Investor Presentation · 2019-03-29 · GKT831 - Liver Fibrosis (NOX1/4 inhibitor) Primary Biliary...
Transcript of Investor Presentation · 2019-03-29 · GKT831 - Liver Fibrosis (NOX1/4 inhibitor) Primary Biliary...
Investor Presentation
April 2019
Inhibiting NOX enzymes to treat multiple diseases with high medical need
Euronext: GKTX
DisclaimerThis 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, havegiven 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 the informationin this document, or any revision thereof, or of any other written or oral information made or to be made available to any interested party or its advisers, including financialinformation (all such information being referred to as “Information”), and liability therefor is expressly disclaimed. Accordingly, neither the Company nor any of its shareholders,directors, officers, agents, employees, affiliates, representatives or advisers take any responsibility for, or will accept any liability whether direct or indirect express or implied,contractual, tortuous, statutory or otherwise, in respect of the accuracy or completeness of the Information or for any of the opinions contained herein or for any errors, omissionsor misstatements or for any loss, howsoever arising from this document.
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 or amended,and thus such information may be subject to significant changes. The Company is not under any obligation to update the information or opinions contained herein which aresubject 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 other informationthat the Company is required to publish in accordance with the rules, regulations and practices applicable to companies listed on the regulated market of Euronext in Paris,including in particular the risk factors and other information in the Company’s Document de référence (Registration Document) registered by the French Autorité des marchésfinanciers (Financial Markets Authority) (the “AMF”) on April 27, 2018 under no. R. 18-037, and in any other periodic report, which are available free of charge on the websites ofthe Company (www.genkyotex.com) and the AMF (www.amf-france.org).
No representation, warranty or undertaking, express or implied, is made as to the accuracy, completeness or appropriateness of the information and opinions contained in thisdocument. The Company, its subsidiaries, its advisors and representatives accept no responsibility for and shall not be held liable for any loss or damage that may arise from theuse of this document or the information or opinions contained herein.
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 drawn fromvarious 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 investors mustmake their own investigation and assessments and consult with their own advisers concerning any evaluation of the Company and its prospects, and this document, or any part ofit, 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 statements relateto the Company's future prospects, developments and marketing strategy and are based on analyses of earnings forecasts and estimates of amounts not yet determinable.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 or may not materializein the future. Forward-looking statements cannot, under any circumstance, be construed as a guarantee of the Company's future performance and the Company’s actual financialposition, results and cash flow, as well as the trends in the sector in which the Company operates, may differ materially from those proposed or reflected in the forward-lookingstatements contained in this document. Even if the Company’s financial position, results, cash-flows and developments in the sector in which the Company operates were toconform to the forward-looking statements contained in this document, such results or developments cannot be construed as a reliable indication of the Company's future resultsor developments. The Company does not undertake any obligation to update or to confirm projections or estimates made by analysts or to make public any correction to anyprospective information in order to reflect an event or circumstance that may occur after the date of this document.
By reading or otherwise accessing this document, you agree to be bound by the foregoing limitations.
Page 2Investor Presentation
Positive PBC interim efficacy data released on November 5 2018 - Full data expected in Spring 2019
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— Two Phase 2 trials ongoing in liver fibrosis (PBC) and kidney fibrosis (DKD)— NIH sponsored Phase 2 trial in idiopathic pulmonary fibrosis (IPF) to be launched in H1 2019— Further potential in NASH and immuno-oncology
PBC trial: Positive interim efficacy results released November 5th, final results expected in Spring 2019 – 100% of patients have completed the full 24 week treatment
Partnership with Serum Institute of India Private Ltd (SIIPL) valued at up to €150 million plus royalties
Trading on Euronext as GKTX since March 2017— Cash and cash equivalents of €10.2 million as of December 31 2018, cash runway to end Q1 2020
Investor Presentation
Seasoned management team with international life sciences experience
Page 4Investor Presentation
Elias Papatheodorou Chief Executive Officer
25 years of experience in biotechnology and multinational companies
Ex- Philip Morris International, The Coca Cola Company, Novosom AG, MedigeneAG and Covagen AG
Covagen was acquired by Janssen Pharmaceuticals, a J&J Company.
Strong track record in fundraising, business and corporate development andlicensing transactions
Philippe WieselChief Medical Officer & EVP
Lead clinical research programs at Serono’s EU and US offices, including the phase3 program (ex-US) for Raptiva in psoriasis, leading to the first EMA approval of abiologic agent 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 and Alexion from2010 to 2012
Financial Auditor with KPMG
Investor Presentation
Discovery platform delivers broad pipeline in diseases with high medical needPositive PBC interim efficacy data released on November 5 2018 - Full data in Spring 2019
Page 5
GKT831 - Liver Fibrosis(NOX1/4 inhibitor)
Primary Biliary Cholangitis (PBC)(Positive interim efficacy data released November 5 2018)
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
Investor Presentation
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
VEGF PI3K TRPV1 NF-κB
NMDA(CNS)
TRPV1 (hearing loss)
TGFβ RAS RANKL TLR4 NA Thyroid hormone iodination
Page 6Investor Presentation
We focus on fibrotic diseases by targeting NOX1 and NOX4 with GKT831
Investor Presentation
NOX 1 & 4 are major drivers of fibrogenesis in multiple organsNOXs act upstream of targets such as TGF-β, MCP-1 and ASK1
*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
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
GKT831 downregulates the activation of multiple clinically validated fibrogenic and apoptotic pathways*
LUNG INJURYSmoking
Toxic chemicalsInflammation
RENAL INJURYHyperglycemia
High blood pressureInflammation
LIVER
FIBROSISKIDNEY
FIBROSISLUNG
Investor Presentation
We focus on key fibrosis markets with GKT831
Fibrosis: ~45% of all deaths in the developed world1
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
Primary Biliary Cholangitis (PBC)│Orphan disease Non-alcoholic steatohepatitis (NASH) Primary biliary sclerosis (PSC) │Orphan disease Viral hepatitis Alcoholic steatohepatitis
Idiopathic Pulmonary Fibrosis (IPF) affects 3 million people
worldwide3
Idiopathic Pulmonary Fibrosis│Orphan disease Cystic fibrosis│ Orphan disease Systemic sclerosis│ Orphan disease Refractory asthma and Chronic Obstructive
Pulmonary Disease (COPD)
Diabetic Kidney Disease develops in 20% to 40% of all
diabetics6
Page 8Investor Presentation
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
Investor Presentation
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 – A Phase 2 asset with therapeutic potential in multiple fibrotic diseases
Page 9
Orally available small molecule (NCE) with nanomolar potency— NOX1 and NOX4 Ki ~ 100nM in membrane based assays— 10-12 hour half life in humans— Solid patent protection in key countries till 2028/2029 without any extension
Favorable clinical safety profile in healthy subjects and susceptible patients— No safety signal and no dose limiting toxicity in 5 Phase 1 clinical studies— No safety signal in patients with long-term type 2 diabetes and multiple diabetic complications— 100% of patients have completed the full 24-week treatment period of the PBC trial
2 SAEs : one case of multiple bone fractures due to a traffic accident and one case of urinary tract infection. Both cases unrelated to study drug.
Over 96% of subjects have completed the full 24-week treatment period - no drop outs or treatment interruptions related to pruritus
— Over 270 subjects exposed to GKT831
Broad therapeutic potential in fibrotic disorders and immuno-oncology— Efficacy in multiple models of fibrotic and inflammatory diseases and in immuno-oncology— Two Phase 2 trials ongoing in liver (PBC) and kidney fibrosis (DKD)— Lung fibrosis (IPF) IIT trial to be initiated in H1 2019
Investor Presentation
PBC: A gateway to the large fibrosis market
Primary Biliary Cholangitis (PBC):an orphan disease in the large liver fibrosis area
A quicker proof of concept (PoC) in smaller and shorter trial
Page 10Investor Presentation
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
Description— Chronic autoimmune liver disease leading to the progressive destruction
of the bile ducts
— Bile, a fluid produced in the liver, plays a role in digesting food but is toxic when it accumulates in the bile ducts and liver cells
Prevalence — Prevalence of between 2 - 40 cases per hundred thousand-population 1
— Women make up about 90% of PBC cases The disease most often develops during middle age and is usually
diagnosed in people between the ages of about 30 to 60 years There appears to be a genetic component to developing PBC
Current treatments— Current medications only slow disease progression and manage
symptoms
GKT831
Primary Biliary Cholangitis
Inflammed Bile DuctsNormal Bile Ducts
Investor Presentation
Phase 2 trial of GKT831 in patients with PBC – Interim analysis results
Page 11Investor Presentation
Phase 2 trial in PBC conducted in 62 centers / 9 countries including U.S.A.
Page 12
GKT831
111 PBC patients Confirmed PBC UDCA non responder Baseline ALP & GGT ≥1.5ULN Normal bilirubin
Randomized, double blind, placebo controlled, parallel group
24-week treatment with interim analysis on week 6 data
UDCA plus placebo or one of 2 doses of GKT831 (400 mg once-daily (OD) and 400 mg twice daily (BID)) – randomization ratio 1:1:1
Trial Patients Design
Markers of liver fibrosis (ELF score, collagen fragments, transient elastography)
Markers of cholestasis (ALP, bilirubin)
Markers of liver injury (AST, ALT, CK-18)
Markers of inflammation (hsCRP, fibrinogen, IL-6)
Quality of life and itching (PBC40 questionnaire and VAS score)
Phase 2
Secondary endpoint
A marker of liver injury (Change in serum Gamma Glutamyl Transferase - GGT)
Primary endpoint
Positive interim analysis conducted when 92 patients completed their week 6 visit and published on November 5th 2018
Sources: 1ALP: alkaline phosphatase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CK-18: cytokeratin-18; hsCRP: high sensitivity C-reactive protein; IL-6: interleukin-6)
Investor Presentation
Baseline characteristics in line with targeted population of active PBC patients
Page 13
GKT831
Well balanced patient characteristics, and active disease at baseline
Placebo GKT831400mg OD1
GKT831400mg BID2 ALL
N 31 31 30 92
Age (years) 56 (10) 56 (10) 55 (9) 56 (9)
Females (%) 97 84 93 91
ALP (IU/L) 304 (151) 282 (89) 350 (177) 312 (145)
GGT (IU/L) 224 (212) 215 (154) 237 (193) 225 (187)
ALT (IU/L) 44 (18) 44 (22) 55 (34) 47 (26)
AST (IU/L) 44 (19) 43 (20) 50 (33) 46 (24)
Total bilirubin (µmol/L) 11 (5) 11 (5) 10 (4) 11 (4)
hsCRP (mg/L) 5.0 (4.9) 5.8 (5.7) 4.7 (5.1) 5.2 (5.2)
Values expressed as mean (SD). Baseline: Day 1 1 Once daily; 2 Twice daily
Investor Presentation
Dose dependent and statistically significant reductions in GGT
Page 14
GKT831
p<0.01
p=0.52
Perc
ent c
hang
e in
GGT
from
Bas
elin
e
-7%
-12%
-23%
-30
-25
-20
-15
-10
-5
00 1 2 3 4 5 6
Mean ± SEM
PlaceboGKT831 400mg ODGKT831 400mg BIDTreatment duration (week)
-7%
-12%
-23%
The progressive reductions from baseline to week 2 and to week 6 suggest that further improvements can be achieved with continued treatment
Investor Presentation
Greater GGT reductions in patients with higher baseline GGT (≥2.5XULN, n=68)
Page 15
GKT831
Placebo400mg
OD400mg
BID
GKT831
Mean ± SEM
Perc
ent c
hang
e in
GGT
from
Ba
selin
e to
Wee
k 6
-8%
-11%
-29%
These results suggest that GKT831 may also benefit patients with more advanced disease
-40
-35
-30
-25
-20
-15
-10
-5
0
p=0.64
p<0.01
-29%
-11%-8%
Investor Presentation
GKT831 also achieves statistically significant reductions in ALP GKT831
Placebo GKT831400mg OD
GKT831400mg BID
Proportion of patients with ≥15%reduction in ALP at Week 6 16.1% 25.8% 53.3%
Page 16
p<0.001
p=0.06
-2%
-2%
-17%
-25
-20
-15
-10
-5
0
50 1 2 3 4 5 6
Perc
ent c
hang
e in
ALP
from
Bas
elin
e
Mean ± SEM
PlaceboGKT831 400mg ODGKT831 400mg BID
Treatment duration (week)
-8%
Investor Presentation
Dose dependent reductions in liver transaminases at week 6
Page 17
GKT831
-12
-10
-8
-6
-4
-2
0
-12
-10
-8
-6
-4
-2
0
Placebo400mg
OD400mg
BID
GKT831
Change in AST Change in ALT
Placebo400mg
OD400mg
BID
GKT831
Med
ian
% c
hang
e in
AST
fr
om B
asel
ine
to W
eek
6
Med
ian
% c
hang
e in
ALT
from
Ba
selin
e to
Wee
k 6
Although enrolled patients had relatively low levels of liver transaminases, dose dependent reductions were observed
Investor Presentation
Changes in inflammatory marker hsCRP at week 6
Page 18
GKT831
-30
-25
-20
-15
-10
-5
0
5M
edia
n %
cha
nge
in h
sCRP
fr
om B
asel
ine
to W
eek
6
Change in hsCRP
Placebo400mg
OD400mg
BID
GKT831
Although enrolled patients had relatively low levels of high sensitivity C-reactive protein, dose dependent reductions were observed
Investor Presentation
Dose dependent reductions in FIB-4 and APRI
Page 19
-25
-20
-15
-10
-5
0
5
-25
-20
-15
-10
-5
0
5
Placebo400mg
OD400mg
BID
GKT831
FIB-4 score APRI score
Med
ian
% c
hang
e in
FIB
-4 sc
ore
from
Bas
elin
e to
Wee
k 6
Med
ian
% c
hang
e in
APR
I sco
re
from
Bas
elin
e to
Wee
k 6
Placebo400mg
OD400mg
BID
GKT831
At weeks 12 and 24, assessments of liver fibrosis will include collagen fragments (e.g. Pro-C3), the Enhanced Liver Fibrosis (ELF) score. Transient elastography (i.e. Fibroscan®) will be done at week 24
GKT831
Investor Presentation
Other Pipeline and Conclusions
Page 20Investor Presentation
Phase 2 trial in type 1 diabetes-induced kidney disease (DKD)
Page 21Investor Presentation
GKT831
142 T1D DKD patients 48-week treatment in up to 15 centers in Australia. Trials
conducted by Baker Heart and Diabetes Institute in Melbourne
GKT831 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
Investor Presentation
Solid IP portfolio with potential of term extensions in the US, Europe and Japan
Solid patent protection in key countries
Page 22Investor Presentation
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
Investor Presentation
Stock information
Page 23Investor Presentation
Stock market information– Markets: Euronext Paris and Euronext Brussels– Number of shares: 7,934,762 (as of Dec. 2018)
Cash Position– €10.2m in Cash & Cash equivalent (31 Dec. 2018)– Cash runway to Q1.2020– €5m gross financing in form of convertible notes
with warrants (Aug. 2018)
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 27, 2018):
Investor Presentation
Appendix – Additional Analysis on Phase 2 PBC Interim Results
Page 24Investor Presentation
Pharmacokinetics analysis indicates good exposure and a dose effect
Page 25
Drug levels were measured at weeks 2 (n=44), 12 (n=29), and 18 (n=17)
The main findings are:
All patients allocated to GKT831 had detectable drug levels indicating good compliance
As expected, patients receiving GKT831 400mg BID had higher plasma levels compared to patients receiving 400mg OD
As anticipated in PBC patients with cholestasis and reduced biliary elimination, drug levels were higher than in healthy subjects or diabetic patients
GKT831
Investor Presentation
Appendix – Additional Information on Genkyotex
Page 26Investor Presentation
A selective NOX1 inhibitor with broad therapeutic potential
GKT771: potential to address multiple pain processing , inflammatory, and angiogenic pathways
Page 27Investor Presentation
GKT771
Analgesic
Anti-inflammatory
Anti-angiogenic
Potent, highly selective NOX1 inhibitor
NOX1 plays key roles in angiogenesis, inflammation, and inflammatory pain
GKT771 targets the NGF / TrkA / TRPV1 pain processing pathway: a clinically validated target for pain therapies
GKT771 blocks angiogenesis through the VEGF1 pathway, a clinically validated anti-angiogenic target
GKT771 shows potent activity in vitro and in vivo models of angiogenesis and inflammatory pain
Combined mechanism of action (MoA) consistent with therapeutic potential in inflammatory pain and chronic inflammatory diseases
Further therapeutic potential in eye diseases and itching
Excellent ADME2 profile
IP protection with NCE3/use patent running until 2035
GKT771
1. VGEF: Vascular endothelial growth factor 2. ADME: Absorption, distribution, metabolism, and excretion3. NCE: New chemical entity
Investor Presentation
Preclinical studies: over 50 publications in leading peer-reviewed journals
Page 28Investor Presentation
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-β mediates muscle weakness associated with bone metastases in miceNat Med. 2015 Nov;21(11):1262-1271
Investor Presentation
“[…] 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
Page 29Investor Presentation
Reduced inflammation and fibrosis despite sustained steatosis
Fast food diet model of NASH
831 831
831 831
Source: Torok N et al, Gastroenterology 2015
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
Page 30
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
Investor Presentation
Four Phase 1 studies: very good safety and pharmacodynamics (PD) profile
Page 31Investor Presentation
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
Investor Presentation
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 32Investor Presentation
GKT831
GKT831 significantly reduces the incidence of adverse events
Adverse events
Severity 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.
Investor Presentation