Corporate Presentation - Inhibiting NOX enzymes to treat multiple diseases with high medical need - Genkyotex
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Corporate Presentation
Inhibiting NOX enzymes to treat multiple
diseases with high medical need
Euronext: GKTX
October 2019
Disclaimer
This document has been prepared by Genkyotex (the "Company") and is for information and background purposes only.
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Page 2
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
Ph2 PBC highlight the potential of setanaxib as an anti-fibrotic therapy in the
liver, lung, skin, kidney and other organs
Page 3
Seasoned management team with international life sciences experience
Elias Papatheodorou 25 years of experience in biotechnology and multinational companies
Chief Executive Officer 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 licensing
transactions
Philippe Wiesel Lead clinical research programs at Serono’s EU and US offices, including the phase 3
program (ex-US) for Raptiva in psoriasis, leading to the first EMA approval of a biologic
Chief Medical Officer & EVP agent for psoriasis
Conducted basic research in the laboratories of Professor Edgar Haber at Harvard
Medical School, and of Professor Hans Brunner at the Division of Hypertension in
Lausanne
Diverse experiences in Finance with Novartis from 2007-2010 & Alexion from 2010 to
Alexandre Grassin 2012
VP Finance & Administration Financial Auditor with KPMG
Page 4
Discovery platform delivers broad pipeline in diseases with high medical need
Setanaxib Phase 2 PBC data support development in multiple fibrotic diseases
Program Preclinical Phase 1 Phase 2 Phase 3
Primary Biliary Cholangitis (PBC)
Setanaxib - Liver Fibrosis
Final results published July 2019
Diabetic Kidney Disease (DKD) in T1D
Setanaxib - Kidney Fibrosis
(IIT1 funded by JDRF2 - Trial launched in H2 2017)
Idiopathic Pulmonary Fibrosis (IPF)
Setanaxib - Lung Fibrosis
(IIT funded by US NIH3 – IND approved by FDA)
NOX1 inhibitors Preclinical
Novel NOX inhibitors Discovery
Pertussis vaccine
Vaxiclase
(Licensed to SIIPL)
1Investigator initiated trial
2 Juvenile Diabetes Research Foundation
3 National Institutes of Health
Page 5
NOX inhibitors: pathway based medicine addressing validated disease targets
NOX stands for a group of enzymes called NADPH Oxidases
A family of 7 enzymes that amplify multiple signaling pathways
NOX NOX1 NOX2 NOX3 NOX4 NOX5 DUOX1 DUOX2
VALIDATED
NF-kB PI3K NMDA TRPV1 TGF-b PDGF
DISEASE TRPV1 VEGF (CNS) (hearing loss) RANKL TLR4
NA Thyroid hormone iodination
PATHWAYS
DISEASE Inflammation Angiogenesis Fibrosis Proliferation
PROCESSES
We focus on fibrotic diseases by targeting NOX1 and NOX4 with setanaxib
Page 6
NOX 1 & 4 are major drivers of fibrogenesis in multiple organs
Setanaxib
NOXs activates pathways such as TGF-b, PDGF, Hedgehog, TLR4, and CCL2
FIBROGENIC PATHWAYS
hog
Hedge Proliferation LUNG
PDGF
FIBROSIS
LUNG INJURY Contractility
Smoking ET-1
Toxic chemicals
Inflammation Fibrogenesis
b1
TGF-
LIVER
NOX/ROS Matrix degradation
MMP-2 FIBROSIS
LIVER INJURY
Steatosis TLR4
Quiescent Cholestasis MCP-1 Chemotaxis Activated
fibroblast Hep C/HepB myofibroblast
Alcohol
PDGF Retinoid loss
RENAL INJURY KIDNEY
Hyperglycemia MCP WBC chemoattraction FIBROSIS
-1
High blood pressure
Inflammation
Pathways amplified by NOX1/4
Setanaxib downregulates the activation of multiple clinically validated
fibrogenic and apoptotic pathways*
*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
Fibrosis: ~45% of all deaths in the developed world1
Setanaxib
We focus on Key fibrosis markets with setanaxib
Idiopathic Pulmonary Fibrosis
Liver fibrosis impacts 300 to
(IPF) affects 3 million people
700 million people worldwide2
worldwide3
1st product in NASH to be approved based 2 approved products in IPF each with
on anti-fibrotic activity in only 23% of sales around 1 billion USD sales per year
patients Pirfenidone to become generic allowing
Fibrosis drives transplants and remains the combination strategies
unmet medical need
Diabetic Kidney Disease Immuno-oncology therapies
develops in 20% to 40% of all not as effective in highly
diabetics6 fibrotic tumors
Diabetic Kidney Disease (DKD) is the Cancer associated fibroblasts (CAFs)
leading cause of end-stage renal disease4 oppose immunotherapies by shielding
Affects 14% to 31% of people with type 1 tumors from T-cells
diabetes after 20 years of diabetes5 Targeting CAFs with setanaxib restores
response to immunotherapies
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: Hovind
P, 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.
Page 8
Rationale for NOX1/4 inhibition with setanaxib in inflammatory and fibrotic disorders
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)
NOX structure TGFb signaling
Page 9
Phase 2 trial of setanaxib in patients with PBC – Final results
Page 10Primary Biliary Cholangitis (PBC): Setanaxib
an orphan disease in the large liver fibrosis market
Disease overview Liver
• Chronic autoimmune liver disease - progressive destruction of bile ducts
• Prevalence of between 2 - 40 cases per hundred thousand-population1 Gallbladder
• Women make up about 90% of PBC cases
Hepatic duct
• Diagnosis based on presence of auto-Abs and elevated markers of cholestasis Common bile duct
including alkaline phosphatase (ALP) & gamma glutamyl transpeptidase (GGT)
Cystic
Therapy duct
• Current medications mainly target cholestasis and include generic anti- Normal bile ducts
cholestatic drugs (UDCA and fibrates) and obeticholic acid (OCA)
Unmet medical need
• Anti-fibrotic agents to delay disease progression and obviate transplant Inflammation and scar
• Effective agents targeting itching and fatigue to restore quality of life tissue destroy ducts
• Safe, well tolerated therapy suitable for combination with anti-cholestatic
therapies (UDCA, fibrates, OCA) Primary Biliary Cholangitis
Setanaxib’s unique efficacy and safety profile can address the unmet medical need
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
Page 11Setanaxib was evaluated in a large 24-week Phase 2 trial Setanaxib
Baseline Week 6 Week 24
Inadequate biochemical Placebo Follow up
response to UDCA
111 randomized Setanaxib 400mg once a day (OD) Follow up
(initial target 102)
ALP ≥1.5XULN
GGT ≥1.5XULN Setanaxib 400mg twice a day (BID) Follow up
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)
Page 12Liver fibrosis progressively disrupt liver structure and function Setanaxib
F1 F2
F3 F4
Liver fibrosis is the best predictor of long-term outcomes in multiple liver
diseases
Page 13Non-invasive assessment of liver fibrosis with Fibroscan®
Setanaxib
In PBC, liver stiffness ≥ 9.6 kPa corresponds to advanced liver fibrosis of ≥F3
Liver stiffness is an indicator of liver inflammation, cholestasis and fibrosis
Liver
stiffness
Elasticity (kPa)
Histologic fibrosis
score
Fibrosis stage
• 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.
Page 14Phase 2 trial of setanaxib in PBC: Baseline patient characteristics Setanaxib
Setanaxib Setanaxib
Baseline patient characteristics Placebo ALL
400mg OD 400mg BID
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) 1 Once daily; 2 Twice daily
Baseline characteristics in line with the targeted population of active PBC
patients
Page 15Setanaxib 400mg BID achieves significant reduction in GGT over the Setanaxib 24-week treatment period (p
Setanaxib 400mg BID achieves significant reduction in ALP over the Setanaxib 24-week treatment period (p
Setanaxib 400mg BID achieved statistical significance for primary endpoint Setanaxib
after correction of non-normal distribution (p=0.02)
Primary endpoint: change in GGT at Week 24
Interim analysis Final analysis
Primary endpoint: change in GGT
(Week 6) (Week 24)
Without correction for With correction for non-
Statistical method
non-normal distribution normal distribution*
400mg BID compared to placebo pIn the full population setanaxib prevents progression of liver stiffness Setanaxib
Percent change in liver stiffness (%) Absolute change in liver stiffness (kPa)
Placebo 400mg OD 400mg BID
5 0,5
+4% +0.4
4 0,4
stiffness at Week 24 (kPa)
3
Absolute change in liver
0,3
stiffness at Week 24 (%)
Percent change in liver
2 +1% 0,2
1 +0.1
N=32 N=33 0,1
0 N=32 N=33
N=26 0
-1 N=26
-0,1
-2
-3 -0,2
-4 -0,3
-5 -0,4
-5% -0.4
-6 Median values -0,5 Median values
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
Page 19Setanaxib achieved clinically meaningful reduction in liver stiffness in
Setanaxib
patients with estimated liver fibrosis score of ≥ F3
Patients with baseline liver Patients with baseline liver
stiffness < 9.6 kPa stiffness ≥ 9.6 kPa
Baseline Week 24
16 16
Upper limit of normal (7 kPa) 14.2 14.1
14 14 13.1
12.7
Liver stiffness at Baseline
Liver stiffness at Baseline
12.2
12 12
and week 24 (kPa)
and week 24 (kPa)
10 10
9.1
8 7.0 6.8 8
6.2 6.2 6.3
6 5.7 6
4 4
2 2
0 0
Placebo 400mg OD 400mg BID Placebo 400mg OD 400mg BID
(n=18) (n=21) (n=20) (n=17) (n=14) (n=14)
Median values Median values
Page 20In just 24 weeks of treatment setanaxib achieves average reduction of Setanaxib
3kPa – an estimated one-point fibrosis score reduction
Percent change in liver stiffness Absolute change in liver stiffness
Placebo (n=17) 400mg OD (n=14) 400mg BID (n=14)
15 Mean ± SEM 2 Mean ± SEM
10
1
stiffness at week 24 (kPa)
5
Absolute change in liver
stiffness at week 24 (%)
Percent change in liver
+4.2 +0.4
0 0
-5.3
-5
-1
-10 -1.9
-15 -2
-2.7
-20 -20.9
-3
-25
-4
-30
p=0.039 ~3 kPa
-35 -5
Setanaxib achieves clinically significant reduction in liver stiffness in PBC
patients with elevated liver stiffness
Page 21Patients with the greatest medical need show marked reductions in GGT Setanaxib
Percent reduction in GGT at week 24
All patientsPatients with the greatest medical need show marked reductions in ALP Setanaxib
Percent reduction in ALP at week 24
All patientsSetanaxib 400mg BID significantly improves Quality of Life domains
Setanaxib
including fatigue
PBC-40 questionnaire 1 Once daily; 2 Twice daily
Setanaxib Setanaxib p value (400mg BID vs
PBC-40 QoL domains Placebo
400mg OD1 400mg BID2 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
• Fatigue is the most common symptom in PBC patients
• Approved therapies do not improve quality of life
Setanaxib 400mg BID improved quality of life across multiple domains
important to PBC patients
Page 24Setanaxib was safe & well tolerated at all doses over the 24-week treatment Setanaxib
period
Setanaxib Setanaxib
Placebo
400mg OD 400mg BID
SAEs 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)
Excellent safety profile supports combination therapy with generically
available anti-cholestatic agents including UDCA and fibrates
Page 25Data supports use of setanaxib in a broad patient population, including
Setanaxib
patients 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
Page 26Appendix – Additional Information on Genkyotex
Page 27Corporate information
§ Stock market information § Shareholding structure (as at April 26, 2019):
– 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 07
E-mail: info@Genkyotex.com
Website: www.genkyotex.com
Page 28Composition of matter protection till 2028/2029 without any extensions Setanaxib
Setanaxib (per se) and its derivatives in treating NADPH related disorders
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
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
Solid IP portfolio with potential of term extensions in the US,
Europe and Japan
Page 29Phase 2 trial in type 1 diabetes-induced kidney disease (DKD) Setanaxib
Trial # patients Design
l 48-week treatment in up to 15 centers in Australia. Trials
Phase 2 l 142 T1D DKD patients conducted by Baker Heart and Diabetes Institute in Melbourne
l Setanaxib 200mg BID against matching placebo, twice daily
Primary endpoint
l Change in urinary albumin to creatinine ratio (UACR), adjusted for baseline
Secondary endpoint
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
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
Page 30Initial phase 2 results in diabetic kidney disease (DKD) Setanaxib
Setanaxib significantly improved multiple predefined secondary efficacy endpoints of liver inflammation and
injury. Importantly, the study confirmed the favourable safety profile of setanaxib
Excellent safety profile up to 200mg BID for 12 weeks Setanaxib significantly reduces the incidence of
— Well tolerated with fewer adverse events than placebo : moderate adverse events
to severe AEs 57 vs 15 (pPreclinical studies: over 50 publications in leading peer-reviewed journals Setanaxib
Excess TGF-b mediates muscle weakness associated with bone metastases in mice
Nat Med. 2015 Nov;21(11):1262-1271
“GKT831 treatment prevented skeletal muscle oxidation and nitrosylation of RyR1, restored calstabin1 binding and
improved EDL muscle–specific force. […]”
NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages
Nat Med. 2016 Sep;22(9):1002-12
“[…] our results demonstrate the potential of the NOX1 and NOX4 inhibitor GKT831, which is currently in phase 2
human clinical trials, as an NLRP3 inflammasome inhibitor […]”
Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance
Sci Transl Med. 2014 Apr 9;6(231):231ra47
“GKT831 treatment led to a reversal of age-associated persistent fibrosis and reduced mortality. […]” in an IPF model
Hepatocyte NADPH Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity
During Development of Steatohepatitis in Mice
Gastroenterology. 2015 Aug;149(2):468-80
“Inhibition of NOX4 by GKT831 improves inflammation and fibrosis in fast food diet-fed mice. […]”
Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4
J Natl Cancer Inst. 2018 Jan 1;110(1)
“[…] pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types. […]”
Page 32Setanaxib markedly reduces fibrosis and inflammation in diet-induced NASH model
Setanaxib
Robust anti-fibrotic activity despite sustained steatosis
Fast food diet model of NASH
831 831
831 831
GKT831
Source: Torok N et al, Gastroenterology 2015 Reduced inflammation and fibrosis despite sustained steatosis
Page 33Setanaxib reverses fibrosis & improves survival in a model of irreversible lung fibrosis Setanaxib
The bleomycin model conducted in aged mice induces irreversible lung fibrosis
Percent survival
GKT
Vehicle
p = 0.043
Days post injury
6 weeks post
injury
Hydroxyproline
GKT
n = 21-23/group
(µg/lung)
Vehicle
Body weight (g)
Start of
treatment
Control Vehicle GKT831
Weeks post injury
Source: Victor Thannickal et al., University of Alabama. Science Translational Medicine, 2014
Page 34Four Phase 1 studies: very good safety and pharmacodynamics (PD) profile Setanaxib
Safety and PK Pharmacodynamics
No dose limiting toxicity Setanaxib reduces ROS production induced by UVB4 in vitro1
120000
No safety signal UV + vehicle
100000
UV + setanaxib 0.2 µM
fluorescence)
Dose proportional PK up to 900mg/day
ROS (relative
80000 UV + setanaxib 2 µM
60000 UV + Trolox
Setanaxib is rapidly absorbed after oral dosing UV + setanaxib 20 µM
40000
(median tmax ~ 1h) UV + DPI
20000
No UV
Mean half-life of parent compound is 8-15 hours 0
0 10 20 30 40 50 60 70
Time after UV (minutes)
Minimal renal elimination (Post-hoc analyses explored the loss of statistical significance at Week 24 and
Setanaxib
the therapeutic benefits achieved with 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
Page 36Normal distribution of GGT data was observed for the placebo Setanaxib
and 400mg BID groups
• 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
Baseline to Week 24 (%)
Change in GGT from
Page 37Post-hoc analyses identified non-normal data distribution in the 400mg OD
Setanaxib
group as the reason for the loss of statistical significance at week 24
Baseline to Week 24 (%)
Change in GGT from
• 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
Page 38Efficacy of setanaxib confirmed by correlated reductions in cholestatic markers Setanaxib
Correlation between changes in ALP and GGT at week 24
Pearson’s correlation coefficient = 0.61
p valueEven patients with modest liver stiffness show significant reductions in ALP Setanaxib
Percent reduction in ALP at week 24
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