Corporate Presentation - Pharnext · Corporate Presentation January 2020. Disclaimer Refere vces...
Transcript of Corporate Presentation - Pharnext · Corporate Presentation January 2020. Disclaimer Refere vces...
DisclaimerReferences herein to this presentation (the “Presentation”) shall mean and include this document, any oral presentation accom panying this document provided by Pharnext SA (the "Company") and any further information that may be made available in connection with the subject matter contained herein.By viewing or receiving or reading this Presentation (as such term is defined herein) or attending any meeting where this Pre sentation is made, you agree to be bound by the limitations, qualifications and restrictions set out below:This Presentation is confidential, is intended for the recipient only and thus may not be forwarded, reproduced, redistributed or passed to any other person or published in whole or in part for any purpose. If this document has been received in error, it must be returned immediately to the Company. By receiving this Presentation, you become bound by the above-referred confidentiality obligation. Failure to comply with such confidentiality obligation may result in civil, administrative or criminal liabilities.This Presentation contains inside information with regard to the Company and/or its securities. Recipients of the Presentation should not deal or encourage any other person to deal in the securities of the Company until the transaction described in thi s Presentation is either announced or abandoned by the Company. Dealing in securities of the Company when in possession of inside information would r esult in liability for breach of insider dealing restrictions under applicable law, including French and U.S. law.
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Experienced Leadership Team
Serguei Nabirotchkin, PhD – Chief Biology Officer & Co-
Founder
Xavier Paoli, MSc – Chief Commercial Officer
Daniel Cohen, MD, PhD – Chief Executive Officer & Co-Founder
Viviane Bertrand, PhD – Chief Preclinical Drug Development Officer
Susanne Dorn, MSc – Chief Regulatory Officer
Philippe Rinaudo, PhD – Chief Data Officer
François Chamoun, Master 2 Business Laws (DESS) & DJCE –
Chief Legal Officer
3
Rodolphe Hajj, PhD – Chief Pharmacology Officer
Peter Collum, Chief Financial Officer & Chief Business
Officer
Corporate Overview
PLEOTHERAPYTM Artificial Intelligence (AI) Platform
Maps disease networks and identifies combination drugs to
hit multiple highly relevant disease targets
Our Mission:
• Leverage proprietary
PLEOTHERAPYTM AI
platform to develop
novel combination
therapeutics using both
generic compounds and
NCEs across various Tx
areas
• Continue development
and gain approval for
PXT3003 in CMT1A and
PXT864 in AD
PXT3003 (CMT1A) – Phase 3
PXT864 (AD) – Pre-Phase 2b
PIPELINE COLLABORATIONS
Over 20 additional indications mapped for further pipeline expansion
Tasly (Chinese rights for PXT3003 and joint venture)
Galapagos (taking multiple programs into preclinical testing)
5
Corporate Highlights
5
PLEOTHERAPYTM AI platform scalable across multiple Tx areas
with both generic and NCE combinations
Identifies drug combos for multiple relevant disease targets
Known safety profile of existing drugs
Faster transit through R&D process and POC
Known safety of generics allowing direct access to Phase 2
Phase 3 CMT1A program (~$1Bn WW sales potential)
Top-line results from extension study of PXT3003 in 1Q20
Large Potential
Opportunity
Enhancing
Probability of
Clinical Success
Improved Capital
Efficiency
Advanced Lead
Program: PXT3003
Phase 2a data in AD
Ability to efficiently grow pipeline with PLEOTHERAPY platform
AD Candidate pre-
Ph2b + Pipeline
Potential
PL
AT
FO
RM
PIP
EL
INE
Pipeline and Expected Milestones*
6
PXT3003
PXT864
CMT1A
Adults
CMT1A
Pediatrics
Extension study results – 1Q2020
Second phase 3 trial:
• Planned launch - 2H-2020
• Topline results expected - late 2022 / early 2023
Alzheimer’s
disease
Amyotrophic
lateral sclerosis
Pre-Phase 2b
Product Indication Preclinical Phase 1 Phase 2a Phase 2b Phase 3 Expected Milestone
* Forward-looking statements, see risk factors set out in Pharnext’s document de base registered by the French Financial Markets Authority under number I.16-0050
Launch of Ped Ph3 trial – TBD
Pre-Phase 2a
PXT3003 Highlights
▪ Addresses Charcot Marie Tooth disease Type 1A (CMT1A): unmet need with no approved drugs to treat
chronic and debilitating disease
▪ Data from first Phase 3 study shows strong efficacy signal
▪ PXT3003 not only halted decline, but demonstrated improvement over baseline
▪ Second Phase 3 study to initiate 2H-2020 based on FDA guidance
▪ Revenue potential of approximately $1Bn worldwide
o More than 100,000 potential patients with mild-to-moderate CMT1A (US and EU5)
▪ IP protection through 2030, including composition of matter
▪ US orphan drug exclusivity1
▪ FDA Fast Track Designation
8 1Assuming late 2023 approval and ODE through 2030, generic entry in late 2031.
Charcot-Marie-Tooth Disease Type 1A
SYMPTOMSMuscle atrophy in extremities causing
severe walking and hand disabilities,
pain, cramps and fatigue
DIAGNOSIS~50% of patients have symptoms
before the age of 20, confirmed by genetic
testing
NATURAL
HISTORY
Genetic disease; symptoms starting in
teenage years, slowly declining
through life, resulting in braces,
surgery and wheelchair
POPULATIONMore than 100,000 people affected
with mild to moderate CMT1A in US
and EU5 (core market)
TREATMENT
OPTIONS
No drug approved; only supportive care
available
No other candidates in late stage clinical
development
9
Chronic, Severe, Debilitating Inherited Neuropathy
BACLOFEN
PXT3003 Novel Design and Mechanism of Action
Opioid/ Alcohol dependence
Spasticity
Constipation
CMT1A disease at-a-glance Network analysis Design of PXT3003
Current Indication
Opioid receptors
GABAreceptors
Muscarinic receptors
Current Dose
50mg
120mg
1.4mg
12mg
OPIOIDReceptors
MUSCARINICReceptors
GABAReceptors
420mg
15g
CMT1A - Axonaldysfunction andmuscle loss
NALTREXONE
SORBITOLNormal
10
Pharnext Dose
All Components of PXT3003 Synergistic to Activity in CMT1A
1 10
1 05
1 00
9 5
9 0
1 1 5
1 25
120
1 3 0M yelin atio n
%Im
pro
ve
m e
nt
m y
elin
len
gth
S
S in g le D u o s
* * *
S
P lac eb o B C L +N L X B C L + S R B N L X + S R B P X T3 0 0 3
4
5
6
7G rip s t re n g th a t e n d o f tr ia l
Gri
ps
tre
ng
th(N
)
(ch
an
ge f
rom
ba
se
lin
e)
***
###
#######
#
In CMT1A neurons on myelination in vitro In CMT1A animals in vivo
***p<0.001 vs CMT1A placebo/Control, ANOVA + Dunnett test#p<0.05, ###p<0.001 vs PXT3003, ANOVA + Dunnett test
S: synergy
BCL = Baclofen (GABA receptor)
NTX = Naltrexone (opioid receptor)
SRB = Sorbitol (muscarinic receptor)
11
Robust Phase 2 Results for PXT3003 in CMT1AExploratory multi-center, randomized, double-blind, placebo-controlled Phase 2 study
DOSE 1n=21
DOSE 3n=19
PLACEBOn=19
DOSE 2n=21
Dose Reduction
1/10001/2001/250
1/5001/1001/125
1/1001/201/25
NAL
BAC
SOR
80Mild to
Moderate Patients
• All doses safe and well
tolerated
• Effect achieved at 12 months with Dose 3, which was used to design the Ph3 study
Source: Attarian et al, Orphanet Journal of
Rare Diseases (2014),9:19912
20%
10%
0%
-10%
%IM
PR
OV
EMEN
Tin
ON
LS
DOSE 3
PLACEBO
BASELINE 12 Mths
DOSE 2
DOSE 1
PHASE 2 DURATION: 12 MONTHS
Efficacy and dose-effect demonstrated with Overall Neuropathy Limitation Scale (ONLS)
PLEO-CMT: First Pivotal Phase 3 Study Design and EndpointsInternational, randomized, double-blind, placebo-controlled
Primary endpoint: ONLS after 12 -15 months
▪ ONLS: a 12-point scale evaluating disability
▪ 90% of the patients scored 2-4 (mild-to-moderate)
▪ A 0.3-point ONLS difference vs. placebo was determined to be
meaningful
- Stabilizing or even improving disease versus placebo or natural
yearly evolution estimated at 0.1/0.2 point.
- 50% Placebo standard deviation (Cohen J., 1988)
▪ FDA and EMA agreed on using ONLS as the primary endpoint
for this study.
Secondary endpoints analysis include:
▪ 10-meter walk test (10-MWT)
▪ Nine-hole peg test (9-HPT)
▪ 2 subsets of CMTNSv2 (CMT Impairment Score)
(Clinical + Electrophysiological items = CMTNSv2)
- Sensory subset*
- Clinical subset = purely clinical items (CMTES)**
ONLS = Overall Neuropathy Limitation Scale
* Sensory subset of CMTNSv2: items 1,4 and 5** CMTES is derived from CMTNSv2, items 1 to 7 excluding nerve conductions
13
PHASE 3 DURATION: 15 MONTHS
SOR
0.7 mg 6 mg 210 mg
PLACEBO
DOSE 3(Phase 2
highest dose)
DOSE 4
(2x Dose 3)
NAL
BAC
SOR
323Mild to
Moderate Patients
(age:16 – 65 y)1.4 mg12 mg420 mg
Phase 3 Study – CMC Event Interrupted High Dose ArmStatistical Significance at Interruption with Original Stat Plan
14
Dec 2015
Study Start
Sept 2017
High
dose stop
Mar 2018
Study End
Oct 2017: Variability
Nov 2017: Futility read
Phase 3 Trial n=323 patients
44 completers + 12 dropouts = 56
41 completers + 13 dropouts = 54
42 completers + 12 dropouts = 54
High Dose (Dose 4) n=113
Low Dose (Dose 3) n=109
Placebo n=101
44 completers + 11 dropouts = 55
38 completers + 9 dropouts = 47
85 completers
80 completers
49 completers5 completers
per original stat plan* at CMC event, ONLS p=0.012
modified SAP*, ONLS p=0.008
per original SAP*, ONLS p=0.04
CMC event
July 2017
Germany stop
( all arms)
52 patients – no data
due to CMC event
Oct 2018
Study
Read-out
*Original statistical plan adapted to account for “missing data” from stopping high dose arm due to CMC event (using ICH guidelines)
Statistical model not modified (ANCOVA) but adaptation of populations considered
• Original plan → primary population = FAS (n=323) / missing data due to drop-out (DO) imputed like placebo for all study arms (conservative)
• Modified SAP → primary population = mFAS (n=235 = completers + DO related to treatment) / missing data due to DO related to drug imputed like Placebo for all
study arms / missing data due to all other DO excluded from analysis (considered at random)
PLEO-CMT: ONLS and 10MWT in SAP# Primary Population
# Statistical Analysis Plan frozen and sent to USFDA before unblinding the data
*, ** Dose 4 vs Placebo, ANCOVA with multiple imputation (Missing data implemented by multiple imputations following the placebo trend) *** Average of 12 and 15 Month, or 12 Month if 15 Month is missing15
Dose 4 (n=55)
Dose 3 (n=93)
Placebo (n=87)
p = 0.008
ONLS
p = 0.016
10mWT
Baseline 6 months 12+15 months*** Baseline 6 months 12+15 months***
PLEO-CMT: Safety and Tolerability
▪ Treatment emergent adverse events (TEAE) similar among three groups; majority mild
▪ TEAEs leading to treatment withdrawal similar in all three groups
▪ Single treatment-related serious TEAE occurred in lower dose group (gastroenteritis)
▪ Safe and well tolerated; showed a similar safety profile as in Phase 2
16
Large Commercial Opportunity in CMT1A
▪ Significant unmet need in CMT1A: no pharmacological treatments currently available; only supportive care
options (PT, surgery, pain management)
▪ No other candidates in late stage clinical development
▪ More than 100,000 potential patients in our core market, mild to moderate CMT1A (US and EU5)
▪ 25,000 potential patients already located via patient associations and market research
▪ 5 pricing / market research studies with consistent feedback on US and EU pricing
17
Other Anticipated PXT3003 Milestones and Anticipated Path Forward
Feb 2, 2019: FDA Fast Track Designation granted
Q1 2020: Expect to receive top-line results of extension study (PLEO-CMT-FU) of long-term
safety and efficacy of PXT3003
1H 2020: Expect to finalize second Phase 3 trial protocol in CMT1A with FDA
2H 2020: Expect to Initiate second Phase 3 trial in CMT1A (potential for data in late 2022/early
2023)
2019 / 2020: Continued assessment of commercialization options for geographical areas within
US, EU, Japan and ROW; China commercialization rights are licensed to Pharnext & Tasly’s joint
venture
18
Novel AD Approach:Correcting chemical imbalance in the diseased brain
20
Glu GABA
PXT864 to break viciouscircle
Disease at-a-glance
GABAreceptors
Glutamatereceptors
Acamprosate
Baclofen
Healthy brain Diseased brain
Glu: Glutamate
Glu GABA
- +
GABA
Glu
GABA
Glu
Aβ -Tau
Vicious circle occurring in AD brain
(Govindpani 2017; Talantova 2013)
GABA
Glu
“Therapeutics that correct the E/I imbalance in early AD may prevent neuronal dysfunction, cell loss and cognitive impairments associated with later stages of the disease”
E/I imbalance = GLU excitation / GABA inhibition
Upstream of Aβ -Tau imbalanced cells overproduce each
21
Working memory: Combination
% A
lte
rnatio
n
Nor
mal
Con
trol
(Place
bo) AC
PBC
L
PXT864
45
50
55
60
65
70
75
******
S
Acamprosate BaclofenAcamprosate Baclofen
Working memory: Dose-response of single drugs
% A
ltern
ati
on
Nor
mal
A+
Place
bo
A+
ACP 0
.032
A+
ACP 0
.08
A+
ACP 0
.2
A+
ACP 0
.4
A+
ACP 0
.8
A+
ACP 1
.6
A+
ACP 8
.2
A+
ACP 4
1
A+
BCL
0.41
A+
BCL
0.48
A+
BCL
1.2
A+
BCL
2.1
A+
BCL
3
A+
BCL
10.3
45
50
55
60
65
70
75
***
PXT864 Demonstrates Synergistic Efficacy in AD Animals
(Chumakov et al., 2015)
PLEODIAL: Exploratory Phase 2a Trial Design
• 45 mild naïve AD patients treated by 3 doses:
• Clinically diagnosed but low mean Log Abeta 42/40
• 7 centers in France
• Assessed at 0,3,6,9 months
• 9 clinical endpoints, open label, single blind
• Biomarker: Plasma Aβ42/40 assessed by Quanterix
Memory Orientation Language Attention Visuospatial Executive function speed Daily activity Social interaction
Adas Cog
CDRSB
IADL
TMT A
TMT B
ZAZZO
Apathy Inventory
DSST
ISAAC
Functions assessed by each endpoint
22
p = 3e-13 Highest drug exposure versus historical placebo
p = 0.013 All patients versus historical placebo
PXT864: CDR-SB Analysis Based on Plasma Drug ExposureHigher Dose Could Rapidly Generate Partial Recovery Vs Less Decline With No Safety Concerns
***
***
*
*
Acamprosate Baclofen
Approved dose 2000 mg 80 mg
Ingested dose 3 40 mg 24 mg
Next dose to be tested 400 mg 24 mg
Imp
rove
me
nt
23
Biogen EMERGE : 9 months high dose Aducanumab: ̴ 0,7 pts decline
Both analyses with patients with sufficient exposure (increasing dose limited by safety concerns)
Biogen ENGAGE : 9 months high dose Aducanumab: ̴ 0,5 pts decline
Plasma Aβ42/40 Analysis Based on Plasma Drug ExposureImprovement at 3 and 6 Months, but a Higher Dose Could Rapidly Generate Sustained Effect
Drug exposure = Cmax for both drugs
(n=45)(n=10)(n=10)(n=25)
Imp
rove
me
nt
24
Plasma Aβ42/40 3-Month Improvement Correlates With Clinical Improvement at 9 Months:
Suggests a Delayed Effect “From Molecular To Clinical”
25
Biomarker 3-Month improvement Biomarker 3-Month improvement
3-M
on
thC
DR
-SB
imp
rove
men
t
3-M
on
thC
om
po
site
sco
re (
CS)
* im
pro
vem
ent
9-M
on
thC
DR
-SB
imp
rove
men
t
9-M
on
thC
om
po
site
sco
re (
CS)
im
pro
vem
en
t
* Composite score of all clinical endpoints.
PXT864 in Alzheimer’s Disease Overview
Higher doses of PXT864 have potential to demonstrate a sustained therapeutic effect on
Alzheimer’s Disease, due to the following advantages:
▪ Strong safety profile
▪ Can be co-administered with already approved drugs in AD
▪ Can be synergistic with other NCEs to create a powerful novel new entity
26
PLEOTHERAPYTM Universal R&D PlatformStarting with Big Data
In Silico AI & Expert System
Disease
Network
Knowledge
Integration
Virtual
Repositioning
Preclinical
2,000+
approved drugs50
candidate drugs(filtered for PK, toxicity, safety, IP)
6 months ≈ 2 years
1
Pleodrug™
In Vitro
Screening
Clinical
≈ 7 years
Phase 1(not always mandatory)
Phase 2A/B
Phase 3
In Vivo
Test
ApprovalDisease
25 Positive Drugs
4 synergistic combos
28
Human geneticsGWAS ( Genome Wide Association Study )
Virtual Repositioning Step 1 Disease Associated Molecular Network
A Fraction of the Whole Interactome
BIG DATA
29
Genome Wide Association Studies(GWAS) e.g. from AD patients
Protein – Protein Interaction
Known Drug-Targetrelationships
Literature
EXPERTS AI
e.g. AD Associated Molecular Network
Virtual Repositioning Step 2 Identifying Candidate Drugs from Drug Data Base and Disease Associated Molecular Network
BIG DATA
30
Genome Wide Association Studies(GWAS) e.g. from AD patients
Protein – Protein Interaction
Literature
EXPERTS AI
e.g. AD Associated Molecular Network
Known Drug-Targetrelationships
Candidate drugs Experimental
Testing
RALBP1
metabolite
metabolite
metabolite
metabolite
metaboliteGRM 5
mTOR
metabolitetransport
metabolite
metabolite
PITPNC1
PITPNC1
SNCA
PLD 1
metabolite
TH EM 2
metabolite
metabolite
ACH E
metabolitePLD 1/2
PLD 2
NFĸB1
metabolite
metabolite
metabolite
metabolite
SGPP2
PPARγ
PD GF
metaboliteeffect
PLA
?
AD CY2
D RD 2
ANXA3
D RD 5
metabolite
ASAH 1
metabolite
metabolite
metabolite
PRIM A1
metabolite
metabolite
PLAUST14
Virtual Repositioning Step 1 Example of Alzheimer’s Disease – Associated Sub Network
metabolite
Proteins
encoded by
genes with
statistical
association
with
Alzheimer’s
Disease
Proteins
encoded by
genes without
statistical
association
with
Alzheimer’s
Disease
32
RALBP1
metabolite
metabolite
metabolite
metabolite
metaboliteGRM 5
mTOR
metabolitetransport
metabolite
metabolite
PITPNC1
PITPNC1
SNCA
PLD 1
metabolite
TH EM 2
metabolite
metabolite
ACH E
metabolitePLD 1/2
PLD 2
NFĸB1
metabolite
metabolite
metabolite
metabolite
SGPP2
PD GF
metaboliteeffect
?
ANXA3
D RD 5
metabolite
ASAH 1
metabolite
metabolite
metabolite
PRIM A1
metabolite
metabolite
PLAUST14
metabolite
Genetic association
Drugged Target
Virtual Repositioning Step 2 Crossing Drug Data Base And Alzheimer’s Disease – Associated Sub Network
Candidate drugs ready for experimental screening
33
AI
con
tin
uu
m
Human (computer assisted)Computer (human assisted)
2007
2007
33
2021
2021
2017
2017
Other omics
Phase 2017-2021 (AI-assisted platform):
1. New generation GWAS module: machine learning &
deep learning-based imputation (by end 2019) +
disease risk prediction (projected 2020)
2. Other Omics data (Big Data)
3. Network building powered by AI, learned from
Pharnext’s existing networks and methods
4. Network analysis powered by AI (ex: synergy
prediction)
• And other ML projects …Network construction
module
DiseaseNetworks
Genetic Data
(GWAS)
GWAS analysis module
LiteraturePatents
Other databases (proteins, pathways,
other PPI, etc.)
IngenuityReaxys
databases
Experts*2
* 1
* 3
* new
ML tools
* 4
AI assisted
Virtual Repositioning Powered by AI and Big Data with New Machine
Learning (ML) ToolsReduced from 1 year to 1 quarter now, aiming to reduce to a few weeks
5-year plan for automation 34
BACLOFEN
Discovery of PXT3003
57 Drugs selected to screen
2,000+ drugs
Virtual screening
Down-regulation of Pmp22 in
Schwann cells 22 positive drugs (39%)
3 prioritized, 1 selected
NALTREXONE
SORBITOL
In CMT1A, excess Pmp22
protein is produced, leading
to instability and loss of
myelin
34
35
33 Drugs selected to screen
2,000+ drugs
Virtual screening
Protection of:
- Neurons
- Synapses
- Vessels25 positivedrugs (76%)
91 combinations tested
In AD, excess of β-Amyloid
is produced, leading to
neuronal/glial dysfunction
and cell death
Discovery of PXT864
Acamprosate Baclofen
Aβ-induced toxicity
32 positivecombos
4 combos prioritized, 1 selected
Summary Corporate Highlights
▪ Pharnext represents an opportunity with a combination of an AI-based drug development platform with an advanced
lead program with Phase 3 data and potential for FDA approval by late 2023
▪ Three distinct value drivers – PXT3003, PXT864 and PLEOTHERAPYTM AI Platform
• PXT3003 in Phase 3 for CMT1A
- Phase 3 data showing strong efficacy
- ~$1B WW potential revenue opportunity / IP through 2030
• PXT864 in Phase 2 for AD – strategy to out-license to commercial partner
- Novel mechanism, upstream of Aβ and tau mechanism approaches
- Subset with high drug plasma concentration showed improved CDR-SB above baseline for mild AD
patients
• PLEOTHERAPYTM AI platform – potential to produce pipeline across all therapeutic areas
- Approximately two years from start to initiation of human POC studies
36