Corporate Presentation - October 2018 - Solebury Trout Access
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Corporate Presentation October 2018
Disclaimer Some of the statements contained in this presentation constitute forward-looking statements. Statements that are not historical facts are forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as “may”, “will”, “expect”, “intend”, “estimate”, “anticipate”, “believe”, “continue” or similar terminology. These statements are based on the Company’s current strategy, plans, objectives, assumptions, estimates and projections. Investors should therefore not place undue reliance on those statements. The Company makes no representation, warranty or prediction that the results anticipated by such forward- looking statements will be achieved, and such forward-looking statements represent, in each case, only one of many possible scenarios and should not be viewed as the most likely or standard scenario. Forward-looking statements speak only as of the date that they are made and the Company does not undertake to update any forward-looking statements in light of new information or future events. Forward-looking statements involve inherent risks and uncertainties. The Company cautions that a number of important factors could cause actual results to differ materially from those contained in any forward-looking statement. 2
Well Diversified Mid-to-Late Stage Metabolic
Pipeline for Large Market Opportunities
• Key focus on type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH)
– Targeting cellular energy (mitochondria and AMPK), underlying root cause of diseases
– Portfolio with balanced R&D risk profile
• Partners funding Imeglimin Phase 3 program and commercialization in T2D
• Two NASH programs w/complementary MOAs for monotherapy and combination use
together or w/other agents
– Opportunity to expand in metabolic, specialty and rare diseases.
• T2D: Imeglimin Phase 3
– Full Phase 3 data readouts for Imeglimin in Japan (2019)
– Initiation of Phase 3 program for Imeglimin in US by Roivant Sciences (2019)
• NASH: PXL770 Phase 2 and PXL065 (DRX-065) Phase 1
– Phase 2a PoC and mechanistic data readout for PXL770 (1H 2020)
– Phase 2 PoC readout for PXL065 (1H 2021)
• Preclinical studies underway for additional metabolic and rare diseases
• Euronext listed (POXEL) with strong cash position
– EUR 76.8 million (USD 88.8 million) in cash & equivalents 9/30/18; runway into 2021
– Potential for up to $857M in Imeglimin milestone payments plus royalties
3
Leadership Team
Highly-Experienced Management Team
Noah Beerman Christophe Arbet-Engels
Thomas Kuhn Anne Renevot (MBA) (MD, PhD, MBA)
(Pharm D, MBA) Chief Financial Officer
Executive VP, CMO and EVP Late
CEO and Co-founder Business Development Development & Medical
and President, US Affairs
Operations
Sébastien Bolze
Sophie Bozec Pascale Fouqueray Jonae Barnes
(Pharm D, PhD)
(MD, PhD) Senior Vice President
Executive Vice President, (PhD)
Investor Relations &
Non-Clinical Development, Senior Vice President, Executive Vice President, Public Relations
Co-founder R&D Pharmacology, Early Development &
Co-founder Translational Medicine,
Co-founder
4
Metabolic Pipeline
Well-diversified Pipeline with Several Mid-to-late-stage Programs
Partner/
Indication MOA Preclinical Phase 1 Phase 2 Phase 3 Next Steps
Rights
• Phase 3 TIMES
Imeglimin
Type 2 Mitochondrial completion
Japan/
Diabetes Bioenergetics Ph 3 • Target JNDA
Asia* submission 2020
• Manufacturing
Imeglimin drug for Phase 3
Type 2 Mitochondrial
US/ EU/ Ph 3 • Differentiation
Diabetes Bioenergetics
Other** studies in CKD
patients w/ T2D
NASH/
Direct AMPK • Initiate Phase 2a
PXL770 metabolic Ph 2
activator program in NASH
diseases
• Complete Phase 1
PXL007 Hepatitis B
FXR agonist Ph 2 program by Enyo
(EYP001) NASH
Pharma
PXL065 • Complete Phase 1,
(formerly NASH MPC Inhibitor Ph 2 tox, CMC
DRX-065) • Initiate Phase 2
Poxel/ Metabolic Direct AMPK
• Complete
DeuteRx (AMN/ALD, activator/ MPC Ph 1 preclinical studies
programs NASH, etc.) Inhibitor
Open arrow designates expected development status in 2019
5
*including: China, South Korea, Taiwan, Indonesia, Vietnam, Thailand, Malaysia, the Philippines, Singapore, Myanmar, Cambodia, and Laos.
**countries not covered in the Sumitomo Dainippon Pharma agreement
Key Value Drivers
Japan is a Phase 3 TIMES Target JNDA
~$5B+* market fully enrolled with over submission
opportunity for T2D 1,100 patients; readouts 2020
with strong growth expected in 2019
Imeglimin
Approx. 2.4 million Study in T2D patients with CKD Phase 3 initiation
patients in the US with and manufacturing anticipated in 2019
T2D have CKD drug for Phase 3 program in T2D patients
stages 3b/4 in 2018 with CKD stages 3b/4
Unique opportunity PXL770 Initiation
PXL770
for NASH and other direct AMPK activator of Phase 2a PoC
chronic metabolic advancing into program In NASH
diseases Phase 2a program Q1 2019
Potential for expedited PXL065; d-R- Initiation
of Phase 2 PoC
PXL065
development in NASH and pioglitazone) a potent
orphan metabolic MPC inhibitor program In NASH
diseases in Phase 1 2H 2019
Focus on metabolic Conducting preclinical Additional metabolic
Preclin
diseases; specialty and studies in metabolic and rare
orphan indications and rare diseases opportunities
6
* Decision Resources, September 2014
Imeglimin
First in a New Class of Potential Anti-diabetic
Treatments with a Differentiated Mechanism of
Action
Imeglimin: A Differentiated
Mechanism of Action in the
Mitochondria Enabling
‘Glucose-plus’ Benefits
ROS: reactive oxygen species mPTP: mitochondrial permeability transition pore
Diabetic state: Impaired mitochondrial function leading to
• Insufficient insulin secretion from pancreas
• Insulin resistance in liver and muscles
• β-cells dysfunction and death
• Endothelial cell dysfunction and death
Imeglimin treatment: Restored normal mitochondrial function
• Glucose lowering related benefits:
– Improve β-cells function and survival
– Increase glucose dependent insulin secretion from pancreas
– Improve insulin sensitivity in liver and muscles
• Beyond Glucose lowering related benefits:
– Improve endothelial dysfunction
– Improve diastolic dysfunction
Sumitomo Dainippon Pharma Strategic
Partnership for Imeglimin in Japan, China, and
11 other Asian Countries
• Sumitomo has extensive track record in late-stage development and commercialization
with an established diabetes franchise
– Trulicity® (dulaglutide), Metgluco® (metformin hydrochloride), Surepost® (Repaglinide)
and Glimicron® (Gliclazide)
• Poxel received upfront payment of $42M (€36M) plus future potential development
milestone payments and sales-based payments of up to approx. $257M (€219M),
and escalating double-digit royalties on net sales
• Poxel and Sumitomo jointly developing Imeglimin for the treatment of type 2 diabetes
in Japan and Sumitomo assumes Phase 3 and commercialization costs
• Sumitomo will be solely responsible for Imeglimin development and commercialization
in China, South Korea, Taiwan and 9 other Southeast Asian countries*
• Phase 3 TIMES program (TIMES 1, TIMES 2 and TIMES 3) for Imeglimin in Japan
underway
– TIMES 1, TIMES 2 and TIMES 3 enrollment completed with over 1,100 patients
– Target JNDA submission in Japan 2020
9 *including: Indonesia, Vietnam, Thailand, Malaysia, the Philippines, Singapore, Myanmar,
Cambodia, and Laos.
Imeglimin Phase 2b Study in Japan Met Primary Endpoint
in Reduction of HbA1c vs. Placebo (N=299)
Change in HbA1c from baseline
European Association of the Study of Diabetes, in Lisbon (Sept. 2017)
10Similar Efficacy in T2D Patients with Renal Impairment
vs with Normal Kidney Function
eGFR ≥ 80 eGFR< 80 eGFR ≥ 80 eGFR< 80 eGFR ≥ 80 eGFR< 80
N =24 N =51 N =24 N =49 N =23 N =50
11Japan Development Strategy: Advance to JNDA
Submission in 2020 for T2D
Mechanism of action relevant for Asian T2D patients
Differentiated and Streamlined Development Program with 1,100 patients
2015 2016 2017 2018 2019 2020
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Phase 2b PMDA Ph 3 Monotherapy vs Placebo JNDA
Phase 1 Subm.
N=300 EOP2 N= ~200; 6-month treatment
Long term safety Mono & Add-on
to oral therapy (Open label)
N=~700; 12 months
Long term safety add-on to insulin
N=~200; 12 months
Non-pivotal trials planned: renal
impaired population
Sumitomo Dainippon Pharma is development and commercialization partner
for Japan
12Japan: Accessible T2D Market with Solid Growth $5B+
Anticipated to Grow to $6B in 2020
• 2nd largest diabetes market Global Type 2 Diabetes Market (Sales in $B)
outside of US/EU $60,0
• ~$5B+ (/year)
• Estimated sales in Japan $50,0
expected to grow to $6B by
$14,7
$13,3
2020; Imeglimin’s target $11,9
EU/ROW
date for JNDA submission
$40,0 $10,7
Japan
$9,6 6,1
$8,5 5,7 US
• Sitagliptin: ~$1.1B+ annual $6,5
5,2
5,4
sales in 3 years*
4,9
$30,0 4,6
4,5
• Clear development path $3,8
defined by PMDA: all recent $20,0 4,4
new agents approved with
34,4
31,3 32,8
28,4 29,8
~1,000 patients in Phase 3
27,0
23,8
$10,0 18,3
• Asia: significant opportunity
in China
$0,0
2013 2014 2015 2016 2017 2018 2019 2020
* Decision Resources, 2015 Report Source: Oppenheimer & Co. estimates
13Roivant Partnership for US/Europe/and
other Countries Worldwide*
• Roivant is an emerging leader with proven commitment to developing
innovative therapies for major disease areas, including type 2 diabetes
• Imeglimin will be a cornerstone program in Metavant
• Total deal value is $625M (~€507M)
– Upfront $50M (~ €40M); including $15M (~€12M) investment at €8.5 per share
– Up to $600M (~€486M) in future potential development and regulatory milestone
payments and sales-based payments
– Escalating double-digit royalties on net sales
• Roivant will be responsible for Imeglimin’s development and
commercialization in the U.S., Europe, and other countries*
– Poxel will contribute $25M (~€20M) to the development program over a two-year
period
• Poxel and Roivant will decide on a potential co-promotion prior to
commercialization
• Phase 3 program-related work is anticipated to begin in 2018
– Clinical studies for differentiation in sensitive patient populations, such as those
with chronic kidney disease due to type 2 diabetes
– Manufacturing of drug product for use in Phase 3 program
• Goal is to initiate Phase 3 Program in 2019
14 *countries not covered in the Sumitomo Dainippon Pharma agreementRoivant Development Focus for Imeglimin (RVT-1501)
• Roivant to develop Imeglimin (RVT-1501) first specifically to treat patients with type
2 diabetes with chronic kidney disease (CKD) stages 3b/41
– Opportunity to study Imeglimin in broader T2D population
• Diabetes is the most common cause of chronic kidney disease
• Patients with type 2 diabetes and CKD stages 3b/4
– Approximately 2.4 million adults in the US2
– Patients have Increased cardiovascular risk
– Challenging glucose management
• Underserved population
– Many approved therapies require dose reduction or are not recommended in the
presence of kidney disease
– Insulin and insulin secretagogues are the most commonly used therapies at
suboptimal doses to prevent risk of hypoglycemia
– Need for a new treatment at optimal dose, providing a strong efficacy and safety
profile with no hypoglycemia risk
• Imeglimin Phase 2 data (Japan & US) showed similar safety & efficacy in patients
with impaired renal function compared to patients with normal renal function
1 CKD stage 3b= eGFR 30-44 ml/min/1.73 m2 inclusive; CKD stage 4 = 15-29 ml/min/1.73m2 inclusive
2 Centers for Disease Control and Prevention (CDC). NCHS. NHANES. Laboratory Data, 2015-2016. Hyattsville,
15
MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2017.PXL770 and PXL065 (DRX-065)
Two Differentiated Drug Candidates with
Complementary Mechanisms of Action for the
Treatment of NASHProgression of Non-alcoholic Fatty Liver Disease (NAFLD)
Metabolic syndrome High morbidity
Excessive caloric intake Dyslipidemia
Type II diabetes Cardiovascular events
sedentary lifestyle (leading cause of death)
Obesity
Hepatic impairment
Hepatocellular carcinoma
NAFLD NASH
25% of the general 12% of the general
population population
>70% in diabetic & 25-70% in diabetic and
Normal obese patients obese patients ≥ 50 Cirrhosis
17 J.Hepatology 2018, 68, 362-375NASH: A Multifactorial Metabolic Disease
Adipose
Tissue
Lipolysis 70%
NASH
Low grade inflammation
Liver
Peripheral STEATOSIS INFLAMMATION FIBROSIS
Insulin
Resistance
Hepatic
Stellate Cells
Muscle Activation and
collagen deposition
Sugar
FFA
Mitochondria
Hepatocytes
Impaired mitochondrial
integrity and functions
De Novo Lipogenesis 20% TG
18Expected Effects of PXL770 for NASH
a Direct AMPK Activator
Effects in Liver
Effects in
Adipose Tissue
NASH
Steatosis
Chronic inflammation
Low grade inflammation
Lipolysis
Effects in
Peripheral insulin resistance Hepatic
Stellate
Cells
Fibrogenesis
Effects in Muscle Hepatic stellate cell activation
Mitochondrial integrity
De novo Mitochondrial functions
lipogenesis
Effects in Mitochondria
Effects in Hepatocytes
19PXL770 Strongly Improves Liver Steatosis and NAS in a Diet
induced Obesity Biopsy-Proven NASH Mouse Model
Male C57BL/6J were fed a diet high in trans fat (40%), fructose (20%) and cholesterol (2%) for a
total of 41 weeks and treated during 8-week treatment
L iv e r s t e a t o s is
0
C h a n g e ( % ) v s D IO c t r l
NAFLD Activity Score (NAS) Liver Triglycerides
-2 0
R e la tiv e liv e r T G
-4 0
100
8
-6 0
80
L iv e r t r ig ly c e r id e ( m g /g liv e r )
6 -8 0
**** H e p a t ic b a llo o n in g ***
-1 0 0
60 ****
****
NAS
4 0 ****
C h a n g e ( % ) v s D IO c t r l
**** 40
2
-5 0 20
****
0
)
le
)
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0
g
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/k
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0
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h
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g
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e
(3
-1 0 0
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(3
(7
m
m
m
S
V
V
A
r
L iv e r in f la m m a t io n
5
5
0
0
0
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o
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-N
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(7
(3
7
7
n
S
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O
ra
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0
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7
X
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-C
fi
7
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P
P
0
ra
IO
L
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la
N
X
X
b
E
D
fi
A
P
P
C h a n g e ( % ) v s D IO c t r l
la
E
L
E
-1 0
P X L 7 7 0 (7 5 m g /k g )
-2 0
P X L 7 7 0 (3 5 m g /k g )
-3 0
E la fib r a n o r ( 3 0 m g /k g )
-4 0
-5 0
20 PXL770 improves steatosis, hepatocytes ballooning and inflammation scores
Poster#4, Global NASH Congress, 26th–27th February 2018, London, UKPXL770 Improves Fibrogenic Gene Expression in a Diet
Induced Obesity Biopsy-Proven NASH Mouse Model
Male C57BL/6J were fed a diet high in trans fat (40%), fructose (20%) and cholesterol (2%) for a
total of 41 weeks and treated during 8-week treatment
21 Poster#4, Global NASH Congress, 26th–27th February 2018, London, UKPXL770 Improves the Main CV Risk Factors Associated with
NASH
• PXL770 improves CV risk
factors in several metabolic
rodent models:
– Glycemic control: basal
glycemia, glucose
tolerance and HbA1c
– Circulating lipids (TGs,
cholesterol)
– Fat mass and body
weight
– Insulin sensitivity
22 European Association for the Study of Diabetes, 12th–16th September 2016, Munich, GermanyPXL770: Favorable Safety, Tolerability and
Pharmacokinetics in Phase 1 Program (n=124)
• Favorable safety after single ascending and multiple ascending doses from
30 mg up to 500 mg:
– Well tolerated
– No serious adverse events or adverse events leading to withdrawal
• Good PK profile
• No drug-drug interaction with rosuvastatin (statin drug)
– Lack of PK interaction between PXL770 and OATP substrates
• No observed cardiac toxicity
– PXL770 had no effect on ECG parameters, including QT interval at all doses
– Dedicated ECG recording (holter) ruled out rhythm or conduction disorders after
13 weeks in dogs
– PXL770 administration in 4-week and 13-week toxicology studies both in rats and
dogs have shown the absence of cardiac hypertrophy and glycogen storage, even
at highest doses
23PXL770 Development Strategy to PoC for NASH
Phase 2a Phase 2a results
initiation (Efficacy, Safety) Phase 2b initiation
PXL770 2017 2018 2019 2020
NASH data in Clinical mechanistic
Phase I MAD animal model part of study Clinical
initiation Phase 1 MAD initiation mechanistic
results (Safety, PK) data
Phase 1 Favorable Results Phase 2 Proof of Concept
• Good safety, tolerance and • Phase 2a in ~100 patients with NAFLD/NASH
pharmacokinetics profile after single and – 12-week treatment
multiple ascending administration up to – Primary endpoint: change in liver fat mass
the highest dose tested of 500 mg based on MRI-PDFF
– No drug-drug interaction with – Initiation in Q1 2019
rosuvastatin (statin drug) • Clinical mechanistic component to assess the
– No observed cardiac toxicity effect of PXL770 on inhibition of lipolysis and
hepatic de novo lipogenesis (DNL)
• Considering additional PoC studies in other
metabolic indications
24PXL065 Target Profile:
Benefits of Pio for NASH with Reduced PPARγ Side Effects
Pioglitazone: A mix of 2 mirror image compounds with different MOAs
S-Pio (stabilized) PXL065 (stabilized R-pio)
MPC inhibitor Potent MPC inhibitor
NIDC 64764-451-26
500 Tablets
Strong PPARγ agonist actos ® NOT a PPARγ agonist
(pioglitazone)
Tablets
45 mg
Undesired side effects: Anti-inflammatory
◦ Weight gain NASH efficacy
◦ Fluid retention
PXL065
deuterium-stabilized R-pio
S-Pio R-Pio
25PXL065 for the Treatment of NASH
Parent Drug Benefits Well Established – Use Limited by PPARγ
• Pioglitazone (parent drug of PXL065) has been extensively studied for NASH
– Pioglitazone efficacy demonstrated for NASH and advanced fibrosis in NASH
• Achieved “Resolution of NASH without worsening of fibrosis” in Phase 4 trial1
• Reduces incidence of hepatocellular carcinoma and other cancers2
• Only drug recommended off-label for NASH by AASLD & EASL Practice Guidelines3
• Has shown better efficacy than other agents studied in NASH
– Currently prescribed by ~14% of physicians to biopsy-proven NASH patients4
• Limited uptake due to PPARγ side effects of weight gain, fluid retention, bone
fractures
• PXL065 MOA provides potential for combination with other agents, including PXL770
• Precedent for derisked and expedited development
– Single isomer from mixtures (chiral switch) via 505(b)(2) or related regulatory path
• Prilosec® to Nexium® and Celexa® to Lexapro®
– 1st deuterated drug approval as NCE via 505(b)(2): Austedo® by Teva / Auspex
• Strong composition of matter patent protection
1. Ann Intern Med. 2016, 165(5), 305-315
2. Hepatology 2012, 55, 5, 1462-1472; J Clin Pharm Ther, 2014, 39, 354-360
3. J Hepatol. 2016, 64(6),1388-402; Hepatology 2018, 67, 328-357
26 4. Therap Adv Gastroenterol. 2016, 9(1), 4-12Pioglitazone (racemate) has been shown to be an Efficacious
Agent in Biopsy-proven NASH
>2 Point Reduction in NAS Resolution of NASH
without worsening of fibrosis without worsening of fibrosis
P < 0.001
80% 80%
P < 0.001
Patients with Improvement, %
Patients with Improvement, %
70% 70%
P = 0.02
60% 60%
P = 0.0002
50% 50%
40% 40%
76%
70%
P = 0.02
30% 30%
56% P = 0.08
P = 0.519 P = 0.018 P = 0.0514
45%
20% 20%
pbo
32% pbo P = 0.494 27%
pbo pbo pbo
10% 10% 25% 22% 20%
19% 21% 19% 16% pbo 17%
pbo
13% 11% pbo 8% pbo pbo
0% 0% 6% 6% 5%
Pio Ocaliva CVC MGL-3196 Pio Ocaliva Elafibranor CVC MGL-3196 Aramchol
Intercept Allergan Madrigal Intercept Genfit Allergan Madrigal Galmed
NAS – Nonalcoholic fatty liver disease (NAFLD) activity score
Pio Cusi Phase 4 trial (45 mg, 18 mos) - Ann Intern Med. 2016, 165(5), 305-315 (only completers with definite NASH at baseline)
OCA FLINT Phase 2 trial (25 mg, 72 wks/16 mos) - Lancet. 2015, 385(9972), 956–965
CVC (Cenicriviroc) CENTAUR Phase 2b trial (150 mg, 1 yr/12 mos) – Hepatology 2017 (doi: 10.1002/hep.29477)
Elafibranor Phase 2 trial (120 mg, 52 wks/12 mos) - Gastroenterology. 2016, 150(5), 1147-1159
MGL-3196 Phase 2 trial (36 wks/8 mos) – press release May 31, 2018. Results from per protocol, not intent to treat (ITT) population. ITT will be lower.
Aramchol Phase 2 trial (600 mg, 52 wks) – press release June 12, 2018. No effect on ”Fibrosis without worsening of NASH”.
27PXL065 Inhibits the Mitochondrial Pyruvate Carrier (MPC)
without PPARγ Agonism
MPC inhibition in HepG2 cells PPARγ agonist activity
P y r u v a te -d r iv e n r e s p ir a tio n
125
100
P P A R γ a c tiv a tio n
100
75
c o n tr o l)
P X L065
75 P io g lita z o n e
50
50
(%
25
25
%
0 0
-8 -7 -6 -5 -4
0 0 .1 1 10 100
C o n c (µ M ) L o g C o n c (M )
IC50 EC50
PXL065: 6.5 µM PXL065: >100 µM
Pioglitazone: 6.8 µM Pioglitazone: 4.6 µM
PPARy activation in fluoresecence-based TRAP220 coactivator recruitment assay
28 Results are expressed as % of response of positive control (10µM rosiglitazone)Expected Effects of PXL065 for NASH
a Mitochondrial Pyruvate Carrier (MPC) Inhibitor
Effects in Liver
Effects in
Adipose Tissue
NASH
Steatosis
Chronic inflammation
Fibrosis
Neoglucogenesis
Peripheral insulin resistance
Effects in Muscle
Mitochondrial integrity
Mitochondrial functions
Effects in Mitochondria
29PXL065 Equal to Pio in NASH mouse Models
Liver NAS & Fibrosis measured in CD & MCD Diet Mouse Models
N A F L D A c tiv ity S c o r e F ib r o s is
C o lla g e n D e p o s itio n S c o r e
10 C D d ie t M C D d ie t 3 C D d ie t M C D d ie t
8 ** *** ** ** **
*** *** *
2
6
NAS
4
1
2
0 0
e
e
e
e
le
le
le
le
5
5
5
5
n
n
n
n
6
6
6
6
ic
ic
u
u
o
o
o
o
0
0
0
0
ic
ic
h
h
z
z
z
z
L
L
L
L
e
e
h
h
ta
ta
ta
ta
X
X
X
X
v
v
e
e
li
li
li
li
P
P
P
P
v
v
g
g
g
g
io
io
io
io
p
P
P
P
Liver histopathology on day 43 in mice fed a Choline Deficient or an Methionine/Choline
Deficient diet, Pioglitazone (30 mg/kg/day) or PXL065 (15 mg/kg/day)
Wilcoxon rank sum test vs vehicle; * p < 0.05, ** p < 0.05, *** p < 0.001
30PXL065 (DRX-065): Favorable Safety, Tolerability and
Pharmacokinetics in Phase 1
• Phase 1a: single oral dose of PXL065 (22.5mg)
or Actos® (45mg) in healthy subjects, 18-40
years old
• Safety & Tolerability
– PXL065 was safe and well-tolerated
• PK Results:
– Confirmation of the stabilisation of d-R-pio
with limited interconversion to S-pio
– Relative exposure (AUC) to R-pio/S-pio
increased ~3x
– No change in elimination half-life
– PKPD simulation predicts PXL065 active dose
at 15mg qd, with similar efficacy as
pioglitazone 45mg qd, and no weight gain
31PXL065 Development Strategy to PoC for NASH
Add. 13-w dog Phase 2 Phase 2 results
Pharmaco. tox data initiation (Efficacy, Safety)
(single species)
data
PXL065 2018 2019 2020 2021
Phase I SAD Phase 2b/3
completion initiation
Phase 1 MAD
results (Safety, PK)
Favorable Preclinical and Phase 1 Results Phase 2 Proof of Concept
• Abbreviated tox package to be • Phase 2 in ~120 patients with NAFLD/NASH
performed due to 505(b)(2) process – 12 to 24 week treatment – 2 doses vs Actos vs
Placebo
• Good safety, tolerance and
– Primary endpoint: change in liver fat mass
pharmacokinetics profile after single
based on MRI-PDFF
administration in comparison to
– Safety including weight
pioglitazone
– Secondary endpoints: metabolic, inflammation
• Completion of SAD
and fibrosis biomarkers
• MAD execution
– Initiation in Q4 2019
32PXL770 and PXL065 Differentiated in NASH
Comparison of drug effects across key measures
Target Agents Current Results from Reduction of Hepatic Parameters Side Effects
MoA Phase
Animal Human Steatosis Ballooning Inflammation Fibrosis
pruritus,LDL-C,
FXR OCA1 3
potential liver damage
Serum creatinine
PPARαδ Elafibranor2 3 limited X
increase (P2)
CCR2,5 CVC3 3 X X X well tolerated (P2)
ASK1 Selonsertib4 2 Limited X X well tolerated (P2)
THRβ MGL-31965 2 X well tolerated (P2)
weight gain, fluid
PPARγ Pioglitazone6 generic
retention, bone fractures
Direct AMPK
PXL770 1 well tolerated (P1)
activator
MPC
PXL065 1 ✓
well tolerated (P1)
inhibitor
1. Lancet. 2015; 385(9972): 956–965
2. Gastroenterology. 2016; 150: 1147–1159
3. Hepatology. 2018; 67(5): 1754-1767
4. Hepatology. 2018; 67(2): 549-559
5 Press release Madrigal’s: MGL-3196 achieves liver biopsy endpoints in patients with NASH at 36 weeks in phase 2 clinical trial. May 2018
6. Annals of Internal Medicine. 2016; 165: 305-315
33 MPC – mitochondrial pyruvate carrierExpected Effects of PXL770 and PXL065 for NASH
Effects in Liver PXL-770
Effects in
Adipose Tissue
NASH PXL-065
PXL-770 Steatosis
Chronic inflammation
PXL-065 Fibrosis
Neoglucogenesis
Low grade inflammation
Lipolysis
Effects in
Peripheral insulin resistance Hepatic
Stellate
Cells
Fibrogenesis
Effects in Muscle Hepatic stellate cell activation
De novo
lipogenesis
Effects in Mitochondria
Effects in Hepatocytes
34Summary
Several Near-Term Catalysts
• Imeglimin for T2D
– Imeglimin data published related to efficacy, safety, pharmacokinetics (2018)
– Phase 3 initiation in US/Europe (2019)
– Phase 3 TIMES program data readouts (beginning in Q2 2019)
– NDA submission in Japan (2020)
• PXL770 for NASH
– Phase 2a PoC study preparation (IND filing & manufacturing) (2H 2018)
– European NASH Summit oral presentation (Q4 2018)
– AASLD abstract and poster presentation (Q4 2018)
– Phase 2a PoC initiation in NASH (Q1 2019)
– Phase 2a PoC results in NASH (1Q 2020)
• PXL065 for NASH
– AASLD abstract and poster presentation (Q4 2018)
– Completion of Phase 1 study (2H 2019)
– Phase 2 PoC initiation in NASH (2H 2019)
– Phase 2 PoC readout (1H 2021)
• Additional preclinical data on other metabolic and rare diseases (2019)
36Corporate Presentation October 2018
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