A Study of AeroVanc for the Treatment of MRSA Infection in CF Patients

This is a Phase III, randomized, multicenter, double-blind, placebo-controlled,
parallel-group study to examine the safety and efficacy of AeroVanc in the treatment of
persistent Methicillin resistant Staphylococcus aureus (MRSA) lung infection in patients
diagnosed with cystic fibrosis (CF). After the Screening period to confirm study eligibility,
subjects will be randomly assigned in a blinded fashion to receive either AeroVanc 30 mg
twice daily (BID), or placebo BID (1:1 active to placebo) by inhalation for 24 weeks or 3
dosing cycles (Period 1). Upon completion of Period 1, subjects will receive open-label
AeroVanc 30 mg BID for an additional 24 weeks or 3 dosing cycles (Period 2), to evaluate
long-term safety of AeroVanc. A dosing cycle is defined as 28 days of treatment followed by
28 days of observation.

Subjects on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen will enter the
Screening period at a time such that the Baseline visit coincides with the end of their
anti-Pseudomonas antibiotic cycle. Study drug will thereby be administered during the
off-cycle, and subjects can then resume anti-Pseudomonal therapy during the 28-day
observation period. Subjects continuing alternating anti-Pseudomonal therapy can continue
their treatment during the study drug administration, and observation period.

The primary and secondary analyses will be conducted in subjects ≤21 years old. Subjects >21
years old will be analyzed separately as a supportive analysis.

Inclusion Criteria

1. Subjects ≥ 6 years of age at time of Informed Consent Form (ICF) or Assent Form
signing.

2. Confirmed diagnosis of CF, determined by having clinical features consistent with the
CF phenotype, plus one of the following:

1. Positive sweat chloride test (value ≥ 60 mEq/L),

2. Genotype with 2 mutations consistent with CF (i.e., a mutation in each of the
cystic fibrosis transmembrane conductance regulator [CFTR] genes).

3. Positive sputum culture or a throat swab culture for MRSA at Screening.

4. In addition to the Screening sample, have at least 2 prior sputum or throat swab
cultures positive for MRSA, of which at least 1 sample is more than 6 months prior to
Screening. At least 50% of all MRSA cultures (sputum or throat swab culture) collected
from the time of the first positive culture (in the previous 1 year) must have tested
positive for MRSA. (Note: Screening sample may count towards 50% positive count)

5. Forced expiratory volume in 1 second (FEV1) ≥ 30% and ≤ 90% of predicted that is
normal for age, gender, race, and height, using the Global Lung Function Initiative
(GLI) equation.

6. At least 1 episode of acute pulmonary infection treated with non-maintenance
antibiotics within 12 months prior to the Baseline visit. (Initiation of treatment
with intermittent inhaled anti-Pseudomonal therapy will not qualify as treatment with
non-maintenance antibiotics).

7. If female of childbearing potential, an acceptable method of contraception must be
used during the study and must be combined with a negative pregnancy test obtained
during Screening; sexually active male subjects of reproductive potential who are
non-sterile (i.e., male who has not been sterilized by vasectomy for at least 6
months, and were not diagnosed with infertility through demonstration of azoospermia
in a semen sample and/or absence of vas deferens through ultrasound) must be willing
to use a barrier method of contraception, or their female partner must use an
acceptable method of contraception, during the study.

For purposes of this study, the Sponsor defines "acceptable methods of contraception"
as:

1. Oral birth control pills administered for at least 1 monthly cycle prior to
administration of the study drug.

2. A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle
prior to the study drug administration but not beyond the 4th successive year
following insertion.

3. Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1
monthly cycle prior to study drug administration.

4. Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1
monthly cycle prior to administration of the study drug and continuing through 1
month following study completion.

5. Hysterectomy or surgical sterilization.

6. Abstinence.

7. Double barrier method (diaphragm with spermicidal gel or condoms with
contraceptive foam).

NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal
contraceptive exposure, reducing the effectiveness and increasing the incidence of
menstruation-associated adverse reactions. Hormonal contraceptives, including oral,
injectable, transdermal, and implantable, should not be relied upon as an effective
method of contraception when co-administered with Orkambi.

8. Able and willing to comply with the protocol, including availability for all scheduled
study visits and able to perform all techniques necessary to use the AeroVanc inhaler
and measure lung function.

9. Agree not to smoke during any part of the clinical trial (Screening visit through end
of study).

10. Subjects with a P. aeruginosa co-infection must either be stable on a regular
suppression regimen of inhaled antibiotics or must be, in the opinion of the
Investigator, stable despite the lack of such treatment.

Exclusion Criteria

1. Use of anti-MRSA treatments prescribed as maintenance therapy (intravenous [IV] or
inhaled treatment within 28 days; oral treatment within 14 days) prior to the Baseline
visit.

2. Use of non-maintenance antibiotic for pulmonary infection or extrapulmonary MRSA
infection (IV or inhaled antibiotic within 28 days; oral antibiotic within 14 days)
prior to the Baseline visit.

3. History of previous allergies or sensitivity to vancomycin, or other component(s) of
the study drug or placebo except for a history of red-man syndrome.

4. Inability to tolerate inhaled products.

5. First time sputum culture or throat swab culture yielding B. cepacia, or
nontuberculous Mycobacteria in the previous 6 months to Screening.

6. History of lung or other solid organ transplantation or currently on the list to
receive lung or other solid organ transplantation.

7. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus
[VRSA], or vancomycin intermediate resistant Staphylococcus aureus [VISA], with
minimum inhibitory concentration [MIC] ≥ 8 μg/mL).

8. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone
every other day, or equipotent doses of other corticosteroids.

9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid
medications within 14 days, or changes in CFTR modulators within 28 days, prior to the
Baseline visit.

10. Abnormal laboratory findings or other findings or medical history at Screening that,
in the Investigator's opinion, would compromise the safety of the subject or the
quality of the study data.

11. Inability to tolerate inhalation of a short acting beta2 agonist

12. SpO2 <90% at Screening.

13. Changes in physiotherapy technique or physiotherapy scheduled within 1 week of the
Baseline visit.

14. Administration of any investigational drug or device within 4 weeks prior to the
Screening visit and during the study

15. Female with positive pregnancy test result during Screening, pregnant (or intends to
become pregnant), lactating or intends to breastfeed during the study.

16. Renal insufficiency, defined as creatinine clearance < 50 mL/min using the
Cockcroft-Gault equation for adults or Schwartz equation for children at the Screening
visit.

17. Abnormal liver function, defined as ≥ 4x upper limit of normal (ULN), of serum
aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT), or known
cirrhosis at Screening.

18. Diagnosed with clinically significant hearing loss.

19. History of positive result for human immunodeficiency virus (HIV), hepatitis B virus
(HBV) or hepatitis C virus (HCV).

20. Planned hospitalizations for prophylaxis antibiotic treatment within 28 days prior to
Baseline visit or during the double-blind period (Period 1).