Evaluation of Safety and Physiologic Changes Following 13 Weeks of Exposure to the Selective
Androgen Receptor Modulator VK5211 (LGD-4033) in Primates
Michael R. Bleavins1, Jeffrey Tepper2, Steven Schoenfeld3, and Brian W. Lian3
1 White Crow Innovation, Dexter, MI, 2 Tepper Nonclinical, San Carlos, CA, 3 Viking Therapeutics, San Diego, CA
INTRODUCTION
VK5211 is a highly selective androgen receptor modulator (SARM) that has
demonstrated potent anabolic effects on bone and muscle with reduced activity
and cross-reactivity to other steroid hormone receptors.
VK5211 is being developed to treat muscle loss associated with injuries such as hip
fracture, as well as age-related muscle loss, cancer cachexia, and chronic illness.
A 13-week daily oral dosing study was conducted in cynomolgus monkeys.
Monkeys received daily oral doses of VK5211 at 0, 0.6, 3, 15, or 75mg/kg/day.
Increases in body weight were progressive through the duration of the
treatment window. Treated animals experienced body weight gains of 20% to
47% from baseline (Figure 1A and 1B).
Significant weight gains were observed at week 13 (Figure 2).
70% of the increased weight was retained after a 4-week recovery period.
In a rat model of male hypogonadism, increased anabolic activity in muscles was
observed with high selectivity for muscle versus prostate tissue. Restoration of
muscle was observed at doses of ~1mg/kg/day (Figure 3).
Anti-resorptive and anabolic activity in bones was demonstrated in an
ovariectomized rat model of post-menopausal osteoporosis (Figure 4).
Safety data from the 13-week study in cynomolgus monkeys included:
Signs of toxicity that were primarily manifestations of exaggerated
pharmacology (Table 1).
Histopathology observed at ~30x the free concentrations relative to observed
concentrations in clinical studies (Table 1).
In humans, VK5211 has demonstrated encouraging safety and improvements in
lean body mass, without changes in fat mass, when dosed for 21 days (Figure 5).
A Phase 2 study with 12 weeks of treatment is on-going to evaluate VK5211 in
elderly patients recovering from hip fracture surgery.
SUMMARY
Figure 5. Increased lean body mass (measured by DXA) and leg press
force (measured using a one-repetition maximum technique) observed
after 3 weeks dosing in healthy male subjects (Clinical Study VK5211-02).
PBO = placebo. * p < 0.05
Increased Lean Mass and Leg Press Force
in Healthy Males Dosed for 3 Weeks with VK5211
VK5211 resulted in:
Significant body weight gain in male and female monkeys during 13
weeks of dosing
Progressive weight gain throughout the dosing window
Retention of body weight gain after 4-weeks without treatment
Restoration of atrophied muscle mass in castrated rats
Improved bone density and femur strength in an ovariectomized rat model
of osteoporosis
Safety signals in monkey, primarily known exaggerated pharmacology,
which largely resolved after 4-weeks without treatment
Increased lean body mass and leg press force, without an increase in fat
mass, in human volunteers after 3-weeks of dosing of up to 1 mg VK5211
Conclusion: These data support the potential use of VK5211 in humans
with hip fracture, as well as age-related muscle loss and other wasting
diseases such as cancer cachexia, and chronic illness.
Figure 3. Two-month-old male Sprague Dawley rats were castrated and left
untreated for 14 days. After 14 days, animals were treated with various doses of
VK5211 (0.03 to 100 mg/kg/day PO) for 14 days. Restoration of levitor ani
muscle was observed at low doses.
Atrophied Levator Ani Muscle Restored in Castrated Rats
Figure 4. Female Sprague-Dawley rats were ovariectomized (OVX) and allowed to
develop osteopenia for 8 weeks. Treatment began 8 weeks post-OVX and lasted for 12
weeks. Bone density was assessed by DXA. Mechanical testing and histomorphometry
were performed on bones harvested at necropsy. * p< 0.05
Femur Bone Mineral Content (BMC) and Femur Strength
Increased in Ovariectomized Rats
A. Body Weight Increased with Daily VK5211 in Male Monkeys
Male Reproductive
Effect
Thymus
Effect
Atrophy
-
Weight
D
Organ Weights
-
Atrophy
I
Maturation
Mismatch
Testosterone
d
Cardio
LH
-
Cardiomyopathy
-
FSH
-
Polycythemia
-
Mammary Secretion/Dialation
I
Monocytos
I
Mammary Hypertrophy
I
Prothrombin
I
Female Reproductive
Liver
Estrodiol
D
Hypertrophy
-
FSH
-
Clinical Chemistry
I
Uterus Weight
D
Weight
-
Uterus hypertrophy
Mismatch Cholesterol
D
Ovary Weight
d
Mammary Hypertrophy
-
Adrenal Gland
Vaginal Cornification
I
Weight
Cortisol
I
Pancreas
Aldosterone
-
Hypertrophy
I
Vacuolation
D
Insulin
-
Zona reticularis loss
-
Glucagon
I
Renal
Body Weight
Intratubular protein
-
Males
i
Basophilic staining
-
Females
I
Summary of Safety Findings at all Doses after 13 Weeks of Treatment in Monkeys
Table 1. Safety parameters in cynomolgus monkeys after 13 weeks of oral dosing with
VK5211. Sexes combined unless noted.
Key: - = no effect, I=increase, i=slight increase, D=decrease, d= slight decrease
0
10
20
30
40
50
Week 0
Week 4
Week 8
Week 13
Body Weight Increase (%)Week of VK5211 Administration
0 mg/kg
0.6 mg/kg
3 mg/kg
15 mg/kg
75 mg/kg
**
0
10
20
30
40
50
Week 0
Week 4
Week 8
Week 13
Body Weight Increase (%)Week of VK5211 Administration
0 mg/kg
0.6 mg/kg
3 mg/kg
15 mg/kg
75 mg/kg
*
*
*
*
B. Body Weight Increased with Daily VK5211 in Female Monkeys
Figure 1A&B. Cynomolgus monkeys were orally dosed with VK5211 for 13
weeks in an attempt to elicit toxicity. Body weights were measured weekly
(N=4-6/sex/group). Toxicity was observed in female monkeys at 75 mg/kg and
dosing was discontinued on Day 48. * p< 0.05
*
Figure 2. Increases in mean body weight following 13 weeks of dosing with
VK5211. Initial mean body weights ranged from 3.4 kg to 3.7 kg. Dosing in
females at 75 mg/kg was discontinued at Day 48 due to signs of toxicity. * p<
0.05
Body Weight Gain was Significant after 13 Weeks Treatment
with VK5211 in Cynomolgus Monkeys
0
0.5
1
1.5
Sexes Combined
Increase in Body Weight at Week 13 (kg)0 mg/kg
0.6 mg/kg
3 mg/kg
15 mg/kg
75 mg/kg
Androgen Receptor Modulator VK5211 (LGD-4033) in Primates
Michael R. Bleavins1, Jeffrey Tepper2, Steven Schoenfeld3, and Brian W. Lian3
1 White Crow Innovation, Dexter, MI, 2 Tepper Nonclinical, San Carlos, CA, 3 Viking Therapeutics, San Diego, CA
INTRODUCTION
VK5211 is a highly selective androgen receptor modulator (SARM) that has
demonstrated potent anabolic effects on bone and muscle with reduced activity
and cross-reactivity to other steroid hormone receptors.
VK5211 is being developed to treat muscle loss associated with injuries such as hip
fracture, as well as age-related muscle loss, cancer cachexia, and chronic illness.
A 13-week daily oral dosing study was conducted in cynomolgus monkeys.
Monkeys received daily oral doses of VK5211 at 0, 0.6, 3, 15, or 75mg/kg/day.
Increases in body weight were progressive through the duration of the
treatment window. Treated animals experienced body weight gains of 20% to
47% from baseline (Figure 1A and 1B).
Significant weight gains were observed at week 13 (Figure 2).
70% of the increased weight was retained after a 4-week recovery period.
In a rat model of male hypogonadism, increased anabolic activity in muscles was
observed with high selectivity for muscle versus prostate tissue. Restoration of
muscle was observed at doses of ~1mg/kg/day (Figure 3).
Anti-resorptive and anabolic activity in bones was demonstrated in an
ovariectomized rat model of post-menopausal osteoporosis (Figure 4).
Safety data from the 13-week study in cynomolgus monkeys included:
Signs of toxicity that were primarily manifestations of exaggerated
pharmacology (Table 1).
Histopathology observed at ~30x the free concentrations relative to observed
concentrations in clinical studies (Table 1).
In humans, VK5211 has demonstrated encouraging safety and improvements in
lean body mass, without changes in fat mass, when dosed for 21 days (Figure 5).
A Phase 2 study with 12 weeks of treatment is on-going to evaluate VK5211 in
elderly patients recovering from hip fracture surgery.
SUMMARY
Figure 5. Increased lean body mass (measured by DXA) and leg press
force (measured using a one-repetition maximum technique) observed
after 3 weeks dosing in healthy male subjects (Clinical Study VK5211-02).
PBO = placebo. * p < 0.05
Increased Lean Mass and Leg Press Force
in Healthy Males Dosed for 3 Weeks with VK5211
VK5211 resulted in:
Significant body weight gain in male and female monkeys during 13
weeks of dosing
Progressive weight gain throughout the dosing window
Retention of body weight gain after 4-weeks without treatment
Restoration of atrophied muscle mass in castrated rats
Improved bone density and femur strength in an ovariectomized rat model
of osteoporosis
Safety signals in monkey, primarily known exaggerated pharmacology,
which largely resolved after 4-weeks without treatment
Increased lean body mass and leg press force, without an increase in fat
mass, in human volunteers after 3-weeks of dosing of up to 1 mg VK5211
Conclusion: These data support the potential use of VK5211 in humans
with hip fracture, as well as age-related muscle loss and other wasting
diseases such as cancer cachexia, and chronic illness.
Figure 3. Two-month-old male Sprague Dawley rats were castrated and left
untreated for 14 days. After 14 days, animals were treated with various doses of
VK5211 (0.03 to 100 mg/kg/day PO) for 14 days. Restoration of levitor ani
muscle was observed at low doses.
Atrophied Levator Ani Muscle Restored in Castrated Rats
Figure 4. Female Sprague-Dawley rats were ovariectomized (OVX) and allowed to
develop osteopenia for 8 weeks. Treatment began 8 weeks post-OVX and lasted for 12
weeks. Bone density was assessed by DXA. Mechanical testing and histomorphometry
were performed on bones harvested at necropsy. * p< 0.05
Femur Bone Mineral Content (BMC) and Femur Strength
Increased in Ovariectomized Rats
A. Body Weight Increased with Daily VK5211 in Male Monkeys
Male Reproductive
Effect
Thymus
Effect
Atrophy
-
Weight
D
Organ Weights
-
Atrophy
I
Maturation
Mismatch
Testosterone
d
Cardio
LH
-
Cardiomyopathy
-
FSH
-
Polycythemia
-
Mammary Secretion/Dialation
I
Monocytos
I
Mammary Hypertrophy
I
Prothrombin
I
Female Reproductive
Liver
Estrodiol
D
Hypertrophy
-
FSH
-
Clinical Chemistry
I
Uterus Weight
D
Weight
-
Uterus hypertrophy
Mismatch Cholesterol
D
Ovary Weight
d
Mammary Hypertrophy
-
Adrenal Gland
Vaginal Cornification
I
Weight
Cortisol
I
Pancreas
Aldosterone
-
Hypertrophy
I
Vacuolation
D
Insulin
-
Zona reticularis loss
-
Glucagon
I
Renal
Body Weight
Intratubular protein
-
Males
i
Basophilic staining
-
Females
I
Summary of Safety Findings at all Doses after 13 Weeks of Treatment in Monkeys
Table 1. Safety parameters in cynomolgus monkeys after 13 weeks of oral dosing with
VK5211. Sexes combined unless noted.
Key: - = no effect, I=increase, i=slight increase, D=decrease, d= slight decrease
0
10
20
30
40
50
Week 0
Week 4
Week 8
Week 13
Body Weight Increase (%)Week of VK5211 Administration
0 mg/kg
0.6 mg/kg
3 mg/kg
15 mg/kg
75 mg/kg
**
0
10
20
30
40
50
Week 0
Week 4
Week 8
Week 13
Body Weight Increase (%)Week of VK5211 Administration
0 mg/kg
0.6 mg/kg
3 mg/kg
15 mg/kg
75 mg/kg
*
*
*
*
B. Body Weight Increased with Daily VK5211 in Female Monkeys
Figure 1A&B. Cynomolgus monkeys were orally dosed with VK5211 for 13
weeks in an attempt to elicit toxicity. Body weights were measured weekly
(N=4-6/sex/group). Toxicity was observed in female monkeys at 75 mg/kg and
dosing was discontinued on Day 48. * p< 0.05
*
Figure 2. Increases in mean body weight following 13 weeks of dosing with
VK5211. Initial mean body weights ranged from 3.4 kg to 3.7 kg. Dosing in
females at 75 mg/kg was discontinued at Day 48 due to signs of toxicity. * p<
0.05
Body Weight Gain was Significant after 13 Weeks Treatment
with VK5211 in Cynomolgus Monkeys
0
0.5
1
1.5
Sexes Combined
Increase in Body Weight at Week 13 (kg)0 mg/kg
0.6 mg/kg
3 mg/kg
15 mg/kg
75 mg/kg