Poxel : Corporate Presentation - English

Corporate Presentation

August 2020

1

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.

In the context of the COVID-19 outbreak, which was declared a pandemic by the World Health Organization (WHO) on March 12, 2020, the Company is regularly reviewing the impact of the outbreak on its business.

The Company anticipates that the COVID-19 pandemic could have a material negative impact on our business operations. The worldwide impact of COVID-19 may notably affect the Company's internal organization and efficiency, particularly in countries where it operates and where confinement measures have been implemented by the authorities.

In addition, the deteriorating market conditions may impact the Company's ability to raise additional funding and/or to

enter into partnerships. Particularly, delays in the supply of drug substance or drug products, in pre-clinical and/or clinical trials, as well as delays linked to the responsiveness of regulatory authorities could occur, which could potentially have an impact on the Company's development programs. The Company will continue to proactively monitor the situation.

2

Mission and Vision

To discover, develop and commercialize innovative therapies for patients suffering from

serious chronic diseases with underlying metabolic pathophysiology

• Mid-to-latestage first-in-class pipeline: Type 2 diabetes (globally partnered) and NASH
• Pipeline expansion in chronic and rare metabolic indications

1. Internal AMPK* and D-TZD# Platforms o External Opportunities

Targeting Defects in Cellular Metabolism

acetyl CoA

METABOLICINFLAMMATION DISORDERS

(cellular energy

homeostasisTISSUE

imbalances) DEGENERATION & CELL DEATH

apoptosis, necrosis

Leveraging AMPK & D -TZD Platforms

Metabolic Component + Unmet Medical Need

• Hereditary Metabolic Disorders: e.g. adrenoleukodystrophy
• Endocrinopathies
• Renal Diseases:
  e.g. diabetic nephropathy, polycystic kidney disease, others
• Other: rare, orphan indications

*AMP activated protein kinase; # Deuterium-stabilized thiazolidinediones

3

Three Mid-to-Late Stage First-in-Class Drug Candidates with Novel Mechanisms and Differentiated Strategies

Global

Partnerships

Novel Mechanisms with Platform Expansion

Proprietary Programs

Cash &

Equiv. EUR 46M (USD 51.5M) as of 6/30/20

Imeglimin

(T2D)

AMPK

PXL770*Platform

PXL065** D-TZD

Platform

Other

Chronic and

Rare Leveraging

Metabolic Platforms &

Indications External

Opportunities

Anticipated first product launch in Japan in 2021 through Imeglimin

partnership with Sumitomo Dainippon Pharma

Several significant milestones in 2020 including results in NASH & other metabolic indications

Highly experienced management team; extensive metabolic R&D expertise & track record in US, EU and Japan

Global company with presence in 3 countries (France, US and Japan); listed on Euronext Paris

4

*PLX770 direct AMP-kinase activator (AMPK) from platform **PXL065 deuterium-stabilizedR-pioglitazone (mitochondrial pyruvate inhibitor) from D-TZD (deuterated thiazolidinediones) platform

Poxel Targets Key Mechanisms that have Distinct Roles in Regulating Cellular Energy Homeostasis

Multiple Entry Points Available to Intervene in Metabolic Diseases

AMPK

ActivatesInhibits

catabolicinflammation

pathwaysapoptosis

Inhibits anabolic

pathways

NASH Other

AMP-activated Protein Kinase (AMPK),

cellular energy sensor - activation:

reduces liver fat, increases insulin sensitivity, decreases inflammation

NASH Other

Mitochondrial Pyruvate Carrier

(MPC), fuel gate-keeper- inhibition:

promotes fat utilization, increases insulin

sensitivity, decreases inflammation

	MPC
	Acetyl
Pyruvate	Co-A
TCA
	cycle

NADH

FADH2

T

T2D

Mitochondrial Respiratory Chain (MRC), cell's energy producing machine - potential to modulate

function: improves β-cell function, increases insulin sensitivity, improves endothelial and diastolic dysfunction

ATP

MRC

5

MITOCHONDRIA

Poxel Mid-to-Late Stage Metabolic Pipeline

Due to COVID-19, the Company Continues to Monitor All Developments that Might Impact the Timelines for Achievement of our Corporate Objectives

	Indication		MOA	Discovery/PC	PH 1	PH 2	PH 3	NDA review	Partner/ Rights Upcoming Milestones
Type 2 Diabetes
Imeglimin	Type 2 Diabetes									▪	Target product launch 2021
Japan /		MRC Modulator
(T2D)
Asia*
Imeglimin	T2D patients									▪ Ongoing Ph3 dialog w/ FDA; initiate
US / EU /	with CKD stages		MRC Modulator
								Ph 3 post-FDA discussion
Other**	3b/4
NASH
PXL770	NASH		Direct AMPK							▪ Ph 2a results late 3Q 20
	Activator
										▪	Utilize 505(b)(2) pathway
PXL065	NASH		MPC Inhibitor							▪	2H 20 Ph 2; initiation subject to
											COVID-19 environment
PXL007	Hepatitis B /		FXR Agonist							▪ Complete Ph 2a program by Enyo
(EYP001)	NASH									Pharma 2H 2020
Other Chronic and Rare Metabolic Indications
Next-Gen	Adreno-		Direct AMPK
AMPK								▪	Complete preclinical studies
leukodystrophy		Activator
								2020
	Chronic Kidney
Next-Gen D-									▪	Select lead candidates
Diseases		MPC Inhibitor
TZD
Undisclosed

*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.

6

Leadership Team

Highly Experienced Management Team; Extensive R&D and Metabolic Expertise

Thomas Kuhn (Pharm D, MBA)

CEO and Co-founder

David Moller (MD)

Executive Vice President, Chief Scientific Officer (CSO)

Sophie Bozec (PhD)

Senior Vice President,

R&D Pharmacology,

Co-founder

Anne Renevot

Chief Financial Officer

Jonae Barnes

Senior Vice President,

Investor Relations & Public Relations

Quentin Durand

Chief Legal Officer

Noah Beerman (MBA)

Executive Vice President,

Business Development &

President, US Operations

Sébastien Bolze

(Pharm D, PhD)

Executive Vice President,

Non-Clinical Development,

Co-founder

Pascale Fouqueray (MD, PhD)

Executive Vice President,

Early Development & Translational

Medicine, Co-founder

7

Type-2-Diabetes

Imeglimin

Global Partnerships

First in a New Class of Potential Anti-diabetic Therapies with a Differentiated Mechanism of Action

8

Successful Completion of Phase 3 Program in Japan

JNDA Under Review; Target Launch 2021

Poxel led Phase 3 TIMES program in >1,100 T2D patients; met endpoints and objectives and observed to be safe and well-tolerated

		2018				2019	2020
Q1	Q2	Q3	Q4		Q1	Q2	Q3	Q4

TIMES 1: Monotherapy vs placebo

N= 213; 6-month treatmentJNDA Review

TIMES 2: Long term safety Mono &

Add-on to oral therapy (Open label)

N=~714; 12 months

TIMES 3: Long term safety add-on to insulin N=215; 12 months

Non-pivotal trials in renal impaired

population

Partnership Details

• Sumitomo commercialization partner for Japan, China and 11 other East and Southeast Asian countries*
• Future potential development milestone payments and sales-based payments of up to approx. $257M
• Double-digitescalating royalties

Business Opportunity Japan: Maximize Product Profile

• Sumitomo #1 diabetes franchise; Guidance FY20 $900M1
• DPP4i's are prescribed to 80% T2D patients2
• Limited treatment options for selected populations,

incl. elderly and patients with renal impairment

• 1. elderly patients account for ~60% of T2D in Japan
• TIMES program observed to show robust efficacy with favorable safety and tolerability profile

* including: South Korea, Taiwan, Indonesia, Vietnam, Thailand, Malaysia, the Philippines, Singapore, Myanmar, Cambodia, and Laos. 1. Sumitomo Fiscal Year April-March 2. IQVIA data FY2016 and NDB data FY2016

9

Imeglimin Phase 3 TIMES Program Overview (N=1,142)

Robust and Consistent Efficacy in Monotherapy and as an Add-on Therapy

		TIMES 1*				TIMES 2						TIMES 3
	Monotherapy		As an Add-on to Standard of Care		Combination with Insulin
Change in HbA1c - 24 Weeks		Change in HbA1c (vs baseline) - 52 Weeks			Change in HbA1c - 16 Weeks
		Placebo	Imeglimin										Placebo	Imeglimin
Patients (n)	(N=107)	(N=106)							Patients (n)		(N=107)	(N=108)
HbA1c (%), mean (SD) 7.93 (0.684)	7.99 (0.764)							HbA1c (%), mean (SD)	8.8 (0.8)	8.7 (0.7)
		1000 mg										1000 mg
Placebo	0		Baseline	0						Placebo	0
						-0,12
from	-0,2		from	-0,2						from	-0,2
	LS mean (SE) = -								LS mean (SE) =
Change		0.87% (0.09)	Change		-0,56		-0,57			Change		-0.60% (0.10)
-0,4		-0,4			-0,46	-0,4		-0,6
MeanLS			MeanLS						MeanLS
-0,6		-0,6		-0,67				-0,6	p < 0.0001
					-0,7
-	-0,8	-0,87	-	-0,8		-0,88	-0,85			-	-0,8
(%)			(%)		-0,92				(%)
HbA1c	-1	p < 0.0001	HbA1c	-1						HbA1c	-1
					SU: Sulfonylurea	GLIN: Glinides	BIG: Biguanides	TZD:
					Thiazolidinediones AGI: Alpha-glucosidase inhibitor
	-1,2			-1,2							-1,2

10

*European Association for the Study of Diabetes meeting 2019

Imeglimin Development Strategy for the US & EU

Targeting Type 2 Diabetes Patients with Chronic Kidney Disease (CKD) Stages 3b/4

• Development and commercialization partner in the US, Europe, and other countries*
• Poxel and Roivant will decide on a potential co-promotion prior to commercialization

Partnership Details

• Upfront payment: $35M1
• Equity Investment: $15M at €8.5/share
• Future potential development and regulatory milestone payments and sales-based payments of up to $600M
• Double-digitescalating royalties

Initial Development Focus: T2D patients with CKD stages 3b/42

• Demonstrated similar efficacy and was well-tolerated in renally impaired patients (TIMES 1 & Phase 2 data; Japan, US and Europe)
• PK/PD trial met primary objective in this patient population

1. • 1. Favorable safety and tolerability profile observed o PK/PD data consistent with previous Poxel data
   • Given FDA feedback and new draft guidance in March 2020, Metavant is adjusting its Phase 3 plan
   • New FDA interactions planned for 2H 2020
2. Poxel contributed $25M (~€20M) to development program over a 2-year period.
3. CKD stage 3b= eGFR 30-44 ml/min/1.73 m2 inclusive; CKD stage 4 = 15-29 ml/min/1.73m2 inclusive.

11

*countries not covered in the Sumitomo Dainippon Pharma agreement

Limitations of Current Therapies to Treat T2D by Kidney Disease Stage Drives Metavant Focus for Imeglimin

T2D patients with CKD stages 3b/4

• Diabetes is the most common cause of CKD
• ~ 2.4 million adults in the US2
• Increased cardiovascular risk and challenging glucose management

Underserved patient population

• Many therapies require dose reduction or not recommended in the presence of kidney disease
• Insulin and insulin secretagogues most commonly used at suboptimal doses to prevent hypoglycemia risk
• We believe there is a need for a new treatment with robust efficacy and safety profile with no hypoglycemia risk

Please note that references for this slide are in the Appendix section.

Therapy1-16

CKD 3a

CKD 3b

CKD 4

Primary Concern of Using

Agent in Advanced CKD

BG

Metformin

Increased risk of lactic

acidosis17

4i

Sitagliptin

Increased risk of precipitating

DPP-

Saxagliptin

symptoms of heart failure2-4

Linagliptin

SGLT2i

Canagliflozin

Empagliflozin

Reduced glucose

Dapagliflozin

lowering effect18

RA

Exenatide ER

Liraglutide

Increased gastrointestinal

GLP1-

adverse effects; risk of

Dulaglutide

worsening kidney function19-21

Semaglutide

SU

Glyburide

Hypoglycemia22

Glimepiride

Glipizide

Contraindicated for patients

TZD

Pioglitazone

diagnosed with heart failure15

Insulin

Titrate to Response

Hypoglycemia22

= no dose reduction

= use with caution

= dose reduction

= should not be used/contraindicated

12

NASH

PXL770

Proprietary Program

Direct AMPK Activator for the Treatment of NASH

13

Progression of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)

	Metabolic syndrome		High Morbidity
	Dyslipidemia
Excessive caloric intake	Type 2 diabetes		Cardiovascular events
Obesity
Sedentary lifestyle		(leading cause of death)
	NASH
	NAFLD	Hepatic impairment
	12% of the general	Hepatocellular carcinoma

Normal

25% of the general	population
population	25-70% in diabetic
>70% in diabetic &	and obese patients
obese patients	≥ 50

Cirrhosis

Estimated Market Opportunity: >$20B by 2025

J.Hepatology 2018, 68, 362-375. Market Research Engine, Jan. 2020.

14

PXL770 & PXL065 Aim to Address Hallmarks of NASH Pathology

NASH is a Complex, Multifactorial Disease

Fat gets released from the adipose tissue and accumulates in the liver cells and stays stored there

Steatosis

HALLMARKS OF NASH

MΦ

	Fat accumulation and
Macrophages (MΦ)	inflammation cause	Hepatic stellate cells
become activated and lead	degenerative structural	become activated and
to inflammation in the liver	changes; ballooning is a sign	create scar tissue
	of cell damage & suffering
Inflammation	Ballooning	Fibrosis

There are no currently approved drugs that treat symptoms & complications across all four categories

15

AMPK Activation Observed to Restore Metabolic Balance

PXL770 is a Direct AMPK Activator

AMPK

Overnutrition (metabolic syndrome, NASH, Type 2 Diabetes)

Caloric Restriction, Exercise

1) Activates catabolic pathways

• Fatty acid oxidation
• Glucose uptake
• Glycolysis

PXL770

1. Inhibits anabolic pathways
2. • Fatty acid & triglyceride synthesis (via ACC inhibition)*
   • Cholesterol synthesis
   • Protein synthesis
   • Mitochondrial biogenesis

3) Other benefits

• Reduces inflammation

↓macrophage and dendritic cell activation

• • pro-inflammatorycytokines
  • Nf-κΒ plus many others
• Reduces tissue damage (e.g. apoptosis via Caspase 6)
• Inhibits lipolysis in adipose

*Acetyl CoA carboxylase; a direct AMPK target; clinically validated; GS-0976 [Gastroenterology 155:1463-, 2018].

16

Activating AMPK Observed to Show Beneficial Effects in NASH

HALLMARKS OF NASH

MΦ

Steatosis

Inflammation

Ballooning

Fibrosis

Improves steatosis by	Decreases inflammation by	Decreases structural	Decreases hepatic
limiting fat flux from	moving from a pro-	degenerative changes	stellate cell activation
adipose tissue and de	inflammatory phenotype to an	and improves cell health	and limits fibrosis
novo lipogenesis	anti-inflammatory phenotype

We believe PXL770 also has the potential to be used in combination with other mechanisms

for additive benefits

17

These results were observed in mouse model preclinical study.

PXL770: Preclinical Data Observed to Show Potential to Treat Underlying Root Causes of NASH

Data Observed in Multiple Rodent Models Supports Potential for PXL770's

Beneficial Clinical Effects	A.	NASH Vehicle	PXL770

1. Improved liver steatosis
2. Decreased liver (and adipose tissue) inflammation

1. Decreased profibrogenic pathways in liver
2. Improved plasma liver enzymes (ALT and AST)
3. Improved NAFLD Activity Score (NAS)

LEAN- Chow vehicle		DIO-NASH PXL770 75mg/kg bid
DIO-NASH vehicle		DIO-NASH PXL770 35mg/kg bid

**: p< 0.01, ***: p< 0.001; **** p<0.0001 compared to DIO-NASH vehicle. n=11-12/group

Poster#4, Global NASH Congress, 26th-27th February 2018, London, UK.

18

B. Total Liver Macrophages	C. Collagen 1A1 (Liver)
	3×10	6		40
Ly6C		(RPKM)velle
		20
++				30
	2×10
Liver		**	Expression
1×10	6		***	***
				10
		****			***
	0		0

D. Plasma ALT			E. NAS Score
	300				8
(U/L)
			NAS
inotransferaseam	200			6
					****
						****
					4
alanine
100	****
Plasma			****		2
****
	0				0

PXL770: Preclinical Data Observed to Show Potential to Treat Underlying Root Causes of NASH

Data Observed in Multiple Rodent Models Supports Potential for PXL770's Beneficial

Clinical Effects

• Improves metabolic syndrome associated with NASH
• • Improves glycemia and lipids in metabolic rodent models:
  • • Increased insulin sensitivity
    • Glycemic control: basal glycemia, glucose tolerance and HbA1c

Insulin Sensitivity

200

-1)

(mg.dL	150
Bloodglucose	50
	100
	0	20	40	60
			Time (min)

Fat Oxidation

ob/+ mice	Vehicle
ob/ob or	HFD mice Vehicle
HFD mice	PL770 75mg/kg bid
HFD mice	Pioglitazone 20mg/kg qd
ob/ob mice	PXL770 100mg/kg bid

• • Lower circulating lipids (TG's, FFA's)
• Induces a metabolic switch toward preferential fat oxidation

19

Mean fat oxydation (g/d/kg0.75)

4

****

3

****

2

1

0

Day 8	Day 22
WD	WD

****P<0.0001 vs. veh group. WD: Whole Day

PXL770: Encouraging Clinical Results Observed (n=148)

Dose-Dependent PK; Favorable Safety/Tolerability; Target Engagement; Efficacy Signals

Phase 1 Healthy Subjects (n=132)

• Linear, dose-proportional exposure with single and multiple* doses
• Terminal half-life 25h
• No drug-drug interaction with rosuvastatin (OATP and BCRP substrate)
• No SAEs or AEs leading to discontinuation
• Good tolerability; low placebo-like incidence of TAE events
• No effect on ECG parameters (no QT prolongation)

PK/PD Trial: Obese, Insulin Resistant (n=16)

• Four-weekplacebo-controlled study in likely- NASH patients
• Study objectives met:
• • Consistent PK profile
  • Target engagement & efficacy signals:
  • • suppression of de-novo lipogenesis∆ (liver synthesis of new lipids)
    • improved glucose tolerance# and indices of insulin sensitivity^
  • Safety and tolerability similar to placebo

Results support potential in NASH and for AMPK platform

in other chronic and rare metabolic diseases

20

* Up to 375 mg (less than dose-proportionate at 500 mg); ∆ DNL assessed via fructose loading with D2O labelled palmitate measurements; #oral glucose tolerance test; ^ HOMA-IR, Matsuda, OGIS .

PXL770 PK/PD Study Demonstrated Target Engagement and Efficacy Signals

• Inclusion criteria: controlled attenuation parameter (CAP) score >300 db/m (measured by FibroScan®) and HOMA- IR* score >2.5
• Treatment arm (n=12): four weeks PXL770 500 mg QD
• PXL770 suppressed de-novolipogenesis◊, which is responsible for ~25% of liver fat accumulation
• PXL770 improved glycemia◊ - both total and incremental glucose AUC
• PXL770 improved insulin sensitivity◊ measured by HOMA-IR (p=0.013); Matsuda# (p=0.014); OGIS∆ (p=0.012)
• AMPK activation demonstrated: beneficial impact on key pathways of liver injury and NASH

Fructose-stimulated de novo lipogenesis

Versus baseline (at week 4) (N=12)

	25
(%)	20
LIPOGENESIS
15
	10
NOVO	5									p = 0.004
							(Peak vs. Baseline)
DE	0
	0	1	2	3	4	5	6	7	8	9	1 0

TIME POST START FRUCTOSE (HOUR)

Oral glucose tolerance

Versus baseline (at week 4) (N=12)

	210
(MG/DL)	190
170
GLUCOSE	150
130
	110				p = 0.022
	90
				(AUC vs. Baseline)
	70
	0	3 0	6 0	9 0	1 2 0 1 5 0 1 8 0

• Versus baseline; no effect in Placebo group

*Homeostatic Model Assessment of Insulin Resistance; # Diabetes Care 1999; 22: 1462-1470; ∆ Oral glucose insulin sensitivity index

21

TIME (MIN)

Baseline PXL770 500 mg OD

PXL770: Ongoing Phase 2a Program for NASH

Phase 2a 12-week, Multicenter, Randomized, Double-blind,Placebo-controlled, Parallel Group Trial

• N = 100 likely-NASH patients with and without Type 2 diabetes
• Inclusion criteria: increased hepatic fat (assessed via CAP and MRI-PDFF)
• Trial to assess efficacy and safety
• Primary endpoint: relative change in % liver fat mass (MRI-PDFF) from baseline

Results expected late 3Q 20

22

Pre-Clinical Data Demonstrate Potential Synergy of PXL770/AMPK Activation with Other Agents in Development

PXL770

Effects in

Adipose Tissue

Low grade inflammation

Lipolysis

Effects in Liver

De novo lipogenesis /

Steatosis

Chronic inflammation

Stellate cell activation /

Fibrosis

Apoptosis / cell death

Effects in Muscle

Peripheral insulin resistance

Other

Mechanisms

PXL770 / Semaglutide (GLP-1)

Mouse NASH Model

(mg)	1500
####
content	#
1000

lipidLiver	****	****	****
500
	0

• p ≤ 0.05, ** p≤ 0.01, *** p≤0.001, **** p≤ 0.0001 vs vehicle
  # p≤ 0.05, ## p≤ 0.01, ### p≤ 0.001, #### p ≤ 0.0001 vs

400	combination
N=12-13

(U/L)ALT	300			#
Plasma	200
100	****	****	****
	0
	Vehicle			Semaglutide
	PXL770			PXL770 + Semaglutide

23

NASH

PXL065

Proprietary Program

MPC Inhibitor for the Treatment of NASH Utilizing the 505(b)(2) Regulatory Pathway

24

PXL065: Leveraging the Benefits of Pioglitazone

With Reduced PPARγ Activity

• Pioglitazone used in T2D for > 20 years • >30 million patient-yearsof exposure1

• Established CV outcomes benefit2

• Pioglitazone extensively studied and has demonstrated resolution of NASH
• • Demonstrated "Resolution of NASH without worsening of fibrosis" in Phase 4 trial3
  • Only drug recommended for biopsy-proven NASH by AASLD & EASL Practice Guidelines4
  • Currently prescribed by ~14% of physicians for biopsy-proven NASH patients5
  • Limited use due to PPARγ-relatedside effects: weight gain, fluid retention, bone loss

• Pioglitazone, TZDs: both genomic (PPAR) and non-genomic (MPC) mechanisms
• PXL065 is an NCE which selectively mediates non-PPAReffects of Pioglitazone
• 1. Takeda 2014. https://www.takeda.com/newsroom/newsreleases/2014
  2. Diab & Vascular Disease Res 2018; 16:133-143
  3. Ann Intern Med. 2016, 165(5), 305-315
  4. J Hepatol. 2016, 64(6),1388-402; Hepatology 2018, 67, 328-357
  5. Therap Adv Gastroenterol. 2016, 9(1), 4-12

Non-Genomic Mechanisms (MPC)

		gene
PPAR	RXR	transcription
•	Enhanced lipid metabolism
		•	Anti-inflammatory

• Contributes to glucose lowering

25

Pioglitazone has Demonstrated Resolution of NASH

Largest Effect of Oral Agents - Use Limited by Weight Gain

80%

Resolution of NASH

P < 0.001

%

70%

without worsening of fibrosis

NA

Improvement,

60%

Phase 3 or 4 Trials

Phase 2 Trials

P < 0.001

50%

P = 0.019

40%

with

70%

P = 0.02

30%

NA

59%

Patients

P = 0.066

45%

20%

39%

P = 0.0514

P = 0.13

pbo

P = 0.494

27%

24%

10%

25%

pbo

19%

pbo

pbo

17%

pbo

12%

15%

pbo

pbo

17%

19%

pbo

8%

9%

pbo

pbo

8%

9%

0%

6%

6%

5%

Pio

Ocaliva

Elafibranor

CVC

Liraglutide

Resmetirom

Aramchol

Alderfermn

Semaglutide

Lanifibranor

ORAL

Intercept

Genfit

Allergan

Novo Nordisk

Madrigal

Galmed

NGM

Novo Nordisk

Inventiva

ORAL

ORAL

ORAL

INJECTION

ORAL

ORAL

INJECTION

INJECTION

ORAL

26

Pio Cusi Phase 4 trial (3045 mg, 18 mos) - Ann Intern Med. 2016, 165(5), 305-315 (only completers with definite NASH at baseline). Patients on placebo benefited from 4% weight loss due to hypocaloric diet Ocaliva REGENERATE Phase 3 trial (25 mg, 18 mos) - Lancet. 2019, 394(10215), 2184-2196

Elafibranor RESOLV-IT Phase 3 trial (120 mg, 52 wks/) - Press release May 11, 2020

CVC (Cenicriviroc) CENTAUR Phase 2 trial (150 mg, 2 yrs) - Hepatology 2020, Jan 13 epub

Liraglutide Phase 2 trial (0.6 increased to 1.8 mg sc weekly 48 wks) - The Lancet, 2016, 387(10019), 679-690

Resmetirom (MGL-3196) Phase 2 trial (80 mg +/- 20 mg, 36 wks) - Lancet 2019 394:2012-24. Results from per protocol, not intent to treat (ITT) population.

Aramchol Phase 2 trial (600 mg, 52 wks) - press release June 12, 2018. No effect on "Fibrosis without worsening of NASH".

Aldaferin (NGM282) Phase 2 trial (1 mg, 24 wks, cohort 4) - Press release Feb 25, 2020. P value not disclosed.

Semaglutide Phase 2 trial (0.4 mg, 72 wks) - Press release May 6, 2020. P value not disclosed.

Lanafibranor Phase 2 trial (1200 mg, 24 wks, ITT population) - Press release Jun 15, 2020(also at 800 mg 33% pts met endpoint, p=0,043)

No head-to-head trials have been conducted. Data derived from different clinical trials with potentially different designs, patient populations, and definition of NASH resolution.

PXL065: A Single Stabilized Stereoisomer of Pioglitazone

Benefits of Pioglitazone for NASH with Reduced PPARγ Side Effects

• Pioglitazone is a mixture of 2 stereoisomers with dramatically different properties
• PXL065 is the deuterium-stabilizedR-stereoisomer

S-Pioglitazone (stabilized)PXL065 (stabilized R-pio)

• MPC inhibitor	500 Tablets	• MPC inhibitor
	NIDC 64764-451-26
• Strong PPARγ agonist	actos®	• Very weak PPARγ
(pioglitazone)
	agonism
	Tablets
	45 mg

• Undesired side effects:

-	Weight gain	•	Anti-inflammatory
-	Fluid retention	•	Activity in NASH

S-Pio

R-Pio

27

PXL065 Targets Inhibition of MPC

Without PPARγ Agonist Activity from S-Stereoisomer

MPC Inhibition in HepG2 Cells

PPARγ Agonist Activity

re s p ir a t io n o l)
r iv e n	c o n tr
te - d	(%
P y r u v a

1 2 5

1 0 0

1. 5

1. 0

1. 5
   0

IC50 (µM)

	P X L 0 6 5 ( d - R - p io )6.5
	d - S - p io		8.5
	P io g lita z o n e	6.8
0 . 0 1	0 . 1		1 . 0	1 0 . 0	1 0 0 . 0
		lo g C o n c	( μ M )

	1 0 0
				EC50 (µM)
		P X L 0 6 5 ( d - R - p io )	>>100
n		d - S - P io		3.5
c tiv a tio		P io g lita z o n e		4.6
5 0
a
P P A R γ
%
	0
	0 . 0 1	0 . 1 0		1 . 0 0	1 0 . 0 0	1 0 0 . 0 0
			lo g C o n c	( μ M )

PPARγ activation in fluorescence-based TRAP220 coactivator recruitment assay Results are expressed as % of response of positive control (10µM rosiglitazone)

28

PXL065 Targets Inhibition of MPC & Modulates Cellular Fuel Utilization

MPC Regulates Transport of Pyruvate Across Mitochondrial Inner Membrane

Pyruvate	MPC Acetyl	TCA
Co-A
		cycle NADH
		FADH2

ATP

MRC

29

MITOCHONDRIA

Regulates cellular fuel selection - Modulates cell signaling

Additional Validation

• MPC inhibition implicated as beneficial for neuroinflammation/ neurodegeneration1
• Liver-selectiveMPC2 -/- mice:

1. Decreased gluconeogenesis; protection from hyperglycemia2

1. Protection from diet-induced NASH - transaminase elevations, fibrosis score, stellate cell activation3

Inhibiting MPC leads to improvements in NASH and metabolic disease endpoints

1. Ghosh et al, Sci Trans Med 2016; 8:368ra174; Shah et al, Curr Alzheimer Res 2014; 11:564-573

2. McCommis et al, Cell Metab 2015; 22:682-694

3. McCommis et al, Hepatology 2017; 65:1543-1556

Decreasing Entry of Pyruvate by Inhibiting MPC has Desirable Effects in NASH

30

HALLMARKS OF NASH

MΦ

Steatosis

Inflammation

Ballooning

Fibrosis

Increasing fat oxidation	Resetting mitochondrial	Resetting mitochondrial	Inhibiting MPC decreases
decreases liver fat	metabolism improves	metabolism protects cells	HSC1 activation and
content	inflammation	from degeneration	markers of fibrogenesis

PXL065 also has the potential to be used in combination with other mechanisms for additive benefits

1. HSC: Hepatic Stellate Cell.

PXL065: Similar Activity to Pioglitazone in NASH Mouse Models

Results Consistent with Potential Beneficial Clinical Effects

Steatosis		Inflammation		Ballooning

C D	d ie t	M C D	d ie t	C D	d ie t	M C D	d ie t	C D	d ie t	M C D	d ie t
4						4						3
3		* * *		* * *	* * *	3	* *	*				2				*	* *
2						2				* * *	* * *
1						1						1
0						0						0
v e h ic le p io	0 6 5	v e h ic le	p io	0 6 5	v e h ic le p io	0 6 5	v e h ic le	p io	0 6 5	v e h ic le p io	0 6 5	v e h ic le	p io	0 6 5

Fibrosis

C D	d ie t	M C D	d ie t
3

2	* *	*		* *	* *
1
0
	v e h ic le p io	0 6 5	v e h ic le	p io	0 6 5

• Liver histopathology on day 43 in mice fed a Choline Deficient (CD) or a Methionine/Choline Deficient (MCD) diet
• Pioglitazone (30 mg/kg/day) or PXL065 (15 mg/kg/day), Wilcoxon rank sum test vs vehicle; *p < 0.05, **p < 0.005, ***p < 0.001

31

Summary of PXL065 Benefits in NASH

PXL065 (R-Pio) Retains Benefits of Pio; S-Pio Drives Weight Gain in Mouse Model

	NASH Rodent Models1	Pio	PXL-065
	Functional Parameters
	Hepatic Triglycerides	✓	✓
	Hepatic Free Fatty Acids	✓	✓
	Hepatic Cholesterol	✓	✓
	Hepatic Steatosis	✓	✓
	Hepatic Inflammation	✓	✓
	Hepatic Ballooning	✓	✓
	Hepatic Fibrosis	✓	✓
 Weight Gain	✓	-
 Edema	✓	-

		Body Weight Gain in Mouse Model2
	6		(0-11 days)
						* * * *	* * * *
		p io
				* * * *	* * * *	* * * *
e
	d -S - p io
				* * *		* * * *	* * * *
g
					* * * *
n		PXL065			* * *	* * * *	* * * *
4		* * * *
a			* * * *
		* * *
h
	v e h ic le		* * *
c
h t			*
ig	2		fir s t d o s e
	*
e
w
o d y	0
b		-5	0		5				1 0
%
	-2		d a y

1. NASH rodent models selected based on literature: C57BL/6J mouse model of weight gain & edema (Nat Med 2005, 11, 861-866) and methionine-choline deficient (MCD) model of NASH (Lab Investig. 2007, 87, 56-65). Additional choline deficient (CD) model of NASH was validated with RenaSci. In MCD model both pio and PXL065 reduced ballooning. d-S-pio was only run in the CD model where no effect on ballooning with any compound was observed.
2. Weight gain measured in C57BL/6J mouse model. Pioglitazone dosed at 30 mg/kg, d-S-pio and PXL065 dosed at 15 mg/kg. Statistical significance determined by 1-way (total day 11) or 2-way (% by day) ANOVA with Dunnett's post-test average ± SEM; * p < 0.05, ** p < 0.01, *** p < 0.001, **** P < 0.0001

32

PXL065 Utilizing 505(b)(2) Regulatory Pathway

1992 FDA guidance document "Development of New Stereoisomeric Drugs"

• Streamlined development expected for single enantiomers of approved racemic drugs
• Existing nonclinical data from the racemate can be relied upon to support the safety of the single enantiomer, and an abbreviated pharmacology and/or toxicology evaluation and initial clinical characterization may be pursued (Section IV of FDA, 1992)

Ability to rely on data generated by others in

• Product label for parent drug
• Published literature

Potential opportunities to bridge to data from parent drug

• Fewer animal toxicity studies
• • Example: 28 day and 90-day studies in 1 species instead of 2
  • Example: no need for 2-year rat carcinogenicity study
• Potential for fewer clinical trials for submission of NDA
• Safety database with <1500 subjects

3333

PXL065: Phase 1 Study Results

15 mg PXL065 vs. 45 mg Actos®1: Similar R-Pio Exposure; S-Pio Exposure Decreased ~5-fold

Exposure to R-pio		Exposure to S-pio

• Single (SAD) and repeated (Ph1b) oral dose studies completed
• Stabilization and sustained higher exposure to R-pio (limited conversion to S-pio)
• • PK dose proportionality; no food effect
  • tablet formulation qualified in Ph1b study
• Well tolerated at all doses tested

34

1. Actos is the branded version of pioglitazone and a registered trademark of Takeda Chemical Industries, Ltd.

PXL065: One Phase 2 Trial in Biopsy-Proven NASH Patients

Leveraging 505(b)(2) Pathway

36-week multicenter, double-blind,placebo-controlled, parallel group, randomized trial to evaluate the safety and efficacy of3 doses in ~120 noncirrhotic biopsy-proven NASH patients

Screening	Double-blind Treatment Period	Follow-Up
Repeated Dose
8 weeks	36 weeks	2 weeks

Placebo

PXL065 7.5 mg

PXL065 15 mg

PXL065 22.5 mg

• Phase 2 objective: identify one or two doses for Phase 3 registration trial
• Primary objective: Assess efficacy of escalating doses by relative change in liver fat (MRI-PDFF)
• Secondary objectives:
• • Assess other efficacy parameters (e.g. ALT, liver histology)
  • Assess safety and tolerability (e.g. body weight gain)

• Assess pharmacokinetics at pre-specified timepoints and PK/PD correlation

35

PXL770 & PXL065 Aim to Have the Following Effects for NASH

Potential for Use in Combination with Other Agents in Development

Effects in

Adipose Tissue

PXL770

PXL065

Low grade inflammation

Lipolysis

Peripheral insulin resistance

Effects in Muscle

De novo lipogenesis

Effects in Hepatocytes

36

NASH

Effects in Liver	PXL770
PXL065
Steatosis
Chronic inflammation
Fibrosis
Gluconeogenesis

Effects in

Hepatic

Stellate Cells

Fibrogenesis

Hepatic stellate cell activation

Effects on Mitochondria Structure and Function

Additional Opportunities

Pipeline Expansion

Chronic and Rare Metabolic

Indications

Next Generation AMPK Activators

Next Generation D-TZD's*

*Deuterium-modified thiazolidinediones

37

AMPK and MPC Dysregulation are Implicated in the Biology of Various Metabolic Diseases

AMPK	MPC
	Pyruvate

Acetyl
Co-A
TCA	ATP
cycle
	NADH

FADH2

MRC

Activates		Inhibits
catabolic
Inhibits	inflammation
pathways
anabolic	apoptosis
	pathways

T

MITOCHONDRIA

Exploring applications of current and next generation AMPK activators and MPC inhibitors in

biologically relevant metabolic diseases

Rare Metabolic	Renal	Endocrine
Adrenoleukodystrophy	Diabetic kidney disease	Type 2 diabetes
(ALD; AMN)	Polycystic kidney disease	Polycystic ovary syndrome
Mitochondrial disorders

38

Potential of AMPK Activation to Treat Adrenoleukodystrophy

ALD AMN

Why AMPK ?

• AMPK is suppressed in brain from ALD patients1
• ABCD2/3 could replace function of missing ABCD1; AMPK activation with metformin elevates ABCD2 levels in patient cell lines and ABCD1-KO mice1
• Deletion of AMPK1 in glial cells of ABCD1-null mice (AMN model) → mitochondrial dysfunction/low ATP 2

	PXL770 reduces VLCFA &	P-ACC
	induces ABCD2/ABCD3 in
	cells from human AMN-ALD
	patients	P-AMPK
			ABCD2
1.	J Neurochem 138:86-, 2016	ABCD3
2.	Singh J, Med Inflamm, 2015
39			T

Potential for AMPK Activation to Treat

Renal Diseases		80
DKD	Albumin/Creatinine mg/mgRation	20
• AMPK activity is reduced in human/rodent DKD tissue samples2
Diabetic Kidney Disease		60
• Multiple pathways engaged; anti-inflammatory,anti-apoptotic,		40
anti-fibrotic effects of AMPK1
• Preclinical efficacy reported with indirect and direct AMPK	Urine
activation3		0

PKD

Polycystic Kidney Disease

• Autosomal dominant; fourth leading cause of CKD
• Significant unmet medical need
• AMPK activation validation:
• • AMPK pathways linked to pathophysiology (eg mTOR4; CFTR5)
  • In vivo efficacy with both indirect and direct AMPK activators6

1. Curr Op Nephrol 2017, 26:375-83; Curr Drug Targets 2018; 19:709-20; 2. J Clin Invest 2013; 123:4888-99

3. J Med Chem 2016; 59:8068-81; JPET July 2019; JPET 2017; 361:303-311; 4. mammalian target of Rapamycin

5. cystic fibrosis transmembrane conductance regulator 6. J Clin Invest 2001; 108:1167-74; PNAS 2011;108: 2462-67; Sci Rep 7:7161,2017; EBioMed 47:436-45, 2019

PXL770 Improves Kidney Function in

ZSF1 Rat Model of DKD

✱✱✱

✱✱✱

Lean	***: p< 0.01
ZSF-1
ZSF-1+PXL770 150 mg/kg bid
ZSF1+Enalapril 10 mg/kg/d

PXL770 Reduces Cyst Volume in vitro

(Madin-Darby Kidney cells)

Significant:

*vs control, & vs. metformin 10 µm (&), vs. metformin 100 µM (§) and 1 mM (#)

Metformin PXL770

40

Upcoming Milestones

41

Cash Through Significant Upcoming Milestones into 2022

	T2D NASH
T2D NASH	• Imeglimin Japanese NDA approval
• EASD presentations:	•	Imeglimin product launch
Imeglimin & PXL770	•	PXL065 Ph 2 recruitment completed

• PXL770 Phase 2a Results

Q3

2020

2021

2022

H2

T2D NASH Other

• Metavant interactions w/FDA for Imeglimin Ph 3 plan
• PXL065 Ph 2 initiation in ~120 biopsy proven NASH patients*
• Imeglimin Japan Diabetes Society presentation
• PXL770 and PXL065: presentations at AASLD and NASH Summit and data published
• Additional preclinical results in rare diseases for AMPK and TZD platforms

NASH CASH

• PXL065 Ph 2 results
• As of 6/30/20 cash & cash equivalents: EUR 46.0 million (USD 51.5 million)
• Cash runway into 2022

42

1. Contingent on a safe and stable environment for patient recruitment and the availability of clinical trial sites during the COVID-19 outbreak.

Appendix

43

Key Financial & Shareholder Information

44

Market data

Ticker: POXEL

ISIN: FR0012432516

Number of shares: 28,471,523*

Key financials

• As of 6/30/20 cash & cash equivalents: EUR 46.0 million (USD 51.5 million)
• Cash runway into 2022

*at June 2020.

Shareholder ownership*

14.6%

Andera Partners

16.7%

54.2% Bpi France Floating

	9.5%
		Founders
	5.0%
	Roivant Sciences
Analyst coverage		Ltd
Degroof Petercam	Benoit Louage
Gilbert Dupont	Guillaume Cuvillier
Jefferies	Peter Welford
JMP Securities	Jason Butler
Kepler Cheuvreux	Arsene Guekam
Oddo	Martial Descoutures

References for Slide 12

1. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018
2. Januvia [package insert]. Whitehouse Station, NJ. Merck & Co, Inc.; 2019
3. Onglyza [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals; 2019
4. Tradjenta [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals; 2019
5. Invokana [package insert]. Titusville, NJ. Janssen Pharmaceuticals; 2020
6. Jardiance [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals; 2020
7. Farxiga [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals; 2020
8. Bydureon [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals; 2019
9. Victoza [package insert]. Plainsboro, NJ. Novo Nordisk; 2019
10. Trulicity [package insert]. Indianapolis, IN. Eli Lilly and Company; 2019
11. Ozempic [package insert]. Plainsboro, NJ. Novo Nordisk; 2019
12. Sanofi-Aventis.Diabeta (glyburide) [package insert]. U.S. Food and Drug Administration. Revised July 2016.
13. Amaryl (glimepiride) [package insert]. Bridgewater, NJ. Sanofi-Aventis; 2018
14. Pfizer. Glucotrol (glipizide) [package insert]. U.S. Food and Drug Administration. Revised September 2008.
15. Takeda Pharmaceuticals. Actos (pioglitazone) [package insert]. U.S. Food and Drug Administration. Revised July 2011.
16. Lantus [package insert]. Bridgewater, NJ. Sanofi-Aventis; 2019
17. Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf. 2010;33(9):727-740.
18. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and Renal Outcomes in Type 2

Diabetes and Nephropathy. N Engl J Med. 2019; 380:2295-2306.

1. Davies MJ, Bain SC, Atkin SL, et al. Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. Diabetes Care. 2016;39:222-230.
2. Idorn T, Knop FK, Jorgensen MB, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and end-stage renal disease: an investigator-initiated, placebo- controlled, double-blind,parallel-group, randomized trial. Diabetes Care. 2016;39:206- 213.
3. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. 2007;64(3):317-327.
4. Avogaro A, Schernthaner G. Achieving glycemic control in patients with type 2 diabetes and renal impairment. Acta Diabetol. 2013;50(3):283-91.

*Centers for Disease Control and Prevention (CDC). NCHS. NHANES. Laboratory Data, 2015-2016. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2017.

45

Imeglimin Observed to Restore Normal Mitochondrial Function in Type 2 Diabetes (T2D)

Diabetic state is caused by an impaired mitochondrial state

Mitochondrial Respiratory Chain (MRC) becomes activated

MRC

Activating the MRC has these desirable downstream effects in T2D:

Increases glucose-	Improves β-cell	Improves insulin	Improves endothelial
dependent insulin secretion	dysfunction	sensitivity in muscle	and diastolic
from pancreas	and survival	cells and liver cells	dysfunction

46

Imeglimin: A Differentiated Mechanism of Action in the Mitochondria Enabling 'Glucose-plus' Benefits

Normal Cell

Diabetic Cell

Treatment with Imeglimin

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-cellsdysfunction and death
• Endothelial cell dysfunction and death

Imeglimin treatment: Restored normal mitochondrial function

• Glucose-loweringrelated 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

47

Imeglimin Phase 2b Trial In Japan Met Primary and Secondary Endpoints (N=299)

• Full Phase 2b data presented at the European Association of the Study of Diabetes, Lisbon (Sept. 2017)

3 weeks	6-10weeks	24 weeks	1 week
Screening	Placebo Run-In	Double-Blind Treatment Period	Follow-Up
(Wash-out)

Placebo

Imeglimin 250 mg BID

Imeglimin 1000 mg BID

Imeglimin 1500 mg BID

• Phase 2b trial in Japan met primary HbA1c endpoint and secondary endpoints
• Demonstrated efficacy in chronic kidney disease patients was similar to patients with normal renal function
• Observed to be well tolerated:
• • Rate of observed adverse events similar to placebo at 500 mg and 1000 mg. Slightly higher rate of GI events at 1500 mg (no adverse event greater than 10%)
  • No serious adverse events related to Imeglimin
• No weight gain

• Optimal dose for Phase 3 program in Japan is 1000 mg

48

Imeglimin Phase 2b Trial in Japan Met Primary Endpoint in Reduction of HbA1c vs. Placebo (N=299)

HbA1c (%) - LS Mean Change from Placebo

Change in HbA1c from Baseline

7.94%			7.85%			7.91%
0
		500 mg			1000 mg			1500 mg
			N=75			N=73			N=73
-0.2
-0.4
	-0.52%
-0.6
	**
-0.8
										-0.94%
-1.0										-1.00%
	** p < 0.0001	**
-1.2	**

European Association of the Study of Diabetes, in Lisbon (Sept. 2017)

49

Phase 2b Trial in Japan: Similar Efficacy Demonstrated in T2D Patients with Renal Impairment vs with Normal Kidney Function

Change in HbA1c - 24 Weeks

HbA1c (%) - LS Mean Change from Placebo

					500 mg						1000 mg						1500 mg
	eGFR ≥ 80	eGFR < 80	eGFR ≥ 80	eGFR < 80	eGFR ≥ 80	eGFR < 80
0
	N=24				N=51				N=24				N=49				N=23				N=50
-0.2
-0.4									-0.44%
		-0.53%
-0.6
-0.8																									-0.83%
																																-0.89%
-1.0																	-0.92%																	-0.92%

-1.2

50

Contacts

Jonae R. Barnes

Senior Vice President, Investor Relations, Corporate Communications and Public Relations

[e-mail] [phone]

Aurélie Bozza

Investor Relations and Communication Director [e-mail]

[phone]

51