FTX-6058 for Sickle Cell Disease

Recruiting at 16 trial locations

Overseen By Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fulcrum Therapeutics

Must not be taking: Hydroxyurea, Voxelotor, Crizanlizumab

Disqualifiers: Severe renal disease, Active malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 89

Duration: 12 weeks

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of Pociredir in participants with sickle cell disease.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking certain medications before joining the trial. Specifically, you must stop taking voxelotor and crizanlizumab at least 60 days before starting the study drug, and L-glutamine at least 24 hours before.

What data supports the effectiveness of the drug FTX-6058 for Sickle Cell Disease?

Research shows that increasing fetal hemoglobin (a type of hemoglobin present in fetuses) can help manage sickle cell disease. Some drugs have been successful in raising fetal hemoglobin levels, which may reduce the symptoms of sickle cell disease. Although FTX-6058 is not specifically mentioned, similar approaches have shown promise in treating this condition. ^{1 2 3 4 5}

How does the drug FTX-6058 differ from other treatments for sickle cell disease?

FTX-6058 is unique because it targets the reactivation of fetal hemoglobin (HbF), which can reduce the severity of sickle cell disease by diluting the sickling hemoglobin. This approach is different from traditional treatments like hydroxyurea, which also induces HbF but can have significant side effects and nonresponders. ^{6 7 8 9 10}

Research Team

Adeyemi Adenola, MD

Principal Investigator

Fulcrum Therapeutics

Eligibility Criteria

Adults aged 18-65 with sickle cell disease (SCD), specific genotypes, and low fetal hemoglobin can join. They must have had multiple SCD complications despite treatment with drugs like Hydroxyurea or be ineligible for chronic transfusions due to side effects.

Inclusion Criteria

Total Hb ≥ 5.5 g/dL and ≤ 12 g/dL (males) or ≤ 10.6 g/dL (females) at screening

Documented HbF ≤ 20% of total Hb

I've been on voxelotor, crizanlizumab, or L-glutamine for 6 months without improvement or couldn't tolerate them.

Exclusion Criteria

I needed medical care for a sickle cell complication within the last 14 days.

I do not have severe kidney disease or require dialysis.

I am currently taking or have taken HU, voxelotor, crizanlizumab, or L-glutamine in the last 60 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pociredir for 12 weeks with varying doses across cohorts

12 weeks

Visits on Days 1, 14, 28, 42, 56, 70, 84

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Visits on Days 88, 91, and 112

Treatment Details

Interventions

• FTX-6058

Trial Overview The trial is testing FTX-6058 oral capsules to see if they're safe and how they affect the body in people with SCD. It looks at how the drug moves through and out of the body, as well as its impact on disease factors.

Participant Groups

Group I: Pociredir oral capsule(s) in Sickle Cell participants Experimental Treatment 1 Intervention

Cohort 1 will receive 6 mg of Pociredir by mouth once daily. Cohort 2 will be dosed at 2 mg once daily by mouth, and cohort 3 will be dosed at 12 mg once daily by mouth. The Sponsor will reinitiate enrolment in the 3rd cohort (12 mg cohort) with the updated inclusion and exclusion criteria. Based on review of available safety and biomarker data and with the recommendation of the DMC, a subsequent 4th cohort of 20 mg and potentially a 5th cohort of 30 mg may be initiated. A total of seven cohorts may be included. Following the first cohort, doses for all subsequent cohorts will be determined following DMC review of the safety and pharmacokinetic data observed in participants from the prior and ongoing cohorts. Alternate dosing schedules may be evaluated in some of the cohorts.

Who Is Running the Clinical Trial?

Fulcrum Therapeutics

Lead Sponsor

Trials

8

Recruited

680+

Headquarters

Cambridge, United States

Findings from Research

Chemotherapeutic agents like 5-azacytidine, hydroxyurea, and cytosine arabinoside can successfully increase levels of hemoglobin F in patients with sickle cell anemia, which is beneficial for reducing sickling.

The response to these treatments varies greatly among individuals, and the exact mechanisms behind the increase in hemoglobin F are still not fully understood, indicating a need for further controlled studies to develop safe and effective treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy to increase fetal hemoglobin in patients with sickle cell anemia. Platt, OS.[2019]

Recent advancements in vector technology are enhancing the safety and effectiveness of gene therapy for sickle cell disease, potentially leading to more successful clinical applications.

Hematopoietic cell transplantation is being improved by exploring alternative stem cell sources and reducing treatment toxicity, which may increase its accessibility for patients with sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic approaches in sickle cell disease. Walters, MC., Nienhuis, AW., Vichinsky, E.[2019]

A new high-throughput drug screening method identified nine FDA-approved drugs that can significantly increase fetal hemoglobin (HbF) levels in both erythroid cell lines and primary erythroblasts from sickle-cell disease (SCD) patients.

Seven out of the nine candidate drugs showed strong HbF expression effects with minimal cytotoxicity, suggesting they could be safely repurposed for treating SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large-Scale Drug Screen Identifies FDA-Approved Drugs for Repurposing in Sickle-Cell Disease. Cannon, M., Phillips, H., Smith, S., et al.[2020]

Long-term treatment with hydroxyurea (HU) in 29 young patients with sickle cell disease led to a significant increase in fetal hemoglobin (HbF) levels, with most patients showing a sustained increase after 6 to 24 months of treatment.

The effectiveness of HU treatment was not directly related to the dosage but was strongly correlated with the initial HbF levels, indicating that patients with higher initial HbF levels had better responses to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients. The French Study Group on Sickle Cell Disease. Maier-Redelsperger, M., de Montalembert, M., Flahault, A., et al.[2021]

Patients with sickle cell disease (SCD) experience significant quality of life impairments due to the disease's complications, highlighting the need for effective disease-modifying therapies.

Recent initiatives, such as the ASH Research Collaborative SCD Clinical Trials Network and the Cure Sickle Cell Initiative, aim to improve clinical trial designs and patient-centered outcomes, emphasizing the importance of patient-reported outcomes in evaluating treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework. Badawy, SM.[2022]

In a study of 38 Kuwaiti children with steady-state sickle cell disease (SCD), plasma levels of TNF-alpha were undetectable, suggesting low systemic inflammation in these patients.

However, when their immune cells were activated, the sickle cell patients showed significantly higher TNF-alpha responses compared to controls, indicating a heightened inflammatory response upon stimulation despite the absence of detectable levels in their plasma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor necrosis factor-alpha is undetectable in the plasma of SS patients with elevated Hb F. Raghupathy, R., Haider, MZ., Azizieh, F., et al.[2019]

The BCH-BB694 lentiviral vector effectively reactivates fetal hemoglobin production while reducing harmful adult sickle hemoglobin in sickle cell disease, showing a 3- to 5-fold increase in fetal hemoglobin levels in transduced cells.

Preclinical studies indicate that BCH-BB694 is non-toxic and can be produced at a clinically relevant scale, supporting its potential for safe and effective use in human trials for treating sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Brendel, C., Negre, O., Rothe, M., et al.[2020]

In a double-blind randomized controlled trial involving patients with sickle cell anemia, treatment with hydroxyurea (HU) reduced the median frequency of painful crises by nearly 50% compared to placebo, indicating its efficacy in managing the disease.

The study found that lower neutrophil counts were strongly associated with reduced crisis rates, suggesting that HU may work by decreasing inflammation and improving blood flow, although the exact mechanism of action remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Charache, S., Barton, FB., Moore, RD., et al.[2022]

Tenofovir disoproxil fumarate (TDF) has been shown to significantly increase fetal hemoglobin (HbF) levels and γ-globin gene expression in both human cell lines and a mouse model, suggesting its potential as a treatment for β-hemoglobinopathies like β-thalassemia and sickle cell anemia.

Importantly, TDF demonstrated no cytotoxic effects at the concentrations required to induce HbF, indicating a safer alternative to existing treatments like hydroxyurea, which has limitations due to toxicity and nonresponse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tenofovir disoproxil fumarate induces fetal hemoglobin production in K562 cells and β-YAC transgenic mice: A therapeutic approach for γ-globin induction. Khan, F., Ali, H., Musharraf, SG.[2021]

Sickle-cell disease, primarily affecting individuals in Africa, has limited treatment options, with allogeneic stem-cell transplantation being the only cure, but it is not accessible to most patients.

Recent advancements in understanding fetal haemoglobin production and genome editing technologies offer promising new therapeutic strategies for sickle-cell disease, potentially leading to innovative treatments that could improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. Lettre, G., Bauer, DE.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Chemotherapy to increase fetal hemoglobin in patients with sickle cell anemia. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Novel therapeutic approaches in sickle cell disease. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Large-Scale Drug Screen Identifies FDA-Approved Drugs for Repurposing in Sickle-Cell Disease. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients. The French Study Group on Sickle Cell Disease. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Tumor necrosis factor-alpha is undetectable in the plasma of SS patients with elevated Hb F. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Tenofovir disoproxil fumarate induces fetal hemoglobin production in K562 cells and β-YAC transgenic mice: A therapeutic approach for γ-globin induction. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. [2019]