FTX-6058 for Sickle Cell Disease
Recruiting in Palo Alto (17 mi)
+17 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Fulcrum Therapeutics
Must not be taking: Hydroxyurea, Voxelotor, Crizanlizumab
Disqualifiers: Severe renal disease, Active malignancy, others
No Placebo Group
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.
12345How 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.
678910Eligibility 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.
+8 more
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.
+3 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Pociredir oral capsule(s) in Sickle Cell participantsExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Virginia Commonwealth UniversityRichmond, VA
Lynn Health Science InstituteOklahoma City, OK
Leo W. Jenkins Cancer Center / East Carolina UniversityGreenville, NC
University of California, Los AngelesLos Angeles, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Fulcrum TherapeuticsLead Sponsor
References
Chemotherapy to increase fetal hemoglobin in patients with sickle cell anemia. [2019]The obvious beneficial effects of hemoglobin F on sickling have motivated numerous investigators to increase this type of hemoglobin artificially in patients with sickle cell anemia. Various chemotherapeutic agents including 5-azacytidine, hydroxyurea, and cytosine arabinoside, have been used successfully in patients. All of these drugs can increase the level of hemoglobin F in sickle cell anemia (SS) patients, but the kinetics and magnitude of the responses are highly individual and variable. The mechanism or mechanisms responsible for the increased synthesis of hemoglobin F remain unknown. Further controlled studies in a limited number of patients with severe sickle cell disease will be necessary in order to work out a rational, safe treatment program suitable for wider use.
Novel therapeutic approaches in sickle cell disease. [2019]In this update, selected clinical features of sickle cell disease and their management are reviewed. In addition, the current status of interventions that have curative potential for sickle cell disease is discussed, with particular attention focused on indications, methodology, recent results, and challenges to wider clinical application. In Section I, Dr. Nienhuis describes recent improvements in vector technology, safety, and replacement gene expression that are creating the potential for clinical application of this technology. In Section II, Dr. Vichinsky reviews our current understanding of the pathophysiology and treatment of pulmonary injury in sickle cell disease. The acute and chronic pulmonary complications of sickle cell disease, modulators and predictors of severity, and conventional and novel treatment of these complications are discussed. In Section III, Dr. Walters reviews the current status of hematopoietic cell transplantation for sickle cell disease. Newer efforts to expand its availability by identifying alternate sources of stem cells and by reducing the toxicity of transplantation are discussed.
Large-Scale Drug Screen Identifies FDA-Approved Drugs for Repurposing in Sickle-Cell Disease. [2020]Sickle-cell disease (SCD) is a debilitating hematological disorder with very few approved treatment options. Therapeutic reactivation of fetal hemoglobin (HbF) is one of the most pursued methods for ameliorating the systemic manifestations of SCD. Despite this, very few pharmacological agents have advanced to clinical trials or marketing for use. In this study, we report the development of an HbF in situ intracellular immunoblot assay coupled to a high-throughput drug screen to identify Food and Drug Administration (FDA) approved drugs that can be repurposed clinically for treatment of SCD. Using this assay we evaluated the National Institute of Health (NIH) Clinical Collection (NCC), a publicly available library of 725 small molecules, and found nine candidates that can significantly re-express HbF in erythroid cell lines as well as primary erythroblasts derived from SCD patients. Furthermore, we show the strong effects on HbF expression of these candidates to occur with minimal cytotoxicity in 7 of the 9 drugs. Given these data and their proven history of use for other indications, we hypothesize that several of these candidate drugs warrant further investigation for use in SCD.
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]We have studied the cellular and molecular responses to long-term hydroxyurea (HU) treatment in 29 severely affected young patients with sickle cell disease (mean age, 10.9 +/- 4.1 years). Patients received HU at 20 mg/kg/d on 4 consecutive days per week initially, with a monthly escalated dose avoiding marrow-toxicity (mean steady-state dose, 34.2 +/- 4.6 mg/kg/d) for 12 to 36 months (mean duration, 22 months). The studied parameters were hemoglobin F (HbF), F reticulocytes (F retics), F cells, the amount of HbF per F cell (F/F cell), polymer tendency at 40% and 70% oxygen saturation, and hemolysis. Initial HbF (Fi) was dispersed (from 0.85% to 13.9%). HbF increased in all patients but 1. HbF at maximal response (Fmax) reached a sustained level varying from a 1.5-fold to a 16-fold Fi after a variable delay (6 to 24 months). Fmax was not related to HU dosage, but triangle upF (Fmax - Fi) was strongly correlated to triangle upMCV (MCVmax - MCVi). HbF increase resulted from the increase of both F cells and F/F cell. In this rather short series, Fi and Fmax were not significantly associated with age, gender, or beta-globin haplotype. Neither Fmax nor triangle upF was related to bone marrow reserve, as measured by baseline reticulocyte or neutrophil counts. However, Fmax was highly dependent on Fi. When patients are individualized into three groups according to Fmax (group 1, Fmax >20% [12 patients]; group 2, 10%
Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework. [2022]Patients with sickle cell disease (SCD) have significant impairment in their quality of life across the life span as a consequence of serious disease burden with several SCD-related complications. A number of disease-modifying therapies are currently available, yet long-term clinical benefits in real-world settings remain unclear. Over the past few years, a number of important initiatives have been launched to optimize clinical trials in SCD in different ways, including: (1) established panels through a partnership between the American Society of Hematology (ASH) and the US Food and Drug Administration; (2) the ASH Research Collaborative SCD Clinical Trials Network; (3) the PhenX Toolkit (consensus measures for Phenotypes and eXposures) in SCD; and (4) the Cure Sickle Cell Initiative, led by the National Heart, Lung, and Blood Institute. Electronic patient-reported outcomes assessment is highly recommended, and patient-reported outcomes (PROs) should be evaluated in all SCD trials and reported using Standard Protocol Items Recommendations for Interventional Trials guidelines. Patient-centered outcomes research (PCOR) approaches and meaningful stakeholder engagement throughout the process have the potential to optimize the execution and success of clinical trials in SCD with considerable financial value. This article reviews several clinical trial considerations in SCD related to study design and outcomes assessment as informed by recent initiatives as well as patient-centered research approaches and stakeholder engagement. A proposed hematology stakeholder-engagement framework for clinical trials is also discussed.
Tumor necrosis factor-alpha is undetectable in the plasma of SS patients with elevated Hb F. [2019]Steady-state sickle cell disease (SCD) patients may have increased plasma levels of acute phase reactants and pro-inflammatory cytokines because of subclinical inflammation. We have estimated TNF-alpha levels in the plasma and in supernatants following peripheral blood mononuclear cell (PBMC) activation with phytohemagglutinin (PHA) in a group of Kuwaiti SCD patients using ELISA. The group consisted of 28 SS, 8 Sbeta-thal, and 2 SD patients all in steady state; 5 SS patients were studied during 7 episodes of painful crisis. The subjects were aged 2 to 16 years, with a mean of 7.3 +/- 3.5 years. The beta(S)-globin gene cluster haplotype, alpha-tha1 status, and spleen function were determined in the SS group using standard techniques. Most (82%) were homozygous for the Saudi Arabia/India haplotype and had elevated Hb F levels ranging from 15% to 35%. There were 24 controls (Hb AA or AS), of whom 14 were healthy and 10 were acutely ill at the time of the study. None of the children with SCD (either in steady state or crisis) had detectable plasma TNF-alpha, but four controls (3 acutely ill and one healthy) had levels ranging from 61.7 to 249.8 pg/mL. Following PHA stimulation most subjects responded with high levels of TNF-alpha, with the median level among the steady-state SS patients being significantly higher than that in the controls (both the acutely ill or healthy). It therefore appears that because of the mild disease among our Arab SS children, TNF-alpha is not detectable in their plasma in steady state; these children, however, had a significantly higher response than controls following PBMC activation.
Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. [2020]In this work we provide preclinical data to support initiation of a first-in-human trial for sickle cell disease (SCD) using an approach that relies on reversal of the developmental fetal-to-adult hemoglobin switch. Erythroid-specific knockdown of BCL11A via a lentiviral-encoded microRNA-adapted short hairpin RNA (shRNAmiR) leads to reactivation of the gamma-globin gene while simultaneously reducing expression of the pathogenic adult sickle β-globin. We generated a refined lentiviral vector (LVV) BCH-BB694 that was developed to overcome poor vector titers observed in the manufacturing scale-up of the original research-grade LVV. Healthy or sickle cell donor CD34+ cells transduced with Good Manufacturing Practices (GMP)-grade BCH-BB694 LVV achieved high vector copy numbers (VCNs) >5 and gene marking of >80%, resulting in a 3- to 5-fold induction of fetal hemoglobin (HbF) compared with mock-transduced cells without affecting growth, differentiation, and engraftment of gene-modified cells in vitro or in vivo. In vitro immortalization assays, which are designed to measure vector-mediated genotoxicity, showed no increased immortalization compared with mock-transduced cells. Together these data demonstrate that BCH-BB694 LVV is non-toxic and efficacious in preclinical studies, and can be generated at a clinically relevant scale in a GMP setting at high titer to support clinical testing for the treatment of SCD.
Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. [2022]Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises. It might also be expected to decrease the severity of anemia, although the pathogenesis of anemia in sickle cell anemia (SS disease) is not clearly understood. Reversion to production of fetal rather than adult hemoglobin became practical with the discovery that HU was an orally effective and relatively safe "switching agent." Preliminary dose-ranging studies led to a double-blind randomized controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), designed to test whether patients treated with HU would have fewer crises than patients treated with placebo. The MSH was not designed to assess the mechanism(s) by which a beneficial effect might be achieved, but it was hoped that observations made during the study might illuminate that question. The 2 MSH treatment groups were similar to each other and were representative of African-American patients with relatively severe disease. The trial was closed earlier than expected, after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and numbers of transfusions were also lower in patients treated with HU. Eight patients died during the trial, and treatment was stopped in 53. There were no instances of alarming toxicity. Patients varied widely in their maximum tolerated doses, but it was not clear that all were taking their prescribed treatments. When crisis frequency was compared with various clinical and laboratory measurements, pretreatment crisis rate and treatment with HU were clearly related to crisis rate during treatment. Pretreatment laboratory measurements were not associated with crisis rates during the study in either treatment group. It was not clear that clinical improvement was associated with an increase in Hb F. Crisis rates of the 2 treatment groups became different within 3 months. Mean corpuscular volumes (MCVs) and the proportion of Hb F containing red cells (F cells) rose, and neutrophil and reticulocyte counts fell, within 7 weeks. When patients were compared on the basis of 2-year crisis rates, those with lower crisis rates had higher F-cell counts and MCVs and lower neutrophil counts. Neutrophil, monocyte, reticulocyte, and platelet counts were directly associated, and F cells and MCV were inversely associated, with crisis rates in 3-month periods. In multivariable analyses, there was strong evidence of independent association of lower neutrophil counts with lower crisis rates. F-cell counts were associated with crisis rate only in the first 3 months of treatment; MCV showed an association over longer periods of time. Overall, the evidence that decreased neutrophil counts played a role in reducing crisis rates was strong. Increased F cells or MCV and evidence of cytoreduction by HU were also associated with decreased crisis rates, but no definitive statement can be made regarding the mechanism of action of HU because the study was not designed to address that question. Future studies should be designed to explore the mechanism of action of HU, to identify the optimal dosage regimen, and to study the effect of HU when combined with other antisickling agents.
Tenofovir disoproxil fumarate induces fetal hemoglobin production in K562 cells and β-YAC transgenic mice: A therapeutic approach for γ-globin induction. [2021]Pharmacologic induction of fetal hemoglobin (HbF) is an effective strategy for treating β-hemoglobinopathies like β-thalassemia and sickle cell anemia by ameliorating disease severity. Hydroxyurea is the only FDA-approved agent that induces HbF, but significant nonresponders and toxicity limit its clinical usefulness. This study relates preclinical investigation of Tenofovir disoproxil fumarate (TDF) as a potential HbF inducing agent, using human erythroleukemia cell line and a β-YAC mouse model. Erythroid induction of K562 cells was studied by the benzidine/H2O2 reaction, total hemoglobin production was estimated by plasma hemoglobin assay kit, and γ-globin gene expression by RT-qPCR, whereas, fetal hemoglobin production was estimated by flow cytometry and immunofluorescence microscopy. We observed significantly increased γ- globin gene transcription and HbF expression mediated by TDF in K562 cells. Subsequent treatment of β-YAC transgenic mice with TDF confirmed HbF induction in vivo through an increase in γ-globin gene expression and in the percentage of HbF positive red blood cells. Moreover, TDF showed no cytotoxic effect at HbF inducing concentrations. These data support the potential development of TDF for the treatment of hematological disorders, including β-thalassemia and sickle cell anemia.
Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. [2019]Sickle-cell disease affects millions of individuals worldwide, but the global incidence is concentrated in Africa. The burden of sickle-cell disease is expected to continue to rise over the coming decades, adding to stress on the health infrastructures of many countries. Although the molecular cause of sickle-cell disease has been known for more than half a century, treatment options remain greatly limited. Allogeneic haemopoietic stem-cell transplantation is the only existing cure but is limited to specialised clinical centres and remains inaccessible for most patients. Induction of fetal haemoglobin production is a promising strategy for the treatment of sickle-cell disease. In this Series paper, we review scientific breakthroughs in epidemiology, genetics, and molecular biology that have brought reactivation of fetal haemoglobin to the forefront of sickle-cell disease research. Improved knowledge of the regulation of fetal haemoglobin production in human beings and the development of genome editing technology now support the design of innovative therapies for sickle-cell disease that are based on fetal haemoglobin.