A Pilot, Dose Escalating Study on VLX103 in Moderate Alcoholic Steatohepatitis

This is an open label, multiple cohorts, dose escalation Phase Ib study, in which up to 3
doses of VLX103 will be assessed for safety, pharmacodynamics and pharmacokinetics in well
defined moderate ASH patients cohorts receiving increasing doses of VLX103. The overall study
design is characteristic for early phase, first in patient clinical evaluation of safety and
pharmacodynamics, especially when prudent dose escalation is recommended. A maximum of 18
moderate ASH patients will be enrolled and treated in at least 4 clinical sites throughout
the US. The open label nature of the study design will allow to efficiently monitor the
safety of VLX103 throughout the trial, and taking rapid decisions about dosing adjustments
(dose reduction or discontinuation within each dosing cohort, for each patient).

After an adequate screening period (Day -7 to -1), all eligible patients of the first dosing
cohort will receive the initial, low dose of VLX103 150 mg per day (QD) for 14 consecutive
days. Subjects will be evaluated only for safety, pharmacodynamics and pharmacokinetics
during this period. Pre-established safety criteria will be used to decide upon dose
escalation, for each subject. If patients tolerate well VLX103 at 150 mg QD , a second cohort
will then receive a 300 mg QD regimen for 14 days. At the end of this period, safety,
pharmacodynamics and pharmacokinetics will be assessed as well. The next dose will be 450 mg
QD for 14 days, with the same monitoring process. Long term safety will also be assessed, at
all 3 doses, at Day 30 and 90 post treatment initiation.

Inclusion Criteria:

Eligible subjects must meet all of the following inclusion criteria:

1. Male and non pregnant female subjects; female subjects must use 2 reliable methods of
contraception

2. 18-70 years

3. BMI less than 30 mg/kg2

4. Established diagnosis of Alcoholic Steatohepatitis (ASH), based on at least 2 of the
following signs and symptoms should be present: nausea, jaundice, anorexia, right
upper quadrant abdominal pain, leukocytosis or hepatomegaly AND

5. Elevation of total bilirubin > 3 mg/dL AND

6. Liver biopsy showing ASH OR ultrasound of liver showing increased echogenicity OR CT
scan showing decreased attenuation of liver compared to spleen OR MRI showing fatty
liver (decreased signaling intensity on T1 weighted images) History of chronic alcohol
consumption, i.e. more than 50 g/day for a minimum of 6 months and at least 2 months
before enrolment

7. AST/ALT ratio greater than 1.5

8. MELD score between 12 and 19

9. Signature of a dated Informed Consent Form (ICF) indicating that the subject has been
informed of all the relevant aspects of the trial prior to enrolment Willingness and
ability to comply with scheduled visits and trial procedures

Exclusion Criteria:

Eligible subjects must not meet any of the following exclusion criteria:

1. Liver disease caused by other etiologies than alcohol (except Hepatitis C and
hemochromatosis)

2. Baseline ALT ≥ 200 IU/L

3. Baseline AST ≥ 500 IU/L

4. Signs of systemic infection: fever > 38°C and positive blood or ascites cultures on
appropriate antibiotic therapy for ≥ 3 days within 3 days of inclusion

5. Presence of portosystemic encephalopathy at enrolment

6. Presence of cancer at enrolment

7. Presence of uncontrolled diabetes, defined as Hb1Ac ≥ 8.5

8. History of clinically significant hypoglycaemia, with fasting blood glucose < 3 mmol/L
within 3 months prior to enrolment

9. Presence of clinically significant renal impairment, defined as serum creatinine ≥ 2.0
x ULN

10. Hypotension with BP < 80/50 mm Hg after volume repletion

11. Current or recent (2 years) history or presence of pancreatitis

12. History of Long QT Syndrome or any significant risk factor for clinically meaningful
QT prolongation and Torsades de Pointe.

13. History of significant gastrointestinal surgery that may interfere with the absorption
of VLX103

14. Previous treatment with corticosteroids or other immunosuppressive drugs including
specific anti-TNF alpha therapy and calcineurin inhibitors within the previous 3
months. Inhaled steroids for asthma are acceptable as long as their use has not been
initiated less than 10 days prior to enrolment and their dosing regimen remain stable
during the study

15. Concomitant therapy with probiotics, oral neomycin or polymyxin B, rifaximin or other
investigational agents or participation in another clinical trial within 3 months of
signature of ICF

16. Previous use of pentamidine with treatment discontinuation of less than 12 months
prior to study enrolment

17. History of allergy or hypersensitivity to pentamidine

18. Pregnancy or breastfeeding. All female subjects of childbearing potential must have a
negative urine pregnancy test prior to first dose of study medication. Breastfeeding
is prohibited during the study.

19. Severe acute or chronic medical or psychiatric condition, or laboratory abnormality
that would impart, in the judgement of the investigator, excess risk associated with
trial participation of study drug administration, or which in the judgement of the
investigator, would make the subject inappropriate for entry into this trial.