About 300,000 children are born each year with SCD(Sickle Cell Disease). It affects the red blood cells within the blood that carries the important function of transporting oxygen to all body parts. Normal red blood cells have a regular circular shape and it is maintained that way in the body. For patients with SCD, their red blood cell takes the shape of a sickle when the body is stressed and clogs the blood vessels, leading to early destruction of the deformed sickled red blood cell and damage of the body parts because of lack of oxygen. The abnormality and many other processes make it difficult for the sickled red blood cell to transport oxygen. The lack of oxygen in the body parts can cause severe body pains which is a key presentation of SCD. Potential cure for SCD such as bone marrow transplant and gene treatment are limited by their high cost and use of advanced medical technology not available in many countries.. About a quarter of patients with SCD develop stroke by the age of 45 years with a very high likelihood of recurrence. Lifelong blood transfusion can be used to prevent stroke recurrence in patients with SCD who have a stroke by reducing the percentage of sickled haemoglobin to below 30 percent. However, this lifelong transfusion has many challenges such as iron overload, heart problems, social and family burden. Currently there are no treatments approved for the reduction of the transfusion burden in these patients and therefore an oral treatment reducing the need for blood transfusion and its associated iron overload will be key in addressing this unmet need for patients on long term transfusion for prevention of stroke. Another drug that prevents initial stroke in patients with SCD is hydroxyurea but is not well tolerated by some patients thus an unmet need still exists. There are other new drugs which are also being developed and what we are proposing is one of them 

Etavopivat (FT-4202) is a potent, selective, orally bioavailable, small-molecule activator of pyruvate kinase-red blood cell (PKR) being developed by Forma Therapeutics, Inc and is intended for use as a treatment for patients with sickle cell disease (SCD). The clinical hypothesis is that PKR activation will reduce the rate of sickle cell polymerization and improve red blood cell (RBC) membrane function, thereby reducing RBC sickling and RBC hemolysis that lead to vascular obstruction and anemia, two hallmarks of SCD pathology.

This multi -centre phase 1/2, study aims to evaluate the pharmacokinetics and safety of Etavopivat in SCD patients aged 12 years to below 18 years in a single arm, open label study. This study will enroll 50 patients aged 12 years to below 18 years with SCD. ACTU site will enroll at least 15 participants into the study.

The participants will be seen at the study sites at screening, day 1, week 2, week 4 then approximately every 4 weeks until week 24, then approximately every 8 weeks until week 96, which is the end of treatment. End of study visit will occur 4 weeks after the last full dose with a tolerant window of 1week. Safety will be monitored throughout the study, and PK, QoLs, and clinical outcome measures will be performed at specified visits.

8. INTRODUCTION

Currently, therapeutic treatment of SCD is inadequate. Potentially curative therapies, such as bone marrow transplant or gene therapies, are invasive and such high-risk procedures are limited to only a subset of patients. For most patients, treatment involves supportive care for management of vaso-occlusive crisis (VOC) or the use of hydroxyurea (HU), to stimulate production of fetal Hb (HbF) and reduce Hb polymerization. While inducing HbF can be effective therapeutically, HU can be myelosuppressive and is a teratogen (Sampson et al. 2010). Although HU is considered to have an acceptable therapeutic index, the myelosuppressive and teratogenic risks limit its effectiveness (Platt 2008).

Chronic transfusion is another way of preventing stroke recurrence in patients with SCD. However, frequent transfusion is associated with significant co-morbidities, such as secondary hemochromatosis; cardiomyopathy and infections; alloimmunization; social and family burden (Franke 2018). An oral therapy reducing the need for RBC transfusion and the associated iron overload, would therefore address a critical unmet medical need for patients with SCD on chronic transfusions for prevention of stroke recurrence.

FT-4202 is a potent, selective, orally bioavailable, small-molecule activator of pyruvate kinase-red blood cell (PKR). Pyruvate kinase R (PKR) is the isoform of pyruvate kinase expressed in RBCs and is a key enzyme in glycolysis (Zanella et al. 2005). Activation of PKR is proposed to directly target both sickling by reducing deoxy-HbS and hemolysis by improving RBC membrane integrity. Specifically, PKR activation inhibits Hb deoxygenation and sickling by decreasing levels of the glycolytic intermediate 2,3- diphosphoglycerate (2,3-DPG) and increasing O2 affinity of HbS. Furthermore, PKR activation increases adenosine triphosphate (ATP), which has been shown to support overall RBC membrane integrity and stress resilience (Betz et al. 2009), thus potentially decreasing hemolysis. ATP also supports elimination of reactive oxygen species (ROS) which damage RBCs and impair their functionality, and reduces vascular adhesion associated with membrane injuries (Banerjee and Kuypers 2004). The combination of antisickling effects, decreased hemolysis, and improved RBC membrane fitness is proposed to reduce the onset and complications of vaso-occlusive events and, in parallel, address the chronic anemia of SCD

A First-in-Human (FIH) clinical study (Protocol 4202-HVS-101) entitled “A Randomized, Placebo-controlled, Double Blind, Single Ascending and Multiple Ascending Dose Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of FT-4202 in Adult Healthy Volunteers and Sickle Cell Disease Patients” has completed enrollment. A total of 90 healthy subjects and 42 SCD patients had been enrolled in the study, including 32 healthy subjects and seven SCD patients in the single ascending dose (SAD) cohorts, 48 healthy subjects and three SCD patients in the multiple ascending dose (MAD) cohorts, and 10 subjects in the food effect (FE) cohort. The 42 SCD patients were enrolled 7 in the SAD cohort,14 in the MAD cohort and 15 in the 12-week open label.

For the healthy subject SAD cohorts, a total of 6 (18.8%) subjects were reported with at least one treatment-emergent adverse event (TEAE), including 5 (20.8%) subjects who received FT-4202 and 1 (12.5%) subject who received placebo. No TEAE was reported in more than 1 subject. No treatment-emergent serious adverse events (TESAEs) were reported and there were no TEAEs that led to dose reduction/interruption or discontinuation of study drug.

For the healthy subject MAD cohorts, a total of 18 (37.5%) subjects were reported with at least one TEAE, including 15 (41.7%) of subjects who received FT-4202 and 3 (25.0%) subjects who received placebo. The most common TEAE was headache, which was reported in 10 (27.8%) subjects receiving FT-4202 and 2 (16.7%) subjects receiving placebo. For headache TEAEs, there was no apparent relationship between daily FT-4202 exposure and incidence. For subjects receiving FT-4202, all other TEAEs were reported in 1 (2.8%) subject each. No TESAEs were reported and there were no TEAEs that led to dose reduction/interruption or discontinuation of study drug.

For the SCD SAD cohort, TEAEs were reported in 2 (100.0%) patients who received placebo and 2 (40.0%) patients who received Etavopivat. For patients who received Etavopivat, 1 TEAE of transient, mild (Grade 1) palpitations was considered possibly treatment-related and resolved without treatment. For the SCD SAD cohort, no TESAEs were reported, and there were no TEAEs that led to dose reduction/interruption or discontinuation of study drug.

For the SCD multiple dose cohorts, TEAEs were reported in 7 (87.5%) patients who received Etavopivat in the MAD-1 cohort (300 mg Etavopivat × 14 days), 6 (75.0%) patients who received Etavopivat in the MAD-2 cohort (600 mg of Etavopivat × 14 days), and 14 (93.3%) patients in the 12-week OL cohort. For patients receiving Etavopivat, treatment-related TEAEs were reported in 2 (25.0%) patients in the MAD-1 cohort and 7 (46.7%) patients in the OL cohort. Treatment-emergent SAEs were reported in 1 (12.5%) patient in the MAD-2 cohort and 5 (33.3%) patients in the OL cohort; 1 (6.7%) patient in the OL cohort had a TEAE that led to study discontinuation (SAE of deep vein thrombosis [DVT]). For patients with SCD receiving Etavopivat in the 14-day cohorts, the TEAEs reported in > 1 patient were sickle cell anemia with crisis (MAD-1, n=3 [37.5%]; MAD-2, n=3 [37.5%]), headache (MAD-1, n=3 [37.5%]; MAD-2, n=1 [12.5%]), nausea (MAD-1, n=2 [25.0%]; MAD-2, n=1 [12.5%]), and vomiting (MAD1, n=1 [12.5%]; MAD-2, n=1 [12.5%]).

In the 12week OL cohort, the TEAEs reported in > 1 patient were sickle cell anemia with crisis (n=7 [46.7%]); headache (n=4 [26.7%]); and dizziness, nausea, and upper respiratory tract infection (n=2 [13.3%] for each). Six patients receiving Etavopivat in the SCD multiple dose cohorts were reported with TESAEs, including 1 (12.5%) patient in the MAD-2 cohort (1 event of unrelated Grade 3 sickle cell anemia with crisis) and 5 (33.3%) patients in the 12-week OL cohort (2 patients with events of unrelated Grade 3 sickle cell anemia with crisis and single-patient events of ACS [unrelated Grade 3], corona virus infection [unrelated Grade 3], DVT [possibly related Grade 3], non-cardiac chest pain [unrelated Grade 3], and syncope [unrelated Grad