2019.06 gktx corp presentation final - biotech agora · primary biliary cholangitis (pbc): an...
TRANSCRIPT
Corporate Presentation
June 2019
Inhibiting NOX enzymes to treat multiple diseases with high medical need
Euronext: GKTX
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Ph2 PBC highlight the potential of GKT831 as an anti-fibrotic therapy in the liver, lung, skin, kidney and other organs
Genkyotex: Establishing NOX inhibition as a new therapeutic class
Page 3
� We discover and develop oral small molecule NOX inhibitors— NOX enzymes are important since they control multiple stress responses pathways simultaneously — Activation of NOX enzymes is key in many multifactorial diseases
� Lead asset GKT831: a potent anti fibrotic oral small molecule currently in Phase 2 testing— JDRF-funded Phase 2 trial in kidney fibrosis (DKD) ongoing— NIH-funded Phase 2 trial in idiopathic pulmonary fibrosis (IPF) to be launched in H1 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 improvement
� 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 €7.3 million as of March 31 2019, cash runway to April 2020
Seasoned management team with international life sciences experience
Page 4
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 AG
and 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 needGKT831 Phase 2 PBC data support development in multiple fibrotic diseases
Page 5
GKT831 - Liver Fibrosis(NOX1/4 inhibitor)
Primary Biliary Cholangitis (PBC)Top-line results published May 2019
GKT831 - Kidney Fibrosis(NOX1/4 inhibitor)
Diabetic Kidney Disease (DKD) in T1D(IIT1 funded by JDRF2 - Trial launched in H2 2017)
GKT831 - Lung Fibrosis(NOX1/4 inhibitor)
Idiopathic Pulmonary Fibrosis (IPF)(IIT funded by US NIH3 - Trial launch H1 2019)
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
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We focus on fibrotic diseases by targeting NOX1 and NOX4 with GKT831
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
Page 7
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
GKT831 downregulates the activation of multiple clinically validated fibrogenic and apoptotic pathways*
LUNG INJURYSmoking
Toxic chemicalsInflammation
RENAL INJURYHyperglycemia
High blood pressureInflammation
LIVER
FIBROSISKIDNEY
FIBROSISLUNG
GKT831
Fibrosis: ~45% of all deaths in the developed world1
We focus on Key fibrosis markets with GKT831
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.
GKT831
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
Page 8
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 GKT831 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
� GKT831 - 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 GKT831 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
— GKT831 shows marked activity in animal models (bile duct ligation, MDR2 KO, STAM, diet-induced NASH, CCL4)
Rationale for NOX1/4 inhibition with GKT831 in inflammatory and fibrotic disorders
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TGFb signalingNOX structure
Phase 2 trial of GKT831 in patients with PBC – Top-line final results
Page 10
GKT831 ideally positioned to complement the anti-cholestatic activity of generically available drugs like UCDA and fibrates
Primary Biliary Cholangitis (PBC):an orphan disease in the large liver fibrosis market
Page 11
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
� 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)
GKT831
Primary Biliary Cholangitis
Inflammation and scar tissue destroy ducts
Normal bile ducts
Gallbladder
Hepatic ductCommon bile duct
Liver
Cystic duct
� 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)
GKT831 was evaluated in a large 24-week Phase 2 trial
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Placebo
GKT831 400mg once a day (OD)
GKT831 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
GKT831
Liver fibrosis progressively disrupt liver structure and function
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GKT831
F3 F4
Liver fibrosis is the best predictor of long-term outcomes in multiple liver diseases
F1 F2
Non-invasive assessment of GKT831 effect on fibrosis with Fibroscan®In PBC, liver stiffness ≥ 9.6 kPa corresponds to advanced liver fibrosis of ≥F3
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GKT831
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
Phase 2 trial of GKT831 in PBC: Baseline patient characteristics
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GKT831
Baseline characteristics in line with the targeted population of active PBC patients
1 Once daily; 2 Twice daily
Baseline patient characteristics PlaceboGKT831
400mg ODGKT831
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 (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)
GKT831 400mg BID achieves significant reduction in GGT over 24-week treatment period (p<0.002)
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GKT831
Perc
ent c
hang
e in
GG
T fr
om B
asel
ine
-7%
-12%
GGT reduction statistically significant over 24-week treatment period. Statistical significance observed at interim not achieved 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)
GKT831 400mg OD (n=38)
GKT831 400mg BID (n=36)
p=NS
p<0.002 400mg BID vs placebo over 24 weeks
p<0.01
Robust GGT reductions in patients with high baseline GGT (≥2.5XULN, n=86)
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GKT831
Perc
ent c
hang
e in
GG
T fr
om
Base
line
to W
eek
24
These results suggest that GKT831 offers superior benefit to patients with more active disease (higher baseline GGT)
Mean ± SEM
-21%
-30
-25
-20
-15
-10
-5
0
-21%
-6%
-14%
Percent changes in GGT (%)
N=27 N=30 N=29
400mgOD
Placebo 400mgBID
p=0.039
GKT831 400mg BID achieves significant reduction in ALP over 24-week treatment period (p<0.001)
GKT831
PlaceboGKT831
400mg ODGKT831
400mg BID
Response rate for composite endpoint1 5% 18% 25%
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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
1 ALP<1.67XULN, ALP reduction≥15%, TB <ULN
Placebo (n=37)
GKT831 400mg OD (n=38)
GKT831 400mg BID (n=36)
p=0.049
p<0.001 400mg BID vs placebo over 24 weeks
Mean ± SEM
GKT831 achieved a positive trend in reduction liver stiffness in full population
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GKT831
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
GKT831 achieved clinically meaningful reduction in liver stiffness in patientswith estimated liver fibrosis score of ≥ F3
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GKT831
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
)
5.7 6.2 6.2 6.37.0 6.8
12.7
14.2 14.113.1
12.2
9.1
In just 24 weeks of treatment GKT831 achieves average reduction of 3kPa –an estimated one point fibrosis score reduction
Page 21
GKT831
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
GKT831 achieves clinically significant reduction in liver stiffness in PBC patients with elevated liver stiffness
~3 kPa
GKT831 400mg BID achieves significantly improves Quality of Life domainsincluding fatigue
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GKT831
GKT831 400mg BID improved quality of life across multiple domains important to PBC patients
1 Once daily; 2 Twice daily
PBC-40 questionnaire
PBC-40 QoL domains PlaceboGKT831
400mg OD1
GKT831400mg BID2
p 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.
GKT831 was safe & well tolerated at all doses over the 24-week treatmentperiod
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GKT831
Excellent safety profile supports combination therapy with generically available anti-cholestatic agents including UDCA and fibrates
PlaceboGKT831
400mg ODGKT831
400mg BIDSAEs 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)
Conclusions & Corporate Information
Page 24
Fibroscan data highlight the potential of GKT831 as an anti-fibrotic therapy
Page 25
GKT831
• Clinically significant reduction in liver stiffness suggests average of 1-point improvement in liver fibrosis score in just 24 weeks
• GKT831 400mg BID achieved statistically significant reduction in GGT and ALP over 24-week treatment period (p<0.002 and p<0.001, respectively)
• Significant improvement in quality of life domains important to PBC patients and especially fatigue
• Company planning to advance GKT831 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
Corporate information
Page 26
§ Stock market information– Markets: Euronext Paris and Euronext Brussels– Number of shares: 8,022,786 (as of Apr. 2019)
§ Cash Position– €7.3 m in Cash & Cash equivalent (31 Mar. 2019)– Cash runway to April 2020
§ Stock codes– Name: GENKYOTEX– Mnemonic: GKTX– ISIN code: FR0011790542
§ 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):
Appendix – Additional Information on Genkyotex
Page 27
Solid IP portfolio with potential of term extensions in the US, Europe and Japan
Composition of matter protection till 2028/2029 without any extensions
Page 28
� GKT831 (per se) and its derivatives in treating NADPH related disorders
GKT831
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
� GKT831 (generically) and its derivatives in treating NADPH related disorders
Phase 2 trial in type 1 diabetes-induced kidney disease (DKD)
Page 29
GKT831
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 GKT831 200mg BID against matching placebo, twice daily
Trial # patients Design
l Renal function: estimated glomerular filtration rate (eGFR), and cystatin Cl Renal injury: NGAL, KIM-1
l Inflammation: hsCRP, fibrinogen, IL-6
l Metabolomics and lipidomics profilesl 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
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)
Page 30
GKT831
� GKT831 significantly reduces the incidence of adverse events
Adverse eventsSeverity Placebo GKT831 Diff.
All 119 69 -42%Mild 62 54 -12%Moderate 44 14 -68%Severe 13 1 -93%
p<0.001 (CMH analysis)
GKT831 significantly improved multiple predefined secondary efficacy endpoints of liver inflammation and injury. Importantly, the study confirmed the favourable safety profile of GKT831
Preclinical studies: over 50 publications in leading peer-reviewed journals
Page 31
GKT831
“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)
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
GKT831
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
Body
wei
ght (
g)
Days post injury
p = 0.043
6 weeks post injury
Hydr
oxyp
rolin
e(µ
g/lu
ng)
Perc
ent s
urvi
val
Control Vehicle GKT831
GKTVehicle
GKTVehicle
GKT831
Four Phase 1 studies: very good safety and pharmacodynamics (PD) profile
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� No dose limiting toxicity
� No safety signal
� Dose proportional PK up to 900mg/day
� GKT831 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
GKT831
Pharmacodynamics
0
2
4
6
8
10
Placebo 100mg OD2
300mg OD
400mg BID3
GKT831900mg
OD
Med
ian
chan
ge in
Min
ima
Eryt
hem
a Do
se (m
J/cm
2 )
ROS
(rel
ativ
e flu
ores
cenc
e)
Time after UV (minutes)
UV + GKT831 2 uM
UV + GKT831 0.2 uM
UV + GKT831 20 uM
No UV
UV + vehicle
UV + Trolox
UV + DPI
120000
100000
80000
60000
40000
20000
0 10 20 30 40 50 60 700
� GKT831 reduces ROS production induced by UVB4 in vitro1
� GKT831 is pharmacologically active in healthy subjects
Safety and PK
Single and multiple doses of GKT831 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