Hepion Pharmaceuticals : Download Corporate Presentation

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

This presentation may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such forward-looking statements are characterized by future or conditional verbs such as "may," "will," "expect," "intend," "anticipate," believe," "estimate" and "continue" or similar words. You should read statements that contain these words carefully because they discuss future expectations and plans, which contain projections of future results of operations or financial condition or state other forward-looking information. Such statements are only predictions and our actual results may differ materially from those anticipated in these forward-looking statements.

We believe that it is important to communicate future expectations to investors. However, there may be events in the future that we are not able to accurately predict or control. Factors that may cause such differences include, but are not limited to, those discussed under Risk Factors in our periodic reports filed with the Securities and Exchange Commission, including the uncertainties associated with product development, the risk that products that appeared promising in early clinical trials do not demonstrate safety and efficacy in larger-scale clinical trials, the risk that we will not obtain approval to market our products, the risks associated with dependence upon key personnel and the need for additional financing. We do not assume any obligation to update forward-looking statements as circumstances change.

This presentation does not constitute an offer or invitation for the sale or purchase of securities or to engage in any other transaction with Hepion Pharmaceuticals or its affiliates. The information in this presentation is not targeted at the residents of any particular country or jurisdiction and is not intended for distribution to, or use by, any person in any jurisdiction or country where such distribution or use would be contrary to local law or regulation.

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

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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

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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

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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
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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

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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 

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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

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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.

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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

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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

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Clinical Timelines/Events

2020

2020/2021

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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

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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
[e-mail]	[e-mail]
	Tel: [phone]

Nasdaq: HEPA