Premier Research

1. Males and females at least 18 years of age who give voluntary written informed consent to participate in the study.
2. Patients with a diagnosis of ILD based on computed tomography imaging, including:
   • Idiopathic interstitial pneumonia, including idiopathic pulmonary fibrosis
   • Connective tissue disease-associated ILD with FVC <70%
   • Hypersensitivity pneumonitis
   • Scleroderma-related ILD
   • Autoimmune ILD
   • Nonspecific interstitial pneumonia
   • Occupational lung disease
   • Combined pulmonary fibrosis and emphysema
3. Patients must meet a total of 2 or more criteria from at least 2 distinct categories below (ie, Category 1, Category 2, Category 3) based on the Investigator’s clinical judgment, within 180 days of Screening.

Category 1: Clinical tests

a. PFTs with at least 1 of the following results:

• DLCO <40%
• DLCO decline of ≥15% based on 2 most recent assessments
• Worsening DLCO (decline >10%) with stable FVC (decline <5%) (ie, worsening FVC/DLCO ratio) based on 2 most recent assessments

b. Historical HRCT with any of the following findings:

• Right ventricle enlargement: RV:LV ratio >1
• Pulmonary artery enlargement
• Pulmonary artery/aorta ratio >1.0
• Ventricular septal flattening
• Enlarged pulmonary arteries in the lung periphery

Category 2: Symptoms, oxygenation, exercise capacity, and BNP/NT-proBNP

• Symptoms disproportionate to ILD severity or changes in symptoms not explained by ILD progression
• Desaturation on 6MWT disproportionate to ILD severity in the opinion of the Investigator
• 6-Minute Walk Distance decline of ≥15% based on 2 more recent assessments
• Worsening desaturation requiring more supplemental oxygen
• Recent worsening desaturation
• BNP >200 pg/mL or NT-proBNP >395 pg/mL
• Physical exam findings (at least 1 of the following): syncope, jugular venous distension, ankle swelling/peripheral edema, ascites, loud P2 or S2 heart sound, or hepatomegaly

Category 3: Echocardiography

• RV systolic pressure >35 mmHg
• Any RV dilation or enlargement
• Other RV abnormalities in the clinician’s judgment
• Tricuspid annular plane systolic excursion <2 cm

Patients are excluded from the study if any of the following criteria apply:

1. Prior RHC with mPAP >20 mmHg
2. Currently on a Food and Drug Administration (FDA)-approved pulmonary arterial hypertension medication
3. Diagnosed with chronic obstructive pulmonary disease
4. Uncontrolled or untreated sleep apnea
5. Pulmonary embolism within the past 3 months
6. History of ischemic heart disease or left-sided myocardial dysfunction within 12 months of Screening, defined as LV ejection fraction <40% or pulmonary capillary wedge pressure >15 mmHg
7. Any other clinical features that, in the opinion of the Investigator, might adversely affect interpretation of study data or study safety, or make the patient unsuitable for RHC

• Age 18 - 75 y, BMI 19.0 - 32.0 kg/m2 (inclusive)
• WHO Group 1 PH (PAH):
• Right heart catheterization (RHC) at screening or within 30 days of screening with the following hemodynamics:
  • PAP ≥ 25 mmHg, PCWP ≤ 15 mmHg, & PVR of ≥ 5 WU
• NYHA/WHO Functional capacity Class II-III
• No evidence of thromboembolic disease
• No more than 2 medications from the following classes: Endothelin receptor antagonists (eg, ambrisentan, bosentan, macitentan), phosphoesterase type 5 inhibitors (eg, sildenafil, tadalafil), guanylate cyclase stimulator (eg, riociguat)
• Stable PH medications for 60 days
• FVC ≥70% within 1 year of Screening

At least two 6MWTs at Screening between 150 - 550 m, both values are w/i 15% of each other

• PH Group 1 as described in IC
• Hypersensitivity / contraindication to TPIP or TRE or mannitol
• Previous intolerance to prostacyclin analogs or receptor agonists (eg, selexipag)
• QTcF interval > 480 ms
• Known ventricular or supraventricular tachyarrhythmia (except for paroxysmal atrial fibrillation), or any symptomatic bradycardia
• LVEF ≤ 40%
• SBP < 90 mmHg
• Renal or liver disease
• HIV or Hep B or C
• Triple therapy of endothelin receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase stimulators

MDI Use

• Proper administration technique - spacers not permitted

Reproduction

• Pregnancy test to be performed on all women of childbearing potential.
• Acceptable contraceptive measures

Permitted Asthma Meds During Screening

• Run-in BFF MDI BID and albuterol prn only;
• SCS or ICS for the treatment of an asthma exacerbation (defined use)

eDiary Compliance

• 14 day compliance ≥70% during screening

Respiratory Infection During Screening:

• Completed treatment more than 4 weeks prior to randomization (V5)

Asthma Exacerbation During Screening

• Completed treatment with SCS and/or additional ICS more than 4 weeks prior to V5

Asthma History

• Life- threatening asthma
• Hospitalization for asthma w/in 2 months of V1

Nebulizer Usage

• Regular use of a nebulizer or a home nebulizer for receiving asthma medications

Oral B2- agonist Usage

• Use of oral 2-agonist within 3 months of V1

SCS Usage

• Oral and IV CS use (any dose) except for exacerbation within 4 weeks of V1

Immuno-modulators/ immuno-suppressive Usage

• Use of any immunomodulators or immunosuppressive meds within 3 months or 5 half-lives, whichever is longer, and not permitted during study duration

Medical conditions

• Historical or current evidence of a clinically significant disease; clinically relevant abnormal findings on P.E., clinical labs, or ECG

Eye Disorders

• Narrow angle glaucoma not adequately treated and/or change in vision that may be relevant, in the opinion of the Investigator, w/in 3 months of V1

Smoking history

• Current smokers, former smokers with >10 pack-years hx or who stopped smoking <6 months prior to V1 (includes marijuana, e-cigs & vaping devices)

• Male or Female > 18 years of age
• Current diagnosis of MAC lung infection. MAC or mixed infection with MACas the dominant species is allowed, with MAC as the intended organism for treatment
• Positive sputum culture for MAC within 6 months prior to Screening
• Positive sputum culture for MAC at Screening
• A chest CT scan, read locally, within 6 months prior to Screening to determine presence and size of pulmonary cavities.
• Willingness and ability to adhere to prescribed study treatment during the study
• WOCBP (ie, fertile following menarche and until becoming postmenopausal unless permanently sterile) and fertile men (ie, all men after puberty unless permanently sterile by bilateral orchiectomy) agree to practice a highly effective method of birth control from Day 1 to at least 90 days after the last dose.
• Provide signed informed consent prior to administration of study drugs or performing any study related procedure
• Be able to comply with study drugs use, study visits, and study procedures as defined by the protocol
• Men with partners who are WOCBP (pregnant or non-pregnant) agree to use condoms and non-pregnant partners should practice a highly effective method of birth control.

• Diagnosis of CF
• History of more than 3 MAC lung infections
• Received any mycobacterial antibiotic treatment for current MAC lung infection
• Relapse of prior MAC lung infection, defined as positive sputum culture for MAC < 6 months of cessation of prior successful treatment
• Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during the study
• Active pulmonary tuberculosis requiring treatment during Screening
• Hospitalization for underlying lung disease during Screening
• Current smoker
• History of lung transplantation
• Use of inhaled or systemic aminoglycosides with activity against MAC (eg, amikacin, kanamycin, or streptomycin) during Screening
• Prior exposure to ALIS (including clinical study)
• Known hypersensitivity or contraindications to use to ALIS, aminoglycosides, or any of their excipients
• Disseminated MAC infection
• Positive pregnancy test or lactation at Screening. All WOCBP will be tested. Women not of childbearing potential are defined as postmenopausal
• Administration of any investigational drug within 8 weeks prior to Screening
• Known or suspected acquired immunodeficiency syndromes
• Significant hearing loss, vestibular dysfunction, or neuromuscular weakness
• Current alcohol, medication, or illicit drug abuse
• Known and active COVID-19 infection

• Male or Female patient aged 40 years or older
• Diagnosis of IPF
• Chest HRCT performed within 12 months prior to Screening
• Able to walk at least 150 m during the 6MWT
• Resting oxygen saturation of < 89% using maximum of 6 L/min
• Patients receiving either pirfenidone or nintedanib
• WOCBP (ie, fertile following menarche and until becoming postmenopausal unless permanently sterile) and fertile men (ie, all men after puberty unless permanently sterile by bilateral orchiectomy) agree to practice a highly effective method of birth control

• Evidence of IPF exacerbation within 3 months prior to and/or during screening
• Current smoker
• History of lung transplant
• Life expectancy of less than 12 months
• Congestive heart failure class III or IV
• Pulmonary hypertension
• Known hypersensitivity to any of the study treatment
• Interstitial lung disease associated with known primary diseases
• History of malignancy within the past 5 years

• Male and Female participants must be 40 to 80 years of age
• A diagnosis of COPD
• Willing to adjust current COPD therapy
• WOCBP (ie, fertile following menarche and until becoming postmenopausal unless permanently sterile) and fertile men (ie, all men after puberty unless permanently sterile by bilateral orchiectomy) agree to practice a highly effective method of birth control
• Capable of giving signed informed consent

• Active diagnosis of asthma within the past 5 years
• History of heart or lung transplant
• History of lung cancer
• Unstable or life-threatening cardiac disease
• Any life-threatening condition, including malignancy, with a life expectancy < 5 years

• Male and Female participants must be > 18 years of age
• Individuals with a diagnosis of severe asthma for at least 12 months

• Not willing and able to sign written informed consent
• Not fluent in English
• Received an investigational therapy for asthma, allergy, atopic disease, or eosinophilic disease as part of a clinical trial within 6 months