A Safety, Pharmacokinetic, Single Ascending Dose Study of Tesevatinib in Pediatric Subjects With Autosomal Recessive Polycystic Kidney Disease (ARPKD)

This study is a phase 1 clinical trial focused on evaluating safety and tolerability of the
Tesevatinib study drug, which is an oral solution at a 15mg/mL concentration.

To determine safety of the tesevatinib liquid formulation in pediatric subjects (age 5-12)
with ARPKD, all participants receive active study drug on Day 1 of the study enrollment. To
evaluate plasma pharmacokinetics (PK) of the single dose of tesevatinib in the ARPKD
pediatric subjects, the blood for PK sampling is drawn on Day 1, 2, and 3 of the study.
Tesevatinib dosing will be followed by a PK and a 2-week safety evaluation. After the
completion of the safety review subjects may continue onto the next dosing group at the
discretion of the investigator and the medical monitor.

There are three dosing arms in this study. Six participants will enroll into first dosing
cohort (0.25mg/kg). Participants may be enrolled in two subsequent cohorts with increased
dose (0.5mg/kg and 1.0mg/kg), if safety reporting is favorable.

Medical history will be taken at Screening Visit. Echocardiogram will be performed at
Screening and Day 14. Subjects will undergo audiology testing, as well as ocular monitoring
at Screening and Day 14. Blood will be drawn for a panel of laboratory tests.

Inclusion Criteria:

- Clinical diagnosis of ARPKD the presence of bilaterally enlarged echogenic kidneys
demonstrating poor corticomedullary differentiation and at least 1 of the following:

1. Biliary ductal ectasia on magnetic resonance cholangiography or biliary duct
ectasia or dilation on ultrasound

2. Absence of renal cysts and/or characteristic imaging findings in both parents

3. Signs of congenital periportal hepatic fibrosis as indicated by the presence of
hepatosplenomegaly and/or esophageal varices and/or coarse liver echogenicity on
ultrasound

4. Hepatic periportal fibrosis on liver biopsy

5. Pathologic (biopsy or autopsy) or genetic diagnosis of ARPKD in a deceased
sibling or a clinical diagnosis of ARPKD in a living affected sibling

- The subject's parents or legal authorized representatives have signed a written
informed consent per local regulations prior to screening. Assent, when appropriate,
has been obtained from the subject according to institutional guidelines.

- The subject has a Lansky Play-Performance score of ≥ 50. Note: Subjects who are unable
to walk because of paralysis, but who are in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score.

- The subject has the following laboratory values:

1. Platelets > 120,000/mm3

2. Hemoglobin > 9 g/dL

3. Total bilirubin ≤ 1.5 mg/dL

4. Aspartate aminotransferase (AST) < 2.5 × upper limit of normal (ULN) for age

5. Alanine aminotransferase (ALT) < 2.5 × ULN for age

6. eGFR ≥ 50 mL/min/1.73 m2 as measured by Chronic Kidney Disease in Children (CKiD)
equation

7. Serum potassium levels and serum magnesium levels above the lower limit of normal
for age

8. Albumin within normal limits for age

9. Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 × ULN

- The subject has a normal ejection fraction by echocardiogram.

- The subject has a mean corrected QTcF of ≤ 450 msec.

- The subject has a blood pressure < 95th percentile for age, height, and gender.
Subject may be on medication for treatment of hypertension.

- The subject has normal auditory function for age.

- If sexually active, the subject agrees to use 2 accepted methods of contraception
during the course of the study and for 3 months after their last dose of study drug.

Exclusion Criteria:

- The subject has had a previous partial or total nephrectomy.

- The subject has any known genetic syndrome involving the kidney or liver other than
ARPKD.

- The subject has had clinically significant gastrointestinal bleeding during the 6
months prior to enrollment.

- The subject has received any investigational therapy within 30 days prior to the first
dose of study drug.

- The subject has a history of pancreatitis, has known risk factors for pancreatitis, or
baseline elevations in serum amylase or lipase.

- The subject meets any of the following cardiac criteria:

1. History of torsade de pointes, ventricular tachycardia or fibrillation,
pathologic sinus bradycardia (< 50 bpm), heart block (excluding first-degree
block, being PR interval prolongation only), congenital long QT syndrome or new
ST segment elevation or depression or new Q wave on ECG. Subjects with a history
of atrial arrhythmias should be discussed with the Medical Monitor

2. Family history of congenital long QT syndrome or unexplained sudden cardiac death

3. History of congenital prolonged QT syndrome, New York Heart Association class III
or IV congestive heart failure

4. History of cardiac arrhythmias, stroke, or myocardial infarction

5. Has a cardiac pacemaker

- The subject has an abnormal baseline audiogram.

- The subject is taking or has taken any medication known to inhibit the cytochrome P450
(CYP) 3A4 isozyme or any drugs that are strong or moderate CYP3A4 inducers within 14
days prior to Day 1 of study drug.

- The subject is taking or has taken any drugs associated with torsades de pointes or
known to prolong the QTc interval, including anti-arrhythmic medications within 2
weeks prior to Day 1 of study drug.

- The subject is receiving systemic anticoagulation.

- The subject has an uncontrolled intercurrent illness that would limit compliance with
study requirements.

- The subject has an uncontrolled infection.

- The subject is known to be positive for the human immunodeficiency virus or hepatitis
B or C.

- The subject is known to be immunocompromised.

- The subject has any medical or surgical conditions that would interfere with
gastrointestinal absorption of this oral agent.

- The subject has received prior solid organ transplantation.

- The subject, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.

- The subject has an allergy or hypersensitivity to components of either the tesevatinib
or the formulation.

- The subject is aphakic.

- The subject is pregnant or breast feeding.