A Phase 1, Randomized, Blinded, Placebo-Controlled, First-in-Human, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of APR002 Administered by Inhalation in Healthy Volunteers

Exclusion Criteria41

• Is mentally or legally incapacitated or has significant emotional problems at the time of the Screening Visit or expected during the conduct of the study.
• History or presence of clinically significant medical (e.g., chronic obstructive pulmonary disease, asthma, COVID-19, etc.) or psychiatric condition or disease in the opinion of the Investigator or designee. For example, pulmonary function test results should
• be within normal range, FEV1 % Predicted: 80 to 120%, FVC % Predicted: 80 to 120%, FEV1/FVC % Predicted: 85 to 110%.
• History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study or poses an additional risk to the participant by their participation in the study.
• History of unexplained syncope.
• History or presence of acute porphyria at the Screening Visit.
• Lymphoma, leukemia, or any malignancy within the past 5 years of the Screening Visit except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years or breast cancer within the past
• years of the Screening Visit.
• Clinically significant cardiac disease (e.g., myocardial infarction, stroke, unstable angina, claudication) within 6 months prior to check-in.
• History of clinically significant hepatic impairment.
• Current or chronic history of liver disease, including but not limited to hepatitis virus infections, drug- or alcohol-related liver disease, nonalcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, ?-1 antitrypsin deficiency, primary biliary
• cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the Investigator.
• Known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
• Participant has had previous episodes of seizures or convulsion (lifetime), including absence seizure and febrile convulsion.
• Participant or any immediate family member has a history of epilepsy (including febrile convulsions).
• Participant has a history of clinically significant neurological abnormalities including known abnormal electroencephalography at screening or brain injury including traumatic injury, perinatal cerebropathy and postnatal brain damage, blood-brain barrier abnormality, and angioma cavernous.
• Participant has a history of cerebral arteriosclerosis.
• Participant has a condition that can potentially reduce drug clearance (e.g., renal or hepatic insufficiency).
• Clinically significant acute illness or infection within 14 days prior to check-in.
• Major surgical procedure within 3 months prior to check-in.
• History or known presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related compounds.
• History or presence of alcohol or drug abuse within the past 2 years prior to the first dosing.
• Positive urine drug or breath alcohol results at the Screening Visit or check-in.
• Drinks alcohol in excess of 14 glasses/units per week, with 1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine. The participant has history of alcoholism, alcohol abuse (a current alcohol consumption of more than 2 drinks per day [a drink is defined as 5 oz (~150 mL) of wine, 12 oz (~355 mL) of beer, or 1 oz (~30 mL) of hard liquor]).
• Current smoker or a history of smoking within 3 months of screening, or a total pack year history of >5 pack years. [number of pack years = (number of cigarettes per day/20) x number of years smoked]. The participant has used any tobacco- or nicotine-containing
• products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 3 months prior to screening, or has positive urine cotinine test (defined as greater than or equal to 100 ng/mL) at screening, or is unwilling to forgo the use of tobacco- or nicotine-containing products throughout the study.
• Is a heavy caffeine drinker (i.e., consumes >5 cups/glasses of caffeinated beverages [e.g., coffee, tea, cola, energy drinks] per day for 3 or more days consecutively within the past 3 months).
• Has a positive pregnancy test at the Screening Visit or check-in, or is lactating.
• Is planning to become pregnant or father a child from the Screening Visit and throughout the study.
• Positive results at the Screening Visit for HIV, hepatitis B surface antigen (HbsAg), HCV, or on Screening or Day 1 for COVID-19
• Unable to refrain from or anticipates the use of:
• Any drugs, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to the first dosing. Thyroid hormone replacement medication will be allowed.
• Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to the first dosing.
• Donation of blood or significant blood loss within 56 days prior to the first dosing. The participant has donated 1 pint or more of blood or had a significant blood loss within 1 month (inclusive) prior to screening. The participant has received blood products within 2
• months (inclusive) prior to check-in.
• Plasma donation within 7 days prior to the first dosing.
• Participant has poor peripheral venous access.
• Participation in another clinical study within 30 days or 5 half-lives prior to dosing. The 30-day window will be derived from the date of the last dosing in the previous study to the first dosing of the current study.
• Participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after the dose of study drug or intending to donate ova during such time period.
• If male, participant intends to donate sperm during the course of this study or within 90 days after the dose of study drug.
• Participant has a risk of suicide per the C-SSRS (a score of 4 or 5 on ideation or any suicidal behavior) or according to the Investigator’s clinical judgment, has made a suicide attempt in the previous 6 months, or has a history of deliberate self-harm in the past 6 months.