Terminated by new sponsor due to funding issues.

The purpose of the study is to evaluate the efficacy of voxelotor for increasing oxygen saturation in 20 patients with hypoxemia. Specifically, the SpO2/FiO2 ratio will be compared before and after voxelotor use at rest and during exercise (ambulatory patients only).

The primary study objective is to evaluate the efficacy of voxelotor for increasing oxygen saturation in patients with hypoxic hypoxemia as a result of end-stage lung disease or acute lung injury.

The secondary objective is to evaluate the efficacy of voxelotor on allowing de-escalation of supplemental oxygen support.

Purpose of the study: Primary study objective is to evaluate the efficacy of voxelotor for increasing oxygen saturation in patients with hypoxic hypoxemia as a result of end-stage lung disease or acute lung injury.

Design and Procedures: The day after obtaining written informed consent, 20 patients will receive 500 mg of voxelotor two times a day (for a total daily dose of 1000 mg per day) for 5 days This dose may increase to a total maximum daily dose of 1500 mg (500 mg three times a day) if subject tolerates initial dose as determined by Principal Investigator (PI).

Physiological data at screening, baseline, study day 1 - 5, and up to two days post voxelotor administration will be recorded from standard of care with the only exception being SpO2/FiO2 (S/F) ratio measurements, which will be obtained at the same intervals but by the qualified and delegated study staff or medical team through the use of an FiO2 weaning maneuver.

Study subjects will be asked to rate their dyspnea symptoms daily to record their perceived shortness of breath.

Blood samples will be collected the day prior to voxelotor administration, on study days 1 - 5, and on the 2 wash-out days following voxelotor administration.

Inclusion Criteria:

• Oxygen dependency due to an end-staged lung disease (pre-lung transplant population) or ALI/acute lung injury (for example but not limited to primary allograft dysfunction, infectious pneumonia, aspiration, non-cardiogenic pulmonary edema). ALI will be defined as per Berlin criteria with a P/F ratio <100 denoting severe ARDS, <200 denoting moderate and <300 mild ARDS. ALI and mild ARDS are considered synonymous. In the event of inability to obtain arterial blood gas analysis to calculate a P/F ratio, we will consider a range of patients requiring standard nasal cannulae flowing at 6l/min to maintain SaO2 >90% as ALI, and Salter High -Flow nasal cannulae at 12-15l/min in order to maintain SaO2>85% as severe ARDS.
• At least 48 hours of stable, increased oxygen requirement or ventilatory support prior to the start of drug administration if consented.

Exclusion Criteria:

• Minors (<18 years)
• Pre-existing congestive cardiac failure (NYHA III or IV)
• Medically significant, non-revascularized coronary artery disease
• Inability to obtain informed consent from LAR
• Pregnancy
• Incarcerated individual.
• Failure of another vital organ.
• Severe hepatic impairment (Childs-Pugh C) or liver enzymes > 4x upper limit of normal (ULN) at screening.
• Unstable acute kidney injury/rising creatinine.
• Chronic neuromuscular disease requiring mechanical ventilation
• Not anticipated to survive >48 hours
• Limited therapeutic goals (do not resuscitate, etc.)
• History of Pulmonary Embolism (PE)
• Requires treatment with Fluconazole or other moderate and strong CYP3A4 inhibitors listed in section 5.6
• A patient with active bleeding complications requiring more than 1 unit of blood transfusion per day, as the PK and PD of Voxelotor in the setting of blood loss and blood transfusion is unknown.
• Participated in another clinical trial of an investigational drug (or medical device) within 30 days or 5-half-lives, whichever is longer, prior to consent, or is currently participating in another trial of an investigational or marketed drug (or medical device)
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
• Any condition or concomitant medication that confounds the ability to interpret data from the study or safely use Voxelotor.

Participants will be followed for AEs from the time of voxelotor administration until 2 days after the last administration of voxelotor as defined by the wash out period.