The purpose of the study is to evaluate if ITU512 is safe and effective and can help you or others who have sickle cell disease. This study will assess the safety of ITU512 and if it is able to reduce complications related to sickle cell disease.

Sickle cell disease is a disease that inhibits the ability of hemoglobin to carry oxygen in red blood cells. Babies are born with hemoglobin that allows their blood to carry oxygen while in the womb. After birth, the type of hemoglobin slowly changes to "adult" hemoglobin, and that is when the effects of sickle cell disease begin to affect your body. The purpose of this study is to test a way (a treatment) to switch back on the fetal/infant hemoglobin. It is known that some patients with the sickle cell genes are protected from illness because they have not completely switched to adult hemoglobin and are protected by having more fetal hemoglobin.

This sickle cell study has 2 parts which are called Part 2A and Part 2B which tests different doses or dosing schedules of ITU512 compared to placebo. Placebo looks like the study treatment but has no study treatment in it. Using a placebo helps researchers better understand the actual effects of a study treatment.

Part 2A is looking at about 3 different dose levels or dosing schedules of ITU512 to better understand the safety and efficacy (how well the treatment works) of the study treatment and to pick dose levels or schedules to further look at in Part 2B. Part 2B is looking at about 2 different dose levels or schedules to better understand the safety and efficacy (how well the treatment works) of the study treatment and to pick a dose and schedule that may be used in other future studies.

Trial Design:

CITU512A12101 is a first-in-human Phase I/II clinical study of ITU512

Part 1 (Healthy participants)

Part 1 will be conducted in healthy participants and will comprise Part 1A single ascending dose (SAD), Part 1B multiple ascending dose (MAD), and Part 1C food effect.

Part 1A SAD with interleaving cross-over

Part 1A is a randomized, placebo-controlled, blinded (participant and investigator) study which will evaluate up to 6 escalating dose levels over six sequential dosing periods in a crossover fashion, interleaved between two cohorts.In each of the two cohorts,12 participants will be randomized to one of three treatment sequences (4 participants in each) such that each participant receives a single dose of two of three possible dose levels of ITU512 and one dose of placebo.

Part 1B MAD

Part 1B is a randomized, placebo-controlled, blinded (participant and investigator) study which will include 5 planned escalating cohorts of 8 participants each (40 participants total). Within each cohort, participants will be randomized to receive study treatment once daily for 14 days.

Part 1C Food Effect

Part 1C is a preliminary evaluation of the effect of food on PK of ITU512 to be conducted in a cross-over manner in approximately 8 participants with a target of 6 PK evaluable participants.

Part 2 (SCD)

Part 2 will be conducted in participants with sickle cell disease and will comprise Part 2A initial dose evaluation, Part 2B dose evaluation, and Part 2C ITU512 extension.

Part 2A: Initial dose evaluation

Part 2A is a randomized, placebo-controlled, blinded (participant and investigator) study in approximately 24 adult participants with SCD with up to 3 dose levels of ITU512 with the goal to confirm the doses for Part 2B dose evaluation.

Part 2B Dose evaluation

Part 2B dose evaluation phase is a randomized, placebo-controlled, blinded (participant, investigator, sponsor) study in approximately 65 adult and adolescent participants with SCD and will evaluate up to 2 levels of ITU512.

Part 2C ITU512 Extension

Following completion of Part 2A or Part 2B (4 months of ITU512 or placebo), eligible participants may consent to the ITU512 extension portion of the study and receive up to 18 months of ITU512 treatment during Part 2C of the study. Participation in Part 2C is optional.

Study Rationale:

The purpose of this first-in-human (FIH) study is to evaluate the safety, tolerability, PK, and preliminary food effect of ITU512 as well as the HbF-inducing capacity of ITU512. While the benefits of ITU512 on HbF induction have been demonstrated in preclinical studies, this will be the first clinical evaluation of the potential therapeutic effect of ITU512 in healthy participants and participants with SCD. The results of the study will be used to inform future development plans for ITU512 in SCD and β-globinopathies.

Study Population:

The study population in Part 1 is male and female (of non-childbearing potential) healthy adults. The study population in Part 2 of the study is male and female adult and adolescent participants (Part 2B and Part 2C) with all SCD genotypes.

Adult (ages 18-55 years inclusive) and adolescent (ages 12-17 years inclusive)

participants with SCD of all genotypes who have received standard age-appropriate care

for SCD and are not currently eligible/receiving hydroxyurea/hydroxycarbamide

Part 2B dose evaluation phase will enroll approximately 65 adult and adolescent participants with SCD. Participants will be randomized to one of up to 2 dose levels as determined following data review from Part 2A, or to placebo, at a 2:2:1 ratio (dose level 1, dose level 2, placebo) and receive ITU512 or placebo once daily for 4 months