Safety and Tolerability of LGD-4033, a Novel Non-Steroidal Oral

Selective Androgen Receptor Modulator (SARM), in Healthy Men

Shehzad Basaria1, Lauren Collins1, Melinda Sheffield-Moore2, Edgar L. Dillon2, Katie Orwoll1, Kishore M. Lakshman1, Renee Miciek1,
Thomas Storer1, Jagadish Ulloor1, Anqi Zhang1, Heather Zientek 3, Keith Marschke3, Joanna Peterkin4, Shalender Bhasin1
University School of Medicine, 2University of Texas Medical Branch, 3Ligand Pharmaceuticals, Inc., 4JJ Peterkin Consulting

No drug-related severe or serious AEs occurred

Total Testosterone

All adverse events were mild or moderate

that are tissue-selective and being developed to treat muscle

wasting associated with cancer, acute and chronic illness
and age-related muscle loss.

No clinically significant changes in LFTs, hematocrit or PSA

were seen at any dose

LGD-4033 is a novel non-steroidal, oral SARM that binds to

No clinically significant changes in ECG were seen at any

AR with high affinity (Ki of ~1 nM) and selectivity.

dose

In animal models, LGD-4033 demonstrated anabolic activity

study, the safety and tolerability of LGD-4033 was evaluated.

STUDY DESIGN AND METHODS

Study Design
In this double-blind, placebo-controlled, single center, multiple
ascending dose study, healthy men age 21-50 years were
randomized to receive 0.1, 0.3 or 1 mg LGD-4033 or placebo oncedaily over 21 days. Liver function tests (LFTs), fasting lipids,
hematocrit, PSA, ECGs and serum sex hormones were monitored
throughout the treatment period and the subsequent 5-week
observation period.

Total Subjects with AE

Trend analysis of change from baseline up to day 28 was computed

using a mixed-model analysis of repeat measures. Placebo subjects
from the 3 cohorts were pooled for analysis. Sample size: PBO
(placebo) N=29; 0.1 mg N=17; 0.3 mg N=10; 1.0 mg N=11

400

40
30
20

200

10

0
0

10 15 20 25 30 35 40 45 50 55 60

-5

0.3 mg
(N=11)

1 mg
(N=14)

4 (12.1)

3 (27.3)

5 (35.7)

Acne

Low density lipoprotein increased

Aspartate aminotransferase increased

Erectile dysfunction

30 35 40

45 50

55 60

1 (9.1)

7.0

100

6.0
5.0
4.0

10 15 20 25 30 35 40 45 50 55 60

2 (14.3)

1 (9.1)

1 (7.1)

Gynaecomastia

1 (7.1)

Rash

1 (9.1)

Decrease in triglyceride levels across all doses

1 (3.0)

Reversible dose-dependent decrease in HDL cholesterol was

seen at doses 0.3 mg; overall, changes are not considered
clinically relevant to target indications

Pooled PBO

Day 1

0.1 mg

Day

0.3 mg

1.0 mg

Treatment duration

Normal range

Changes in lipid profile are as follows:

No significant changes in total and LDL cholesterol

PHARMACOKINETICS

Figure 3: Dose-dependent increase in total lean body mass with

~1.2 kg increase at 1 mg dose. Fat mass appeared to decrease
with LGD-4033 treatment. LS-Mean (SE) change from baseline
up to day 28 (kg).
Total Lean Mass

Total Fat Mass

2.0

1.0

10

0.1 mg (n=5)
0.3 mg (n=10)
1.0 mg (n=11)

10

1.5
1.0
0.5
0.0

0.5

10

20

30

Time (h)

40

50

30

60

90

Time (h)

120

150

180

--0.5
0.5

PBO

0.1 mg

0.3 mg

1 mg

-0.5

-1.0

40

20

-0.1

-0.2

-0.3

0
PBO

0.1 mg

0.3 mg

1 mg

-0.4

PBO

0.1 mg

0.3 mg

1 mg

In young healthy men:

LGD-4033 was safe and well tolerated at all doses
following daily oral administration for 3 weeks.
No clinically significant changes in LFTs, PSA, hematocrit
or ECG were seen.

FUTURE DIRECTION

0.0

0.1

0.1

60

Positive trends in lean body mass and functional measures

were seen, consistent with anabolic activity.

100
0.1 mg (n=6)
0.3 mg (n=11)
1.0 mg (n=14)

Stair Climb Speed

0.0

CONCLUSIONS

EXPLORATORY MEASURES

Day 21

100

1 mg

80
-5

10 15 20 25 30 35 40 45 50 55 60
Day

Figure 1: Dose proportional increase in systemic exposure on

days 1 and 21.

0.3 mg

0.0

1 (7.1)

hours), linear pharmacokinetics, and predictable accumulation

with multiple dosing.

0.1 mg

Stair Climb Power

2.0

-5

LGD-4033 displayed a prolonged elimination half-life (2436

PBO

3.0

1 (9.1)

Somnolence

Figure 5: Trend toward an increase in physical performance

measures (stair climb power and speed) over the short treatment
period. LS-Mean (SE) change from baseline up to day 28.

8.0

150

*MedDRA dictionary V12

50

-50

1.0

100

10.0
9.0

0.1 mg
(N=18)

3 (9.1)

15 20 25

Day

250

PBO
(N=33)

Dry mouth

10

150

LH

50

Plasma Conc. (ng/mL)

Stair climbing power and speed

600

LH (U/L)

Preferred Term*, n (%)

To assess the effects of treatment with LGD-4033 on:

Maximal voluntary leg press strength measured by 1-RM method

800

200

Secondary Objectives

Lean body mass (LBM) measured by (DEXA) scan

50

Day

Table 1: Related treatment-emergent adverse events.

To assess the safety and tolerability of escalating doses of LGD-4033.

Exploratory Objectives

60

Free Testosterone

Primary Objectives

To assess pharmacokinetics and pharmacodynamics of LGD-4033.

70

1000

Change from Baseline (kg)

safety and tolerability of LGD-4033 up to doses of 22 mg.

In this randomized, double-blind, placebo-controlled Phase I

1200

-5

Free T (pg/mL)

A previous Phase I single ascending dose study established

Total T (ng/dL)

No event led to study discontinuation

SHBG

SHBG (nmol/L)

SARMs are a new class of androgen receptor (AR) ligands

in muscles, anti-resorptive and anabolic activity in bones,

and robust selectivity for muscle versus prostate.

Figure 2: Dose dependent decrease in testosterone (T), free T

and SHBG. Significant reversible changes at all doses. Consistent
with AR-mediated activity. No significant change in LH or FSH.

Change from Baseline (sec)

LGD-4033 was safe and well tolerated at all doses

Adverse Event Profile:

strength, but concerns regarding potential adverse effects on

the prostate have restrained enthusiasm for its use as
anabolic therapy.

Figure 4: Positive trend towards an increase in maximal voluntary

leg press strength with LGD-4033 treatment. LS-Mean (SE)
change from baseline up to day 28.

Change from Baseline (Watts)

Testosterone administration increases muscle mass and

PHARMACODYNAMICS

Change from Baseline (Newton)

SAFETY RESULTS

BACKGROUND

Change from Baseline (kg)

1Boston

Plasma Conc. (ng/mL)

Abstract
P3-207

PBO

0.1 mg

0.3 mg

1 mg

Phase II studies with 12 weeks of treatment are planned to

evaluate LGD-4033 in conditions such as muscle wasting
associated with cancer, rehabilitation and acute illness.