Investor Presentation€¦ · Setanaxib - Liver Fibrosis Primary Biliary Cholangitis (PBC) Final...

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Investor Presentation February 2020 Inhibiting NOX enzymes to treat multiple diseases with high medical need Euronext: GKTX

Transcript of Investor Presentation€¦ · Setanaxib - Liver Fibrosis Primary Biliary Cholangitis (PBC) Final...

Page 1: Investor Presentation€¦ · Setanaxib - Liver Fibrosis Primary Biliary Cholangitis (PBC) Final results published July 2019 Setanaxib - Kidney Fibrosis Diabetic Kidney Disease (DKD)

Investor Presentation

February 2020

Inhibiting NOX enzymes to treat multiple diseases with high medical need

Euronext: GKTX

Page 2: Investor Presentation€¦ · Setanaxib - Liver Fibrosis Primary Biliary Cholangitis (PBC) Final results published July 2019 Setanaxib - Kidney Fibrosis Diabetic Kidney Disease (DKD)

Disclaimer

• This document has been prepared by Genkyotex (the "Company") and is for information and background purposes only.

• While the information contained herein has been prepared in good faith, neither the Company, nor its shareholders, directors, officers, agents, employees, or advisors give,have given or have authority to give, any representations or warranties (express or implied) as to, or in relation to, the fairness, accuracy, reliability or completeness of theinformation in this document, or any revision thereof, including financial information (all such information being referred to as “Information”), and liability therefor isexpressly disclaimed. Accordingly, neither the Company nor any of its shareholders, directors, officers, agents, employees, affiliates, representatives or advisors take anyresponsibility for, or will accept any liability whether direct or indirect express or implied, contractual, tortuous, statutory or otherwise, in respect of the accuracy orcompleteness of the Information or for any of the opinions contained herein or for any errors, omissions or misstatements or for any loss, howsoever arising from thisdocument.

• The Information and opinions contained in this document are provided as of the date of this document only and may be updated, supplemented, revised, verified oramended, and thus such information may be subject to significant changes. The Company is not under any obligation to update the Information or opinions contained hereinwhich are subject to change without prior notice.

• The information contained in this document has not been subject to independent verification and are qualified in their entirety by the business, financial and otherinformation that the Company is required to publish in accordance with the rules, regulations and practices applicable to companies listed on the regulated market ofEuronext Paris and Euronext Brussels, including in particular the risk factors and other information in the Company’s Universal Registration Document (Documentd’enregistrement universel) filed with the French Autorité des marchés financiers (Financial Markets Authority) (the “AMF”) on January 16, 2020 under no. 20-0012, and in anyother periodic report, which are available free of charge on the websites of the Company (www.genkyotex.com) and the AMF (www.amf-france.org).

• This document contains information on the Company’s markets and competitive position, and more specifically, on the size of its markets. This information has been drawnfrom various sources or from the Company’s own estimates which may not be accurate and thus no reliance should be placed on such information. Any prospective investorsmust make their own investigation and assessments and consult with their own advisers concerning any evaluation of the Company and its prospects, and this document, orany part of it, may not form the basis of or be relied on in connection with any investment decision.

• This document contains certain forward-looking statements. These statements are not guarantees of the Company's future performance. These forward-looking statementsrelate to the Company's future prospects, developments and marketing strategy and are based on analyses of earnings forecasts and estimates of amounts not yetdeterminable. Forward-looking statements are subject to a variety of risks and uncertainties as they relate to future events and are dependent on circumstances that may ormay not materialize in the future. Forward-looking statements cannot, under any circumstance, be construed as a guarantee of the Company's future performance and theCompany’s actual financial position, results and cash flow, as well as the trends in the sector in which the Company operates, may differ materially from those proposed orreflected in the forward-looking statements contained in this document. Even if the Company’s financial position, results, cash-flows and developments in the sector in whichthe Company operates were to conform to the forward-looking statements contained in this document, such results or developments cannot be construed as a reliableindication of the Company's future results or developments. The Company does not undertake any obligation to update or to confirm projections or estimates made byanalysts or to make public any correction to any prospective information in order to reflect an event or circumstance that may occur after the date of this document.

• The information contained herein do not constitute either an offer to sell or purchase, or the solicitation of an offer to sell or purchase, securities of the Company.

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Ph2 PBC highlight the potential of setanaxib as an anti-fibrotic therapy in the liver, lung, skin, kidney and other organs

Genkyotex: Establishing NOX inhibitors as a new therapeutic class

We discover and develop oral small molecule NOX inhibitors

— Activation of NOX enzymes is key in many multifactorial diseases

— World Health Organization (WHO) recognized NOX inhibitors as a new therapeutic class

Lead asset setanaxib (GKT831): a potent anti fibrotic oral small molecule

— JDRF-funded Phase 2 trial in kidney fibrosis (diabetic kidney disease)

— NIH-funded Phase 2 trial in idiopathic pulmonary fibrosis (IPF)

— Further potential in NASH, PSC, and immuno-oncology

PBC Phase 2 provides clinical evidence of anti-fibrotic activity in liver fibrosis – a reduction of ~3kPa indicating an average of 1 point liver fibrosis reduction

Trading on Euronext as GKTX since March 2017

— Cash and cash equivalents of €2.4 million as of December 31, 2019

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Seasoned management team with international life sciences experience

Elias Papatheodorou

Chief Executive Officer

More than 25 years of experience in biotechnology and multinational companies

Ex- Philip Morris International, The Coca Cola Company, Novosom AG, Medigene AGand Covagen AG

Covagen was acquired by Janssen Pharmaceuticals, a J&J Company

Strong track record in fundraising, business development and M&A

Philippe Wiesel

Chief Medical Officer & EVP

Lead clinical research programs at Serono’s EU and US offices, including the phase 3program (ex-US) for Raptiva in psoriasis, leading to the first EMA approval of a biologicagent for psoriasis

Conducted basic research in the laboratories of Professor Edgar Haber at HarvardMedical School, and of Professor Hans Brunner at the Division of Hypertension inLausanne

Alexandre Grassin

VP Finance & Administration

Diverse experiences in Finance with Novartis from 2007-2010 & Alexion from 2010 to2012

Financial Auditor with KPMG

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Discovery platform delivers broad pipeline in diseases with high medical needSetanaxib Phase 2 PBC data support development in multiple fibrotic diseases

Setanaxib - Liver FibrosisPrimary Biliary Cholangitis (PBC)Final results published July 2019

Setanaxib - Kidney FibrosisDiabetic Kidney Disease (DKD) in T1D(IIT1 funded by JDRF2 - Trial launched in H2 2017)

Setanaxib - Lung FibrosisIdiopathic Pulmonary Fibrosis (IPF)(IIT funded by US NIH3 – Trial launch Q1 2020)

NOX1 inhibitors Preclinical

Novel NOX inhibitors

VaxiclasePertussis vaccine (Licensed to SIIPL)

Preclinical Phase 1 Phase 2 Phase 3Program

Discovery

1Investigator initiated trial2 Juvenile Diabetes Research Foundation3 National Institutes of Health

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Fibrosis: ~45% of all deaths in the developed world1

We focus on Key fibrosis markets with setanaxib

Source 1: The Journal of Clinical Investigation; Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases; March 2007. Source 2: The global impact of hepatic fibrosis and end-stage liver disease ; Lim YS1,Kim WR.ClinLiver Dis.2008 Nov;12(4):733-46, vii. doi: 10.1016/j.cld.2008.07.007. Source 3: Nalysnyk L., et al. Incidence and Prevalence of Idiopathic Pulmonary Fibrosis: Review of the Literature. Eur Respir Rev. 2012;21(126):355-361. Source 4: HovindP, Tarnow L, Rossing K, et al. Diabetes care 2003;26:1258-64. Source 5: Groop PH, Thomas MC, Moran JL, et al. Diabetes 2009;58:1651-8. Source 6: Diabetes Care, American Diabetes Association, 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014.

Liver fibrosis impacts 300 to 700 million people worldwide2

1st product in NASH to be approved based on anti-fibrotic activity in only 23% of patients

Fibrosis drives transplants and remains the unmet medical need

Idiopathic Pulmonary Fibrosis (IPF) affects 3 million people

worldwide3

2 approved products in IPF each with ~ 1 billion USD sales per year

Pirfenidone to become generic allowing combination strategies

Diabetic Kidney Disease develops in 20% to 40% of all

diabetics6

Immuno-oncology therapies not as effective in highly

fibrotic tumors

Cancer associated fibroblasts (CAFs) oppose immunotherapies by shielding tumors from T-cells

Targeting CAFs with setanaxib restores response to immunotherapies

Diabetic kidney disease is the leading cause of end-stage renal disease4

Affects 14% to 31% of people with type 1 diabetes after 20 years of diabetes5

Setanaxib

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Liver fibrosis progressively disrupts liver structure and function

Page 7

F3 F4

Liver fibrosis is the best predictor of long-term outcomes in multiple liver diseases

F1 F2

Setanaxib

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Fibroscan data from PBC phase 2 trial indicates potential in multiple fibrotic diseases

Setanaxib is the first compound to reduce liver stiffness, indicating possible regression of

fibrosis

• Setanaxib achieved clinically meaningful reductions in liver stiffness (-22% reduction vs +4%

for placebo) in patients with elevated liver stiffness at baseline (≥9.6 kPa)

• Patients with even modestly elevated liver stiffness (≥7.3 kPa) benefit from to setanaxib, for

both liver stiffness and markers of cholestatic injury (GGT and ALP)

Setanaxib is also the first compound to significantly improve quality of life, with a marked

effect on fatigue (the most common and debilitating symptom in PBC patients)

Setanaxib was safe and well tolerated at all doses

These phase 2 results support advancing setanaxib into phase 3 in PBC

Data also supports exploring higher doses in PBC phase 3 and other programs

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NOX inhibitors: pathway based medicine addressing validated disease targets

NOX stands for a group of enzymes called NADPH Oxidases

NOX NOX1 NOX2 NOX3 NOX4 NOX5 DUOX1 DUOX2

VALIDATED DISEASE

PATHWAYS

DISEASE PROCESSES

Inflammation Angiogenesis Fibrosis Proliferation

A family of 7 enzymes that amplify multiple signaling pathways

NF-kB PI3K TRPV1 VEGF

NMDA(CNS)

TRPV1 (hearing loss)

TGF-b PDGF RANKL TLR4 NA Thyroid hormone iodination

We focus on fibrotic diseases by targeting NOX1 and NOX4 with setanaxib

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NOX 1 & 4 are major drivers of fibrogenesis in multiple organsNOXs activates pathways such as TGF-b, PDGF, Hedgehog, TLR4, and CCL2

*Sources: Brenner DA, Hepatology 2012, Brenner DA, PLoS One, 2015, Torok N, Free Radic Biol Med, 2012. Torok N, Gastroenterology, 2015; Thannickal V, Science Trans Med, 2014; Gray SP, Circulation, 2013

Quiescentfibroblast

LIVER INJURY

NOX/ROS

Proliferation

Contractility

Fibrogenesis

Matrix degradationMMP-2

Chemotaxis

Retinoid loss

WBC chemoattraction

FIBROSIS

Pathways amplified by NOX1/4

Activated myofibroblast

SteatosisCholestasis

Hep C/HepBAlcohol

FIBROGENIC PATHWAYS

Setanaxib downregulates the activation of multiple clinically validated fibrogenic and apoptotic pathways*

LUNG INJURYSmoking

Toxic chemicalsInflammation

RENAL INJURYHyperglycemia

High blood pressureInflammation

LIVER

FIBROSIS

KIDNEY

FIBROSIS

LUNG

Setanaxib

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Setanaxib’s unique efficacy and safety profile can address the unmet medical need

Primary Biliary Cholangitis (PBC):an orphan disease in the large liver fibrosis market

Source 1 : In Europe, USA and Japan. Boonstra K. et al. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012 May;56(5):1181-8

Disease overview

• Chronic autoimmune liver disease - progressive destruction of bile ducts

• Prevalence of between 2 - 40 cases per hundred thousand-population1

• Women make up about 90% of PBC cases

• Diagnosis based on presence of auto-Abs and elevated markers of cholestasis including alkaline phosphatase (ALP) & gamma glutamyl transpeptidase (GGT)

Therapy

• Current medications mainly target cholestasis and include generic anti-cholestatic drugs (UDCA and fibrates) and obeticholic acid (OCA)

Unmet medical need

• Anti-fibrotic agents to delay disease progression and obviate transplant

• Effective agents targeting itching and fatigue to restore quality of life

• Safe, well tolerated therapy suitable for combination with anti-cholestatic therapies (UDCA, fibrates, OCA) Primary Biliary Cholangitis

Inflammation and scar tissue destroy ducts

Normal bile ducts

Gallbladder

Hepatic ductCommon bile duct

Liver

Cystic duct

Setanaxib

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Primary efficacy endpoint: change in GGT at week 24

Key secondary endpoints: liver stiffness assessed by Fibroscan®, changes in ALP & QoL

Key eligibility criteria

— ALP ≥1.5XULN & GGT ≥1.5XULN (stratification according to baseline GGT (> or < 2.5XULN)

— On UDCA for ≥ 6 months & stable dose for ≥ 3 months – stable UDCA dose continued throughout 24-week treatment period

— Exclusion of history of cirrhosis with complications or current MELD score ≥ 15

— ALT > 3XULN or total bilirubin > 1XULN

— Prohibited medications: fibrates and obeticholic acid (12-week wash out)

Setanaxib was evaluated in a large 24-week Phase 2 trial

Placebo & UDCA

Setanaxib 400mg once a day (OD) & UDCA

Setanaxib 400mg twice a day (BID) & UDCA

Follow up

Follow up

Follow up

111 randomized (initial target 102)

ALP ≥1.5XULNGGT ≥1.5XULN

Inadequate biochemical response to UDCA

Baseline Week 6 Week 24

Setanaxib

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Non-invasive assessment of liver fibrosis with Fibroscan®In PBC, liver stiffness ≥ 9.6 kPa corresponds to advanced liver fibrosis of ≥F3

Elas

tici

ty (

kPa)

• In multiple liver diseases including PBC, NASH and PSC, liver stiffness correlates with the histologic liver fibrosis stage (F0 to F4)1

• In PSC, elevated liver stiffness is associated with adverse disease outcomes, including liver transplant, hepatic complication and death1

• Our pre-defined cutoff value of 9.6 kPa has been extensively validated and used in previous trials1

1Corpechot C et al. Baseline Values and Changes in Liver Stiffness Measured by Transient Elastography Are Associated With Severity of Fibrosis and Outcomes of Patients With Primary Sclerosing Cholangitis. Gastroenterology 2014;146:970–979. Corpechot C et al. Assessment of Biliary Fibrosis by Transient Elastography in Patients With PBC and PSC. Hepatology 2006;43:1118-1124. Park CC et al. Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients with Biopsy-proven Nonalcoholic Fatty Liver Disease. Gastroenterology 2017; 152(3): 598–607.

Liver stiffness is an indicator of liver inflammation, cholestasis and fibrosis

Fibrosis stage

Histologic fibrosis score

Liver stiffness

Setanaxib

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Phase 2 trial of setanaxib in PBC: Baseline patient characteristics

Baseline characteristics in line with the targeted population of active PBC patients

1 Once daily; 2 Twice daily

Baseline patient characteristics PlaceboSetanaxib

400mg OD

Setanaxib

400mg BIDALL

N 37 38 36 111

Age (years) 56 (9) 57 (9) 56 (9) 56 (9)

Females (%) 95 79 94 89

Body weight (kg) 73 (15) 73 (13) 70 (16) 72 (15)

UDCA dose (mg/kg) 13.0 (4.1) 15.9 (5.6) 16.4 (10.4) 15.1 (7.3)

Liver stiffness measurement (kPa) 10.7 (7.0) 12.5 (13.7) 8.3 (3.7) 10.7 (9.5)

GGT (IU/L) 227 (200) 242 (167) 242 (181) 237 (182)

ALP (IU/L) 300 (141) 302 (121) 346 (164) 315 (143)

ALT (IU/L) 43 (16) 45 (22) 56 (35) 48 (26)

AST (IU/L) 43 (17) 44 (21) 50 (31) 46 (24)

Total bilirubin (mmol/L) 10.7 (4.3) 11.1 (4.6) 10.4 (4.6) 10.7 (4.5)

hsCRP (mg/L) 4.8 (4.6) 5.8 (5.2) 5.1 (5.1) 5.3 (4.9)

Values expressed as mean (±SD)

Setanaxib

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Setanaxib 400mg BID achieves significant reduction in GGT over the24-week treatment period (p<0.002)

Pe

rce

nt

chan

ge in

GG

T fr

om

Bas

elin

e

-7%

-12%

Change in GGT for 400mg BID is highly significant at week 6 (IA) and over 24-week treatment period. At week 24 significant only after log transformation correction

Treatment duration (week)

Percent changes in GGT (%)

-6,2-7,5

-5,5

-5,2

-8,4-7

-11,8

1,7

-4,5 -4,9

-17

-22

-18,6 -18,7 -19

-30

-25

-20

-15

-10

-5

0

5

10

15

0 2 6 12 18 24

Mean ± SEM

Placebo (n=37)

Setanaxib 400mg OD (n=38)

Setanaxib 400mg BID (n=36)

p=0.3 without correctionP=0.02 with correction

p<0.002 400mg BID vs placebo over 24 weeksp<0.01

Setanaxib

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Pe

rce

nt

chan

ge in

GG

T at

We

ek

24

(%

)

400mg ODPlacebo 400mg BID

Percent reduction in GGT at week 24

<9.6 kPa(n=59)

All patients(n=104)

≥9.6 kPa(n=45)

Patients with higher liver stiffness have greater unmet medical need & show marked reductions in GGT after treatment with setanaxib

Setanaxib

-40

-30

-20

-10

0

10

20

30

-19%

-13%

-32%

-10%

+9%

-5%

-15%

-8%-5%

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Setanaxib 400mg BID achieves significant reduction in ALP over the24-week treatment period (p<0.001)

Pe

rce

nt

chan

ge in

ALP

fro

m B

ase

line

Treatment duration (week)

-3,6-1,4

-0,6 -0,5

-3,1

-5,5

-8,6

-3,9

-7,8

-9,7

-13

-16,3

-14,6-15,8

-12,9

-20

-15

-10

-5

0

5

0 2 6 12 18 24

Percent changes in ALP (%)

p<0.001

p=0.049

p<0.001 400mg BID vs placebo over 24 weeksMean ± SEM

Placebo (n=37)

Setanaxib 400mg OD (n=38)

Setanaxib 400mg BID (n=36)

Setanaxib

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Patients with higher liver stiffness have greater unmet medical need & show marked reductions in ALP after treatment with setanaxib

Pe

rce

nt

chan

ge in

ALP

at

We

ek

24

(%

)

<9.6 kPa(n=59)

400mg ODPlacebo 400mg BID

All patients(n=104)

≥9.6 kPa(n=45)

Percent reduction in ALP at week 24

Setanaxib

Mean values-30

-25

-20

-15

-10

-5

0

-9%

-13%

-3%

-6%

-14%

-3%

-10%

-2%

-24%

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Setanaxib achieved clinically meaningful reduction in liver stiffness inpatients with estimated liver fibrosis score of ≥ F3

Patients with baseline liver stiffness < 9.6 kPa

Patients with baseline liver stiffness ≥ 9.6 kPa

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

Week 24Baseline

Median values Median values

Live

r st

iffn

ess

at

Bas

elin

e

and

we

ek

24

(kP

a)

Placebo(n=18)

400mg OD(n=21)

400mg BID(n=20)

Placebo(n=17)

400mg OD(n=14)

400mg BID(n=14)

Live

r st

iffn

ess

at

Bas

elin

e

and

we

ek

24

(kP

a)

12.7

14.2 14.113.1

12.2

9.1

Upper limit of normal (7 kPa)

Setanaxib

5.76.2 6.2 6.3

7.0 6.8

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In just 24 weeks of treatment setanaxib achieves average reduction of3kPa – an estimated one-point fibrosis score reduction

Percent change in liver stiffness Absolute change in liver stiffness

400mg OD (n=14)Placebo (n=17) 400mg BID (n=14)

Ab

solu

te c

han

ge in

live

r st

iffn

ess

at

we

ek

24

(kP

a)

-5

-4

-3

-2

-1

0

1

2

+0.4

-1.9

-2.7

Mean ± SEM

Pe

rce

nt

chan

ge in

live

r st

iffn

ess

at

we

ek

24

(%

)

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

+4.2

-5.3

-20.9

Mean ± SEM

p=0.039

Setanaxib achieves clinically significant reduction in liver stiffness in PBC patients with elevated liver stiffness

~3 kPa

Setanaxib

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Setanaxib 400mg BID significantly improves Quality of Life in PBC

Setanaxib is the first compound to significantly improve quality of life in PBC

1 Once daily; 2 Twice daily

PBC-40 questionnaire

PBC-40 QoL domains PlaceboSetanaxib

400mg OD1

Setanaxib

400mg BID2

p value (400mg BID vs

placebo at week 24)

General symptoms 1.1 1.1 -3.7 0.156

Itch (Pruritus) -6.8 -11.4 -9.5 0.443

Emotional 8.7 4.9 -16.9 0.031

Fatigue 2.4 0.3 -9.9 0.027

Social 9.3 8.1 -7.7 0.003

Cognitive 5.2 16 -1.9 0.332

Mean percent changes from Baseline to Week 24 in Quality of Life domains included in the PBC-40 questionnaire.p values for comparison of changes in the 400mg BID dose against placebo are shown.

• Reduced quality of life is one of the main unmet medical need in PBC, in particular fatigue

• Approved therapies do not improve quality of life

Setanaxib

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Setanaxib was safe & well tolerated at all doses over the 24-week treatmentperiod

Setanaxib

Excellent safety profile supports combination therapy with generically available anti-cholestatic agents including UDCA and fibrates

PlaceboSetanaxib

400mg OD

Setanaxib

400mg BIDSAEs 1 0 1

AEs 121 119 100

AEs leading to patient discontinuation 0 2 2

AEs leading to drug interruption 1 1 2

Gastrointestinal 22 25 25

Infections 24 12 11

Skin and subcutaneous tissue 12 15 14

Nervous system 12 17 9

General disorders 14 6 12

Musculoskeletal and connective tissue 10 12 6

Investigations 3 7 7

Injury, poisoning, procedural complications 4 4 5

Respiratory, thoracic, and mediastinal 4 5 4

Psychiatric disorders 7 1 0

Incidence of Treatment-Emergent Adverse Events by System Organ Class (top 10 system organ classes ranked according to AE incidence)

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Phase 2 trial in IPF funded by the NIHIndustry standard design similar to other Phase 2 trials

⚫ 60 IPF patients in two arms

⚫ 24-week treatment in 5 centers part of the NIH Clinical Research Network (IPFnet)

⚫ Setanaxib 400mg BID on top of standard of care (SoC) vs SoC & Placebo

Trial # patients Design

⚫ Forced vital capacity (FVC)

⚫ 6-minute walking distance (6-MWD)

⚫ High resolution CT

⚫ Plasma levels of collagen fragments

⚫ Safety of setanaxib in IPF patients

Phase 2

Secondary endpoint

⚫ Change in plasma o’, o’ dityrosine, a validated marker of pulmonary oxidative stress

Primary endpoint

IPF is an orphan disease with unmet medical need

Setanaxib

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Appendix – Additional Information on Genkyotex

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Corporate information

▪ Stock market information (as of January 15, 2020)

– Markets: Euronext Paris and Euronext Brussels

– Number of shares: 9,101,265

– Average trading volume: 70,081 shares/day

▪ Stock codes

– Name: GENKYOTEX

– Mnemonic: GKTX

– ISIN code: FR0013399474

▪ Contacts Genkyotex

– Elias Papatheodorou – CEO

– Alexandre Grassin – VP Finance and Administration

Tel.: +33 4 80 16 06 07

E-mail: [email protected]

Website: www.genkyotex.com

Andera Partners funds

20,47%

Eclosion2 & Cie SCPC

15,31%

Vesalius Biocapital7,60%

NEOMED5,98%

Wellington Partners

1,77%N5 Investment AS

0,37%

Management & employees

4,78%

Treasury shares0,10%

Others43,62%

▪ Shareholding structure at January 15, 2020

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Solid IP portfolio with potential of term extensions in the US, Europe & Japan

Composition of matter protection till 2028/2029 without any extensions

Setanaxib (per se) and its derivatives in treating NADPH related disorders

Country Application No. Patent No. Anticipated expiry Type of protection

USA 12/532,336 8,389,518 12.04.2028 Pharmaceutical formulations/use

USA 13/734,205 9,073,919 20.03.2028 Pharmaceutical formulations/use

Europe 08718102.0 2139477 20.03.2028 Pharmaceutical formulations/use

Europe 12187254.3 2545918 20.03.2028 Pharmaceutical formulations/use

Japan 2009-554036 5715340 20.03.2028 Pharmaceutical formulations/use

Japan 2015-050104 6047189 20.03.2028 Pharmaceutical formulations/use

Country Application No. Patent No. Anticipated expiry Type of protection

USA 13/120,440 9,096,588 22.09.2029 NCE/use

USA 14/750,019 Pending - NCE/use

Europe 9787271.7 2344492 22.09.2029 NCE/use

Europe 14190340.1 Pending - NCE/use

Japan 2011-527466 5700837 22.09.2029 NCE/use

Japan 2014-254651 5932008 22.09.2029 NCE/use

Setanaxib (generically) and its derivatives in treating NADPH related disorders

Setanaxib

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Page 27: Investor Presentation€¦ · Setanaxib - Liver Fibrosis Primary Biliary Cholangitis (PBC) Final results published July 2019 Setanaxib - Kidney Fibrosis Diabetic Kidney Disease (DKD)

Phase 2 trial in type 1 diabetes-induced kidney disease (DKD)

⚫ 142 T1D DKD patients

⚫ 48-week treatment in up to 15 centers in Australia. Trials conducted by Baker Heart and Diabetes Institute in Melbourne

⚫ Setanaxib 200mg BID against matching placebo, twice daily

Trial # patients Design

⚫ Renal function: estimated glomerular filtration rate (eGFR), and cystatin C

⚫ Renal injury: NGAL, KIM-1

⚫ Inflammation: hsCRP, fibrinogen, IL-6

⚫ Metabolomics and lipidomics profiles

⚫ Exploratory epigenetics and transcriptomics studies

Phase 2

Secondary endpoint

⚫ Change in urinary albumin to creatinine ratio (UACR), adjusted for baseline

Primary endpoint

The IIT DKD phase 2 trial funded by JDRF is currently recruiting

Sources 1NGAL: neutrophil gelatinase-associated lipocalin; KIM-1: kidney injury marker 1; hsCRP: high sensitivity C-reactive protein; IL-6: interleukin-6; T1D: type 1 diabetes

Setanaxib

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Initial phase 2 results in diabetic kidney disease (DKD)

Excellent safety profile up to 200mg BID for 12 weeks

— Well tolerated with fewer adverse events than placebo : moderate

to severe AEs 57 vs 15 (p<0.001) n=68/arm

Primary endpoint: no significant difference on renal

outcomes

— Possible reasons:

▪ Duration of treatment: 12 weeks sufficient for drugs acting on intra-renal

hemodynamics, but not to demonstrate direct anti-inflammatory or anti-

fibrotic effects

▪ Dose

Secondary endpoints: pharmacological activity

demonstrated

— Statistically significant reduction in liver enzymes – GGT (p<0.05)

— Strong trend for reduction in triglycerides (p=0.066)

— Statistically significant reduction in inflammation - hsCRP (p<0.05)

— Strong trend for reduction in additional inflammatory markers –

serum amyloid protein A (p<0.08), IL-6 (p=0.2)

Setanaxib significantly reduces the incidence of adverse events

Adverse events

Severity Placebo setanaxib Diff.

All 119 69 -42%

Mild 62 54 -12%

Moderate 44 14 -68%

Severe 13 1 -93%

p<0.001 (CMH analysis)

Setanaxib significantly improved multiple predefined secondary efficacy endpoints of liver inflammation and injury. Importantly, the study confirmed the favourable safety profile of setanaxib

Setanaxib

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Preclinical studies: over 50 publications in leading peer-reviewed journals

“Inhibition of NOX4 by GKT831 improves inflammation and fibrosis in fast food diet-fed mice. […]”

Hepatocyte NADPH Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity During Development of Steatohepatitis in MiceGastroenterology. 2015 Aug;149(2):468-80

“GKT831 treatment led to a reversal of age-associated persistent fibrosis and reduced mortality. […]” in an IPF model

Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox ImbalanceSci Transl Med. 2014 Apr 9;6(231):231ra47

“[…] our results demonstrate the potential of the NOX1 and NOX4 inhibitor GKT831, which is currently in phase 2human clinical trials, as an NLRP3 inflammasome inhibitor […]”

NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages Nat Med. 2016 Sep;22(9):1002-12

“GKT831 treatment prevented skeletal muscle oxidation and nitrosylation of RyR1, restored calstabin1 binding andimproved EDL muscle–specific force. […]”

Excess TGF-b mediates muscle weakness associated with bone metastases in miceNat Med. 2015 Nov;21(11):1262-1271

“[…] pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types. […]”

Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4 J Natl Cancer Inst. 2018 Jan 1;110(1)

Setanaxib

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GKT831 markedly reduces fibrosis and inflammation in diet-induced NASH modelRobust anti-fibrotic activity despite sustained steatosis

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Reduced inflammation and fibrosis despite sustained steatosis

Fast food diet model of NASH

831 831

831 831

Source: Torok N et al, Gastroenterology 2015

GKT831

Setanaxib

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Source: Victor Thannickal et al., University of Alabama. Science Translational Medicine, 2014

GKT831 reverses fibrosis & improves survival in a model of irreversible lung fibrosisThe bleomycin model conducted in aged mice induces irreversible lung fibrosis

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n = 21-23/group

Start of treatment

Weeks post injury

Bo

dy

we

igh

t (g

)

Days post injury

p = 0.043

6 weeks post injury

Hyd

roxy

pro

line

(mg/

lun

g)

Pe

rce

nt

surv

ival

Control Vehicle GKT831

GKTVehicle

GKT

Vehicle

Setanaxib

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Five Phase 1 studies: very good safety and pharmacodynamics (PD) profile

No dose limiting toxicity

No safety signal

Dose proportional PK up to 900mg/day

Setanaxib is rapidly absorbed after oral dosing(median tmax ~ 1h)

Mean half-life of parent compound is 8-15 hours

Minimal renal elimination (<2%)

Multiple dosing does not affect PK parameters

Very low probability of DDI* through CYP3A4

Low variability in PK parameters when taken with meals

Successful transition from 100mg capsules to 400mg tablets

Pharmacodynamics

0

2

4

6

8

10

Placebo 100mg OD2

300mg OD

400mg BID3

Setanaxib

900mg OD

Med

ian

ch

ange

in M

inim

a Er

yth

ema

Do

se (

mJ/

cm2)

RO

S (r

elat

ive

flu

ore

sce

nce

)

Time after UV (minutes)

UV + setanaxib 2 mM

UV + setanaxib 0.2 mM

UV + setanaxib 20 mM

No UV

UV + vehicle

UV + Trolox

UV + DPI

120000

100000

80000

60000

40000

20000

0 10 20 30 40 50 60 700

Setanaxib reduces ROS production induced by UVB4 in vitro1

Setanaxib is pharmacologically active in healthy subjects

Safety and PK

Single and multiple doses of setanaxib were well-tolerated and pharmacologically active in healthy subjects

• Drug-drug interactions studies

• Sources: 1 In vitro studies conducted at StratiCELL for Genkyotex, unpublished; 2 Once-daily; 3 Twice a day; 4Ultra-violet

Setanaxib

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Efficacy of setanaxib confirmed by correlated reductions in cholestatic markers

400mg ODPlacebo 400mg BID -24%

-13%

-9%

Correlation between changes in ALP and GGT at week 24

Percent change in ALP at Week 24 (%)

Pe

rce

nt

chan

ge in

GG

T at

We

ek

24

(%

)

Pearson’s correlation coefficient = 0.61p value <0.0001 Placebo

Setanaxib 400mg OD

Setanaxib 400mg BID

Setanaxib

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Even patients with modest liver stiffness show significant reductions in ALPP

erc

en

t ch

ange

in A

LP a

t W

ee

k 2

4 (

%)

<7.3 kPa(n=40)

400mg ODPlacebo 400mg BID

All patients(n=104)

≥7.3 kPa(n=64)

Percent reduction in ALP at week 24

Setanaxib

-25

-20

-15

-10

-5

0

-19%

-12%

-10%

-3%

-10%

-13%

-2%-3%

-6%

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