2019.10 gktx corporate presentation - genkyotex.com€¦ · diabetic kidney disease develops in 20%...

Corporate Presentation

October 2019

Inhibiting NOX enzymes to treat multiple diseases with high medical need

Euronext: GKTX

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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 inhibition 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 (DKD) ongoing

— NIH-funded Phase 2 trial in idiopathic pulmonary fibrosis (IPF) to be launched in 2019— 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

� Partnership with Serum Institute of India Private Ltd valued at up to €150 million + royalties

� Trading on Euronext as GKTX since March 2017— Cash and cash equivalents of €3.1 million as of September 30 2019, cash runway to March 2020

— French research tax credit of €0.9 million for 2018 was received in October

Seasoned management team with international life sciences experience

Elias Papatheodorou Chief Executive Officer

� 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 & corporate development and licensingtransactions

Philippe WieselChief 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 GrassinVP Finance & Administration

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

� Financial Auditor with KPMG

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

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

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

Setanaxib - Lung Fibrosis Idiopathic Pulmonary Fibrosis (IPF)(IIT funded by US NIH3 – IND approved by FDA)

NOX1 inhibitors Preclinical

Novel NOX inhibitors

Vaxiclase Pertussis vaccine (Licensed to SIIPL)

Preclinical Phase 1 Phase 2 Phase 3Program

Discovery

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

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

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

ProliferationHedgehog

PDGF

ContractilityET-1

FibrogenesisTGF-b1

Matrix degradationMMP-2

ChemotaxisTLR4

MCP-1

Retinoid lossPDGF

MCP-1WBC 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

FIBROSISKIDNEY

FIBROSISLUNG

Setanaxib

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 sales around 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 (DKD) 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

� Setanaxib - Orally available small molecule (NCE) with nanomolar potency— NOX1 and NOX4 inhibitor with Ki ~ 100nM in membrane assays

— ~12 hour half-life in humans

— Composition of matter protection till 2028/2029 without any extensions

� Rationale for NOX1/4 inhibition in liver fibrosis— NADPH oxidases NOX1 & NOX4 produce ROS and modulate signaling through oxidation of signaling proteins

— NOX1/4 drive multiple inflammatory & fibrogenic pathways (TGFb, PDGF, TLR4, Hedgehog, NF-kB, CCL2,…)

— NOX1 also activates pathways thought to mediate itching, such as TRPV1

— Setanaxib shows marked activity in animal models (bile duct ligation, MDR2 KO, STAM, diet-induced NASH, CCL4)

Rationale for NOX1/4 inhibition with setanaxib in inflammatory and fibrotic disorders

TGFb signalingNOX structure

Phase 2 trial of setanaxib in patients with PBC – Final results

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

� 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

Setanaxib 400mg once a day (OD)

Setanaxib 400mg twice a day (BID)

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

Liver fibrosis progressively disrupt liver structure and function

Setanaxib

F3 F4

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

F1 F2

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

Elas

ticity

(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

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 PlaceboSetanaxib400mg OD

Setanaxib400mg BID

ALL

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 (µmol/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

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

Perc

ent c

hang

e in

GG

T fr

om B

asel

ine

-7%

-12%

Change in GGT for 400mg BID is highly significant at week 6 (IA) and throughout the 24-week treatment period. Unexpectedly, statistical significance was lost at week 24

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=NS

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

Setanaxib

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

Perc

ent c

hang

e in

ALP

from

Bas

elin

e

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

50 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

Setanaxib 400mg BID achieved statistical significance for primary endpointafter correction of non-normal distribution (p=0.02)

-13%

Primary endpoint: change in GGT at Week 24

Primary endpoint: change in GGT Interim analysis (Week 6)

Final analysis(Week 24)

Statistical method Without correction for non-normal distribution

With correction for non-normal distribution*

400mg BID compared to placebo p<0.01 p=0.3 p=0.02

Secondary endpoints (as per protocol) Final analysis

Change in GGT over 24-week treatment period p<0.002

Change in ALP over 24-week treatment period p<0.001

Secondary endpoints: change in GGT & ALP over the 24-week treatment period

*Log transformation

Setanaxib

In the full population setanaxib prevents progression of liver stiffness

Perc

ent c

hang

e in

live

r st

iffne

ss a

t Wee

k 24

(%)

Trend seems to be dose dependent. Baseline values are 10.7 for placebo, 12.5 for 400mg OD and 8.3 kPa for 400mg BID

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

0,4

0,5

Abso

lute

cha

nge

in li

ver

stiff

ness

at W

eek

24 (k

Pa)

Percent change in liver stiffness (%) Absolute change in liver stiffness (kPa)

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5 +4%

-5%

+1%

+0.4

+0.1

-0.4

N=32 N=33

N=26N=32 N=33

N=26

400mg ODPlacebo 400mg BID

Median values Median values

Setanaxib

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 stif

fnes

s at B

asel

ine

and

wee

k 24

(kPa

)

Placebo(n=18)

400mg OD(n=21)

400mg BID(n=20)

Placebo(n=17)

400mg OD(n=14)

400mg BID(n=14)

Live

r stif

fnes

s at B

asel

ine

and

wee

k 24

(kPa

)

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

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)

Abso

lute

cha

nge

in li

ver

stiff

ness

at w

eek

24 (k

Pa)

-5

-4

-3

-2

-1

0

1

2

+0.4

-1.9

-2.7

Mean ± SEM

Perc

ent c

hang

e in

live

r st

iffne

ss a

t wee

k 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

Perc

ent c

hang

e in

GG

T at

Wee

k 24

(%)


Percent reduction in GGT at week 24<9.6 kPa

(n=59)All patients

(n=104)≥9.6 kPa

(n=45)

Patients with the greatest medical need show marked reductions in GGT Setanaxib

-40

-30

-20

-10

0

10

20

30

-19%

-13%

-32%

-10%

+9%

-5%

-15%

-8%-5%

Patients with the greatest medical need show marked reductions in ALP

Perc

ent c

hang

e in

ALP

at W

eek

24 (%

)

<9.6 kPa(n=59)


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%

Setanaxib 400mg BID significantly improves Quality of Life domainsincluding fatigue

Setanaxib 400mg BID improved quality of life across multiple domains important to PBC patients

1 Once daily; 2 Twice dailyPBC-40 questionnaire

PBC-40 QoL domains PlaceboSetanaxib

400mg OD1Setanaxib

400mg BID2p value (400mg BID vs placebo at week 24)

General symptoms 1.1 1.1 -3.7 0.156Itch (Pruritus) -6.8 -11.4 -9.5 0.443Emotional 8.7 4.9 -16.9 0.031Fatigue 2.4 0.3 -9.9 0.027Social 9.3 8.1 -7.7 0.003Cognitive 5.2 16 -1.9 0.332Mean 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

• Fatigue is the most common symptom in PBC patients

• Approved therapies do not improve quality of life

Setanaxib

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

PlaceboSetanaxib400mg OD

Setanaxib400mg BID

SAEs 1 0 1AEs 121 119 100AEs leading to patient discontinuation 0 2 2AEs leading to drug interruption 1 1 2Gastrointestinal 22 25 25Infections 24 12 11Skin and subcutaneous tissue 12 15 14Nervous system 12 17 9General disorders 14 6 12Musculoskeletal and connective tissue 10 12 6Investigations 3 7 7Injury, poisoning, procedural complications 4 4 5Respiratory, thoracic, and mediastinal 4 5 4Psychiatric disorders 7 1 0

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

Data supports use of setanaxib in a broad patient population, includingpatients with advanced fibrotic liver disease

• Setanaxib shows marked efficacy in difficult to treat patients with advanced disease

• Setanaxib achieved clinically meaningful reductions in liver stiffness in patients with elevated liver stiffness at baseline (≥9.6 kPa)

• Patients with even modest elevation in liver stiffness (≥7.3 kPa) benefit from setanaxib for both liver stiffness and markers of cholestatic injury (GGT and ALP)

• Setanaxib is the first compound to improve quality of life, with a marked effect on fatigue

• Setanaxib was safe and well tolerated at all doses

• Company plans to advance setanaxib into late stage clinical trials in PBC and other fibrotic liver diseases, like NASH and PSC

• JDRF-funded Phase 2 diabetic kidney disease (DKD) trial ongoing

• NIH-funded Phase 2 idiopathic pulmonary fibrosis (IPF) trial to be launched in the next months

Setanaxib

Appendix – Additional Information on Genkyotex

Corporate information

§ Stock market information– Markets: Euronext Paris and Euronext Brussels– Number of shares: 8,245,483 (as of 30 Sept. 2019)

§ Cash Position– €3.1 m in Cash & Cash equivalent (30 Sept. 2019)– French research tax credit of €0.9 million for 2018

was received in October– Cash runway to March 2020

§ 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 07E-mail: [email protected]: www.genkyotex.com

§ Shareholding structure (as at April 26, 2019):

mailto:[email protected]

http://www.genkyotex.com/

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

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

l 142 T1D DKD patientsl 48-week treatment in up to 15 centers in Australia. Trials

conducted by Baker Heart and Diabetes Institute in Melbourne

l Setanaxib 200mg BID against matching placebo, twice daily

Trial # patients Design

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

l Renal injury: NGAL, KIM-1

l Inflammation: hsCRP, fibrinogen, IL-6

l Metabolomics and lipidomics profiles

l Exploratory epigenetics and transcriptomics studies

Phase 2

Secondary endpoint

l 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

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 eventsSeverity 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

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

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

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

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

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

n = 21-23/group

Start of treatment

Weeks post injury

Body

wei

ght (

g)

Days post injury

p = 0.043

6 weeks post injury

Hyd

roxy

prol

ine

(µg/

lung

)

Perc

ent s

urvi

val

Control Vehicle GKT831

GKTVehicle

GKTVehicle

Setanaxib

Four 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

Pharmacodynamics

0

2

4

6

8

10

Placebo 100mg OD2

300mg OD

400mg BID3

Setanaxib900mg

OD

Med

ian

chan

ge in

Min

ima

Eryt

hem

a D

ose

(mJ/

cm2 )

ROS

(rel

ativ

e flu

ores

cenc

e)

Time after UV (minutes)

UV + setanaxib 2 µMUV + setanaxib 0.2 µM

UV + setanaxib 20 µM

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

Post-hoc analyses explored the loss of statistical significance at Week 24 andthe therapeutic benefits achieved with setanaxib

Setanaxib

• Exploring week-24 GGT data

• Analyses explored potential causes for the loss of statistical significance at week 24

• Correlation between changes in GGT and ALP at week 24

• The correlation between changes in GGT and ALP was assessed to confirm that the observed reductions in GGT and ALP reflected a consistent reduction in cholestatic injury

• Responder analysis

• Analyses were carried out to further explore the therapeutic benefits achieved with Setanaxib

• A key question was whether setanaxib also reduced cholestatic injury in patients with elevated liver stiffness, in addition to reducing liver stiffness

Normal distribution of GGT data was observed for the placeboand 400mg BID groups

Chan

ge in

GG

T fr

om

Base

line

to W

eek

24 (%

)

• A normal distribution of data is one in which the majority of data points occur within a small range, with few outliers on the higher and lower ends of the data range

• Mean (average) and median values are similar

• Standard deviations are small compared to the mean value

• At week 24, distribution of GGT data in the placebo and 400mg BID groups was normal

Setanaxib

Post-hoc analyses identified non-normal data distribution in the 400mg ODgroup as the reason for the loss of statistical significance at week 24

Chan

ge in

GG

T fr

om

Base

line

to W

eek

24 (%

)

• At week 24, distribution of GGT data in the 400mg OD group was considered as non-normal

• Non-normal data distribution in the 400mg OD group caused the loss of statistical significance at week 24 for the 400mg BID group

Setanaxib

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 (%)

Perc

ent c

hang

e in

GG

T at

Wee

k 24

(%)

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

Setanaxib 400mg OD

Setanaxib 400mg BID

Setanaxib

Even patients with modest liver stiffness show significant reductions in ALP

Perc

ent c

hang

e in

ALP

at W

eek

24 (%

)

<7.3 kPa(n=40)


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%

2019.10 gktx corporate presentation - genkyotex.com€¦ · diabetic kidney disease develops in 20%...

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