A Phase 1b/2a, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate Nebulized Bacteriophage Treatment in Outpatient Adult Cystic Fibrosis (CF) Subjects with Chronic Pseudomonas aeruginosa (PsA) Pulmonary Infection

Cystic fibrosis (CF) is an autosomal recessive disease arising from a mutation
in the gene coding for the adenosine triphosphate (ATP)-driven chloride ion
channel CF Transmembrane Conductance Regulator (CFTR). In the lung, CFTR
mutations result in reduced mucociliary clearance, progressive obstructive
pulmonary disease, and chronic respiratory infections, which are a major cause
of morbidity and mortality in CF patients. Pseudomonas aeruginosa (PsA) is the
most prevalent pulmonary pathogen in CF patients. Chronic PsA pulmonary
infection is an independent risk factor for accelerated loss of pulmonary
function and decreased survival. Chronic PsA infection often results in a
mucoid bacterial phenotype and the formation of biofilms that render bacteria
refractory to antimicrobial therapy. The eventual acquisition of multi-drug
resistant (MDR) PsA strains and antibiotic resistant PsA biofilms that are
difficult to eradicate leaves CF patients with few available treatment options.
Over time, chronic lung infections lead to excessive inflammation and
bronchiectasis, resulting in either a need for lung transplantation or in death
due to respiratory failure.
Lytic bacteriophage therapy offers a novel alternative to antibiotics in the
treatment of chronic PsA infections, including those involving MDR strains and
biofilm formation. Bacteriophage therapy (BT) has been used for over 100 years,
particularly in Eastern Europe, where multiple case reports have demonstrated
the safety and tolerability of BT with few adverse events (AEs). However, to
date, BT has not been approved as a therapy. Inhalation BT has the advantage of
achieving higher drug concentrations at the site of infection without the
systemic exposure and AEs of IV or enterally administered therapy. No
placebo-controlled, double-blind clinical studies have been conducted to date.

Primary Objective:
To evaluate the safety and tolerability of nebulized BX004-A in CF subjects
with chronic PsA pulmonary infection.

Exploratory Objective:
To evaluate the effect of BX004-A on sputum PsA burden, lung function,
frequency of APEs, and quality of life at various timepoints.

The clinical development program for BX004-A will be initiated with a Phase
1b/2a randomized, double-blind, placebo-controlled, multicenter study
evaluating the safety and tolerability of twice daily inhaled bacteriophages
(BX004-A) for up to 10 days. In the Netherlands, subjects are being asked to
participate in Part 2 only. This study is descriptive and designed to evaluate
the treatment effect of twice daily BX004-A in addition to standard of care
inhaled antibiotics in the setting of background CF therapy.
Subjects will receive bacteriophages in addition to their usual inhaled
antibiotic regimen so that they receive appropriate antimicrobial coverage
according to their usual schedule, and will be included in a 6-month safety
follow-up. Final safety assessments will include phone calls 28 days and 6
months after the last dose of study medication to assess adverse events (AEs).
A Data Monitoring Committee (DMC) will monitor safety during both parts of the
study. The Sponsor will be unblinded after all subjects complete the Day 28
visit, to allow generation of topline results prior to complete data analysis
after the final phone call at 6 months.
The study includes a Screening period followed by a Treatment period. Patients
will be enrolled in the study if they are infected with PsA at a minimum
density of 10*5 CFU/gram of sputum, and all PsA morphotypes are susceptible to
at least one bacteriophage in BX004-A. Eligible subjects will be randomized
(2:1) to receive either twice daily High Dose inhaled BX004-A (minimum n=16) or
placebo (minimum n=8) for 10 consecutive days in addition to their usual
regimen of inhaled antibiotics. Following 10 days of study drug treatment, all
subjects will discontinue either inhaled BX004-A or placebo and continue
receiving inhaled antibiotics as per their usual regimen. The standard of care
inhaled antibiotic administered daily from Days 1-28 must be the same
throughout.

Either twice daily High Dose inhaled BX004-A or placebo for 10 consecutive days
in addition to the usual regimen of inhaled antibiotics.

Lytic bacteriophage therapy offers a novel alternative to antibiotics in the
treatment of chronic PsA infections for CF patients.

Possible benefit:
Subject's chronic PsA lung infection may improve from taking part in this study
and they may feel better. However, this cannot be guaranteed, especially if
they receive placebo (randomization ratio 2:1).

Based on the general understanding of the safety profile of phage, including
outcomes of the compassionate phage treatments reported in this indication, it
is considered that for cases of chronic PsA pulmonary infections, associated
with increased morbidity, the risk of administering nebulized phage that is
thoroughly characterized for intrinsic safety and manufactured to meet
pre-determined specifications for safety concern parameters, such as
endotoxins, exotoxins and sterility, is low.

Burden - Subjects will undergo the following tests/assessments during a period
of 6 months, where the largest burden is in the first 28 days:
Venapunction: 2 times;
CFQ-R (Cystic Fibrosis Questionnaire Revised): 3 times;
CFRSD-CRISS (Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory
Infection Symptom Score: To be completed daily by subject from Day 1 to Day 38;
Physical Examination of the Lungs: 5 times;
Height, weight and BMI: 4 times;
SpO2, blood pressure, respiratory rate, heart rate, and temperature: 5 times;
Collect Sputum (provided spontaneously by coughing or by undergoing sputum
induction): 5 times;
For WOCBP urine pregnancy test: 2 times;
Spirometry: 4 times;
To keep daily drug diary: For 10 days.

Possible risks and discomforts from the procedures subjects may experience
during the study:
• Blood draws: The risk of blood draws includes discomfort at the site of the
blood draw with bruising, bleeding, pain and/or redness at the site of the
needle stick, infection, or fainting. Very rarely subjects may get an infection
in their blood or a blood clot may form. In very rare cases, the needle might
damage a nerve or a blood vessel.
• Sputum induction procedures: If subjects undergo sputum induction, they may
experience mild bronchospasm from the medication given to help them cough up
sputum.
• Subjects will be asked to complete questionnaires. Some of the questions may
make them feel anxious or upset. Subjects does not have to answer any questions
that upsets them.

Risks/burden related to study treatment:
BX004-A is administered by inhalation, and it is possible that inhaled BX004-A
could cause respiratory side effects and/or bronchospasm soon after inhalation.
These include:
• Wheezing,
• Cough,
• Productive cough,
• Rales,
• Dyspnea,
• Acute pulmonary exacerbation,
• Respiratory failure.

Rare risk: Anaphylactic reaction (include hives, itching, tremor, swelling of
the face and/or neck, hypotension, difficulty breathing, choking, nausea,
vomiting, dizziness, or fainting).

During manufacture of BX004-A, harmful substances made by PsA, like endotoxin
and exotoxin, are removed from the final drug product. However, it is always
possible that a small amount of bacterial endotoxin or exotoxin escapes the
removal process and is present in the vials of bacteriophage that subjects
receive.

It is possible that the PsA strains subjects have in their lung become
resistant to the bacteriophages in BX004-A and because of this, they may not
receive much benefit or clinical improvement from BX004-A.