Download US Results for End of Phase II Meeting Modified Endometriosis

Developing clinical stage small molecule
therapeutics to treat hormonal and
reproductive system disorders
Forward-Looking Statements
This presentation contains forward-looking statements and information
regarding the future performance and actions of Repros Therapeutics Inc.
(RPRX) that involve risks and uncertainties that could cause actual results
and actions to differ materially. These risks include those discussed in this
presentation and others that can be found in Repros’ Form 10-K for the year
ended December 31, 2007 and in the subsequently filed Form 10-Q’s, which
contain additional important risk factors that could cause actual results to
differ from its current expectations and from the forward-looking statements
made in this presentation. RPRX is providing this information as of this date
and does not undertake any obligation to update any forward-looking
statements contained in this document as a result of new information, future
events or otherwise. No forward-looking statement can be guaranteed and
actual results may differ materially from those we project. The results of
initial clinical trials do not necessarily predict the results of later-stage clinical
trials. RPRX cannot guarantee that data collected from clinical trials of any
product candidate will be sufficient to support FDA or other regulatory
approval.
Repros Strategy
• Focus on small molecule therapeutics for hormonal
and reproductive system disorders that exhibit
significant market potential and that are currently
underserved
• Late stage development of highly differentiated drugs
– Proellex for the treatment of female reproductive system disorders
• Acute anemia associated with uterine fibroids
• Chronic relief of uterine fibroid symptoms
• Chronic relief of the symptoms associated with endometriosis
– Androxal for the treatment of endocrine disorders
• Treatment of Type II Diabetes in men with hypogonadotropic hypogonadism
• Fertility preservation/improvement in treatment of 2º hypogonadism
• Proven track record of efficient and rapid clinical
development
Repros Market Opportunity
Proellex
Uterine fibroid anemia
Uterine fibroid symptoms
Endometriosis symptoms
$140 million/year
$1.75 billion/year
$1.70 billion/year
Androxal
Fertility preservation
Type II Diabetes
2º hypogonadism ex-US
Total Potential Market
$250 million/year
$>1 billion/year
$100 million/year
~$5.0 billion/year
Repros Pipeline
®
Proellex
CH 3
N
OMe
O
H3C
OAc
Proellex Overview
O
• New class of selective progesterone receptor modulator
(SPRM)
– Suitable for chronic and acute indications
• Potential significant advantages over existing GnRHa
standard of care
– No loss of bone mineral density in clinical trials
– No chronic drug treatments available
• Excellent, long-term IP protection
– US issued composition of matter patent to 2017
– Eligible for Hatch-Waxman extension
– Potential use applications with life to 2027
• Worldwide exclusive rights
– In-licensed from NIH
– Includes 43 additional compounds
Uterine Fibroids
Large Underserved Market
•
Most common tumor of the female
reproductive tract
Number of Women in Millions
– Heavy bleeding / anemia
– Abdominal pressure / pain /
urinary frequency
•
Women with Severe Fibroids Requiring Surgery
Women with Symptomatic Fibroids
Conservative Estimate, 15% of
women of reproductive age with
symptomatic uterine fibroids
–
–
–
–
Potentially 26,000,000 women in US,
Japan, France, Germany, Italy, Spain,
& UK with symptomatic fibroids
Estimated 700,000 severe cases
currently requiring surgery or radical
treatment in large market countries
Mean age of women seeking UF
treatment, 39
Potential years on therapy, 10
•
Uterine Fibroids regress when a woman
reaches menopause
30
20
10
If only 25% of severe population use
0
drug option
$1,750,000,000/yr Market ($140 million for anemia)
Key Symptom Driving Women to Seek Therapy
for Uterine Fibroids
Excessive Menstrual Bleeding
Pictorial Blood Loss Assessment
Placebo
Proellex 25 mg
Menorrhagia=PBAC>80
140
120
100
80
60
40
20
0
Proellex stops bleeding
P<0.0001
BL
Mo 1
Mo 2
Mo 3
US Phase IIb
(n=127)
•Basis for Commencement of US Phase III Studies
Basis for Anemia IND and Ongoing Phase III Studies
Change in hemoglobin (g/dl)
Change in Hemoglobin Levels in Anemic Patients (<10.5g/dl)
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
-0.5
-1
-1.5
-2
-2.5
Roughly 40% of women seeking therapy for fibroids are anemic
and therefore surgical risks
Comparison of Means
p=0.00000055
Std. Dev.
1 g increase = ~1 pint of blood
Mean
Placebo
n=8
25 mg Proellex
n=11
Phase 2 Uterine Fibroid Trial
UFSQOL (Co-primary endpoint in Phase III)
UFSQOL Uterine Fibroid Symptom Survey
High score > severity
Month 3 significance values v.s. placebo; 25 mg p <0.0001
60
50
40
Placebo
25 mg Proellex
Normal
30
20
10
0
BL
MO 1
Mo 2
Mo 3
Spies et al, Obstetrics & Gynecology, vol. 99, No. 2, February 2002
Endometriosis
• Epithelial & stromal endometrial cells outside the uterine
cavity
–
–
–
–
Pelvic and back pain
Infertility
Pain during sex
Severe menstrual cramps
• 5% of reproductive-age women – more that are
undiagnosed
– 71-87% of women with chronic pelvic pain
– 25-40% (2-4 million) infertility cases could be due to endometriosis
– 53% of teenagers with cramps
• Unmet medical need – chronic condition, poor treatment
options
– Lupron, OCs, Danazol, laparoscopic procedures
• High recurrence rates after treatment
US Phase 2 EndometriosisUS
study
Phase II Endpoint
MESSS Questionnaire
US Results for End of Phase II Meeting
Modified Endometriosis Symptom Survey
Total MESS Score Max.=15 (Last Observation Carried Forward)
Placebo
25 mg
50 mg
After week 4 all p values < 0.01
10
9
8
7
6
5
4
3
2
1
0
Screening
Week 4
Week 8
Week 12
Week 16
Total possible score = 15
15 patients in placebo group and 14 each in 25 & 50 mg
No statistical difference between 25 & 50 mg
US Results for End of Phase II Meeting
Modified Endometriosis Symptom Survey
Patient Reported Outcomes Total Scores (Last Observation Carried Forward)
8
7
6
5
4
Placebo
25 or 50 mg
P=0.007
3
P<0.0001
2
P<0.0001
1
P<0.0001
0
Baseline Week 4
Week 8 Week 12 Week 16
Total possible score =9
15 patients in placebo group and 28 in 25 & 50 mg combined
No statistical difference between 25 & 50 mg
US Results for End of Phase II Meeting
Modified Endometriosis Symptom Survey
Dysmenorrhea (Painful Menses) (Last Observation Carried Forward)
3
2.5
2
P=0.0002
1.5
Placebo
25 or 50 mg
P<0.0001
1
P<0.0001
0.5
P<0.0001
0
Baseline Week 4
Week 8 Week 12 Week 16
Total possible score =3
15 patients in placebo group and 28 in 25 & 50 mg combined
No statistical difference between 25 & 50 mg
US Results for End of Phase II Meeting
Modified Endometriosis Symptom Survey
Deep Dyspareunia (Painful Sex) (Last Observation Carried Forward)
2.5
2
1.5
P=NS
1
Placebo
25 or 50 mg
P=0.0056
P=0.0005
0.5
P=0.004
0
Baseline Week 4
Week 8 Week 12 Week 16
Total possible score =3
15 patients in placebo group and 28 in 25 & 50 mg combined
No statistical difference between 25 & 50 mg
US Phase II Results
Modified Endometriosis Symptom Survey
Non Menstrual Pelvic Pain (Last Observation Carried Forward)
2.5
2
1.5
Placebo
25 or 50 mg
P=NS
1
P=NS
P=0.014
0.5
P=0.003
0
Baseline Week 4
Week 8 Week 12 Week 16
Total possible score =3
15 patients in placebo group and 28 in 25 & 50 mg combined
No statistical difference between 25 & 50 mg
US Phase 2 Endometriosis study
Analgesic Use (narcotic & non narcotic)
% of Patients Not Taking Analgesics
Analysis based on Patients last observation carried forward
80
70
60
p=.0025 50 vs Pbo
p=.0078 25 vs Pbo
50
Placebo
25 mg Proellex
50 mg Proellex
% 40
30
20
10
0
Baseline
Week 16
Study Dropouts
•
50 mg (5 patients)
– 2-Lost to follow up
– 2-Non compliance with study protocol
– 1-Found to be Osteopenic on day of first dose
•
25 mg (7 patients)
– 2-elected hysterectomy upon completion of study
– 1-osteopenic, should not have been randomized
– 1-preexisting condition of auto immune disorder, should not have been
randomized
– 1-endometrial stripe not measureable
– 1-exacerbation of depression and anxiety (never dosed)
– 1-non compliance, patient stopped taking drug
•
Placebo (14 patients)
–
–
–
–
–
9-lost to follow up
1-no diagnosis of endometriosis
1-adverse event (burning throat when taking drug)
2-lack of relief
1-osteopenic, should not have been randomized.
US Phase II Endometriosis Study
25 mg Patients Electing Hysterectomy
Situations Leading to Election of Hysterectomy
• Open Label Study not available for dosing until March/April ’09.
Patients completed double blind study in Nov. 2008.
• Hysterectomy to treat severe endometriosis is relatively common
option (120,000 procedures in the US annually)
– Subject 1 was informed about the extension study (not yet dosing), but
reported that due to her long history of endometriosis and severity of her
condition she proceeded with the hysterectomy. This subject is now 36
years old.
– Subject 2 was informed about the extension study but withdrew after
completing Visit 7. She did not have worsening symptoms, only that she
did not want to go without medications. The subject recently obtained
insurance, which enabled her to have the procedure. This subject is
now 43 years old.
Proellex
Safety Experience
• Well tolerated at all doses
• No observed QT effects at up to 4X
maximum clinical dose
• Potential for break through vaginal
bleeding significantly reduced by
incorporating “off-drug” intervals
• Open-label extension study confirming
positive impact of “off-drug” interval
“Off Drug Interval” Treatment Strategy
4 Month Dosing Cycle
Off Drug Interval to allow for:
•Menses
•Refresh the endometrium
•Experience to date suggests
menses returns in 25-35 days
•Return of symptoms
4 Month Dosing Cycle
Concept has been accepted by the FDA
as noted in End of Phase II meeting minutes
4 Month Dosing Cycle
Continue as needed
Proellex
Summary of FDA meetings
• FDA will entertain multiple label indications
– First NDA: Preoperative treatment of Anemia
– 2nd NDA: Chronic treatment of symptoms associated with fibroids
– 3rd NDA: Chronic treatment of symptoms of endometriosis
• Initial Phase III programs – anemia and fibroids
– Initiated Two 65-patient trials – Anemia prior to surgery for fibroids
– Initiated Two 75-patient trials – Symptoms associated with uterine fibroids
• Ongoing Phase II endometriosis study (n=75)
– Interim results reported
• Open label extension studies as required to satisfy safety data base
– Initiated 400 patient 2-cycle study with holiday until symptoms return (25mg or
50mg Proellex )
– Initiated 400 patient 3-cycle study with holiday until menses returns to satisfy
FDA need for 200 patients for one year of dosing
– Protocols submitted to FDA for input
• Total pooled safety data base ( 1,500 patients) Phase I-III trials as part
of submission
Proellex Market Opportunity
• Uterine fibroid anemia
•
Uterine fibroid symptoms
• Endometriosis symptoms
+$3.5 Billion/Year Market
Androxal
Androxal
•
Trans isomer of clomiphene citrate
– Cis isomer opposes action and has increased side effect risk
•
Antiestrogen that normalizes pituitary responsiveness in 2º
hypogonadal men
Highly statistically significant results in 6 month Phase III study
showing restoration of pituitary responsiveness resulting in
normalization of testicular function and testosterone levels
•
•
Multiple patents and patent applications including pure isomer
composition
RO
RO
Cl
C
C
C
Cl
trans
R=(C2H5)2NCH2CH2
cis
C
Androxal Regulatory Strategy &
Development Status
Ongoing Phase II incorporating FDA comments
– Preservation of fertility and testicular function
and normalization of testosterone in
hypogonadal men of reproductive age
Based on FDA correspondence
– Submission of IND for Type II Diabetes
Impact of Androxal on Male Fertility
Basis for Ongoing US Phase II
Comparison of Means p=0.011
Comparison of Median p=0.0045
15
2.5
12
2
FSH
9
Testicular
1.5
Volume
Change by
1
Prader
0.5
Orchidometer
0
6
3
0
Baseline
Androgel
6 Months
12.5 mg Androxal
Androxal
Androgel
-0.5
25 mg Androxal
•Estimated 1/3 of current T market ($750 million) are men of reproductive age
•32% of men in Repros study under age of 50
•Exogenous testosterone suppresses pituitary secretion of FSH
•FSH required for stimulation of sertoli cell spermatogenesis
•Suppressed FSH suppresses spermatogenesis as evidenced
by reduction in testicular size
Ongoing Androxal Phase II
Impact on sperm function and testosterone levels
• Three arm (n=24) open label study with active
comparator (Testim) in hypogoandal men previously
treated with testosterone
– 8 men with 3 week washout followed by 25 mg Androxal for 6
months
– 8 men with 3 month washout followed by 25 mg Androxal for 6
months
– 8 men with 3 week washout followed by Testim for 6 months
• Endpoints
– Change in sperm function from baseline to months 3 & 6
– Change in pituitary hormones and testosterone from baseline to
months 3 & 6
Impact of Hypogonadism on Insulin
Sensitivity and Metabolic Syndrome
Glucose Disposal Rate M
(mg/kg min)
•
8
7
P<0.05
American Heart Association definition
of Metabolic Syndrome
– Elevated waist circumference, ≥ 40“
6
5
– Triglycerides, ≥ 150 mg/dl
4
3
– Reduced HDL, < 40 mg/dl
2
1
– Elevated Blood Pressure, ≥ 130/85
0
T<280
T>280
T<280 90% Metabolic Syndrome
T>280 29% Metabolic Syndrome
– Elevated Fasting Glucose, ≥ 100 mg/dl
“In men, low T levels predisposes to central obesity and predicts the development of both
the metabolic syndrome and DM2.”
Pitteloud et al, Journal of Clinical Endocrinology & Metabolism 90(5):2636-2641
Change in Serum Glucose
Subset of Men BMI>26, Glucose >99
(+50% patients studied)
Change in Glucose (mg/dl)
10
5
0
Androxal Pooled
Androgel
Placebo
-5
-10
-15
-20
-25
0
1
2
3
Months of Treatment
No significant change in Placebo or Androgel arms
Significant mean change in Androxal arm p<0.01
Recent and Upcoming Milestones &
Goals
















2Q07 Reported top-line Proellex Phase 2b fibroid data
3Q07 Commenced US Proellex Phase 2 endometriosis trial
3Q07 Reported non-pivotal Phase 3 Androxal data
1Q08 Submitted Anemia IND
1Q08 Commence Phase 3 registration trials for Anemia
1Q08 Report data from ongoing Proellex open-label fibroid trial
1Q08 Commence Phase 3 registration trials for fibroid symptoms
3Q08 Report interim Proellex Phase 2 endometriosis data
3Q08 Commence Phase 2b Androxal fertility preservation trial
2Q09 Request endometriosis end of Phase 2 meeting with FDA
H209 Report Phase 3 Anemia registration trial top-line data
H209 Report Phase 3 Fibroid registration trial top-line data
H209 Commence Phase 3 registration trials for Endometriosis
H209 Report Androxal Phase 2b fertility preservation trial
H209 Submit Proellex Anemia indication NDA
H210 Submit Proellex Chronic Fibroid indication NDA
Repros Fundamentals
• Shares Outstanding
– 15,174,904 (all common, no warrants)
• No Debt
• 2006 Net Loss
– $14,195,000
• 2007 Net Loss
– $13,700,000
• 2008 Net Loss (through 9/08)
– $19,300,000
• Unaudited Cash on 12/31/08 : approximately $19.4 million
Thank you