Sickle Cell Anemia (SCA)
Disclaimer: Not medical or professional advice. Always seek the advice of your physician.
Sickle cell anemia is a group of genetic disorders caused by mutations in the hemoglobin protein that lead to the deformation of erythrocytes.
Erythrocytes (red blood cells) are the most numerous cell type in the blood that carries oxygen to the body’s organs and tissues. Healthy red blood cells are round and flexible. This shape provides better circulation for moving through extremely small blood vessels.
In sickle cell anemia, red blood cells contain an abnormal type of hemoglobin. Normally, this protein is located inside the red blood cell in its main form of HbA. The mutation changes hemoglobin form to HbS. As a result, mutated hemoglobin acquires differences in structure and functions. Erythrocytes also undergo changes in shape and take the form of a crescent or sickle.
All these consequences cause adverse effects on the body.
- It leads to a reduction in the life span of red blood cells. They get stuck in the spleen and die. Red blood cells affected by sickle cell anemia only live for about 10-20 days instead of 120 days.
- Deformed erythrocytes lose their elasticity, clump together, and stick to the walls of blood vessels.
- Sickle cell anemia may result in renal functional disturbances.
Prevalence of Sickle Cell Anemia
Sickle cell anemia is a worldwide health problem. It is estimated that it affects more than 4 million people globally and 100,000 Americans.
About 1 in 365 African American babies are born with sickle cell anemia. More than 75% of cases are found in Sub-Saharan Africa. The disease is also common in India, Saudi Arabia, and Mediterranean countries.
Symptoms of Sickle Cell Anemia
- pain from different visceral organs
- skin ulcers
- blurred vision
- renal complications like kidney failure
- bone loss and structural changes
- joint pain and swelling
- reduced sensation in the limbs
Causes of Sickle Cell Anemia
Sickle cell anemia is not contagious. This disease is passed down from parent to child through genes. It arises from a mutation in one or two genes that encode hemoglobin.
Sickle cell anemia is inherited in an autosomal recessive pattern. It means that both parents have to be asymptomatic or symptomatic gene mutation carriers for their child to be affected by this disease. When the sickle cell gene is inherited from only one parent, the child is usually asymptomatic. In this case, they have a sufficient amount of normal hemoglobin to prevent the cells from sickling. Carriers of the sickle cell gene have an increased risk of chronic kidney disease. Rarely, they may notice blood in their urine.
So far, scientists have not found a way to determine the exact cause of gene mutations that lead to sickle cell anemia. Several studies consider a number of factors that may trigger this type of mutation.
- Malaria infection. The causative agent of the disease is plasmodium parasites. They invade red blood cells (erythrocytes) and cause their mutation and death.
- Viral infection. The virus releases its genetic material into the inside of the healthy cell to replicate and produce viral particles. This process can also lead to irreversible changes in the chromosomes. Viruses that can trigger sickle cell anemia include cytomegalovirus (CMV), rubella, measles, hepatitis, and many others.
- Adverse environmental factors. This group involves exposure to various chemicals during the life course.
There is no cure for sickle cell anemia. However, patients can extend their life expectancy if they follow all medical recommendations.
Sickle Cell Clinical Trial: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058.
This is a Phase 1 multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), fetal hemoglobin (HbF) induction and biological activity of FTX-6058 in subjects 18-65 years of age, inclusive with sickle cell disease (SCD).
This study will comprise 2 parts and will be conducted in subjects 18-65 years of age, inclusive with sickle cell disease (SCD) either taking hydroxyurea (HU) at a stable dose for at least the preceding 3 months, or not taking hydroxyurea (HU).
Part A, the main study will consist of two phases. Cohort one will receive 6 mg of FTX-6058 by mouth once daily for 4 weeks. Second cohort may receive up to and including 20 mg of FTX-6058 by mouth once daily for 4 weeks depending on the Data Monitoring Committee [DMC] review. A third cohort may be added based on the safety and pharmacokinetic data observed in subjects from the prior and ongoing cohorts. Up to 10 subjects will be enrolled in each treatment arm.
Part B is the extension study. Eligible subjects who consent to continue in the extension study will continue on treatment at the same dose level selected in Part A for an additional 8 weeks. Subjects who decline to participate in the extension study will be followed for an additional 2-3 weeks.
The primary endpoints of the study are to evaluate the safety and tolerability of FTX-6058 as measured by the frequency of adverse events and to evaluate single and multiple-dose pharmacokinetics of FTX-6058 in subjects with sickle cell disease. Secondary endpoints include evaluating the effect of FTX-6058 on fetal hemoglobin induction in peripheral blood in subjects with sickle cell disease.
Inclusion Criteria
- Subject is 18 to 65 years of age, inclusive at the time informed consent is obtained.
- Subject has signed and dated informed consent form (ICF) before any study-specific procedures are performed and is willing and able to comply with the study procedures and restrictions.
- Subjects, who if female and of childbearing potential, agree to use 2 highly effective methods of contraception or practicing abstinence starting at the time of the ICF signing to 90 days after the last dose of study drug, and, who if male, agree to use 2 methods of contraception or practice abstinence from the time of ICF signing to 90 days after the last dose of study drug.
- Body mass index between 18 and 32 kg/m2, inclusive at screening, and with a minimum weight of 50 kg.
- Documented SCD at the time of screening (S/S, S/β0 and S/β+ genotypes only) as confirmed through review of medical record or HPLC.
- If on hydroxyurea (HU) at time of first dose of study drug, a stable dose for a minimum of 3 months is required. If not on HU at time of first dose of study drug, the subject must have been off HU for a minimum of 60 days.
- Documented HbF ≤ 20% of total Hb as confirmed through review of medical records or HPLC). If from medical record review, the value must be within the past 12 months.
- SCD characterized by both of the following: Total hemoglobin ≥ 5.5 g/dL and ≤ 12 g/dL (males) or ≤ 10.6 g/dL (females) at screening 0-6 Vaso-Occlusive Crisis (VOC) episodes over the 12 months prior to screening. A VOC is defined as any event that requires an acute care visit for IV fluid or IV opioid administration.
- Subject must meet both of the following laboratory values prior to Week 1 Day 1: Absolute neutrophil count ≥ 1.5 × 109/L; Platelets ≥ 80 × 109/L.
Exclusion Criteria
- Major surgery, hospitalization, infection, fever, significant bleeding, cerebrovascular accident or seizure, or transfusion within 14 days prior to study enrollment through conclusion of study follow-up period; elective surgery planned for the time period of the trial.
- Sickle cell complication requiring hospitalization in the past 14 days or > 6 total VOCs over the past 12 months requiring hospitalization for ≥ 24 hours.
- Use of voxelotor within 60 days prior to starting study drug.
- Use of anticoagulants, L-glutamine, crizanlizumab, or medications that induce or inhibit cytochrome P4503A4 (CYP3A4) within 14 days prior to first dose of study drug or anticipated need for any of these medications during the study. (Refer to Protocol Section 7.2 and Appendix 3).
- Participation in any other investigative treatment studies other than with FTX-6058 within the past 60 days.
- History of bone marrow transplant or human stem cell transplant or gene therapies.
- Vaccination (including against COVID-19) in the previous 30 days.
- Alanine aminotransferase ≥ 3× the upper limit of normal (ULN), albumin < 2.0 mg/dL, direct (conjugated) bilirubin ≥ 1.5 mg/dL, or prothrombin time > 1.5 ULN.
- Subjects with a history of severe renal disease defined as estimated glomerular filtration rate < 30 mL/min/1.73m2. Subjects on dialysis of any kind are excluded.
- Subjects with abnormal laboratory results or medical history indicative of any significant medical disease that, in the opinion of the Investigator, would preclude the subject's participation in the study or potentially obscure the interpretation of the scheduled assessments. Screening laboratory assessments may be repeated up to twice at the discretion of the Investigator.
- Subjects being treated with antiretroviral agents (such as didanosine and stavudine) because of a higher risk for potentially fatal pancreatitis, hepatic failure, hepatitis, and severe peripheral neuropathy when co-administered with HU.
- Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C such that subjects are currently on therapy or will be placed on therapy during the trial.
- Subjects receiving regularly scheduled transfusions to reduce levels of sickle hemoglobin, or any subject who has been transfused in the last 60 days.
- Clinically diagnosed substance use disorder for alcohol or other illicit drugs of abuse. A positive urine drug screen for illicit drugs of abuse (other than opioids and marijuana/ tetrahydrocannabinol [THC]/ cannabidiol [CBD]) is exclusionary.
- Pregnant or lactating female; or female of childbearing age unable or unwilling to comply with birth control or abstinence during the course of the study. (Refer to Protocol Section 7.3).
- Febrile illness in the 7 days prior to baseline visit.
- Subject is investigative site personnel or member of their immediate family (spouse, parent, child or sibling whether biological or legally adopted).
- Heart rate corrected QT interval-Frederica's method (QTcF) > 450 msec male or > 470 msec female.
Data taken from the site clinicaltrials.gov
Sign Up to Be a Volunteer