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Overview of the Endocrine
Society Guidelines for the
Treatment of Hypogonadism
Edward D. Kim, M.D.
Professor of Surgery/Urology
Objectives
w Primary
focus on treatment options
w Overview of criteria for treatment of
hypogonadal men
w Detrimental effect of testosterone
therapies on sperm production
Testosterone: Adult Physiological Effects
How Is Hypogonadism Defined by
Endocrine Society?
A clinical syndrome that results from
failure of the testis to produce
physiological levels of testosterone
(androgen deficiency) and the normal
number of spermatozoa caused by the
disruption of one or more levels of the
hypothalamic-pituitary testicular (HPT)
axis.
Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab . 2010;96(6):2536-2559.
DIAGNOSIS
w
Clinical hypogonadism is defined as
symptoms + low testosterone (<300 ng/dL)
w
Main symptoms and signs: low sexual
desire, ED, ejaculatory dysfunction, low
energy, low mood, decreased mental
concentration, high fat mass/low muscle
mass, decreased muscle strength,
osteoporosis, anemia, and others
Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab . 2010;96(6):2536-2559.
TESTOSTERONE SALES ARE
INCREASING
“We recommend testosterone therapy for men
with symptomatic androgen deficiency to
induce and maintain secondary sex
characteristics and to improve their sexual
function, sense of well-being muscle mass and
strength, and bone mineral density.”
http://www.endo-society.org/guidelines
Endocrine Society Recommendations-1
“We suggest initiating testosterone therapy
with any of the following regimens, chosen
on the basis of the patient’s preference,
consideration of pharmacokinetics,
treatment burden, and cost.”
• 75–100 mg of testosterone enanthate or
cypionate administered IM weekly, or 150–200
mg administered every 2 weeks.
• One or two 5-mg nongenital, testosterone
patches applied nightly over the skin of the
back, thigh, or upper arm, away from pressure
areas.
Endocrine Society Recommendations-2
• 30 mg of a bioadhesive buccal testosterone
table applied to buccal mucosa every 12
hours.
• Testosterone pellets implanted SQ at
intervals of 3 to 6 months; the dose and
regimen vary with the formulation used.
• Oral testosterone undecanoate, injectable
testosterone undecanoate, testosterone-inadhesive matrix patch, and testosterone
pellets where available.
Intramuscular Injections
Pros
Cons
History (available for
50 years)
Pain
Self administration
Frequency of injections
(every 1 – 2 weeks)
Inexpensive
Symptomatic peaks and
troughs resulting in
variations in breast
tenderness, libido,
emotional stability,
energy
Flexibility of dosing
Erythrocytosis
Dandona P, Rosenberg M. Int J Clin Pract. 2010;64(6):682-696.
Transdermal Patches
Pros
Cons
Nonscrotal patches
Skin irritation
Nighttime
application results
in good
approximation of
normal circadian
plasma
testosterone levels
Need for daily,
continuous
application
Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6):682-696.
Transdermal Gels
Pros
Cons
Application sites
(upper arms,
shoulder, axilla)
Transfer to others
(risk is minimized
with high-dose, lowvolume preparations)
Low skin irritation
Cost
Invisibility of
application
Daily application
Skin residue
Various
concentrations
Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6):682-696.
PHARMACOKINETIC PROFILES
Injectable administration results in considerable fluctuation in testosterone
levels.
Buccal Tablets: Striant™
Pros
Cons
Application site
Application site
Relative invisibility
Inadvertent loss of
tablet
Bypass first-pass
hepatic metabolism
Gum and buccal
irritation, alteration in
taste
Slow release
Twice daily dosing
No dose titration
Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6), 682-696.
Subcutaneous Pellets
Pros
Cons
History (started in
1940s)
Painful application
Relative invisibility
Surgical procedure
unlikely to be used
by the PCP
Long acting
Long acting
Slow release
Inconvenient removal
Procedure can result
in infection, fibrosis
or pellet extrusion
Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6), 682-696.
Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab. 2010, 96(6): 2536-2559.
Oral Testosterone
w
Not approved in U.S.
w
Methytestosterone
¾ Methitest, Android, and
Testred
Poor absorption
w High risk of hepatic
toxicity, hepatoma and
cholestatic jaundice
w Risk of anaphylaxis
w
Edelstein D, et al. Expert Opin Emerg Drugs. 2006;11:685-707.
TESTOSTERONE PRESCRIBING
INFORMATION
“Potential for adverse
effects on
spermatogenesis”
“Exogenous
administration of
androgens may lead
to azoospermia”
These warnings are not
based on clinical trials
Topical gel prescribing information
Why Testosterone Therapy Is
Detrimental To Sperm Production
• Exogenous T
Leydig cells produce
testosterone
decreases
intratesticular
testosterone (ITT)
concentrations
• Profound decreases in
spermatogenesis,
including
azoospermia, may
result
Higher Centers
Hypothalamus
Germinal
Epithelium
Inhibin
Anterior
Pituitary
+
Sertoli Cells
GnRH
FSH
Testosterone
-
+ LH
Leydig Cell
WHO CONTRACEPTIVE EFFICACY
• 271 men
• 12 months efficacy phase
• IM-TE 200 mg/wk
Time to azoospermia:
120 days
Estimated time to recovery:
To >20 million sperm/ml 3.7 months
To baseline
6.7 months
Lancet. 1990;336(8721):955-9.
DISCONTINUATION OF IMTESTOSTERONE CAN RESTORE
SPERM PRODUCTION
• 93% developed
azoospermia
Median time
of 108 days
• Method failure
rate of 6.1%
• Median time to
recovery was 3.5
months
>99% of men had spermatogenesis return to normal
fertile range by 15 months after T discontinuation

Exogenous T supplementation decreases sperm
production.
Studies of hormonal contraception indicate that
most men have a return of normal sperm
production within 1 year after discontinuation.
SERMs are a safe and effective therapy for men
who desire to maintain future fertility.
Fertil Steril 2013; 99:718-24. .
Androxal Improves T without
Affecting Sperm Count
p<0.00001
No statistical difference
Androxal Exhibits No Negative Effects on
Important Sperm Parameters
No statistical difference
ZA-203: Effect of Treatment on Median
Sperm Concentration versus Testim
100
p=0.012
90
Sperm count in millions/ml
80
p=0.0021
70
p=0.0049
60
50
Baseline
EOS
40
30
20
10
0
12.5 mg
25 mg
PL
Testim
Symptoms and Signs Suggestive
of Hypogonadism-Summary
w
No symptoms are unique to hypogonadism
w
Screening with testosterone level is
appropriate when presented with symptoms
w
Diagnosis of hypogonadism is made when
one or more symptoms are combined with
low testosterone concentration
Dandona P, Rosenberg M.. Int J Clin Pract. 2010;64(6):682-696.
Treatment Options-Summary
w Current
choices: Injections, topicals,
buccal and pellets
w No effective oral therapies in U.S.
w Testosterone replacement has
negative effects on sperm production
w Androxal does not have adverse
effects on sperm
PROGRESSION OF
TESTOSTERONE THERAPIES
What does Enclomiphene
mean to me?
Andrew R. McCullough, MD
Professor of Surgery/Division of Urology
Director of Men’s Health
Albany Medical College, Albany, New York
Overweight and Obesity among U.S.
Adults
Obesity
Prevalence (%)
Overweight
2012- Overweight/Obese= 149.3 Million
Age 2-19- overweight =23.6
obese= 12.6
1960–
1962
1971–
1974
1976–1980 1988–1994 1999–2002 2003–2004
NHANES Data Collection Period
Flegal KM et al. JAMA 2002;288:1723-1727. | Hedley AA et al. JAMA 2004;291:2847-2850. |
Ogden CL et al. JAMA 2006;295:1549-1555.
Are we Over Diagnosing
low T?
}Are we Over Diagnosing Obesity?
}Are we Over Diagnosing Diabetes?
}Are we Over Diagnosing Aging?
Hypogonadism: Treatment
} Topical: patch
or gel. Daily
} Injected: I.M.
testosterone q
1-2 weeks
} Implant:
testosterone
pellets q 4-6
months
Current
Treatments
}Gels and Patches
} Compliance:
} Daily application required!!!
} 1 year refill rate is less than 20%
} Expense: Variable Co-pays and shifting playing field for
re-imbursement
} Hassle of controlled substance script (in NY):
Monthly hard copy prescription needed
} Transference: Partners and young children
} Skin Reaction:
} Suppresses endogenous production:
} Causes testicular atrophy
} Infertility
Current Treatments
}Injections
} Bimonthly IM Injections
} Erratic Levels
} Increased Hematocrit
} Hassle of controlled substance script in NY
} Suppresses endogenous production
} Results in Infertility
} Generic (less expensive)
} No transference
Current Treatments
}Pellets
} Surgical Procedure
} Risk of Infection, Extrusion, Pain
} Prior Auth Hassle
} Suppresses endogenous production
} Results in Infertility
} Burden of expense is on Physician
} Better “Compliance”
} Sustained levels
Change in Paradigm is Needed
} Do we treat all diabetics with Insulin?
} The PCP WILL NOT prescribe off label
treatments
} WE NEED an FDA approved SERM!!!!!!!!!!!!!
T (pg/ml)
} Currently we can use clomiphene off label
with great efficacy in normalizing T
21.2
Free
} Why are we ignoring the testes?
25
20
15
10
5
Part Non0RespResp
Resp
18
9.3
9.2
17.6
9.8
Base
4moRx
Summary
} We are not over diagnosing low T!
} T will not correct Obesity, Type 2 Diabetes or
Aging.
} Stimulating endogenous production makes
sense
}The time for a paradigm shift in the treatment
of low T is now.
SHARED CARE: THE
INTERFACE BETWEEN THE
PATIENT, PRIMARY CARE
PHYSICIAN AND SPECIALIST
DR JOHN DEAN
PRIMARY CARE
• PRIMARY HEALTH CARE PROVIDES THE FIRST POINT OF CONTACT IN THE
HEALTHCARE SYSTEM; THE EXEMPLAR PRIMARY CARE PROVIDER IS THE
FAMILY PHYSICIAN
• THE AIM OF PRIMARY CARE IS TO PROVIDE AN EASILY ACCESSIBLE ROUTE
TO CARE, WHATEVER THE PATIENT’S PROBLEM.
• PRIMARY HEALTH CARE IS BASED ON CARING FOR PEOPLE RATHER THAN
SPECIFIC DISEASES
• FAMILY PHYSICIANS ARE GENERALISTS, DEALING WITH A BROAD RANGE
OF PHYSICAL, PSYCHOLOGICAL AND SOCIAL PROBLEMS, NOT A SINGLE
DISEASE AREA
MANAGING THE INTERFACE
• THE FAMILY PHYSICIAN ACTS AS THE PATIENT’S ADVOCATE WITHIN THE HEALTHCARE
SYSTEM AND WITH SPECIALISTS
• FAMILY PHYSICIANS MANAGE THE INTERFACE BETWEEN PRIMARY AND SPECIALIST CARE
• THEY CO-ORDINATE THE CARE OF THE MANY PEOPLE WHO HAVE MULTIPLE HEALTH
PROBLEMS
• THEY OFTEN CARE FOR PEOPLE OVER EXTENDED PERIODS OF TIME, THE RELATIONSHIP
BETWEEN PATIENT AND DOCTOR IS PARTICULARLY IMPORTANT
• THEY MANAGE MANY COMPLEX, MULTI-SYSTEM, LONG-TERM HEALTH PROBLEMS, AND
ALSO PREVENT FUTURE PROBLEMS THROUGH ADVICE, IMMUNISATION AND SCREENING
PROGRAMMES
AN ALWAYS-MOVING INTERFACE
• OVER RECENT DECADES, MANY HEALTH PROBLEMS PREVIOUSLY CONSIDERED AS
“SPECIALIST” PROBLEMS ARE SAFELY AND SUCCESSFULLY MANAGED IN PRIMARY
CARE, WITH BENEFIT TO PATIENTS, THROUGH ACCESSIBILITY, AND TO THE
HEALTHCARE SYSTEM, THROUGH COST SAVING
• SOME EXAMPLES INCLUDE:
• PEPTIC ULCER DISEASE
• ASTHMA
• DIABETES
• ERECTILE DYSFUNCTION
• HYPOGONADISM IS CURRENTLY CROSSING THE GENERALIST/SPECIALIST
INTERFACE
WHAT ARE THE CHARACTERISTICS OF A
HEALTH PROBLEM SUITABLE FOR
PRIMARY CARE MANAGEMENT?
• A WELL-DEFINED AND RELATIVELY PREDICTABLE NATURAL HISTORY
• DOES NOT USUALLY REQUIRE EXPENSIVE, DIFFICULT-TO-ACCESS, HIGH-RISK OR
HIGHLY-INVASIVE DIAGNOSTIC TESTING
• HAS A CLEARLY-DEFINED MANAGEMENT PROTOCOL
• DOES NOT REQUIRE HIGHLY-SPECIALISED SKILLS (E.G. SURGICAL SKILLS) FOR
MANAGEMENT
• HAS READILY-AVAILABLE, APPROVED, LOW-RISK, AFFORDABLE TREATMENT
OPTIONS
CHRONIC CONDITIONS ARE PARTICULARLY WELL-SUITED TO PRIMARY CARE
MANAGEMENT
HYPOGONADISM: A MULTISYSTEM DISORDER, AFFECTING
MIND AND BODY
Target Organ
• Bone
• Musculature
• Adipose tissue
• Blood
•Vascular system
• Brain
• Sexual organs
Patient/Social Consequences
• ↓ Quality of life
• Disability
• ↓ Productivity
• ↑ Dependency on
carers
• Impact on relationships
45
Clinical Features
• ↓ Bone mineral density
• ↓ Muscle mass/strength
• ↑ Abdominal fat
• ↓ Haemoglobin
• Dyslipidaemia
• Mood changes, impaired cognition
• ↓ Libido, erectile dysfunction, subfertility
Clinical Consequences
• Osteopenia, osteoporosis, ↑ fracture risk
• Muscle atrophy, ↑ accidents, ↓ physical activity
• Metabolic abnormalities, endothelial dysfunction,
increased cardiovascular risk
• ↓ Sexual activity, erectile and ejaculatory dysfunction
• ↓ Orgasm quality
• ↓ Spermatogenesis, semen volume,
• Depression, ↓ visual-spatial ability, ↓ memory
WELL-ESTABLISHED NORMAL VALUES
• TOTAL TESTOSTERONE:
• <230 NG/DL (< 8 NAMOL/L) = OVERT
HYPOGONADISM
• 230-346 NG/DL (8-12 NMOL/L) = EQUIVOCAL,
«GREY» ZONE
• > 346 NG/DL (> 12 NMOL/L) = EUGONADISM
TOTAL TESTOSTERONE
8 nmol/L
230 ng/dL
12 nmol/L
350 ng/dL
Vermeulen, JCEM, 1999
AGE-RELATED CHANGES IN
TESTOSTERONE IN MEN
FT (ng/dL) x 100
1250
1000
750
500
SHBG (nmol/dL)
T (ng/dL)
250
0
47
25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 75 - 84 85 - 100
Age (years)
Comhaire FH Eur Urol 2000, 38: 655-662.
HIDDEN HYPOGONADISM IN PRIMARY
CARE
• TYPE 2 DIABETES
• HISTORY OF PITUITARY PATHOLOGY/SELLAR IRRADIATION OR SURGERY
• OBESITY/METABOLIC SYNDROME
• COPD
• CHRONIC RENAL DISEASE
• HIV DISEASE
• DEPRESSION
• UNEXPLAINED FATIGUE
• THE HEART-SINK PATIENT (“OH, NO! NOT HIM AGAIN”)
48
HYPOGONADISM TREATMENT AIMS
• “THERAPY SHOULD AIM TO RAISE SERUM
TESTOSTERONE LEVELS INTO THE MID-NORMAL
RANGE
• “WE RECOMMEND TESTOSTERONE THERAPY FOR
SYMPTOMATIC MEN AIMED AT…”
• INDUCING AND MAINTAINING THEIR SECONDARY
SEX CHARACTERISTICS
• IMPROVING SEXUAL FUNCTION
• IMPROVING THEIR SENSE OF WELLBEING
• IMPROVING THEIR BONE MINERAL DENSITY
Bhasin S (2006). J Clin Endocrinology & Metabolism, Vol. 91, issue 6, pages 1995‐2010
IMPACT ON THE MAN
“How did I end up like this?”
•Insidious onset, typically
from middle age
•Increased risk of lifechanging health problems
•Impairment of work and
home life
•Financial consequences
“What can I do about it”
•Concern over self-efficacy resistant to modification by
lifestyle change
•Concern over self-image
•“Life in years”, not just
“years on life”
•Confusion over convenience
and safety of treatment
Androxal: Effects on Fertility
A Clinical Perspective
Larry I. Lipshultz, M.D.
Professor of Urology
Chief, Division of Male Reproductive Medicine
and Surgery
Baylor College of Medicine
Houston, Texas
Case Study
• A 42 year old man with a 30 year old wife is
referred by his PCP after symptomatic
failure on anti-depressants
• He is complaining of mild depression,
increased fatigue, impaired libido, and
progressive erectile dysfunction
• His laboratory evaluation reveals:
• Testosterone: 175 ng/dl (normal 250-1000)
• FSH: 4 mIU/ml (normal 4-10)
• LH: 6 mIU/ml (normal 4-12)
2*
•
Can
we
safely
and
effectively
treat
• This man demonstrates adult-onset
this man’s
low testosterone?
idiopathic
secondary
hypogonadism
How told
willof
treatment
impact
his he
• •When
his hormone
deficiency,
ability to
establishtherapy!
a pregnancy?
requests
testosterone
2*
Testosterone Replacement Therapy
Treatment Options
Intramuscular
Injections
Oral Tablets
Transdermal
Patches
Transdermal
Gels
Pellet Implants
5*
Transdermal Gels are the Most
Commonly Prescribed Form of
TRT
Gels
Injectables
Patches
17%
Other
10%
70%
IMS NPA; 2006.
3%
1*
T Gel Therapy 2013
WARNING:
SECONDARY EXPOSURE TO TESTOSTERONE
(TRANSFERRENCE)
• Virilization has been reported in children who were
secondarily exposed to testosterone gel.
• Children should avoid contact with unwashed or
unclothed application sites in men using testosterone gel.
• Healthcare providers should advise patients to strictly
adhere to recommended instructions for use.
Fortesta, Testim, Androgel, Axiron Package Insert, 2011
1*
T Testosterone ng/dL
Testosterone Levels after Replacement
Therapy with Patch, Gel or Injection
Patch or Gel
Normal range
Injection
1400
1200
1000
800
600
400
200
0
0
3
5
7
12
Day
17
21
30
34
Adapted from Bhasin and Bremner. J Clin Endocrinol Metab. 1997;82:3-8
Testosterone gel (AndroGel ®1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, 2002
2*
Higher Centers
Hypothalamus
Germinal
Epithelium
Inhibin
-
Anterior
Pituitary
+
Sertoli Cells
GnRH
FSH
Testosterone
-
+ LH
Leydig Cell
4*
Higher Centers
Hypothalamus
Germinal
Epithelium
Inhibin
-
Anterior
Pituitary
+
Sertoli Cells
GnRH
FSH
Testosterone
-
+ LH
Leydig Cell
4*
The Ideal Testosterone Therapy
• Effective in correcting signs and symptoms
of androgen deficiency
• Convenient and acceptable route of
administration
• A pill would be best
• Predictable pharmacokinetics
• Safe
• Would not interfere with sperm production
3*
SERMs
• Selective Estrogen Receptor Modulators
(SERMs) are a class of compounds that act
on the estrogen receptor
• A characteristic that distinguishes SERMS
from pure receptor agonists and antagonists
is that their action is different in various
tissues
• In the brain they act as antagonists
2*
Higher Centers
Hypothalamus
SERMs:
Estrogen
GnRH
Clomiphene
Germinal
Epithelium
Inhibin
-
Anterior
Pituitary
+
Sertoli Cells
FSH
Testosterone
-
+ LH
Leydig Cell
2*
Androxal (enclomid)
Background
• Clomiphene Citrate (ClomidTM) is considered a
selective estrogen receptor modulator (SERM)
• First used clinically in early 60’s to enhance ovulation
• Used off label for secondary hypogonadism and male
infertility
• Mixture of 2 geometric isomers
• Trans-isomer (Enclomiphene) → Androxal
• Zu-isomer (Zuclomiphene): longer acting
• Both isomers modulate estrogen receptor → increased
production of LH and FSH → increased testosterone
2*
Effects of Clomid and its Isomers on T
Pre-clinical Studies in Baboons1
Testosterone (ng/dl)
1400
Last Day of Dosing
1200
Enclomid
(Androxal)
Clomid
1000
800
600
Zuclomid
400
200
0
0
6
Days
1. Int. Congress Endocr. Abstract # 1212, Lisbon, 2004
12
18
Clomid Pharmacokinetics
ng/dl
24 hour Comparison of Isomers
8
7
6
5
4
3
2
1
0
Zu-clomid
En-clomid
0
10
hours
20
Zu isomer still detected after 300 hours
~2.75 ng/ml after single dose
Mikkelson et al. Fertility and Sterility Vol. 46, No. 3, September 1986
30
ZA-201 Protocol Summary
Proof of Concept Study
• Androxal vs Topical T in previous topical T users
• A randomized, open-label, fixed dose, active-control,
phase IIB study to evaluate fertility in men previously
treated with topical testosterone (Testim®) for at least 6
months
• All men had secondary hypogonadism
• After stopping treatment with topical gels, Androxal®
was compared to Testim® at 3 and 6 months
• Visit 2 was start of comparison
• Last visit was 1 month after treatment discontinued
5*
Total Testosterone
1000
900
800
700
600
500
400
300
200
100
0
Testim
Androxal
300
V1
V2
V4
V5
V6
Sperm (million/ml)
Testosterone (ng/dl)
Only Androxal Restores both T
and Sperm Counts
Sperm Concentration
250
200
Testim
150
Androxal
100
50
0
V2
V4
V5
V6
1*
Only Androxal Raises LH and FSH
8
Testim
6
Androxal
4
2
10
0
V1
V2
V4
V5
V6
FSH (mIU/ml)
LH (mIU/ml)
Luteinizing Hormone
10
Follicle Stimulating Hormone
8
Testim
6
Androxal
4
2
0
V1
V2
V4
V5
V6
1*
Androxal™ Clinical Trial
ZA-203
• Multicenter, double-blind, placebo-controlled, multi-dose
study of hypogonadal males on Androxal (N=120)
• Primary endpoint
• Changes in baseline T level in men on Androxal 12.5 mg and 25
mg on Day 90 compared to placebo and Testim
• Secondary endpoints
• Changes in FSH and LH levels in men on Androxal 12.5 mg and
25 mg on Day 90 compared to placebo and Testim
• Ophthalmic safety as assessed by visual acuity changes and slit
lamp examinations
• Reproductive safety as assessed by changes in semen quality at
month 3 comparing Androxal 12.5 and 25 mg to placebo and
Testim
2*
ZA-203 Patient Disposition
920 Screened
•
•
•
•
Double-blind
Randomized
Placebo-controlled
Open-label for TRT
124 Entered Study
50 (40%) patients
discontinued:
• 3 due to AEs
• 7 early termination
• 17 non-compliance
• 2 exclusion criteria
74 (60%) Completed
Study
• 10 withdrew
• 11 lost to follow up
TT (ng/dl)
ZA-203 Clinical Findings
500
450
400
350
300
250
200
150
100
50
0
Effect of Treatment on Median Serum TT
Comparison to Placebo
P < 0.00001
Before
P = 0.0002
After
12.5 mg
25 mg
PL
Testim
Treatment
2*
Effect of Treatment on Median LH
Comparison to Testim
12
10
Before
After
P < 0.00001
LH
8
6
P = 0.0004
4
2
0
12.5 mg
25 mg
PL
Testim
Treatment
2*
Effect of Treatment on Median FSH
14
12
P < 0.00001
Before
After
FSH
10
8
P = 0.0004
6
4
2
0
12.5 mg
25 mg
PL
Testim
Treatment
2*
Sperm (Millions/ml)
Effect of Treatment on Median Sperm Concentration
100
90
80
70
60
50
40
30
20
10
0
P = 0.012
12.5 mg
Baseline
P = 0.0021
P = 0.0049
25 mg
PL
EOS
Testim
Treatment
2*
Effects on Semen Parameters
Sperm Concentration (Millions/ml)
Average of all assessments after dosing has stopped (2 or more analyses)
120
Placebo
12.5 mg
25 mg
Testim
100
80
60
40
20
0
Mean
Median
ZA-203
Effects on Semen Parameters
Average of all assessments after dosing has stopped (2 or more analyses)
60
Motility
% Motile Sperm
50
Placebo
40
12.5 mg
30
25 mg
Testim
20
10
0
Mean
Median
ZA-301
Protocol Summary
• Three parallel arms
• Placebo, 12.5 mg, 25 mg Androxal
• Three and Six month dosing duration
• Assessing morning T, semen quality, LH
and FSH between groups at end of dosing
• Up to two additional semen assessments
after dosing is completed
• Randomized 152 men; Treated 149 men
1*
Androxal Improves T without
Affecting Sperm
450
Baseline
400
End of Study
350
300
250
200
150
100
50
60
Sperm Concentration X 106
Total T (ng/dL)
83 % in Normal Range
79% in Normal Range ITT
Placebo
Androxal
Androxal Up‐titration
50
40
NSD
30
20
10
0
0
Androxal
P <Placebo
0.00001
Baseline
End of Study
3*
Androxal Exhibits No Negative Effects
on Important Sperm Parameters
60
80
70
Androxal
50
% Motile
Placebo
Placebo
% Normal Morphology
70
Androxal
60
Sperm
50
Motility
40
30
20
40
20
10
0
0
End of Study
Sperm
Morphology
30
10
Baseline
NSD
NSD
Baseline
End of Study
1*
Overall Observations
• ZA-201 restores T and sperm counts in former
topical T users
• ZA-203 maintains T and sperm counts in naïve
men
• ZA-301 meets the FDA requirements for T and
sperm counts
• In all:
•
•
•
•
Marked increase in T
Marked increase in LH and FSH
Maintains normal sperm count, motility, morphology
Few adverse effects
3*
Thank You
Texas Medical Center, Houston
ZA-203
Conclusions: Androxal
• Represents a potential oral option for
treatment of hypogonadism
• Significantly raised total testosterone
equivalent to FDA approved topical gel
• Its ability to maintain semen quality and
raise T will be attractive to many patients
• Androxal will be a potential FDA approved
option to the widespread off-label use of
Clomid
3*
Androxal (enclomid)
Background
• The trans-isomer (Enclomiphene) has been purified and
patented as Androxal
• Only therapy in development that restores testicular
function
• Therapy addresses majority of men with low T
• Avoids the longer half-life and unwanted estrogenic
activity of Zuclomiphene
1*
ANDROXAL
Safety Review
6 June 2013
Potential Safety Issues
• Clomiphene
• Testosterone
– Cataracts
– Increased estrogen
(opposes testosterone
increase)
• Hypogonadism
- osteopenia
– Deep Vein Thrombosis
(DVTs)
– Prostate Specific Antigen
(PSA) Elevation
– T level above normal
– Decreased sperm count
(infertility)
– Gynecomastia
ANDROXAL
Safety Review
6 June 2013
Treatment Emergent Adverse Events
(TEAEs)
Discontinuation due to Adverse Events
(DCAEs)
Serious Adverse Events(SAEs)
Testosterone
Prostate Specific Antigen (PSA)
Other Safety Issues Related to Testosterone
Therapy
ANDROXAL
Safety Review
TOPICS
STUDIES
• Treatment Emergent Adverse Events
(TEAEs)
• Discontinuation due to Adverse
Events (DCAEs)
• Serious Adverse Events(SAEs)
• Testosterone
• Prostate Specific Antigen
003: Phase 3
301: Phase 3
300: long-term safety
303: bone density
300: long-term
safety
TREATMENT EMERGENT ADVERSE
EVENTS
Studies 301, 300, and 303
Data for
300 and
303 is
interim
and not
fully
monitored
and
validated
Study 301
Preferred
Term
N
Any Event
Upper
respiratory
infection
Headache
Study 300
12.5
25 mg PBO
mg
(%)
(%)
(%)
90
22
37
28
23
24
Study 303
12.5
12.5
25 mg
25 mg PBO
mg
mg
(%)
(%) (%)
(%)
(%)
259
240
94
69
104
38
44
19
39
30
6
5
0
6
5
4
6
5
3
9
5
5
3
1
1
2
Muscle twitch
2
0
0
0
0
0
0
0
Diarrhea
2
0
3
<1
1
2
1
0
Dyspepsia
2
0
0
1
1
0
0
0
Influenza
2
0
3
3
1
1
1
0
Lethargy
2
0
0
<1
0
0
0
0
Pollakiuria
Sinus
congestion
2
0
0
1
1
0
0
0
2
0
0
<1
1
0
0
0
Any
event
occurri
ng in 2
or more
subjects
in
pivotal
Study
301.
Data for 300 and 303 are interim and not fully monitored and validated
DC/AEs: Studies 301, 300, 303
(green font indicates single subject)
N=
Any DCAE
(n = )
PREFERRE
D TERM
Study 301
12.5 25 mg PBO
mg
90
22
37
0
1
1
Study 300
12.5 mg
25 mg
Study 303
12.5 mg
25 mg
PBO
12.5 mg
Study 003
25 mg
Androgel
PBO
259
240
94
69
104
47
50
48
49
5
1
1
2
0
1
1
5
1
Ocular
Nause Abdomina Hot flush
discomfo a
l pain
rt
Erectile
Blood
dysfuncti luteinising
on
hormone
increased
Breast
Upper
respirator enlargeme
nt
y tract
infection
Prostatic
specific
antigen
increased
Fatigue
Muscle
spasms
Erectile
dysfunctio
n
Abnormal Testicular
weight
atrophy
gain
Change in
sustained
attention
Diplopia
Vision
blurred
Hemoglob Hot flash
in
Increase
Hematocrit
Increased
Hypertensi Hemoglobin
on
Increased
Edema due
to cardiac
disease
Hypertensi
on
Renal function Cellulitis
tests elevated
Hemoglobin
Increase
Hemoglobin
Increase
Allergic
Dermatitis
Serious Adverse Events Reported in Studies 301, 300,
and 303
(green font indicates single subject)
Study 301
Study 300
12.5
25 mg PBO
mg
Study 303
12.5 mg
25 mg
12.5 mg
25 mg
PBO
104
n
90
22
37
259
240
94
69
Any SAE
(number of
subjects)
0
0
0
2
5
0
2
Preferred
Terms
Atrial
Skin injury
flutter
Nephrolithi
Knee arthroplasty Cholelithia
sis
asis
Diverticuliti
Hypotension
s (2)
deep vein
Kidney
thrombosis *
infection
* DVT - Tightness in leg after 5 hour flight, treated
with anticoagulants
Bradycardia
Data for 300 and 303 is interim and not fully monitored and validated
TESTOSTERONE
Study 300 at 6-month point
TESTOSTERONE LEVELS ON LAST
DAY OF DOSING (Study 300)
1000
800
600
400
200
0
86% in NORMAL RANGE (300-1040)
1200
Plasma Testosterone concentration
No
excursions
beyond
normal
range at
6-months
PSA: baseline, end of treatment, follow-up
Study 300 (only subjects with data after Vis 5)
7
6
PSA (ng/mL)
5
4
3
2
1
0
BASELINE
VIS 3, 4, 5, ET
VIS 6,7,ET
PSA
• PSA elevation is NOT an Adverse Drug
Reaction
• PSA elevation is an expected result of
testosterone increase
• PSA is not a cancer marker but a normal
enzyme
• Elevated PSA included in package insert for
Axiron
• Incidence and magnitude noted in Androxal
studies is not alarming and has been reviewed
by a panel of experts
OTHER SAFETY ISSUES RELATED
TO TESTOSTERONE THERAPY
• Cataracts
• Osteoporosis
• Deep Vein Thrombosis
Safety Profile - Cataracts
• 1)
– After 4 months, nuclear cataract in left eye disappeared,
cortical cataract in right eye progressed
– Described as age-related progression of senile cataract
• 2)
– Described as having cataract after 5 months of therapy, but
all entries are “0”, same as baseline.
Safety Profile - DVT
• Deep Vein Thrombosis
– One subject taking 12.5 mg Androxal developed a DVT after
a 5 hour flight
– Treated with anticoagulants to resolution
• No other adverse events suggest incidence of DVT
or other thrombotic events
Safety Profile – Bone Health
• Hypogonadism is associated with osteopenia
• Study ZA-303 captures bone mineral density
assessments via DEXA for subjects over one year of
Androxal exposure
• Some subjects have completed DEXA analyses after
6 months of treatment
– Early data suggests that Androxal subjects are no worse
than placebo subjects in study at 6 months
– Subjects bone loss associated with low testosterone may
be reversed
•
Relevant events reported in Phase 3
– 3 foot fractures, 12.5 mg Androxal 1/443 (0.2%), 25 mg Androxal 2/331
(0.6%)
– 1 spinal column injury, 12.5 mg Androxal
– 1 compression fracture, 12.5 mg Androxal
CONCLUSIONS
• Androxal is well tolerated
• Findings are consistent with known
pharmacology
• No new safety issues
Clinical and Regulatory Team
• J.F. Wernicke, Ph.D., M.D., Chief Medical Officer
– 30 years in clinical research
– Ph.D. Biochemistry and MD Neurologist
– Eli Lilly and Company, Clinical Research and Patient Safety
• Jaye Thompson, Ph.D., Senior VP Clinical and Regulatory
– Ph.D. Biostatistics
– 25 years in clinical trials
– Founder and President of full-service Contract Research
Organization
• Jennifer Wike, Director of Regulatory Affairs and Clinical
Quality Assurance
– 30 years in research and clinical development
– 15 years with a full-service Contract Research Organization
Clinical and Regulatory Team
• Jennifer Nydell, Androxal Clinical Program Director
– 17 years clinical research and development
– 13 years Boehringer Ingelheim
• Michele Rosner, Clinical Program Director
– MS Biological Chemistry and Management
– 16 years clinical development
– 13 years with Pfizer
Androxal Study Status
NDA Preparations
• Building team
– Contracting consultants and acquiring some additional staff
• Evaluating and purchasing software and hardware
for electronic NDA filing
• Conducting audits of key clinical sites and vendors
– No findings to date jeopardize data
– Completed audit of central laboratory with excellent results
– Preparing sites for NDA site audits
• Weekly team meetings
• Begun publishing files for the NDA
NDA Timeline
Potential benefits of
testosterone
supplementation
Dr John Dean
The Massachusetts Male Aging Study
• 3,518 men were followed for 17 years
• Total Testosterone levels were
measured and divided into five
categories at 200 ng/dL increments
• Multivariate Analysis depicting the
association with overall mortality,
CVD, and Prostate Cancer specific
mortalities was conducted
Araujo AB, et al: Total Testosterone as a Predictor of Mortality in Men.
The Endocrine Society 2005 Annual Meeting, San Diego, CA, June 4-7.
Low T associated with increased
probability of
all-cause mortality, cancer and CVD
death
Findings from follow up of 17 years:
• Age-adjusted Hazard Ratio for men with total
T< 200 ng/dL vs. total T 410-509 ng/dL
• 1.93 or two fold for all-cause mortality
• 3.30 or three fold for cancer death
• 1.93 or two fold for CVD death
* Hazard Ratio
Araujo AB, et al: Total Testosterone as a Predictor of Mortality in Men.
The Endocrine Society 2005 Annual Meeting, San Diego, CA, June 4-7.
% Hypogonadal
Type 2 diabetic men with
hypogonadism
Age Range
Dhindsa S, et al. J Clin Endocrinol Metab. 2004;89:5465
Hypogonadism and Metabolic
Syndrome – The HIM Study
• 2165 men >45 in 95 US practices attending
for routine appointments with primary care
physicians (87% acceptance rate)
• Bloods taken between 8am and Noon for TT (by RIA),
FT (Equilibrium Dialysis), BAT and SHBG
• Co-morbid conditions, weight, BMI, BP recorded
• Hypogonadism defined as <10.4nmol/l
• Prevalence 38.7% by TT, 40% by FT and 45%
by BAT
Mulligan et al IJCP 2006
HIM study: odds ratios for association of
hypogonadism with co-morbid conditions
Obesity
Prevalence Range
%
52.4
(47.9-56.9)
Odds
Ratio
2.38
Diabetes
50
(45.5-54.5)
2.09
Hypertension
42.4
(39.6-45.2)
1.84
Hyperlipidaemia
40.4
(37.6-43.3)
1.47
Osteoporosis
44.4
(25.5-64.7)
1.41
BPH
41.3
(36.4-46.2)
1.29
Mulligan et al IJCP 2006
The Metabolic Syndrome
People with metabolic syndrome have:
•waist circumference of 40 inches or more
(men) and 35 inches or more (women)
•dyslipidaemia
•high blood pressure (>140/90mmHg)
•insulin resistance and/or diabetes
•increased risk of developing blood clots
•tendency to develop tissue inflammation
6
Risk of Metabolic Syndrome rises with
low T
tT 23.4-51.7 nmol/L
tT 17.0-23.3 nmol/L
tT 1.1-16.9 nmol/L
tT < 11 nmol/L
5
4
p<0.001*
p<0.001*
3
p=0.002*
2
1
0
Odds Ratio (95% c/i)
Model 1
Model 2
Model 3
adjusted for age, smoking, alcohol,
adjusted for age category
adjusted for age, smoking, alcohol,
CVD,
socioeconomic status, and BMI
CVD, socioeconomic status
* for linear trend
N=1,865 Non-diabetic Men
Laaksonen DE et al. Eur J Endocrinol 2003, 149: 601-608.
2-y depression incidence (%)
35
Hypogonadism and
Depression
278 Elderly Men (mean age 62.4 years)
30
25
Declining testosterone
level
20
15
10
5
0
150 ng/dL
5.21 nmol/L
200 ng/dL
6.94 nmol/L
250 ng/dL
300 ng/dL
350 ng/dL
8.68 nmol/L 10.41 nmol/L 12.14 nmol/L
Shores MM et al. Arch Gen Psychiatry 2004, 61: 162-167.
The BLAST STUDY
• Conducted in the UK cities and towns of
Birmingham, Lichfield, Atherstone, Sutton
Coldfield and Tamworth)
• The first double blind placebo controlled
intervention study in a primary care type 2
diabetic population
• Routine screening of diabetic populations of
8 high-performing family medicine practices
to determine men with symptomatic
hypogonadism
The BLAST study
A 30 week double blind placebo controlled study of long acting
testosterone undecanoate versus placebo in men with type 2 diabetes
211 patients screened (mean age 62)
1 AF, 10 raised PSA of which 9 were BPH and 1
new CaP – 1 withdrew consent)
12 screen failues
199 Randomised
97 randomised to TESTOSTERONE
UNDECANOATE 1000mg for 30 weeks
102 randomised to matching placebo for 30
weeks
190 Completed
4 SAEs – 3 treatment unrelated deaths and 1 new
CaP in PLACEBO arm – 5 withdrawn consent
106 entered 52 week open label extension
Baseline, 18 and 30 week data for
HbA1c and Waist Circumference
HbA1c
N
T
(%)
N
Placebo
Estimated
Mean
Baseline
97
7.74±1.31
18 Weeks
95
7.49±1.26
Waist
91n
T
7.68±1.26
Baseline
96
18 Weeks
96
30 Weeks
91
115.1±13. 102 112.6±13.
1
3
114.7±13. 100 113.5±13. -0.5
5
2
112.8±14. 95 112.0±12. -1.6
0
4
30 Weeks
(cm)
102 7.47±1.2
4
100 7.44±1.1 -0.20
4
n
Placebo -0.11
Estimated
95 7.54±1.2
Mean
4
95%
Confidence
Interval
(-0.34,-0.05)
P-Value
p=0.007
95%
P-Value
(-0.34,0.13)
p=0.36
Confidence
Interval
(-1.8,0.9)
p=0.49
(-3.0,-.2)
p=0.023
RESULTS – HbA1c
Testosterone Undecanoate
1000mg (TU) significantly
lowered HbA1c at 18 weeks
versus placebo and in the
poorly controlled group this
reduction was 0.42% at 30
weeks and 0.72% after
further 52 weeks open label
medication
HbA1c (%)
7.8
7.75
7.7
7.65
7.6
7.55
7.5
7.45
7.4
7.35
7.3
7.25
P=0.007
P=0.36
Baseline 18 weeks 30 weeks
Nebido
Placebo
HbA1c in poorly vs. wellcontrolled men
Poorly-controlled
Well-controlled
T therapy reduces abdominal visceral fat (determined by
MRI) in 36 Elderly Men
(age: ≥ 60, BMI ~ 25.5, WC ~ 94.5 cm, T ~ 14 nmol/L)
p=0.480
p=0.001
% change in abdominal subcutaneous fat
% change in abdominal visceral fat
Allan CA et al. J Clin Endocrinol Metab 93: 139-146 (20
Testosterone patch
Placebo
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
0
12
24
36
Time (months)
Change in fat mass (kg)†
Change in lean mass (kg)*
T therapy improves body
composition in 108 elderly men
1.0
0.0
-1.0
-2.0
-3.0
-4.0
0
12
24
36
Time (months)
Men aged ≥65 years (N=108).
*P=0.001.
†P<0.001.
Snyder PJ, et al. J Clin Endocrinol Metab. 1999;84:2647-2653. Figure 1.
T improves depression scores in ageing males
(T Rx in Refractory Depression; n=22; T<350)
Mean Score
22
Hamilton Depression Rating
Scale
20
18
Testosterone
Placebo
16
14
12
0
1
2
4
6
8
Weeks
Pope HG et al. Am J Psychiatry. 2003;160(1):105-111.
BMD (% Change)
T therapy increases bone mineral density (BMD)
1 Changes in Lumbar Spine BMD
1
42
T
T+F
0
8
6
P <0.001
4
2
Placebo
0
-2
2-4
0
Mean ± SEM
0
T= testosterone
F= finasteride
10
20
30
Time (months)
40
n=70
Amory JK, et al. J Clin Endocrinol Metab. 2004;89:503-510.
70
60
50
40
* * * * * * * * * *
* * * * *
* * * * *
30
20
Satisfaction with sex life
10
0
70
60
50
40
*
* * * *
* * * *
* * * * * * * **
* *
30
20
10
0
S 0 3 6 9 12151821242730 Weeks
70
60
50
40
30
20
10
0
Sexual interest/desire
Sexual thought/fantasy
T improved sexual parameters in 40 hypogonadal men
(mean age 41, range: 18 - 74)
S 0 3 6 9 12151821242730 Weeks
T-Enanthate
T-Undecanoate
*
* * * * * * *
* *
* *
*
* * * *
* * *
* p < 0.05
#
S 0 3 6 9 12151821242730 Weeks
Huebler D et al. Int J Impot Res 14 (Suppl. 4), Abstract P52
(2002)
T increases spontaneous morning
erection rate in 40 hypogonadal men
(mean age 41, range: 18 - 74)
4,5
SME per
4 week
3,5
3
*
2,5
2
1,5
1
0,5
0
-6-30 3 6 9 1215182124273030 95Weeks
Schulmann C et al. J Sex Med 3 (Suppl. 1): 57
(2006)
Summary
• Restoring testosterone to the eugonadal range has the
potential not only to improve well-being, but also aids in
the management of some chronic health problems
• It may also reduce the risk of developing chronic health
problems
• Not only might this benefit the individual, it may reduce
the overall cost of chronic illness to society
A Clinical Perspective of Androxal’s Effects on Carbohydrate and Bone Metabolism Glenn Cunningham, MD
Baylor College of Medicine
Distribution of Total and Free T Levels
in the FHS, EMAS and Mr. OS Samples
Bhasin S et al. JCEM 2011;96:2430-2439
©2011 by Endocrine Society
European Male Aging Study
Distribution and Selected Characteristics of Men Ages 40‐70 (Tajar et al)
Low Testosterone
Signs and Symptoms
TTFT
Low Frequency
Morning Erections
Erectile
Dysfunction
Low Frequency
Sexual Thoughts
FHS
EMAS
MrOS
Low Walking Speed
Difficulty Climbing Stairs
Frailty
Diabetes
Composite
0.5
1.0
2.0
Odds Ratio
FT, free testosterone; TT, total testosterone.
Bhasin S, et al. J Clin Endocrinol Metab. 2011;96(8):2430-2439.
3.0
Age‐specific Prevalence (95% Confidence Interval) of Symptomatic Androgen Deficiency (AD) Araujo, A B, et al. J Clin Endocrinol Metab 2007;92:4241‐4247
Patients With AD
40
30
20
10
0
30-39
Copyright 2007 The Endocrine Society.
40-49
50-59
60-69
Age, y
70-79
Age & BMI of Subjects in Repros Androxal Studies
Study
IND
# of Subjects
Mean Age Mean BMI ZN‐018
65,396
52
51.2
31.95
ZA‐003
65,396
194
52.6
32.4
ZA‐202
104,921
116
57.3
33.5
ZA‐203
65,396
108
50.7
32.0
ZA‐204
65,396
60
53.1
31.8
ZA‐203
– Impact of Androxal on glycemic control in men with 2° hypogonadism and type 2 diabetes currently receiving oral hypoglycemic agents
– 3 month treatment, double blind study comparing placebo, 12.5 and 25mg Androxal
– Endpoints
• Testosterone
• HbA1c
• HOMA
– 19 clinical sites randomizing up to 120 subjects
• 252 screened, 92 randomized, 39 completed dosing
BMI Distribution in ZA‐003
ZA‐203
Total T After 12 Weeks Dosing
N=39
ZA‐203
Changes in Metabolic Parameters after 12 Weeks
(Men<65)
25 mg Dose
p versus Placebo
A1c = 0.09
HOMA = 0.05
Mean (95% CI) percentage change from baseline in HOMAIR and change from baseline in HbA1c among patients
with type 2 diabetes
Jones T H et al. Dia Care 2011;34:828-837
Copyright © 2011 American Diabetes Association, Inc.
ZA‐204 Protocol
• 48 subjects • Data reflects the difference between Androgel and an anti‐estrogen (enclomiphene citrate, Androxal)
• At weeks 2 and 4, the AndroGel group morning T was assessed at 4 hours post application, and the Androxal groups were assessed between 8 and 10 am.
– Few values out of normal range for Androxal – Many more for AndroGel
• Good correlation exists between morning T, Tavg, and Tmax for the Androxal arms
• “Legacy Effects” Summary of ZA‐204
Dose
Baseline T
ng/dl (stdev)
Week 6 T
Follow‐up T
ITT LOCF
24 hr
Average T
Subjects
With 24 hr Avg. T<300ng/dl @Week 6
Subjects with any T >1100 ng/dl @ Week 6
6.25 mg
247 (75.6)
392
(154.2)
341
(150.7)
n=15
402
(159.3)
N=12
392
(152.8)
4 out of 12
0 out of 12
12.5 mg
312
(110.5)
495
(170.4)
437
(188.2)
n=14
493
(163.9)
n=9
461
(129.2)
2 out of 10
0 out of 10
25 mg
248
(114.8)
577
(133.4)
612
(125.4)
n=16
541
(159.0)
n=13
587
(142.1)
0 out of 13
0 out of 13
Androgel
293
(117.5)
452
(243.0)
242.3
(89.3)
n=14
452
(243.1)
n=13
544
(230.1)
2 out of 13
3 out of 13
ZA‐204 Total Testosterone max @ Week 6
6.25 mg
12.5 mg
25 mg
Androgel
ZA‐204
Total Testosterone Levels
ZA‐202 Increased Estradiol Levels 1 Month after Stopping Treatment
Group
before TxT
E2‡
SD
12.5 mg Androxal
20.8
12.4
25 mg Androxal
24.7
26.3
22.3
Testim
Placebo
* different vs. before TxT
^ different vs. Testim
¶ different vs. Placebo
6 weeks
E2
SD
3 months
after TxT
E2
SD
E2
SD
52.1*¶ 35.3
56.7*¶
31.5
39.1*
24.2
15.9
48.3*¶ 28.3
46.3*¶
30.7
40.2*
27.4
21.8
15
44.2*¶ 27.1
26.5 20.3
37.9*¶
23.9
21.7
17.9
29
33.3
16.6
26.1
Change in Total Hip BMD by Quintile of Baseline B‐Estradiol, B‐T and SHBG
Cauley JA, et al. J Clin Endocrinol Metab 95: 4314–4323, 2010
Bioavailable T
Bioavailable E2
SHBG
Results have been adjusted for age, race, baseline weight, and weight change.
Effects of Androxal on Bone
Markers of Bone Turnover
• P1NP‐1 (type‐1 procollagen peptide) is made by osteoblasts and measures bone formation. Lower levels indicate lower bone formation. • CTX (type‐1 C‐terminal collagen peptide) is a product of osteoclastic activity. It reflects bone resorption.
• observations suggest an antiresorptive effect of Androxal, as is seen in women with another SERM, Raloxifene ZA‐202 Effect of Treatment on Serum CTx Levels (Bone Resorption)
ZA‐202 Effect of Treatment on Serum P1NP‐1 Levels (Bone Formation)
Androxal appears to enhance Bone Mineral Density
top line results from ZA‐303
Is the Active Form of Enclomiphene Like Raloxifene?
Does this explain the DEXA Effects?
Summary
• Studies ZA‐202, ZA‐203, ZA‐204 indicate that Androxal has effects on carbohydrate and bone metabolism
• Larger, longer and more rigorous studies are needed • Androxal effects on LH, T and E2 persist for some time after stopping treatment
– implications for dosing
24 Hour T & LH Androgel Subject Study ZA‐204
Subject 2‐049 Age: 58 , BMI: 24.1 Baseline 0 time: 7:31 AM
Week 6 0 time: 6:19 AM
Day to Day Morning T Variability
Sampling of Placebo Subjects ZA‐003
Key Study Discussion Points for Upcoming Type B Meeting 2012
• ZA‐204 Results
– Predictable Cmax and Cavg for Androxal compared to testosterone
– Continuing benefit for Androxal after stopping treatment
• ZA‐203 Results
– No negative impact on sperm parameters compared to testosterone
– Equivalent impact on testosterone levels
24 Hour T & LH 25 mg Androxal Subject Study ZA‐204
Subject 2‐003 Age: 55, BMI: 32 Baseline 0 time: 8:09 AM
Week 6 0 time: 7:25 AM
“Legacy Effect”
Prolongation of Testosterone in Serum after 1 Week Cessation
Effects of Aging on Hormone Levels Feldman HA et al. J Clin Endocrinol Metab. 2002;87:589‐598
Massachusetts Male Aging Study (MMAS)
-6
-4
-2
0
2
4
6
-4
-2
0
2
4
6
T
FT
Albumin-bound T
SHBG
Trend
-6
Cross-sectional, baseline, N=1,709
Cross-sectional, follow-up, N=1,156
Longitudinal
FT=free testosterone.
SHBG=sex hormone-binding globulin.
T=testosterone.
Age Trend (%/year)
`
`
Benign, monoclonal, hormone
sensitive, smooth muscle tumors of
the uterus
Most common tumor of the female
reproductive tract
◦Heavy bleeding / anemia
◦Abdominal pressure / pain / urinary
frequency
`
`
`
Affect 20-77% of women age 35 –
55
600,000 hysterectomies annually
Infertility—particularly with delayed
childbearing
Courtesy of Jay Goldberg, MD, MSCP
Director, Jefferson Fibroid Center
Director, Division of General OB/GYN
Jefferson Medical College, Philadelphia, PA
`
Patient
◦ Relieve symptoms
x Bleeding
x Bulk symptoms
◦ Shrink tumors
`
Physician
◦ Patient Acceptance
◦ Normal menses
◦ Simple, effective (medication compliance)
`
FDA: Reduce heavy menstrual bleeding
related to fibroids
`
`
`
`
This was a Phase II, randomized, single-blinded study
of four doses of Proellex® (Telapristone) vaginally
administered 12 weeks.
12 subjects in each arm (36) were 18 – 47 years
old with symptomatic uterine fibroids ultrasound
confirmed.
At the three-month treatment visit, subjects were
entered into an open-label extension treatment
protocol, if deemed eligible.
24 hr PK, MRI where performed at beginning and
UFSQOL at each visit.
Proellex induced amenorrhea
Mimics early follicular phase
Without progesterone
Average: PK Oral (1, 3, 6, 9 and 12 mg vs Vaginal 12 mg)
Conc. (ng/ml)
600
500
400
300
200
100
0
0
4
8
12
16
20
Time (Hr)
1 mg oral
3 mg oral
6 mg oral
9 mg oral
12 mg oraql
12 mg vaginal
24
Validated method for the determination of blood loss during menses
•All patients provided with same sanitary product
Menstrual Pad Scoring
Score
(ml of blood)
1
2
3
4
5
Wyatt et al. Fertil Steril 2001; 76:125-131
Number per
Category per period
x
x
x
x
x
Score
Total Score
Validated method for the determination of blood loss during menses
•All patients provided with same sanitary product
Clot scoring added to pad scoring to yield PBAC total score
Clot Size
Dime
(1 ml)
Penny
(3 ml)
Number
Wyatt et al. Fertil Steril 2001; 76:125-131
Quarter
(5ml)
Total
score
PBAC Score >80 = menorrhagia
(Normal menses 60 cc)
1.
2.
3.
4.
5.
6.
7.
8.
Heavy bleeding during your menstrual period
Passing blood clots during your menstrual period
Fluctuation in the duration of your menstrual
period compared to your previous cycle
Fluctuation in the length of your monthly cycle
compared to your previous cycles
Feeling tightness or pressure in your pelvic area
Frequent urination during the daytime hours
Frequent nighttime urination
Feeling fatigued
Each question can be scored as follows:
Not at
all
A little
bit
Somewhat
A great
deal
1
2
3
4
Sum Item Values:
Lowest and Highest Possible Scores;
Possible Raw Score Range:
A very
great
deal
Questions 1-8
8, 40
32
Formula for Transformation of Symptom Severity Raw Scores
Transformed Score = (Actual raw score – lowest possible raw score)X 100
Possible raw score range
5
Paired Comparison for Subjects Dosed at 12 Throughout Study
•Baseline to Cycle 1 p=0.005
•Cycle 1 to Cycle 2 p= 0.003
`
Observations
◦ Significant reduction in menstrual bleeding
(amenorrhea in most cases)
◦ Significant improvement in bulk symptoms and
quality of life with most subjects becoming
symptom free while on drug
◦ Significant reduction in tumor burden over time
`
If approved 12 mg daily vaginal dosing of
Proellex may offer women suffering from the
symptoms of uterine fibroids medical
treatment and an alternative to surgery
Projected Cash Requirements Through H1
2015 (in millions)
2014
H1 2015
Total
Androxal
$7.5
$0
$7.5
Proellex
$8.0
$6.0
$14.0
General Corporate
$8.0
$4.5
$12.5
Total Cash Required
Through Androxal
Approval
$34.0
Assumptions:
Androxal - NDA filed in mid-2014, expected approval mid-2015; includes FDA filing fee
Proellex - Phase 3 requirements: 300 – 600 subjects treated for 6 months; 200 subjects treated for
1 year; NDA projected to be filed in 2016
General Corporate – Includes all personnel related costs, facilities, legal, accounting, patent and
patent application costs and all costs related to being a public company
Financial Summary
• Cash and equivalents (as of 4/1/13-unaudited) $17.2 M
• Cash runway: Q1 2014
• Current shares outstanding: 18.7 M shares
– Warrants Outstanding – Series A – 877,137 (purchased in unit deal @ $2.45); Series B
– 810,496 @ $2.49 exercise price.