (2.6) 4.4 (3.7)

0.1 mg 91.0 (29.6) − 5.5 (3.3) − 4.5 (4.9)

0.3 mg 101.5 (15.9) − 2.8 (4.5) 1.7 (3.7)

1 mg 106.8 (31.6) 7.1 (7.1) 4.42 (4.0)

Triglycerides (mg/dL)

Placebo 92.6 (36.8) − 4.3 (4.7) 1.9 (7.5)

0.1 mg 80.0 (31.0 ) − 21.4 (8.1) 7.2 (9.1)

0.3 mg 84.4 (26.1) − 24.0 (4.3) 20.8 (8.0)

1 mg 95.4 (39.1) − 10.1 (6.7) − 15.6 (8.0)

Notes : * Number of subjects with at least one post - baseline test: placebo =

30, 0.1 mg = 17, 0.3 mg = 10 , and 1 mg = 14. LDL = Low density lipoprotein.

Total Body

PBO 0.1 mg 0.3 mg 1 mg

-0.5

0.0

0.5

1.0

1.5

2.0

*

* p =0.047 vs. Placebo

A

Total Body

PBO 0.1 mg 0.3 mg 1 mg

-1.0

-0.5

0.0

0.5

B 1.0

C

PBO 0.1 mg 0.3 mg 1 mg

-50

0

50

100

150

Change from Baseline (Newton) Change from Baseline (kg) Change from Baseline (kg)

Figure 3. (A) Mean ( SE ) lean mass (kg) change from baseline up to day 28.

Change from baseline in lean body mass is shown. The data are mean ± standard

error of the mean , n = 30 in the placebo group pooled from the three cohorts,

17 in the 0.1 - mg dose, 10 in the 0.3 - mg group, and 11 in the 1.0 - mg group. BL =

baseline. * p < .05 vs placebo. PBO = placebo; p for trend = .04. ( B ) Mean ( SE )

fat mass (kg) change from baseline up to day 28. Change from baseline in fat

mass is shown. The data are mean ± standard error of the mean , n = 30 in the

placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the

0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo. p for trend = .261.

( C ) Change in leg press strength (Newton) from baseline. Change from baseline

in fat mass is shown. The data are mean ± standard error of the mean , n = 30 in

the placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the

0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo; p for trend = .203.

expression of each is associated with reduced HDL cholesterol

( 28,29,30,31). Thus, clinical signifi cance 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

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894 BASARIA ET AL.

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 fi bers ( 34 ). Muscle fi ber hypertrophy can result

from either increased muscle protein synthesis or decreased

muscle protein degradation. Our studies did not reveal a signifi

cant 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 signifi cant gains in muscle mass and strength, paves

the way for longer term effi cacy 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:benefi t profi le for initial trials of

SARMs than long-term indications such as aging-associated

sarcopenia.

F unding

This trial was supported by Ligand Pharmaceuticals.

S upplementary M aterial

Supplementary material can be found at: https://biomedgerontology.

oxfordjournals.org/

Acknowledgment

The authors thank the Data and Safety Monitoring Board: Glenn

Cunningham, MD, and Ronal S. Swerdloff, MD.

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Estou praticando musculação numa média de 1 vez a cada 15 dias, não estou sedentário pratico lutas quase todo dia

Segunda feira dia 30/04/2018 retornarei a rotina de treinos para hipertrofia

Duas semanas depois, dia 14/05/2018 irei iniciar o sarms

Qualquer duvida ou sugestão sobre o ciclo estou a disposição

PROTOCOLO

Será utilizado 5mg por dia durante 15 dias, dependendo dos resultados dos 15 dias iniciais optarei pelos seguintes protocolos

1-4 5mg lgd-4033/dia

4-6 10mg lgd-4033/dia

ou

1-2 5mg lgd-4033/dia

2-5 10mg lgd-4033/dia

TPC

Utilizarei tribulus junto ao ciclo como tentativa de menor inibição do eixo

E tamoxifeno 20mg, durante a ultima semana do ciclo e uma semana após

MEDIDAS

Altura aproximada 172cm

Peso 74kg

BF aproximado 14%

Por que escolheu essa TPC logo de cara ?

Em 28/04/2018 em 21:51, ShreddedBrah disse:

Por que escolheu essa TPC logo de cara ?

O Estudo que eu tenho acesso mostrou uma queda significativa no FSH em 21 dias em uma dose de 1mg

Levando isso pra 40 dias em uma dose de 5 a 10 vezes maiores, tenho medo da morte do meu pau, prefiro prevenir do que remediar, até pq só ha vantagens, tanto em saude quanto em manter os ganhos

Atualizando 28/05/2018

Voltei a treinar 30/04/2018

Inicio do uso 14/05/2018 (5mg/dia)

De quando comecei treinar até aqui foram +3kg, atuais 77kg, sem aumento do bf e bastante aumento de força, estou gostando dos resultados

Supinando com 80kg pra 6 reps, que é um recorde pessoal

Estou suplementando Whey, Tribulus, Creatina e Vitamina D

hoje (28/05/2018) começo a dose de 10mg/dia e sigo assim até acabar o pote

Boa mano, acompanhando.

Alguma diferença no eixo?

Em 28/05/2018 em 16:57, gabrielfreiberger disse:

Boa mano, acompanhando.

Alguma diferença no eixo?

ATUALIZANDO 07/06/2018

    Ontem e hoje senti um pouco de desanimo e libido um pouco baixa, eu diria que esta começando a inibir o eixo, daqui poucos dias vou começar com o tamoxifeno 20mg/dia com o objetivo de aumentar o LH e FSH, ja vou comprar amanhã

    Sexta feira atualizo os resultados

editado

Editado 12/06/2018 às 01:58 06/12, 2018 por Ph007

Em 28/05/2018 em 16:57, gabrielfreiberger disse:

Boa mano, acompanhando.

Alguma diferença no eixo?

A "queda no eixo" que tinha sentido estava mais ligado a cansaço e falta de sono

Descansei bem ontem hoje to 100% disposto, então eixo deve estar ok, se continuar assim nem vou mandar tamox, se der farei exames no final

Se der pra fazer, tenho curiosidade, não deixe de postar.

Acompanhando!

Eae amigo, como foram os resultados até o presente momento? Se der relata pra nós.. valeu!

pode relatar o resto aqui??