Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects

To Assess Safety, PK of Inhaled Voriconazole (ZP-059) Single Doses in Healthy Subjects (Part 1), ZP-059 Multiple Doses in Stable Asthma (Part 2) and in a Crossover Trial of ZP-059 and Oral Voriconazole Single Doses in Stable Asthma (Part 3)

The primary safety objectives were:

• Part 1: To determine the safety and tolerability of single doses of ZP-059 in healthy subjects
• Part 2: To determine the safety and tolerability of multiple doses of ZP-059 in subjects with mild stable asthma
• Part 3: To determine the safety and tolerability of single doses of ZP-059 in subjects with mild to moderate stable asthma.

The primary PK objectives were:

• Part 1: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 in healthy subjects
• Part 2: To characterize systemic PK of voriconazole and N-oxide voriconazole after multiple doses of ZP-059 in subjects with mild stable asthma
• Part 3: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 and single doses of oral voriconazole in subjects with mild to moderate stable asthma.

This was an integrated Phase 1, single centre, multi-part, open-label study in both healthy subjects (Part 1), subjects with mild stable asthma (Part 2) and subjects with mild to moderate stable asthma (Part 3). In all three parts of the study every effort was made to include as close as possible an equal balance between male and female subjects.

This study assessed safety, tolerability and PK of single and multiple ascending doses of ZP-059 capsules administered as dry powder for inhalation in Part 1 to healthy volunteers (single ascending dose; SAD) and in Part 2 to subjects with mild asthma (multiple ascending dose; MAD), respectively.

In Part 3, the bioavailability of ZP-059 in subjects with mild to moderate stable asthma were compared to that of oral voriconazole. Part 3 started only after review of safety data from cohorts 1 to 4 of Part 1 (SAD) have been completed. Parts 2 and 3 of the study also explored voriconazole concentrations in induced sputum samples in asthmatic subjects.

As part of the safety and tolerability assessment, this study investigated the effects of ZP-059 on airway function in both mild and mild to moderate stable asthma subjects.

Inclusion Criteria (part 1):

• Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
• Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s)
• Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
• BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
• Are willing and able to comply with all aspects of the protocol.
• FEV1 ≥80% of the predicted value and FEV1/FVC ratio > 0.70; at screening.
• Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1.

Inclusion Criteria (part 2):

• Subjects with mild stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening.
• Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to Day 1.
• Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
• Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s).
• Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
• Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
• Are willing and able to comply with all aspects of the protocol.
• Subject is being treated with short acting beta-agonists alone or in conjunction with low to medium doses of ICS.
• Pre-bronchodilator FEV1 ≥70% of the predicted value at screening.
• Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1.

Inclusion Criteria (part 3):

• Subjects with mild to moderate stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening.
• Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to randomisation.
• Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method .
• Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s)
• Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
• BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
• Are willing and able to comply with all aspects of the protocol.
• Subject is being treated with low to medium doses of ICS with or without long-acting beta-agonists.
• Pre-bronchodilator FEV1 ≥70% of the predicted value at screening.
• Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1, Treatment Period 1.
• Able to produce a sputum sample with a minimum weight of 50 mg at screening.

Exclusion Criteria (part 1):

• Subjects who are Chinese or Japanese.
• Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1.
• Participation in other interventional studies for the duration of the study.
• Subjects who are study site employees or immediate family members of a study site or sponsor employee.
• History of any drug or alcohol abuse in the past 2 years prior to screening.
• Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type).
• Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1.
• A confirmed positive urine cotinine test at screening or Day -1.
• Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1.
• Smoking history of >5 pack years at screening.
• Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause).
• Female subject with a positive pregnancy test at screening or pre-dose on Day 1.
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
• Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required.
• Positive urine drugs of abuse test or alcohol breath test result at screening or Day -1.
• History of or currently infected with/carrier of human immunodeficiency virus (HIV).
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
• Evidence or history of clinically significant cardiovascular, renal, hepatic, endocrine, immunological or autoimmune, dermatological, ophthalmological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
• Subjects with congestive heart failure or a history of congestive heart failure.
• 12-lead ECGs demonstrating a mean QTcF interval >450 msec for males or QTcF interval >470 msec for females at screening or pre-dose Day 1.
• History of severe cough or bronchospasm upon inhalation of any inhalation product.
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
• Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles.
• Presence or history of clinically significant allergy, including drug allergies, but excluding untreated, mild seasonal allergies, as judged by the investigator. Hay fever is allowed unless it is active.
• Major trauma or surgery within the last 3 months prior to screening or prior to Day 1.
• Planned or elective surgery or hospitalisations for the duration of the study that may interfere with study logistics or safety.
• Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening.
• Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than ≤4 g per day of paracetamol, hormonal contraception or hormone replacement therapy), dietary supplements or CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the Principal Investigator and sponsor's medical monitor.
• Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1.
• Any use of voriconazole in the 3 months prior to Day 1.
• Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1.
• Upper respiratory tract infection (excluding otitis media), fever, acute or chronic cough within 14 days of Day 1, or lower respiratory tract infection within the last 4 weeks prior to Day 1.
• Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.
• Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the investigator would make the subject inappropriate for entry into the study.
• Failure to satisfy the investigator of fitness to participate for any reason.

Exclusion Criteria (part 2 and 3):

• Subjects who are Chinese or Japanese.
• Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1.
• Participation in other interventional studies for the duration of the study.
• Subjects who are study site employees, or immediate family members of a study site or sponsor employee.
• Subjects who have previously received IMP in this study.
• History of any drug or alcohol abuse in the past 2 years prior to screening.
• Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type).
• Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1.
• A confirmed positive urine cotinine test at screening or Day -1.
• Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1.
• Smoking history of >5 pack years at screening.
• Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause).
• Female subject with a positive pregnancy test at screening or pre-dose Day 1.
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
• Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required.
• Positive urine drugs of abuse test result (unless in the opinion of the investigator this can be explained by the subject's current medications) at screening or Day -1; unexpected positive results may require discussion with sponsor).
• Positive alcohol breath test at screening or Day -1.
• History of or currently infected with/carrier of HIV.
• Positive HBsAg, HCV Ab or HIV results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
• Evidence or history of clinically significant cardiovascular, renal, hepatic, dermatologic, ophthalmologic or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
• Evidence of history of endocrine, immunological, autoimmune disease that would affect the subject's safety or confound the assessment of study endpoints in the opinion of the investigator.
• Current diagnosis of any chronic airways disease other than asthma such as Chronic Obstructive Pulmonary Disease, pulmonary fibrosis, CF, Churg-Strauss syndrome, bronchiectasis.
• Evidence of ventricular dysfunction such as congestive cardiac failure (CCF) or a history of CCF assessed at screening and pre-dose Day 1.
• 12-lead ECG demonstrating a mean QTcF interval >450 msec for males or >470 msec for females at screening or pre-dose Day 1.
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
• Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles.
• Presence or history of clinically significant allergy, including drug allergies, as judged by the investigator. Hay fever is allowed unless it is active.
• Major trauma or surgery within the last 3 months prior to screening or prior to Day 1.
• Planned or elective surgery, hospitalisations for the duration of the study that may interfere with study logistics or safety.
• Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening.
• Subjects who are taking, or have taken, any prescribed or over-the-counter drugs that are CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study.
• Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1.
• Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1.
• Presence of hoarseness or oropharyngeal candidiasis at screening or prior to dosing on Day 1.
• Any use of voriconazole in the 3 months prior to Day 1.
• History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest and/or hypoxic seizures.
• Hospitalisation (including accident and emergency visits) for the treatment of asthma within 3 months prior to screening or prior to Day 1 or have been hospitalised or have attended the accident and emergency for asthma more than twice in the 12 months prior to screening.
• Occurrence of asthma exacerbations or respiratory tract infections within 4 weeks prior to screening or prior to Day 1.
• Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.
• Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the Investigator would make the subject inappropriate for entry into the study.
• Failure to satisfy the investigator of fitness to participate for any reason.