Download Alcobra Corporate Presentation November 2014 NASDAQ: ADHD

Alcobra Corporate Presentation
November 2014
NASDAQ: ADHD
MDX is an investigational new drug and is not available for commercial distribution
1
Forward-Looking Statements
This presentation includes statements that are, or may be deemed, ‘‘forward-looking statements.’’ In some cases, these forward-looking statements can be
identified by the use of forward-looking terminology, including the terms “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,”
“might,” “will,” “should,” “approximately,” potential” or, in each case, their negative or other variations thereon or comparable terminology, although not all
forward-looking statements contain these words. They appear in a number of places throughout this presentation and include statements regarding our
intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the expected milestones of the development of the
various indications and next steps with respect thereto, including meeting such milestones (if met) successfully and at the time indicated in this presentation,
the potential of MDX to address the market opportunity in ADHD and the potential to use MDX to treat Fragile X Syndrome. In addition, historic results of
scientific research and clinical and preclinical trials do not guarantee that the conclusions of future research or trials would not suggest different conclusions or
that historic results referred to in this press release would not be interpreted differently in light of additional research and clinical and preclinical trials results.
By their nature, forward-looking statements involve risks and uncertainties because they relate to events, competitive dynamics, and healthcare, regulatory
and scientific developments and depend on the economic circumstances that may or may not occur in the future or may occur on longer or shorter timelines
than anticipated. Although we believe that we have a reasonable basis for each forward-looking statement contained in this presentation, we caution you that
forward-looking statements are not guarantees of future performance and that our actual results of operations, financial condition and liquidity, and the
development of the industry in which we operate may differ materially from the forward-looking statements contained in this presentation as a result of,
among other factors, the factors referenced in the “Risk Factors” section of the annual report on Forma 20-F for the year ended December 31, 2013 filed with
the Securities and Exchange Commission on March 28, 2014. In addition, even if our results of operations, financial condition and liquidity, and the
development of the industry in which we operate are consistent with the forward-looking statements contained in this presentation, they may not be
predictive of results or developments in future periods. Any forward-looking statement that we make in this presentation speaks only as of the date of such
statement, and we undertake no obligation to update such statements to reflect events or circumstances after the date of this presentation.
MDX is an investigational new drug and is not available for commercial distribution
2
Alcobra’s Value Proposition
• MDX is a proprietary extended-release oral formulation of metadoxine
Metadoxine
Extended
Release (MDX)
(pyridoxol L-2-pyrrolidone-5-carboxylate)
• MDX has shown pro-cognitive benefits in attention, executive function,
learning and memory in multiple clinical and pre-clinical studies
• MDX was well-tolerated in clinical studies, had no effect on CV measures,
and has shown no potential for abuse or addiction
Attention
deficithyperactivity
disorder
(ADHD)
Fragile X
Syndrome
• Unlike most drugs available in the $8.3bn US ADHD market, MDX is a not a
stimulant and has a differentiated MoA
• Showed efficacy signal in multiple, placebo-controlled ADHD trials
• Analysis of secondary endpoints and sub-scales suggest impact on attention
and executive function
• Fragile X Syndrome is a rare neuro-genetic disorder associated with Autism
• Company obtained Orphan Drug Designation from FDA in December 2013
• MDX showed significant improvements in working memory, learning and
social interaction in pre-clinical Fragile X mouse studies
MDX is an investigational new drug and is not available for commercial distribution
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About Metadoxine Extended Release (MDX)
MDX
• MDX contains Pyridoxine Pyroglutamate
(Metadoxine)
• MDX is a once-daily, proprietary dual-release
formulation of Metadoxine
Metadoxine Experience
• Since the 1980s, Metadoxine has been available in immediate release forms for
acute treatment of Alcohol Intoxication and chronic treatment of Alcoholic Liver
Disease in Italy, Portugal, Hungary, Russia, India, China, Mexico and Thailand
• An estimate of 13+ million patient days of therapy on Metadoxine have been
administered since its introduction; To our knowledge, in 30+ years of product
availability, no major safety/tolerability issues have been published
• Multiple peer reviewed papers have been published on the use of Metadoxine at
~1500mg levels(1)
1.
Caballeria et al (J Hep, 1998) – n=69, 3 months, 1500mg
Cacciatore et al (Clin Trial J, 1988) – n=30, 300mg IM twice daily for 30 days, then 500mg tablet 3 times a day for 5 months (6 months – 1500mg)
Bono et al (Int J Clin Pharm Res, 1991) – n=20, 900mg IV twice daily (10 days - 1800mg)
MDX is an investigational new drug and is not available for commercial distribution
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Intellectual Property
Over 30 submitted patents globally may provide
multiple layers of protection to 2028 and beyond:
• Protection of Extended Release/Slow Release formulations of Metadoxine –
US PATENT #8,476,304 ISSUED JULY 2013
• Protection of use of Metadoxine for cognitive disorders and impairments –
US PATENT #8,710,067 ISSUED APRIL 2014
• Protection of new Metadoxine derivatives –
US PATENT #8,889,715 ISSUED NOVEMBER 2014
• Protection of combination therapies containing Metadoxine
• Protection of Metadoxine manufacturing process
MDX is an investigational new drug and is not available for commercial distribution
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Metadoxine Mechanism of Action
Metadoxine is a monoamine-independent GABA
transmission modulator
• Monoamine-independent MOA
• Metadoxine is a 5-HT2B receptor antagonist
• Metadoxine shows no effect on dopamine, norepinephrine, or
serotonin levels in vivo
• Metadoxine shows no binding to dopamine, norepinephrine, or
serotonin transporters in vitro
• GABA transmission modulator
• Metadoxine binds the GABA transporter
• Metadoxine displays a dose-dependent, reversible enhancement of
GABAergic inhibitory transmission via presynaptic modulations in
striatal medium spiny neurons
Rubin J, et al, US Psychiatric & Mental Health Congress; September 20–23 , 2014; Orlando, FL.
MDX is an investigational new drug and is not available for commercial distribution
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Metadoxine PhMRI Pre-Clinical Study
• Metadoxine mainly affects the Prefrontal
Cortex, thalamus, striatum, primary
somatosensory cortex, and the cerebellum
Placebo
Metadoxine
• These regions are involved in executive
function, learning and memory, motivation,
information integration and processing,
attention and cognition
• Metadoxine does not affect the mesolimbic
dopaminergic regions, including the nucleus
accumbens, which are areas associated with
abuse potential
• Multiple pre-clinical findings additionally demonstrate
that metadoxine is likely to be devoid of recreational
abuse potential in humans
MDX is an investigational new drug and is not available for commercial distribution
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ADHD Market
Attention deficit-hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by
difficulty in maintaining attention, and in some cases, hyperactivity and impulsive behavior.
70
US ADHD Market TRxs (millions)
TRxs (millions)
60
50
40
30
20
40.0
43.7
2008
2009
49.1
54.2
56.7
60.2
2011
2012
2013
10
0
2010
2013 Total ADHD Sales = $8.3 billion
ADHD affects 8-10% of school-aged children and 4-5% of the adult population
Source: IMS, NPA, TRxs
MDX is an investigational new drug and is not available for commercial distribution
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Marketed ADHD Treatments
Ritalin, Concerta, Adderall, Vyvanse
Strattera, Intuniv, Kapvay
Psychostimulants
Non-stimulants
Strong Effect
Non-Scheduled
Rapid Onset
Scheduled Substance
Significant Side Effects
Titration required
Moderate Effect
Delayed onset
Significant Side Effects
Titration required
MDX is an investigational new drug and is not available for commercial distribution
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ADHD Medications have shown Rapid
Market Uptake and Revenue Growth
Product
(launch)
Class
Owner
Years to Peak
Share
Peak Share
Peak Sales
Concerta
(2000)
Stimulant
J&J
2
26%
$1.3 BB
Adderall XR
(2001)
Stimulant
Shire
5
26%
$1.1 BB
Strattera
(2002)
Non-Stimulant
Eli Lilly
2
18%
$667 MM
Focalin XR
(2005)
Stimulant
Novartis
3
6%
~$400 MM
Vyvanse
(2007)
Stimulant
Shire ($2.6bn
acquisition)
6
17%
$1.2 BB*
Intuniv
(2009)
Non-Stimulant
Shire
4
4%
$335 MM
MDX is an investigational new drug and is not available for commercial distribution
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ADHD Clinical Studies with MDX
Phase of
Study
Study
Identifier
Number of
Subjects & Sites
Study
Assessments
Study Design & Type of
Control
Duration of
Treatment
Results
Phase I
AL0098
NCT01933997
16 healthy adult
subjects
1 site
Safety, tolerability and
PK
Single center, open-label,
repeated-dose study
5 days
Bioavailability parameters
met the U.S. FDA criteria.
Favorable safety profile.
Phase IIa
AL0064,5
NCT00995085
40 adult subjects
1 site
Efficacy, safety and
tolerability
Open-label, single-dose,
single center study.
Single dose
Endpoints reached with
statistical significance.
Favorable safety profile.
Phase IIb
AL0081,2,3,4,5
NCT01243242
120 adult subjects
2 sites
Efficacy, safety and
tolerability
Randomized, double-blind,
placebo-controlled, parallelgroup, multicenter study.
6 weeks
Endpoints reached with
statistical significance.
Favorable safety profile.
Phase IIb
AL0114,5,6
NCT01685281
36 adult subjects
1 site
Efficacy, safety and
tolerability of two doses
Randomized, double-blind,
placebo-controlled,
crossover-comparison, singlecenter study.
Single dose
Rapid onset of efficacy on
objective performance
test; Favorable tolerability
profile.
Phase III
AL0125,7,8
NCT02059642
300 adult subjects
20 sites
Efficacy, safety and
tolerability
Randomized, multicenter,
double-blind, parallel, fixeddose Study
6 weeks
Primary efficacy endpoint
did not reach statistical
significance. Trend
observed. Other secondary
measures showed strong
or statistically significant
trends. Favorable safety
profile.
Phase II
AL015
NCT02189772
82 adolescent
subjects
6 sites
Safety, tolerability and
PK
Randomized, double-blind,
multi-center, fixed dose,
single administration study
Single dose
Study ongoing.
1. Manor I, et al. J Clin Psychiatry. 2012;73:1517-1523. 2. Manor I, et al. Postgrad Med. 2013;125:181-190. 3. Manor I et al. Postgrad Med 2013; 125(4): 181190. 4. Adler L. Symposium presentation at the 60th Annual Meeting of the American Academy of Child & Adolescent Psychiatry; October 19–27, 2013;
Orlando, FL. 5. Adler L. Symposium presentation at the 61st Annual Meeting of the American Academy of Child & Adolescent Psychiatry; October 20–25, 2014;
San Diego, Ca 6. Manor I et al. Postgrad Med 2014; 126(5): 7-16. 7. Posters presented at AACAP’s 61st Annual Meeting, San Diego, CA, October 23, 2014 8.
Data on file
MDX is an investigational new drug and is not available for commercial distribution
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MDX Safety & Tolerability
 Treatment with MDX once daily in multiple trials has been well
tolerated
 The number of patients reporting AEs has been similar between the
MDX and placebo treatment groups
 The most common AEs reported have been headache (15.1% in the
MDX group vs 12.3% in the placebo group), nausea (8.6% vs 6.2%),
and fatigue (7.2% vs 8.2%)1
 No drug-related serious AEs have been reported
 No clinically significant abnormalities in laboratory values, vital sign
measurements, ECG parameters, C-SSRS, or findings during clinical
examination, including neurological examination, have been
observed
1. Data based on AL012, largest trial to date.
MDX is an investigational new drug and is not available for commercial distribution
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MDX Trials: Efficacy and Variability
in Context
LS Mean ± SD
MDX Studies
Phase III MDX Study; N=300
Week
0
1
−12.0 ± 12.6
MDX
2
3
Phase IIb MDX Study1; N=120
−12.5 ± 8.8
MDX
−8.9 ± 9.2
Placebo
Atomoxetine Studies
Mean ± SD
Michelson D et al, 20032
Study 1
N = 267
Atomoxetine
−9.5 ± 10.1
Placebo
−6.0 ± 9.3
Study 2
N = 248
Atomoxetine
Placebo
CAARS change from baseline
−9.9 ± 11.4
Placebo
4
5
6
Placebo
MDX
-5.9
-6.5
-8.5
-8.7
-9.4
-10.1
-9.9
-12
-12
-11
−10.5 ± 10.9
−6.7 ± 9.3
Phase III study affected by high placebo response and variability
1. Manor I, et al. J Clin Psychiatry. 2012;73:1517-1523. 2. Michelson D, et al. Biol Psychiatry. 2003;52:112-120.
MDX is an investigational new drug and is not available for commercial distribution
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Summary of MDX ADHD Clinical Studies
Overall findings to date:
 Efficacy signal in multiple, placebo-controlled trials
 Analysis of secondary endpoints and sub-scales suggest impact on
attention and executive function
 Rapid response, within first day, as demonstrated on objective
performance tests
 Favorable tolerability
 Absence of cardiovascular effects
 No potential for abuse or addiction seen
 Fixed dose (no need for dose titration)
MDX is an investigational new drug and is not available for commercial distribution
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Next Steps in MDX ADHD Development
 Complete analysis of Phase III Adult study in 4Q 2014
 Complete patient enrollment in Phase IIb pediatric study in 4Q 2014
 Post FDA meeting, Company plans to initiate Phase III studies in
adults and pediatric
 More rigorous patient selection to address suggestibility and severity
of patients
 Enhanced real-time monitoring
 Evaluate structural elements of study design (e.g., placebo lead-in1,
Sequential parallel comparison design2)
1
2
Michelson D, et al. Biol Psychiatry. 2003;52:112-120.
Fava M, et al. Psychother Psychosom. 2003;72:115-127.
MDX is an investigational new drug and is not available for commercial distribution
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MDX – Potential Use in Fragile X
 A rare neuro-genetic disorder caused by loss of FMR1 protein
 Most common known genetic cause of autism
 Most common inherited form of intellectual disability
 Unmet need: No FDA approved therapies
 Rationale for MDX study:
 Fragile X is associated with GABA transmission imbalance1
 Pro-cognitive properties of MDX observed in other trials
 Pre-clinical animal model
1
Berry-Kravis EM et al. Sci Transl Med 2012; 152(4): 1-7
MDX is an investigational new drug and is not available for commercial distribution
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Fragile X Market
Assumptions by Age Group
Adult
Pediatric
1/4,000 males
1/8,000 females
Prevalence1
Diagnosed Patients 2
95%
FXS Patients with Attention Problems 3
Patients Treated for Attention Problems 4
85%
80%
~35%
~50%
1 FXS prevalence NIH, April 2012: http://ghr.nlm.nih.gov/condition/fragile-x-syndrome
2 Bailey DB et al. (2009). No change in the age of diagnosis for fragile x syndrome: findings from a national parent survey
3 Estimated from caregiver surveys (Bailey, AJMG, 2008)
4 Estimated from caregiver surveys (Bailey, 2008 & 2012; Berry-Kravis, 2012).
MDX is an investigational new drug and is not available for commercial distribution
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Pre-Clinical Studies of MDX in Fragile X
 In a well-validated animal model for Fragile X, Metadoxine showed
in two separate studies:
 Significant improvements in working memory, learning and social interaction
 Significant changes in brain & blood biomarkers including pAkt and pERK
Fear conditioning task
Social interaction
NS
NS
p<.0001
p<.0001
40
ns
Sniffing duration (Sec)
Freezing (% of 5 min)
25
p<.0001
30
20
10
0
p<.0001
ns
20
15
10
5
0
Wild typePlacebo
FX KO-Placebo
Wild typeMetadoxine
FX KOMetadoxine
Wild typePlacebo
FX KO-Placebo
Wild typeMetadoxine
MDX is an investigational new drug and is not available for commercial distribution
FX KOMetadoxine
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MDX Ongoing Phase IIb Clinical
Trial in Fragile X (AL014)
 Phase 2, 6-week, randomized, multicenter, placebo-controlled,
double-blind, parallel group, dose-ranging study of MDX once daily
in adults and adolescents with FXS
 60 adults and adolescents (Age 15-55), 13 study sites (12 in US)
 Primary endpoint: Inattentive subscale of ADHD RS-IV
 Secondary endpoints include several efficacy and safety measures
Screening
Treatment Period
Follow-up
Period
(Double-blind, Placebo-controlled, 1:1)
Period
V3
D7
V4
D14
V5
D21
2 Weeks
V6
D28
V7
D35
MDX low dose once daily for
2 weeks, then increase to high
dose once daily as tolerated
during Weeks 3 and 4; maintain
dose during
Weeks 5 and 6
Matching placebo
V8
D42
V9
D56
Follow-up
V2
Day 0
Randomization
Screening
V1
Day −14
6 Weeks
Study Termination
2 Weeks
MDX is an investigational new drug and is not available for commercial distribution
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MDX Potential in Fragile X – Next Steps
 Company enrolling patients in a Phase IIb study in adolescents and
adults with Fragile X Syndrome
 Post completion of enrollment and meeting with the FDA,
Company to launch Phase III study in Fragile X by YE 2015
 Company obtained Orphan Drug Designation in December 2013
 Unique formulation/dosing possible
MDX is an investigational new drug and is not available for commercial distribution
20
Financial highlights
Financial metric
As of June 30th 2014
Cash, Cash Equivalents, and ST investments
$38.9 million
Average quarterly operating expenses YTD (exc. non-cash)1
$6.7 million
Average quarterly cash outflows YTD1
$5.6 million
Debt
$0
Shares outstanding
13.7 million
1
Future expenses and cash outflows may significantly differ from past figures presented above.
Future expenses will be a function of the clinical development plan and regulatory pathway
MDX is an investigational new drug and is not available for commercial distribution
21
Summary
 MDX has demonstrated a pro-cognitive effect in multiple clinical and
pre-clinical studies and was well tolerated
 Company holds three issued patents in the US on the extendedrelease PK profile of MDX, the use of MDX to treat cognitive
disorders, and new MDX derivatives
 Upon approval, MDX will address a significant patient need in the
ADHD market
 A rapidly effective non-abusable, non-addictive drug candidate with a
differentiated mechanism of action and favorable tolerability
 Findings suggest an opportunity for MDX in Fragile X Syndrome, a
rare neuro-genetic disease and the most common inherited form of
autism
 Multiple data readouts from advanced clinical studies in pediatric
and adult ADHD and Fragile X Syndrome expected in 2015
MDX is an investigational new drug and is not available for commercial distribution
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Alcobra Ltd.
NASDAQ:ADHD
http://www.alcobra-pharma.com/
MDX is an investigational new drug and is not available for commercial distribution
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