C O R P O R AT E P R E S E N TAT I O N • 2 0 1 9
Nasdaq: HEPA
Forward-Looking | 2 |
Statements |
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Nasdaq: HEPA
Snapshot | 3 |
A Liver Disease Company |
Committed to developing pleiotropic drug therapy for treatment of chronic liver diseases, including NASH (non- alcoholic steatohepatitis) and other liver diseases (HBV, HCV, HDV)
"…Nearly 45% of all deaths in the developed world
are attributed to some type of chronic
fibroproliferative disease. Therefore, the demand
for antifibrotic drugs that are both safe and
effective is likely to be enormous..."
-
J Clin Invest. 2007 Mar;117(3):524-9. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.
Wynn TA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804380/
Nasdaq: HEPA
Corporate Overview | 4 |
Lead Asset |
CRV431: Novel, high-potency, cyclophilin inhibitor that targets multiple stages of liver disease, including NASH
- Anti-fibrotic,anti-viral, and anti-cancer properties (pleiotropic)
- Strong preclinical proof of concept
- Strong safety profile in preclinical and Phase 1 clinical studies
- Orally active, once daily
- Robust IP
- Built upon 30 years' experience in this very specific field of chemistry
- Core team that founded Aurinia Pharmaceuticals, and discovered and developed voclosporin (Phase 3), and other autoimmune indications (Nasdaq:AUPH) is same core team that has discovered and is developing CRV431
Nasdaq: HEPA
Development Phase | 5 |
Discovery | Phase 1 | Phase 3 |
CRV431
Preclinical | Phase 2 |
- IND for HBV - Phase 1 Single Ascending Dose completed
- IND for HBV - Multiple Ascending Dose in progress, Q3-2019
- IND for NASH - Approved, Q3-2019
"In our large combined tertiary center cohorts, patients with concomitant NASH and CHB (chronic hepatitis B) had more advanced fibrosis, and shorter time to development of liver-related outcomes of death, compared to patients with CHB alone. Among patients with advanced fibrosis, superimposed NASH
predicted poorer clinical outcomes in our cohort" | H.S.J. Choi et al., Hepatology, 68(1, suppl.), 2018 |
Nasdaq: HEPA
CRV431 in NASH | 6 |
Cyclophilin Inhibitors Target Multiple Liver Disease Stages |
INJURY/STEATOSIS
-
Antiviral activity
(HBV, HCV, HDV, HIV-1) - Suppress cell death by inhibiting mitochondrial pore regulator, cyclophilin D
INFLAMMATION | FIBROSIS |
• Suppress pro-inflammatory | • Reduce collagen production |
pathways mediated by | from hepatic stellate cells |
extracellular cyclophilin A | • Reduce collagen hydroxyl- |
binding to CD147 | ation and crosslinking |
CIRRHOSIS/CANCER
- Block cancer cell adaptation to hypoxia
- Suppress metastasis-related gene expression
- Suppress cell proliferation
- Sensitize to cell death
NAFLD/
NASH
Alcohol
Viral Hepatitis (HBV/HCV/HDV)
Cell injury/death | Stellate cell | Collagen | Cellular | |
activation | deposition | transformation | ||
(scarring) | and metastasis | |||
Inflammatory cell infiltration/activation
Nasdaq: HEPA
Anti-Fibrotic Activity in NASH Models
STAM Mouse Model
(High fat diet + streptozotocin)
3 - 11 weeks oral CRV431 treatment | ||||||||||||
p < 0 . 0 1 | ||||||||||||
srofibeitivsop-dreis )areadlepmasfo | 4 | p = 0 . 0 3 | 6 | p = 0 . 0 1 | ||||||||
issrofibeitivsop-dre )areadlepmasfo | ||||||||||||
2 .5 | n s | 1 | issrofibeitivsop-dre )areadlepmasfo | |||||||||
2 .0 | 3 | |||||||||||
4 | ||||||||||||
1 .5 | 2 | |||||||||||
1 .0 | 2 | |||||||||||
iriu s | (% | 0 .5 | iriu s (% | iriu s | (% | |||||||
0 .0 | 0 | |||||||||||
S | S | S | 0 | |||||||||
V e h i c l e | 5 m g / | 2 0 m g / | V e h i c l e | 5 0 m g / | V e h i c l e | 5 0 m g / | ||||||
k g /d a y | k g /d a y | k g /d a y | k g /d a y | |||||||||
C R V 4 3 1 C R V 4 3 1 | C R V 4 3 1 | C R V 4 3 1 |
3 weeks treatment | 6 weeks treatment | 11 weeks treatment |
57%reduction in fibrosis | 46%reduction in fibrosis | 37%reduction in fibrosis |
Nasdaq: HEPA
7
"Friedman" Mouse Model
(Western diet + CCl4)
6 weeks oral CRV431 treatment
10 | P≤0.0001 | ||||
of area) | |||||
8 | |||||
6 | |||||
(% | |||||
Red | 4 | ||||
Sirius | 2 | ||||
0 | Vehicle | CRV431 | OCA | CRV431 | |
Normal | |||||
50 mg/kg | 10 mg/kg | + OCA |
Western Diet + CCl4
6 weeks treatment: 82%reduction in fibrosis
Anti-Fibrotic Activity in Liver Toxin Models | 8 |
Rat Thioacetamide Model
9 weeks thioacetamide
9 weeks vehicle or CRV431
Carbon Tetrachloride Mouse Model
6 weeks CCl4
6 weeks vehicle, CRV431, or obeticholic acid (OCA)
Fibrosis (% Sirius Red)
Fibrosis (% Sirius Red)
15 | P=0.008 | |
area) | 10 | |
red (% of | ||
5 | ||
Sirius | ||
0 | Vehicle CRV431 | |
40 mg/kg |
9 weeks treatment
48%reduction in fibrosis
Fibrosis score
score | Cirrhotic |
4 | |
histologic | 3 |
2 | |
Fibrosis | 1 |
0 | |
Vehicle CRV431 | |
40 mg/kg |
No cirrhotic livers
in CRV431 treatment group
P = 0.008 | |||||||
Sirius red-positive fibrosis | 4 | P = 0.32 | |||||
P = 0.005 | P = 0.03 | P = 0.05 | |||||
(%of sampled area) | |||||||
3 | |||||||
2 | |||||||
1 | |||||||
0 | |||||||
Non-CCl4 | Vehicle | CRV431 | OCA | CRV431 | |||
50 mg/kg | 10 mg/kg | + OCA |
Carbon tetrachloride (CCl4)
Nasdaq: HEPA | 6 weeks treatment: 43%reduction in fibrosis |
Anti-Cancer Activity in Late-Stage NASH Model
9
STAM Mouse Model
(streptozotocin + high fat diet)
10 weeks oral CRV431 treatment
Sirius red-positive fibrosis | 5 | p = 0.014 | ||
(%of sampled area) | 4 | |||
3 | ||||
2 | ||||
1 | ||||
0 | Vehicle | 50 mg/ | ||
kg/day | ||||
CRV431 |
Number of Tumor Nodules
p = 0.05 | ||
per liver | 15 | |
10 | ||
of nodules | ||
5 | ||
Number | 0 | |
CRV431 | ||
Vehicle |
44%reduction in tumor number
Tumor Score (number x size)
p = 0.02 | ||
score | 7 | |
6 | ||
5 | ||
nodule | ||
4 | ||
3 | ||
HCC | ||
2 | ||
1 | ||
0 | CRV431 | |
Vehicle |
Score 0
Score 2
Score 5
10 weeks treatment | 52%reduction in tumor |
44%reduction in fibrosis | composite score |
Nasdaq: HEPA |
Score 7
CRV431 on Human Precision Cut Liver Slices | 10 |
CRV431 Decreases Inflammation and Fibrosis (UK Study Group) |
Picrosirius Red Staining of Fibrotic Collagen
(%) | 12 | Time 0 (baseline) | ||||||||
stained | ||||||||||
10 | Vehicle | |||||||||
11 | Control (non-stimulated) | |||||||||
area | 9 | ALK5i (TBGβR inhibitor) | ||||||||
Percentage | 8 | CVR431 1 ∝M | ||||||||
0Time | Control | Vehicle | ALK5i | 1CVR431 | 5CVR431 | 10OCA | 20ELF | |||
7 | CVR431 5 ∝M | |||||||||
Obeticholic acid 10 ∝M | ||||||||||
6 | ||||||||||
Elifibranor 20 ∝M | ||||||||||
+ TGFβ 1 + PDGFβ β |
CONCLUSIONS
- TGFβ +PDGF stimulation increased inflammation and fibrosis
markers, and TGFβ/PDGF receptor inhibition (Alk5i) blocked the effects
- CRV431 decreased all markers of inflammation and fibrosis:
- GENE EXPRESSION - e.g. collagen, IL-6
- SECRETED CYTOKINES AND EXTRACELLULAR MATRIX PROTEINS
- FIBROTIC TISSUE COLLAGEN
- CRV431 had similar or better efficacy than OCA (FXR agonist) and elafibranor (PPAR agonist)
- CRV431 5 µM completely prevented the Day 0-4 increase in fibrosis in similarity to TGFβ receptor inhibition (Alk5i)
- CRV431 was more efficacious than OCA and elafibranor
Nasdaq: HEPA
Anti-Fibrotic Mechanisms of Action | 11 |
CRV431 is proposed to decrease fibrosis by affecting two processes in hepatic stellate cells, the primary, collagen-producing cell type in hepatic fibrosis:
- decrease expression of fibrosis-related genes
- decrease cyclophilin B-dependent collagen synthesis and secretion
Representative Experiments on LX-2 Hepatic Stellate Cells
Fibrosis-related gene expression reduced by CRV431
Procollagen secretion reduced by CRV431 or Cyp B knockdown
Collagen-1α 1 | ||||||||||||||||||||||||
DMSO | 8 | |||||||||||||||||||||||
6 | ||||||||||||||||||||||||
vs | ||||||||||||||||||||||||
expression | 4 | |||||||||||||||||||||||
2 | ||||||||||||||||||||||||
Relative | ||||||||||||||||||||||||
0 | CRV431 | CRV431 | CRV431 | OCA | ||||||||||||||||||||
DMSO | DMSO | ∝ M | ||||||||||||||||||||||
β | + | M | M | M | 1 | |||||||||||||||||||
TGF | . 2 | ∝ | 1 | ∝ | 5 | ∝ | β | + | ||||||||||||||||
0 | + | + | TGF | |||||||||||||||||||||
+ | TGF | β | TGF | β | ||||||||||||||||||||
TGF | β | |||||||||||||||||||||||
LOX (crosslinking enzyme)
DMSO | 2.5 |
2.0 | |
vs | |
expression | 1.5 |
1.0 | |
Relative | 0.5 |
0.0 |
DMSO | + | DMSO | CRV431 | CRV431 | CRV431 | ∝ | M | OCA | ||||||||||||||||
TGF | β | . 2 | ∝ | M | 1 | ∝ | M | 5 | ∝ | M | β | + | 1 | |||||||||||
+ | 0 | β | + | β | + | TGF | ||||||||||||||||||
β | TGF | TGF | ||||||||||||||||||||||
TGF | ||||||||||||||||||||||||
(normalized) | Procollagen | |||||||||||
40 | ||||||||||||
30 | ||||||||||||
ng/well | 20 | |||||||||||
Procollagen | 10 | |||||||||||
0 | CRV431 | CRV431 | CRV431 | CRV431 | ||||||||
Untreated | CRV431 | Untreated | CRV431 | |||||||||
M | M | M | M | |||||||||
M | M | |||||||||||
∝ | ∝ | ∝ | ∝ | |||||||||
2 | ∝ | 5 | 2 | ∝ | 5 | |||||||
. | 1 | . | 1 | |||||||||
0 | 0 | |||||||||||
+ 0.1 ng/ml TGFβ |
(normalized) | Procollagen | |||||||||||||||||||
40 | ||||||||||||||||||||
30 | ||||||||||||||||||||
ng/well | 20 | |||||||||||||||||||
Procollagen | 10 | |||||||||||||||||||
0 | siRNA | siRNA | siRNA | siRNA | siRNA | siRNA | siRNA | siRNA | siRNA | siRNA | ||||||||||
Control | A | B | C | D | Control | A | B | C | D | |||||||||||
Cyp | Cyp | Cyp | Cyp | Cyp | Cyp | Cyp | Cyp | |||||||||||||
+ 0.1 ng/ml TGFβ |
Nasdaq: HEPA
Summary of Nonclinical Anti-fibrotic Activities | 12 | |||||
Species | Model | Location | Treatment | Fibrosis Reduction | Other CRV431 Effects | |
Duration | (% Sirius Red) | |||||
Mice | Friedman NASH model | Scripps (USA) | 6 weeks | 82% | Weight gain | |
(CCl4 + Western diet) | ||||||
Mice | STAM NASH model | Stelic (Japan) | 3 weeks | 57% | none | |
(streptozotocin + HFD) | ||||||
Mice | STAM NASH model | Scripps (USA) | 6 weeks | 46% | none | |
(streptozotocin + HFD) | ||||||
Mice | STAM NASH model | Scripps (USA) | 11 weeks | 37% | Weight gain | |
(streptozotocin + HFD) | NAS score | |||||
Mice | STAM NASH model | Scripps (USA) | 10 weeks | 44% | Liver tumor number and size 52% | |
(streptozotocin + HFD) | (late disease) | Liver weight | ||||
Mice | Carbon tetrachloride (CCl4) | Scripps (USA) | 6 weeks | 44% | none | |
Rats | Thioacetamide | Physiogenex | 9 weeks | 48% | Prevented progression to cirrhosis | |
(France) | ||||||
Human | Precision cut liver slice (PCLS) | FibroFind (UK) | 4 days | 100% | RNA levels and secretion of | |
cultures with TGFβ+PDGF-BB | inflammatory/fibrotic proteins | |||||
Human | LX-2 hepatic stellate cell | Hepion | 1-2 days | 30-50% | Fibronectin secretion | |
cultures (± TGFβ) | collagen secretion | Fibrotic gene expression | ||||
Nasdaq: HEPA
Single Ascending Dose (SAD) Study | 13 |
(CTRV-CRV431-101) |
Objectives
- To evaluate the safety and tolerability of single oral doses of CRV431 at increasing dose levels
- To evaluate the pharmacokinetics of CRV431
Design
-
Randomized, Partially blinded, Placebo-controlled, sequential SAD Study in healthy volunteers
SAD
CRV431 525 mg
CRV431 375 mg
Healthy | CRV431 225 mg |
Subjects |
CRV431 75 mg
Nasdaq: HEPA
N = 32 (24 CRV431; 8 Placebo)
CRV431 | 14 |
Mean Pharmacokinetic Parameters |
Tmax, h | Cmax, ng/mL | AUC0-inf, | t½, h | |
Dose | ng*h/mL | |||
(range) | (SD) | (SD) | ||
(SD) | ||||
75 mg | 4 (2-10) | 334±106 | 20,917±3,780 | 73.6±15.2 |
225 mg | ||||
1.3 (1-2) | 1,368±221 | 84,422±32,373 | 97.3±18.4 | |
375 mg | ||||
1.5 (1-3) | 1,488±176 | 103,833±30,916 | 110.8±36.2 | |
525 mg | ||||
1 (1-1) | 1,655±250 | 102,087±43,612 | 98.5±24.1 | |
- Drug exposure is linear up to 375mg (r2=0.914)
- Pharmacokinetic profile supports once daily dosing.
Nasdaq: HEPA
Safety Profile and Conclusions | 15 |
SAD Study |
Safety Profile
- No SAE's were reported in the SAD Study
- AE's from the SAD study have been mild to moderate and mostly unrelated to study drug
- There were no Grade 3 or Grade 4 laboratory abnormalities
- Vital signs and ECGs were unremarkable
Conclusions
- In the SAD doses were tested up to 525 mg with no concerns
- The collective data from the SAD demonstrate a favorable pharmacological, pharmacokinetic, and safety profile for CRV431 with acceptable safety margins that support the proposed clinical development program
Nasdaq: HEPA
CRV431 Advantages | 16 |
in Treating Liver Disease |
- Cyclophilin inhibitor (inhibits peptidyl prolyl isomerase)
- Broad range of liver-protective mechanisms (pleiotropic) due to targeting multiple cyclophilins
- The only investigational drug targeting bothviral hepatitis and liver disease
- Later-stagedisease focus (fibrosis, HCC) differentiates CRV431 from many NASH compounds in development
- Accumulates to 5-fold higher concentrations in the liver compared to blood
- Excellent safety profile in preclinical and clinical studies is backed up by approximately 35 years of cyclosporine A experience
Of the histologic features of NASH, fibrosis is considered the strongest predictor of adverse
clinical outcomes, including liver-related death.
- the FDA encourages sponsors to focus drug development on the area of greatest need and potential effect on health (i.e., non-cirrhotic NASH with liver fibrosis).
Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment
FDA Guidance for Industry, December 2018
Nasdaq: HEPA
Clinical Timelines/Events
2020
2020/2021
Nasdaq: HEPA
2019 | 17 |
- NASH IND, authorization to proceed
- Initiated Clinical 28-day study, oral CRV431 escalating dose, once daily repeat doses
H1
- Data from Clinical 28-day study, oral CRV431 Multiple Ascending Dose (MAD), once daily
- Initiate Phase 2 NASH biomarker pilot study, 1-month CRV431 repeat dose
Q3
- Data from Phase 2 NASH pilot study, 1 month, CRV431 repeat dose
Q4/Q1
- Initiate Phase 2 NASH, approx. 100 subjects, CRV431 orally, once daily for 24 weeks
Non-Clinical Events
2019
2020
Nasdaq: HEPA
2019 | 18 |
- Data from Human Precision Cut Liver Slice culture
H2
- Data from In-housein vitro - stellate cells
- Ongoing Mode of Action studies, ongoing and collaborations
Q4
- Data from rat thioacetamide, fibrosis study
- Data from NASH Western Diet, fibrosis study
- Data from Precision Cut Liver Slices (PCLS, Part B), UK, fibrosis study
Q1
- Initiate chronic dosing safety, animals (rat and monkey),
Q2
- Data from NASH Western Diet, in vivo model, TSRI, HCC
- Data from HCC xenograft model
H2
- Data from chronic dosing safety, animals (rat and monkey),
- Data from Diamond NASH mice
-
Data from cyclophilin knockout animal models for
NASH/HCC
Thank You
Corporate Contact: | Investor Relations: |
Robert Foster | Stephen Kilmer |
rfoster@hepionpharma.com | skilmer@hepionpharma.com |
Tel: 646.274.3580 |
Nasdaq: HEPA
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Hepion Pharmaceuticals Inc. published this content on 03 December 2019 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 03 December 2019 19:02:01 UTC