LGD-4033 ENDO 2011 Poster Final
1
Abstract P3-207 BACKGROUND STUDY DESIGN AND METHODS PHARMACOKINETICS 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 once- daily 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. Primary Objectives To assess the safety and tolerability of escalating doses of LGD-4033. Secondary Objectives To assess pharmacokinetics and pharmacodynamics of LGD-4033. Exploratory Objectives To assess the effects of treatment with LGD-4033 on: • Lean body mass (LBM) measured by (DEXA) scan • Maximal voluntary leg press strength measured by 1-RM method • Stair climbing power and speed 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 • Testosterone administration increases muscle mass and strength, but concerns regarding potential adverse effects on the prostate have restrained enthusiasm for its use as anabolic therapy. • SARMs are a new class of androgen receptor (AR) ligands that are tissue-selective and being developed to treat muscle wasting associated with cancer, acute and chronic illness and age-related muscle loss. • LGD-4033 is a novel non-steroidal, oral SARM that binds to AR with high affinity (Ki of ~1 nM) and selectivity. • In animal models, LGD-4033 demonstrated anabolic activity in muscles, anti-resorptive and anabolic activity in bones, and robust selectivity for muscle versus prostate. • A previous Phase I single ascending dose study established safety and tolerability of LGD-4033 up to doses of 22 mg. • In this randomized, double-blind, placebo-controlled Phase I study, the safety and tolerability of LGD-4033 was evaluated. Figure 1: Dose proportional increase in systemic exposure on days 1 and 21. Table 1: Related treatment-emergent adverse events. CONCLUSIONS 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. • Positive trends in lean body mass and functional measures were seen, consistent with anabolic activity. Safety and Tolerability of LGD-4033, a Novel Non-Steroidal Oral Selective Androgen Receptor Modulator (SARM), in Healthy Men Shehzad Basaria 1 , Lauren Collins 1 , Melinda Sheffield-Moore 2 , Edgar L. Dillon 2 , Katie Orwoll 1 , Kishore M. Lakshman 1 , Renee Miciek 1 , Thomas Storer 1 , Jagadish Ulloor 1 , Anqi Zhang 1 , Heather Zientek 3 , Keith Marschke 3 , Joanna Peterkin 4 , Shalender Bhasin 1 1 Boston University School of Medicine, 2 University of Texas Medical Branch, 3 Ligand Pharmaceuticals, Inc., 4 JJ Peterkin Consulting PHARMACODYNAMICS • LGD-4033 was safe and well tolerated at all doses • Adverse Event Profile: – No drug-related severe or serious AEs occurred – All adverse events were mild or moderate – No event led to study discontinuation • No clinically significant changes in LFTs, hematocrit or PSA were seen at any dose • No clinically significant changes in ECG were seen at any dose SAFETY RESULTS Preferred Term*, n (%) PBO (N=33) 0.1 mg (N=18) 0.3 mg (N=11) 1 mg (N=14) Total Subjects with AE 4 (12.1) 0 3 (27.3) 5 (35.7) Dry mouth 3 (9.1) 0 1 (9.1) 0 Acne 0 0 1 (9.1) 1 (7.1) Low density lipoprotein increased 0 0 0 2 (14.3) Aspartate aminotransferase increased 0 0 1 (9.1) 0 Erectile dysfunction 0 0 0 1 (7.1) Gynaecomastia 0 0 0 1 (7.1) Rash 0 0 1 (9.1) 0 Somnolence 1 (3.0) 0 0 0 *MedDRA dictionary V12 EXPLORATORY MEASURES 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. 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. • Changes in lipid profile are as follows: – No significant changes in total and LDL cholesterol – Decrease in triglyceride levels across all doses – Reversible dose-dependent decrease in HDL cholesterol was seen at doses ≥ 0.3 mg; overall, changes are not considered clinically relevant to target indications PBO 0.1 mg 0.3 mg 1 mg -50 0 50 100 150 Change from Baseline (Newton) PBO 0.1 mg 0.3 mg 1 mg -50 0 50 100 150 Change from Baseline (Newton) Day 1 0.1 1 10 100 0 10 20 30 40 50 Time (h) Plasma Conc. (ng/mL) 0.1 mg (n=6) 0.3 mg (n=11) 1.0 mg (n=14) Day 21 0.1 1 10 100 0 30 60 90 120 150 180 Time (h) Plasma Conc. (ng/mL) 0.1 mg (n=5) 0.3 mg (n=10) 1.0 mg (n=11) 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). -0.5 0.0 0.5 1.0 1.5 2.0 Change from Baseline (kg) PBO 0.1 mg 0.3 mg 1 mg - Total Lean Mass Total Fat Mass - - PBO 0.1 mg 0.3 mg 1 mg - 1.0 - 0.5 0.0 0.5 1.0 Change from Baseline (kg) -0.5 0.0 0.5 1.0 1.5 2.0 Change from Baseline (kg) PBO 0.1 mg 0.3 mg 1 mg - -0.5 0.0 0.5 1.0 1.5 2.0 Change from Baseline (kg) PBO 0.1 mg 0.3 mg 1 mg - Total Lean Mass Total Fat Mass - - PBO 0.1 mg 0.3 mg 1 mg - 1.0 - 0.5 0.0 0.5 1.0 Change from Baseline (kg) - - PBO 0.1 mg 0.3 mg 1 mg - 1.0 - 0.5 0.0 0.5 1.0 Change from Baseline (kg) FUTURE DIRECTION • LGD-4033 displayed a prolonged elimination half-life (24–36 hours), linear pharmacokinetics, and predictable accumulation with multiple dosing. 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. PBO 0.1 mg 0.3 mg 1 mg -0.4 -0.3 -0.2 -0.1 0.0 Change from Baseline (sec) PBO 0.1 mg 0.3 mg 1 mg -0.4 -0.3 -0.2 -0.1 0.0 Change from Baseline (sec) PBO 0.1 mg 0.3 mg 1 mg 0 20 40 60 80 Change from Baseline (Watts) PBO 0.1 mg 0.3 mg 1 mg 0 20 40 60 80 Change from Baseline (Watts) Stair Climb Speed Stair Climb Power • 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. Treatment duration Normal range Pooled PBO 0.1 mg 0.3 mg 1.0 mg Total Testosterone 0 200 400 600 800 1000 1200 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 Day Total T (ng/dL) SHBG 0 10 20 30 40 50 60 70 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 Day SHBG (nmol/L) LH 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 Day LH (U/L) Free Testosterone 0 50 100 150 200 250 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 Day Free T (pg/mL) Free Testosterone 0 50 100 150 200 250 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 Day Free T (pg/mL)
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Transcript of LGD-4033 ENDO 2011 Poster Final
AbstractP3-207
BACKGROUND
STUDY DESIGN AND METHODS
PHARMACOKINETICS
Study DesignIn 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 once-
daily 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.
Primary ObjectivesTo assess the safety and tolerability of escalating doses of LGD-4033.
Secondary ObjectivesTo assess pharmacokinetics and pharmacodynamics of LGD-4033.
Exploratory ObjectivesTo assess the effects of treatment with LGD-4033 on:
•
Lean body mass (LBM) measured by (DEXA) scan
•
Maximal voluntary leg press strength measured by 1-RM method
•
Stair climbing power and speed
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
•
Testosterone administration increases muscle mass and strength, but concerns regarding potential adverse effects on the prostate have restrained enthusiasm for its use as anabolic therapy.
•
SARMs are a new class of androgen receptor (AR) ligands that are tissue-selective and being developed to treat muscle wasting associated with cancer, acute and chronic illness and age-related muscle loss.
•
LGD-4033 is a novel non-steroidal, oral SARM that binds to AR with high affinity (Ki
of ~1 nM) and selectivity.
•
In animal models, LGD-4033 demonstrated anabolic activity in muscles, anti-resorptive and anabolic activity in bones, and robust selectivity for muscle versus prostate.
•
A previous Phase I single ascending dose study established safety and tolerability of LGD-4033 up to doses of 22 mg.
•
In this randomized, double-blind, placebo-controlled Phase I study, the safety and tolerability of LGD-4033 was evaluated.
Figure 1: Dose proportional increase in systemic exposure on days 1 and 21.
Table 1: Related treatment-emergent adverse events.
CONCLUSIONSIn 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.
•
Positive trends in lean body mass and functional measures were seen, consistent with anabolic activity.
Safety and Tolerability of LGD-4033, a Novel Non-Steroidal OralSelective 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
Bhasin11Boston University School of Medicine, 2University of Texas Medical Branch, 3Ligand Pharmaceuticals, Inc., 4JJ Peterkin Consulting
PHARMACODYNAMICS•
LGD-4033 was safe and well tolerated at all doses
•
Adverse Event Profile:
–
No drug-related severe or serious AEs
occurred
–
All adverse events were mild or moderate
–
No event led to study discontinuation
•
No clinically significant changes in LFTs, hematocrit or PSA were seen at any dose
•
No clinically significant changes in ECG were seen at any dose
SAFETY RESULTS
Preferred Term*, n (%) PBO (N=33)
0.1 mg (N=18)
0.3 mg (N=11)
1 mg (N=14)
Total Subjects with AE 4 (12.1) 0 3 (27.3) 5 (35.7)
Dry mouth 3 (9.1) 0 1 (9.1) 0
Acne 0 0 1 (9.1) 1 (7.1)
Low density lipoprotein increased 0 0 0 2 (14.3)
Aspartate aminotransferase increased 0 0 1 (9.1) 0
Erectile dysfunction 0 0 0 1 (7.1)
Gynaecomastia 0 0 0 1 (7.1)
Rash 0 0 1 (9.1) 0
Somnolence 1 (3.0) 0 0 0
*MedDRA
dictionary V12
EXPLORATORY MEASURES
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.
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.
•
Changes in lipid profile are as follows:–
No significant changes in total and LDL cholesterol
–
Decrease in triglyceride levels across all doses
–
Reversible dose-dependent decrease in HDL cholesterol was seen at doses ≥
0.3 mg; overall, changes are not considered clinically relevant to target indications
PBO 0.1 mg 0.3 mg 1 mg-50
0
50
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PBO 0.1 mg 0.3 mg 1 mg-50
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0 10 20 30 40 50Time (h)
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c. (n
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L)
0.1 mg (n=6)0.3 mg (n=11)1.0 mg (n=14)
Day 21
0.1
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0 30 60 90 120 150 180Time (h)
Plas
ma
Conc
. (ng
/mL)
0.1 mg (n=5)0.3 mg (n=10)1.0 mg (n=11)
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).
-0.5
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PBO 0.1 mg 0.3 mg 1 mg-
Total Lean Mass Total Fat Mass
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PBO 0.1 mg 0.3 mg 1 mg-1.0
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PBO 0.1 mg 0.3 mg 1 mg-
Total Lean Mass Total Fat Mass
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PBO 0.1 mg 0.3 mg 1 mg-1.0
-0.5
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FUTURE DIRECTION
•
LGD-4033 displayed a prolonged elimination half-life (24–36 hours), linear pharmacokinetics, and predictable accumulation with multiple dosing.
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.
PBO 0.1 mg 0.3 mg 1 mg-0.4
-0.3
-0.2
-0.1
0.0
Cha
nge
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Bas
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ec)
PBO 0.1 mg 0.3 mg 1 mg-0.4
-0.3
-0.2
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PBO 0.1 mg 0.3 mg 1 mg0
20
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60
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elin
e (W
atts
)
Stair Climb SpeedStair Climb Power
•
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.
Treatment duration Normal range Pooled PBO 0.1 mg 0.3 mg 1.0 mg
Total Testosterone
0
200
400
600
800
1000
1200
-5 0 5 10 15 20 25 30 35 40 45 50 55 60
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Tota
l T (n
g/dL
)
SHBG
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-5 0 5 10 15 20 25 30 35 40 45 50 55 60
Day
SHB
G (n
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LH
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1.02.0
3.0
4.05.0
6.0
7.0
8.09.0
10.0
-5 0 5 10 15 20 25 30 35 40 45 50 55 60
Day
LH (U
/L)
Free Testosterone
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-5 0 5 10 15 20 25 30 35 40 45 50 55 60Day
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L)
Free Testosterone
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-5 0 5 10 15 20 25 30 35 40 45 50 55 60Day
Free
T (p
g/m
L)
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