Transcript Orexigen Therapeutics

Orexigen Therapeutics, Inc.
BioInvestor Forum Presentation
September 2007
Slide 1
Forward-Looking Statements
This presentation contains forward-looking statements about Orexigen Therapeutics, Inc. Words such as
“believes,” “anticipates,” “plans,” “expects,” “will,” “intends,” “potential,” “assuming” and similar expressions
are intended to identify forward-looking statements. These statements are based on Orexigen’s current
beliefs and expectations. These forward-looking statements include statements regarding the efficacy and
safety of Contrave™ or Empatic™, and the potential to obtain regulatory approval for, and effectively treat
obesity with, any of Orexigen’s product candidates. The inclusion of forward-looking statements should not
be regarded as a representation by Orexigen that any of its plans will be achieved. Actual results may differ
from those set forth in this presentation due to the risk and uncertainties inherent in Orexigen’s business,
including, without limitation: the progress and timing of Orexigen’s clinical trials; the potential that earlier
clinical trials may not be predictive of future results; the ability for Contrave or Empatic to receive regulatory
approval on a timely basis or at all; the potential for adverse safety findings relating to Empatic or Contrave
to delay or prevent regulatory approval or commercialization, or result in product liability claims; Orexigen
and its licensors may not be able to obtain, maintain and successfully enforce adequate patent and other
intellectual property protection of its product candidates; and other risks described in Orexigen’s filings with
the Securities and Exchange Commission (SEC), including those detailed under the heading “Risk Factors”
in Orexigen’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2007 filed with the SEC on
August 10, 2007. You are cautioned not to place undue reliance on these forward-looking statements,
which speak only as of the date hereof, and Orexigen undertakes no obligation to revise or update this
presentation to reflect events or circumstances after the date hereof. All forward-looking statements are
qualified in their entirety by this cautionary statement. This caution is made under the safe harbor
provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
Slide 2
Orexigen at a Glance
▪
Focus on CNS therapeutics and their application to medical
problems with high unmet needs e.g., obesity
▪
Business model: CNS screening of approved drugs to create
synergistic, patentable combinations




▪
Novel therapeutic applications
Improves speed to market
Increases technical probability of success
Reduces development costs
Two late stage products with strong Phase II clinical results
Contrave™ (bupropion SR + naltrexone SR) in Phase III
 Empatic™ (bupropion SR + zonisamide SR) in Phase IIb (formerly
known as Excalia™)
 Screening and plan to advance additional product candidates

▪
Experienced management team
Slide 3
Market Continues to be Underserved
▪
Attractive commercial opportunity
Global: >1 billion overweight adults (BMI  25)
 US: Approx. 30% of population classified as obese (BMI>30)
 High degree of public awareness
 A leading cause of morbidity & mortality; annual costs > $100B

▪
Approved treatments have weak-to-moderate efficacy, with
clinically significant side effects

Classical weight loss plateau
 Do not address underlying behavioral aspects
▪
Product candidates designed to not only cause, but extend weight
loss

Reduce the body's ability to compensate for acute weight loss
 Attenuate food-craving and associated reward mechanisms
 Rational combinations based on understanding of complex neural circuits
Slide 4
Scientific Rationale
Behind Orexigen Programs
Slide 5
Rational Pharmacology: Two Distinct Candidates to Offset
Compensatory Weight Loss Mechanisms
Weight loss
Naltrexone:
b-endorphin-mediated
POMC autoregulation
leading to:
a-MSH release
Contrave™
MC-4
(naltrexone SR /
bupropion SR)
a-MSH
B-endorphin
Bupropion:
DA leading to POMC
activation:
a-MSH release
AgRP
POMC
Empatic™
Zonisamide:
5-HT and DA and
AgRP leading to:
a-MSH release
(zonisamide SR /
bupropion SR)
Monoamines
(DA, 5-HT)
Slide 6
CNS Reward Pathways: Obesity as an
Addictive Disorder
▪
▪
Contrave’s components (bupropion, naltrexone) both approved in addictive
disorders (smoking cessation, alcohol and opioid dependence)
Act on the same pathways that mediate other addictive behaviors
Slide 7
Clinical Programs:
Contrave™
(bupropion / naltrexone)
Slide 8
Contrave™ Phase II Proof-of-Concept Trial
Completer Population
0.0
Placebo + Placebo*
Mean Change (%)
Placebo + Naltrexone*
-2.5
Bupropion + Placebo
-5.0
Contrave™(Bup+Nal)
-7.5
BL
4
8
12
16
Week
N=217 randomized subjects. Presented at ADA Annual Meeting 2006
Slide 9
20
24
28
Contrave™ Phase IIb Trial Design
▪
Study Design: 24 week multi-center (8), randomized, double-blind,
placebo-controlled dose ranging study with an additional 24 week
open-label extension for bupropion and Contrave™ subjects
▪
Primary Outcome: 24 week weight loss (%) from baseline (ITT-LOCF)
▪
Patient Population


▪
389 subjects with uncomplicated obesity *
BMI > 30
Six Treatment Arms:






*
Bupropion SR 400mg + Naltrexone IR 48mg
Bupropion SR 400mg + Naltrexone IR 32mg*
Bupropion SR 400mg + Naltrexone IR 16mg
Naltrexone IR 48mg + Placebo
Bupropion SR 400mg + Placebo
Placebo + Placebo*
Cohort 2 conducted subsequently to Cohort 1 with separate placebo
control based on results of PET scan data
Slide 10
Contrave™ Phase IIb Mean Weight Loss at 24 Weeks
Completer population
Intent-to-treat population
P+P
(N=84)
Nal + P
(N=49)
Bup + P
(N=57)
Bup +
Nal 48
(N=54)
Bup+
Nal 32
(N=63)
Bup +
Nal 16
(N=54)
P+P
(N=60)
Nal + P
(N=33)
Bup + P
(N=44)
Bup +
Nal 48
(N=25)
Bup +
Nal 32
(N=45)
Bup +
Nal 16
(N=37)
0%
-1%
-1%
-1.1%
-0.8%
-1.7%
-1.2%
-3%
-3%
Mean Weight Loss
Mean Weight Loss
-2%
-2.7%
-4%
-3.1%
-5%
-7%
-4.3%
-7.1%
-5%
-7.5%
Combination therapy vs.
-6%
-7%
Placebo + Placebo
Naltrexone + Placebo
Bupropion + Placebo
-5.4%
-5.4%
-9%
P<0.0001 P<0.0001 P<0.0001
P=0.0009 P<0.0001 P<0.0001
P=0.0684 P=0.0015 P=0.0026
Combination therapy vs.
Placebo + Placebo
Naltrexone + Placebo
Bupropion + Placebo
-11%
Slide 11
-7.6%
P<0.0001 P<0.0001 P<0.0001
P<0.0001 P<0.0001 P<0.0001
P=0.0004 P=0.0002 P<0.0001
Contrave™ Phase IIb Mean Weight Loss at 48 Weeks
Completer population
Intent-to-treat population
P + P*
(N=84)
Nal + P*
(N=49)
Bup + P
(N=57)
Bup +
Nal 48
(N=54)
Bup +
Nal 32
(N=63)
Bup +
Nal 16
(N=54)
Placebo*
(N=60)
Nal+ P*
(N=33)
Bup + P
(N=36)
Bup +
Nal 48
(N=18)
Bup +
Nal 32
(N=38)
Bup +
Nal 16
(N=32)
0%
-1%
-1%
-1.1%
-0.8%
-1.7%
-1.2%
-3%
Mean Weight Loss
Mean Weight Loss
-2%
*Weight loss
at 24 weeks
-3%
(for comparison only)
-2.7%
-4%
*Weight loss
at 24 weeks
(for comparison only)
-4.0%
-5%
-7%
-5%
-5.0%
-8.0%
-5.5%
-9%
-8.8%
-6%
-7%
-6.6%
-11%
Combination therapy vs.
Bupropion + Placebo
P=0.0892 P=0.0026 P=0.0389
Slide 12
Combination therapy vs.
Bupropion + Placebo
-10.7%
P=0.0023 P=0.0066 P=0.0290
Contrave™ Phase IIb Categorical Response
Percent of patients losing 5% of baseline body weight
Completer population
Intent-to-treat population
Placebo
(n=13)
Nal 48
(n=5)
Bup
(n=15)
NB 48
(n=21)
NB 32
(n=32)
NB 16
(n=28)
Placebo
(n=12)
0
Bup
(n=14)
NB 48
(n=16)
NB 32
(n=31)
NB 16
(n=26)
69%
70%
0
15%
10%
20
15%
20%
26%
40
39%
51%
60
52%
Percent of Patients
Percent of Patients
20
Nal 48
(n=5)
32%
40
60
64%
80
80
100
100
Slide 13
Contrave™ Phase IIb Mean Weight Loss over 48 Weeks
Completer Population
0
-1
B-Placebo + N-Placebo
Naltrexone IR 48mg + Placebo
-2
Mean Change (%)
-3
Bupropion SR 400mg +
Placebo
-4
-5
-6
-7
Bupropion SR 400mg +
Naltrexone IR 16mg
-8
Bupropion SR 400mg +
Naltrexone IR 32mg
-9
-10
Bupropion SR 400mg +
Naltrexone IR 48mg
-11
-12
-13
BL
4
8
12
16
20
24
28
Slide 14
32
36
40
44
48
Contrave Phase IIb: AEs Resulting in Discontinuation
Through Week 24
Placebo
Naltrexone
monotherapy
Bupropion
monotherapy
NB 48
NB32
NB 16
% of Subjects
Discontinuing
8.2%
10.7%
8.3%
29.5%
15.9%
25%
Gastrointestinal
1.2%
7.1%
1.7%
19.7%
7.9%
12.5%
- Nausea
0
5.4%
0
18.0%
7.9%
9.4%
- Abdominal Pain
0
0
0
0
0
3.1%
1.2%
5.4%
0
11.5%
4.8%
4.7%
- Dizziness
0
3.6%
0
6.6%
0
3.1%
- Headache
0
1.8%
0
3.3%
1.6%
1.6%
- Irritability
0
3.6%
0
3.3%
0
1.6%
CNS
▪
No Serious Adverse Events attributed to ContraveTM
Slide 15
Contrave™ Clinical Development Plan
▪
Received written agreement from FDA on registration requirements
 Strength of ContraveTM Phase IIb pivotal study enables future studies to
compare against placebo
 Phase III program will require 1,500 patients exposed to active drug in
blinded studies over 1 year
 Agreement on primary endpoints (ITT – LOCF)
 No additional safety studies expected
Trial
Status
NB-302 (Behavior Modification)
Enrolling
NB-304 (Diabetes)
Enrolling
NB-301, NB-303
Commence 2H 2007
Slide 16
™
Clinical Programs: Empatic
(bupropion / zonisamide)
Slide 17
Empatic™ Phase II POC Study
Mean Weight Loss at 24 Weeks
Completer population
Intent-to-treat population
Placebo
(N=51)
Placebo
(N = 51)
Bupropio
Bupropion
n++
Placebo
Placebo
(N=53)
(N
= 53)
Zonisami
Zonisamide
de+ +
Placebo
Placebo
(N=59)
(N
= 59)
Empatic
(N=56)
Empatic
(N = 56)
Placebo
(N=38)
Placebo
(N = 38)
0%
Empatic
(N=30)
Empatic
(N = 30)
-0.4%
-2%
-2%
-3.1%
-4%
-4.5%
-5.8%
Mean Weight Loss
Mean Weight Loss
Zonisamid
Zonisamide
e++
Placebo
Placebo
(N=37)
(N
= 37)
0%
-0.6%
-6%
Bupropion
Bupropion
+
+
Placebo
Placebo
(N=32)
(N
= 32)
-4%
-3.6%
-6%
-6.5%
-8%
-8%
-10%
-10%
-9.2%
Slide 18
Empatic™ Phase II Mean Weight Loss over 24 Weeks
Completer Population
0.0%
Placebo + Placebo
-2.5%
Mean Weight Loss
Bupropion + Placebo
-5.0%
Zonisamide + Placebo
-7.5%
Zonisamide + Bupropion
-10.0%
-12.5%
BL
4
8
12
16
Week
Slide 19
20
24
28
.
Empatic Phase II: AEs Resulting in Discontinuation
Through Week 24 with Zonisamide Immediate Release
Placebo (a)
Zonisamide
IR
monotherapy
Bupropion
monotherapy
TM(
Empatic
((
% of Subjects Discontinuing
9.4%
20.3%
21.8%
37.3%
Headache
1.9%
3.4%
1.8%
3.4%
Rash
0%
1.7%
0%
3.4%
Hypoesthesia
0%
0%
0%
3.4%
Nausea
0%
3.4%
0%
1.7%
Insomnia
0%
0%
1.8%
1.7%
Dyspepsia
0%
0%
0%
1.7%
Dizziness
0%
1.7%
1.8%
1.7%
Nervousness
1.9%
0%
0%
1.7%
All Other AEs
5.6%
10.1%
16.4%
18.6%
▪
No Serious Adverse Events attributed to EmpaticTM
(a) Placebo arm through 16 weeks
Slide 20
Empatic™ Phase IIb Dose Optimization Study
▪
Objectives:

▪
▪
▪
Double-blind, placebo-controlled, randomized study
Zonisamide (ZNS) + Bupropion (BUP) combination x 24 blinded weeks;
additional 24 week open label extension
Target Population: 620 obese subjects; 14 sites

▪
Identify optimal dose ratio using a novel, sustained release zonisamide formulation
Nonsmokers; BMIs >30; no major medical complications
Treatments*
Zonisamide SR
mg/day
Bupropion SR
mg/day
Group 1
120
280
Group 2
120
360
Group 3
240
280
Group 4
240
360
Group 5
360
280
Group 6
360
360
Group 7
Placebo
Placebo
*Titration schedules occur over either 6 or 8 weeks
Slide 21
Empatic™ Phase IIb Mean Weight Loss over 24 Weeks
Bupropion SR 360mg / Zonisamide SR 360mg
Completer population
Intent-to-treat population
Placebo
Empatic
Placebo
0%
0%
-1.1%
-1.2%
-2%
Mean Weight Loss
-2%
Mean Weight Loss
Empatic
-4%
-6%
-8%
-4%
-6%
-8%
-8.6%
-10%
-10%
Slide 22
-10.3%
Empatic™ Conclusions
▪
The EmpaticTM combination has delivered substantial and early weight
reduction in two separate trials



▪
Phase II at 24 weeks: 5.8% (ITT), 9.2% (completers) vs. approx. 0.5% placebo rate
(127 patients)
Phase IIb at 24 weeks: 8.6% (ITT), 10.3% (completers) vs. approx. 1.2% placebo
rate (620 patients). All six active groups were statistically superior to placebo in the
mean percent weight change from baseline (ITT-LOCF)
No weight plateau or rebound evident
Adverse event experience



Rate of discontinuation due to AEs down from 37% in Phase II (zonisamide IR)
to 14% pooled in Phase IIb (zonisamide SR). The SR discontinuation rate was not
significantly different from that seen with placebo (9%)
AE discontinuation rate in the highest dose group (360/360) was also not statistically
different from the rate seen with placebo
Most common AEs in Phase IIb: headache, nausea, insomnia, anxiety, dry mouth
Slide 23
Empatic™ Clinical Development Plan
Will closely mirror ContraveTM clinical plan, 12-18 months behind
▪
Same FDA guidelines to apply (1,500 patients on drug over 1
year, no additional safety studies required)
▪
One additional Phase II study will be required to demonstrate
superiority of combination over monotherapy
 ZB-202 to begin early 2008
▪
Phase III trials to begin 1H 2009
▪
File NDA 2011
Slide 24
Commercial Considerations
Slide 25
IP Portfolio Strategy
Orexigen has a three-tiered patent protection strategy
1. Composition of matter
 Issued patent no. 7,109,198 provides Empatic™ Composition of Matter
protection (exclusively in-licensed)
 Issued patent nos. 5,817,665 and 5,512,593 provide Contrave™ Composition
of Matter protection (exclusively in-licensed)
2. Methods of use
 Treatment and prevention of obesity, drug-associated weight gain
3. Formulations / Dose
 Zonisamide SR and Naltrexone SR patents filed
 Novel Tri-layer tablet and Titration Pack patents filed
Slide 26
Market Research / Generic Risk
▪
Conducted market research among primary care and specialists
▪
Study showed a minimal risk of generic substitution:
 General discomfort with liability issues
▪ FDA label seen as critical
 Lack of familiarity with naltrexone or zonisamide
 Dose ratio and PK profile also important barriers
 Titration packaging to maximize patient compliance (MDs responded
very favorably)
 Expensive generics; no economic incentive
 Multiple co-pays for generic combinations
Slide 27
Commercial Considerations
Contrave™ Positioning
 Launch in 2010 and establish a significant share of Class I/II market
 Focus on the female patient with mild-to-moderate obesity with an
emphasis on the behavioral aspects of eating e.g., craving and food
obsessionality
Empatic™ Positioning
 Launch approximately 12-18 months later
 Focus on moderate-to-severe obesity market requiring more aggressive
therapy, including patients with medical co-morbidities e.g. diabetes,
cardiovascular, etc.
Commercial strategy
 Global commercial rights currently
 May consider licensing and/or co-promotion, US and/or OUS
Slide 28
Strong Financial Position
Financing history


Raised $96.6m in IPO in April 2007
Had raised $76 million in three rounds privately
As of June 30, 2007:
Cash and equivalents $109.5 million
Long term debt
$10.0 million (a)
Borrowing capacity
$7.0 million (a)
(a) Reflects $10 million drawn down in March 2007 under $17 million Merrill Lynch credit and
security agreement
Slide 29
Orexigen Major Milestones
Contrave™






Initiation of Phase III clinical program
Initiation of fMRI craving study
Initiation of MDD/smokers studies
Phase III clinical results
File NDA
Launch
Q2 2007 (Done)
2H 2007
1H 2008
2H 2008 / 1H 2009
2H 2009
2010
Empatic™








Phase IIb 48 week data (ZB-201)
Initiation of Phase IIb trial vs. monotherapy
(ZB-202)
Phase IIb 24 week data (ZB-202)
End of Phase II FDA meeting
Initiation of Phase III clinical program
Phase III clinical results
File NDA
Launch
* Final data analysis ongoing
Slide 30
Done
Q1 2008
Q1 2008
2H 2008
Q4 2008
1H 2009
2H 2010
2011
2012
Management
▪
President & CEO: Gary D. Tollefson, M.D., Ph.D.


▪
COO: Anthony McKinney

▪

Associate Neuroscience Medical Director, Eli Lilly
VP - General Counsel: Heather Turner, Esq.

▪
Medical Advisor, program phase Neuroscience, Eli Lilly
VP - Medical & Regulatory Affairs: Ron Landbloom, M.D.

▪
Faculty member Oregon Health & Science University and highly published on the
mechanism of the hypothalamic weight control circuit
Co-founder
CMO: Eduardo Dunayevich, M.D.

▪
Director, Healthcare Investment Banking @ Deutsche Bank (8 years)
CSO: Michael Cowley, Ph.D.

▪
Member of founding management team at Novazyme; Sr. VP @ Genzyme
CFO: Graham Cooper

▪
Previously Product Group President for Neuroscience, Eli Lilly
Clinical Professor in Psychiatry, Indiana University School of Medicine
Associate General Counsel, Conor Medsystems
VP - Commercial Affairs: James Lancaster

Executive Director, Global Neuroscience Marketing, Eli Lilly
Slide 31
Conclusions
▪
Business model: Lower cost, lower risk
▪
Novel approach with two late stage clinical candidates
▪ Demonstrated weight loss efficacy without the classic early plateau
▪ Attractive safety / tolerability profiles
▪
Proprietary SR formulations of naltrexone and zonisamide that
have shown meaningful improvements in tolerability
▪
Exclusive licenses to issued composition patents supporting both
Contrave™and Empatic™
▪
Screening and plan to advance additional clinical candidates in
other potential CNS applications
▪
Very experienced management & scientific team
Slide 32
Slide 33