aramchol phase 2 results & phase 3/4...

Aramchol Phase 2 Results & Phase 3/4 Outlook

Life Sciences & MedTech ConferenceJune 18-19, 2019

New York

Liat Hayardeny – Brück (PhD, MBA)Chief Scientific Officer

This presentation contains forward-looking statements about our expectations, beliefs or intentions regarding, among other things, our product development efforts, business, financial condition, results of operations, strategies or prospects. In addition, from time to time, we or our representatives have made or may make forward-looking statements, orally or in writing. Forward-looking statements can be identified by the use of forward-looking words such as “believe,” “expect,” “intend,” “plan,” “may,” “should” or “anticipate” or their negatives or other variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical or current matters. These forward-looking statements may be included in, but are not limited to, this presentation, various filings made by us with the SEC, press releases or oral statements made by or with the approval of one of our authorized executive officers. Forward-looking statements relate to anticipated or expected events, activities, trends or results as of the date they are made. Because forward-looking statements relate to matters that have not yet occurred, these statements are inherently subject to risks and uncertainties that could cause our actual results to differ materially from any future results expressed or implied by the forward-looking statements. Many factors could cause our actual activities or results to differ materially from the activities and results anticipated in forward-looking statements, including, but not limited to, the factors summarized below.

These factors include, but are not limited to, the following: the timing and cost of Galmed's planned Phase III ARMOR trial for Aramchol™, or whether a Phase III ARMOR trial will be conducted at all; completion and receiving favorable results of a planned Phase III ARMOR trial for Aramchol™; regulatory action with respect to Aramchol™ by the FDA or the EMA; the commercial launch and future sales of Aramchol™ or any future product candidates; Galmed's ability to comply with all applicable post-market regulatory requirements for Aramchol™ in the countries in which it seeks to market the product; Galmed's ability to achieve favorable pricing for Aramchol™; Galmed's expectations regarding the commercial market for NASH; third-party payor reimbursement for Aramchol™; Galmed's estimates regarding anticipated capital requirements and Galmed's needs for additional financing; market adoption of Aramchol™ by physicians and patients; the timing, cost or other aspects of the commercial launch of Aramchol™; the development and approval of the use of Aramchol™ for additional indications or in combination therapy; and Galmed's expectations regarding licensing, acquisitions and strategic operations. More detailed information about the risks and uncertainties affecting Galmed is contained under the heading "Risk Factors" included in Galmed's most recent Annual Report on Form 20-F filed with the SEC on March 13, 2019, and in other filings that Galmed has made and may make with the SEC in the future.

These statements are only current predictions and are subject to known and unknown risks, uncertainties and other factors that may cause our or our industry’s actual results, levels of activity, performance or achievements to be materially different from those anticipated by the forward-looking statements. Given these uncertainties, you should not rely upon forward-looking statements as predictions of future events.

All forward-looking statements attributable to us or persons acting on our behalf included in, but not limited to, this presentation speak only as of the date hereof and are expressly qualified in their entirety by the foregoing. We undertake no obligations to update or revise forward-looking statements to reflect events or circumstances that arise after the date made or to reflect the occurrence of unanticipated events. In evaluating forward-looking statements, you should consider these risks and uncertainties.

This presentation shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction.

2

Safe Harbor and Disclaimer Statement

Aramchol – Liver Targeted SCD 1 Modulator

• FABAC- fatty acid Bile acid conjugate• MW = 702.12• BCS Class IV• T1/2 ss = 72.4 hrs

• Aramchol in pre clinical models:• Down regulation of liver FA in multiple dietary models• Down regulation of collagen in TAA animal models for liver

fibrosis• Target directly HSC’s to down regulate collagen and a SMA

production (Friedman S et al. Poster 2060 AASLD 2018)

• Aramchol in Phase 2a showed significant reduction in liver fat: relative change in MRS

1. Aramchol Reduces Established Fibrosis in MCD Diet Animal Model, EASL 2017 poster2. Role of Aramchol in steatohepatitis and fibrosis in mice. Mato et al. Accepted to Hepatology Communications. 2017.3. R. Golan-Gerstl1, M. Valitsky1, R. Oren1, E. Brazovski2, L. Hayardeny1, S. Shimon Reif. "The anti-fibrotic effect of Aramcholon liver fibrosis in TAA animal model" (2017); The international liver congress (EASL), Amsterdam, the Netherlands.

Cholic acid

Arachidic acid

Scientific Rationale for SCD1 Down Regulation in NASH

4

NAFLD (Steatosis)

NASH (Steatohepatitis)

NASH + Fibrosis

De-compensatedCirrhosis/ HCC

Pathophysiology of NASH


NAFLD (Steatosis)


NASH + Fibrosis

Down Regulation of SCD1 in Hepatocytes Leads to Reduction in Liver Fat

1. Aramchol Reduces Established Fibrosis in MCD Diet Animal Model, EASL 2017 poster2. Role of Aramchol in steatohepatitis and fibrosis in mice. Mato et al. Hepatology Communications, 2017 Nov 1 (9):911-927

Lipid Droplets VLDL

AMPK MUFA

DG

TG

Food Consumption Serum FA

Fatty Acid

ACC

FA Oxidation

SPT1

Malonyl-Co A

Fibrosis & Liver Damage

PARAMCHOL

In Hepatocytes

SCD1

Scientific Rationale for SCD1 Down Regulation in NASH

6

NAFLD (Steatosis)


NASH + Fibrosis


Pathophysiology of NASH


NAFLD (Steatosis)


NASH + Fibrosis

Direct Effect on Fibrosis via Down Regulation of SCD 1 in HSC’s

LRPs

Fz P P

TGF-RI/II

CK1

APCGSK3β

AXIN

p38

Wnt

p

Nucleus

TGF-βI

β-cat

P P

p Ser9

β-cat

β-cat

COL1FN

α-SMA

1. Aramchol Reduces Established Fibrosis in MCD Diet Animal Model, EASL 2017 poster2. Role of Aramchol in steatohepatitis and fibrosis in mice. Mato et al. Accepted to Hepatology Communications. 2017.3. R. Golan-Gerstl1, M. Valitsky1, R. Oren1, E. Brazovski2, L. Hayardeny1, S. Shimon Reif. "The anti-fibrotic effect of Aramchol on liver fibrosis in TAA animal model" (2017); The international liver congress (EASL), Amsterdam, the Netherlands.

Direct Effect on Fibrosis via Down Regulation of SCD 1 in HSC’s

ARAMCHOL In Hepatic Stellate cellsSCD 1

0

0.4

0.8

1.2

1.6

2

Rel

ativ

e G

ene

Expr

essi

on SCD 1 in Hepatic Stellate Cells

**

0

2

4

6

8

10

12

Rel

ativ

e G

ene

Expr

essi

on

PPARγ ***

0

0.5

1

1.5

2

48h

Rel

ativ

e G

ene

Expr

essi

on Collagen 1a1

Vehicle

Aramchol 10µM

***

0

0.5

1

1.5

2αSMA

***

Rel

ativ

e G

ene

Expr

essi

on

LRPs

Fz P P

TGF-RI/II

CK1

APCGSK3β

AXIN

p38

Wnt

p

Nucleus

TGF-βI

β-cat

P P

p Ser9

β-cat

β-cat

COL1FN

α-SMA

PPARγ

1. Aramchol Reduces Established Fibrosis in MCD Diet Animal Model, EASL 2017 poster2. Role of Aramchol in steatohepatitis and fibrosis in mice. Mato et al. Accepted to Hepatology Communications. 2017.3. R. Golan-Gerstl1, M. Valitsky1, R. Oren1, E. Brazovski2, L. Hayardeny1, S. Shimon Reif. "The anti-fibrotic effect of Aramchol on liver fibrosis in TAA animal model" (2017); The international liver congress (EASL), Amsterdam, the Netherlands.

ARMOR – ARaMchol for NASH Resolution & Fibrosis Improvement

9

EOS*Visit Every 4 months

Visits Schedule

Phase 3 - Histology based (52w)

Phase 4 - Clinically based (~5 years)

Placebo

Aramchol 300mg BID

Week 52 biopsy

NASH resolution w/o worsening of fibrosisor

Fibrosis improvement w/o NASH worsening

Screening biopsy 5 years biopsy

*EOS will occur at the time when a pre-specified number of clinical events have been observed or when the last randomized subject completes 5 years of treatment, whichever comes first.

2:1 randomization

Composite of clinical events related to disease progression

2000 patients


10


Visits Schedule



Placebo

Aramchol 300mg BID

Week 52 biopsy





2:1 randomization


2000 patients Patient Population

Patient Population - Key Inclusion Criteria

11

ARREST ARMOR

BMI: 25kg/m2 - 40kg/m2 BMI: 25kg/m2 - 40kg/m2

Known type II Diabetes Mellitus or Pre-diabetes Known type II Diabetes Mellitus or Pre-diabetes

Histologically proven steatohepatitis with NAS ≥4:Central reading performed by Prof. Carolin Lackner at the University of Graz Austria

Histologically proven steatohepatitis with NAS ≥4:Central reading performed by Prof. Carolin Lackner at the University of Graz Austria

Fibrosis stage 0-3 Fibrosis stage 2-3

Normal synthetic liver function Normal synthetic liver function

AST > 20 IU/L

Patient Population - Key Exclusion Criteria

12

ARREST ARMOR

Cirrhosis Cirrhosis

Patients with other active (acute or chronic) liver disease

Patients with other active (acute or chronic) liver disease

Weight loss of more than 5% within 6 months Weight loss of more than 5% within 3 months

Bariatric surgery within 5 years Bariatric surgery within 5 years

HIV HIV

Diabetes mellitus other than type II Diabetes mellitus other than type II

Treatment with other anti-diabetic medications, Unless started prior to biopsy (6/12 months depending on drug) and stable

Treatment with other anti-diabetic medications, Unless started prior to biopsy (6/12 months depending on drug) and stable

Uncontrolled arterial hypertension Uncontrolled arterial hypertension

Uncontrolled hypothyroidism Uncontrolled hypothyroidism

Renal dysfunction eGFR< 40 ml/min Renal dysfunction eGFR< 40 ml/min


13


Visits Schedule



Placebo

2000 patients2:1 randomization

Week 52 biopsy






Aramchol 300mg BID


14


Visits Schedule



Placebo

Aramchol 300mg BID2000 patients

2:1 randomization

Week 52 biopsyScreening biopsy 5 years biopsy





ARAMOR - Primary Histology Based Endpoint

15

0%

5%

10%

15%

20%

25%

7.55

16.7

Placebo (N=40) Aramchol 400 (N=80) Aramchol 600 (N=78)

Pro

po

rtio

n o

f p

atie

nts

Aramchol 600 vs. Pbo p=0.051OR 4.74 (95% CI: 0.99-22.7)

NASH resolution without worsening of fibrosis

0%

5%

10%

15%

20%

25%

30%

35%

21.317.5

29.5


Pro

po

rtio

n o

f p

atie

nts Aramchol 600 vs. Pbo p=0.2110

OR 1.88 (95% CI: 0.70-5.04)

Fibrosis improvement (≥1 stage) without worsening of NASH

ARMOR Endpoints:

NASH resolution without worsening of fibrosis

OR

Fibrosis improvement (≥1 stage) without worsening of NASH

• Similar definitions used

• The study is powered for both endpoints

• One of these endpoints is required for study success

ARREST ARMOR

6/80 (7.5%)

3/40 (7.5%)

1/78 (1.3%)

0%

1%

2%

3%

4%

5%

6%

7%

8%

Pro

po

rtio

n o

f p

atie

nts

ARMOR - Primary Clinically Based Endpoint

16

Progression to Cirrhosis *

Placebo (N=40)

Aramchol 400 (N=80)

Aramchol 600 (N=78)

* Post hoc analysis; Although limited by sample size and duration, there was a smaller number of patients that progressed to cirrhosis in the 600 mg arm.

Clinical Endpoint:

• Composite of clinical events related to disease progression based on FDA guidelines

• Histological progression to cirrhosis included in this endpoint

ARREST ARMOR

Change From Baseline - ALT and AST

17

-25.0

-20.0

-15.0

-10.0

-5.0

0.0

5.0

10.0

15.0

20.0

Ch

ange

fro

m B

ase

line

Placebo

Aramchol 400

Aramchol 600

Change from Baseline in ALT (U/L)

Week 52Week 40Week 24

Aramchol 400 vs. Pbo : p<0.001Aramchol 600 vs. Pbo : p<.0001

-15.0

-10.0

-5.0

0.0

5.0

10.0

15.0

Ch

ange

fro

m B

ase

line

Placebo

Aramchol 400

Aramchol 600

Change from Baseline in AST (U/L)


Aramchol 400 vs. Pbo : p=0.001Aramchol 600 vs. Pbo : p<.0001

Placebo Aramchol 400 mg Aramchol 600 mg

13.3 21.9 29

Placebo Aramchol 400 mg Aramchol 600 mg

4.4 18.8 22.6

ALT normalization, % AST normalization, %

Change From Baseline - HbA1c

18

Week 52 AnalysesAramchol 400 vs. Pbo: p=0.006Aramchol 600 vs. Pbo: p<0.001


19


Visits Schedule



Placebo

2000 patients2:1 randomization

Week 52 biopsy






Aramchol 300mg BID

Aramchol 300mg BID

Dose Response Pattern in ARREST Study

20

-5

-4

-3

-2

-1

0

1

2

Placebo (N=41) Aramchol 400(N=90)

Aramchol 600(N=83)

Ch

ange

fro

m B

ase

line

in

Me

an

Liv

er

Fat

Liver fat - Mean Change from Baseline

24.4%36.7%

47.0%

0%

10%

20%

30%

40%

50%


Aramchol 600(N=83)

MRI Responders - Reduction ≥ 5% absolute change

5.0%7.5%

16.7%

0%

5%

10%

15%

20%


Aramchol 600(N=78)

Pro

po

rtio

n o

f p

atie

nts

NASH Resolution without Worsening of Fibrosis

17.5% 21.3%29.5%

0%

5%

10%

15%

20%

25%

30%

35%


Aramchol 600(N=78)

Pro

po

rtio

n o

f p

atie

nts

Fibrosis Improvement Without Worsening of NASH

-25.0

-20.0

-15.0

-10.0

-5.0

0.0

5.0

10.0

15.0

20.0

Ch

ange

fro

m B

asel

ine

ALT – mean change from Baseline


Liver EnzymesBiopsyMRS

-15.0

-10.0

-5.0

0.0

5.0

10.0

15.0

Ch

ange

fro

m B

ase

line

AST – mean change from Baseline


Aramchol – Liver Targeted SCD 1 Modulator

• FABAC- fatty acid Bile acid conjugate• MW = 702.12• BCS Class IV• T1/2 ss = 72.4 hrs

• Aramchol in pre clinical models:• Down regulation of liver FA in multiple dietary models• Down regulation of collagen in TAA animal models for liver

fibrosis• Target directly HSC to down regulate collagen and a SMA

production (Friedman S et al. Poster 2060 AASLD 2018)

• Aramchol in Phase 2a showed significant reduction in liver fat: relative change in MRS

1. Aramchol Reduces Established Fibrosis in MCD Diet Animal Model, EASL 2017 poster2. Role of Aramchol in steatohepatitis and fibrosis in mice. Mato et al. Accepted to Hepatology Communications. 2017.3. R. Golan-Gerstl1, M. Valitsky1, R. Oren1, E. Brazovski2, L. Hayardeny1, S. Shimon Reif. "The anti-fibrotic effect of Aramcholon liver fibrosis in TAA animal model" (2017); The international liver congress (EASL), Amsterdam, the Netherlands.

Cholic acid

Arachidic acid

Significant Increase in Exposure Using “Dose Split” Method

22

Treatment N Geometric Mean 90% Lower CI 90% Upper CI CV%

300mg BID 16 110860 97000 126701 25.1

600 mg QD 16 72537 63468 82902 34.6

Ratio 1.53 1.38 1.69

AUC 0-24 ng*h/mL summary data by treatment regimen

Change in Exposure is Responsible for More Significant Response (ARREST Population analysis)

5.0%7.5%

16.7%

0%

5%

10%

15%

20%


Pro

po

rtio

n o

f p

ati

en

ts

NASH Resolution without Worsening of Fibrosis

In ARREST - Increasing the exposure by 22% change the response rate significantly.

Dose split results in 53% increase in exposure with the potential of pushing efficacy even higher in ARMOR.

23

0

1000

2000

3000

4000

5000

Ara

mch

olC

on

cert

rati

on

(ng/

mL)

300 mg Q12H600 mg QD400 mg QD

Arithmetic mean ± error deviation

ARREST Phase I

ARREST - Excellent Safety and Tolerability Profiles

24

• Discontinuation due to adverse events was less than 5% :• 4.2%, 3% and 4.1% of patients in placebo, Aramchol 400mg and 600mg arms respectively

• SAEs reported in 12.5%, 8.9% and 9.2% of patients in placebo, 400mg and 600mg arms respectively; no deaths• No signal for hepatotoxicity• No change in weight • No change in lipid profile: TG, HDL, LDL and total cholesterol levels.

Adverse event N (%) Placebo (N=48) 400 mg (N=101) 600 mg (N=98)

Constipation 6 (12.5) 5 (5) 8 (8.2)

Cough 4 (8.3) 4 (4) 5 (5.1)

Fatigue 4 (8.3) 8 (7.9) 3 (3.1)

Headache 6 (12.5) 14 (13.9) 15 (15.3)

Influenza 2 (4.2) 8 (7.9) 5 (5.1)

Nausea 6 (12.5) 10 (9.9) 9 (9.2)

Pruritus 3 (6.3) 7 (6.9) 11 (11.2)

UTI 3 (6.3) 15 (14.9) 13 (13.3)

Most frequent AEs (≥7% of subjects in at least one study arm)

Aramchol Target Product Profile

25

Product DescriptionAramchol is a small molecule, liver targeted, fatty acid bile acid conjugate. It is a first in class SCD1 modulator that reduces FFA and collagen production in the liver that result in reduction of steatosis and fibrosis in NASH patients.

Indication Treatment of non-alcoholic steatohepatitis (NASH) with fibrosis

Population Patients with NASH with Fibrosis stage 2-3 who are overweight or obese and have prediabetes or type 2 diabetes

MoA

• SCD1 modulator. Aramchol down-regulates Stearoyl-CoA desaturase-1 (SCD1) expression in hepatocytes and HSCs. • In hepatocytes down regulation of SCD1 results in improvement of fatty acid oxidation with a concomitant reduction in the generation of oxidative stress. Aramchol

Improves liver glucose homeostasis. Lower diabetes parameters. • In Hepatic Stellate Cells down regulation of SCD1 results in reduction in collagen and a SMA production.

Efficacy

Base case (based on phase 2b data)

Potential for better efficacy(based on higher exposure with BID regimen)

Resolution of NASH and no fibrosis worsening Placebo 5%; Aramchol 17% Placebo 5%; Aramchol 25%

Improvement in fibrosis and no worsening of NASH Placebo 17%; Aramchol 29% Placebo 17%; Aramchol 35%

Significant reductions in ALT, AST and HbA1C

RoA and dosage Twice-daily oral administration (BID) of 300mg

Safety

• Excellent safety and tolerability• Early discontinuation below 5% per year• No signal in serious adverse event• No signal for hepatotoxicity • No change in lipid parameters• No pruritus

ARREST – Global Distribution

26

USA, 64

26%

Mexico, 68

27%

Chile, 21

9%

Italy, 18

7%

France, 27

11%

Germany, 7

3%

Romania, 3

1%

Lithuania, 2

1%

Georgia, 2

1%

Israel, 33

13%

Hong Kong, 3

1%

80

Sites

12

Countries

4

Continents

ARMOR Study – Designed to Show an Effect on NASH & Fibrosis

27

• Aramchol is a novel, first in class liver targeted, SCD1 modulator:• Down regulation of SCD 1 in hepatocytes and HSC’s results in reduction in FFA and collagen production

• ARREST results:• Aligned with MoA and show effect on NASH resolution & fibrosis improvement

• The ARMOR study• Based on ARREST results and FDA recommendations (F2F meeting March 20)

• Powered for both endpoints; NASH resolution and fibrosis improvement at 52 weeks

• Employs a dose split method (300mg BID) to increase exposure and potential for even better efficacy

• Designed to be a robust global study

Thank You!

NASDAQ: GLMD

aramchol phase 2 results & phase 3/4...

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