Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, Gene therapy, Lentiviral vector, Vaso-occlusive events, CD34+ hematopoietic stem cells, Hematopoietic stem cells transplantation
Brief summary
The purpose of this study is to evaluate the Safety and Efficacy of DREAM01, a gene therapy for Sickle Cell Disease (SCD). The therapy consists of transplanting autologous CD34+ cells transduced ex vivo with a bifunctional lentiviral vector expressing βAS3m-globin and an anti-βS miRNA. It aims to reduce or eliminate vaso-occlusive events and long-term organ damage in severe SCD patients lacking a Human Leukocyte Antigen (HLA) identical sibling donor.
Detailed description
Sickle cell anaemia is a hereditary disease caused by a mutation in the gene for beta haemoglobin, essential for oxygen transport by red blood cells. This genetic mutation causes a deformation of the red blood cells, giving them a crescent shape (also known as a sickle) and leading to their massive destruction, resulting in anaemia. Other serious consequences are linked to this disease, such as recurrent painful obstructive crises, known as vaso-occlusive crises (VOC), as well as strokes, acute respiratory syndromes (ARS) and multi-organ damage. All these complications are linked to the obstruction of capillaries caused by deformed red blood cells. Management of the disease consists of regular transfusions of healthy red blood cells and/or specific drug therapy such as hydroxyurea (HU). HU increases the production of foetal haemoglobin, which can prevent the deformation of red blood cells characteristic of sickle cell disease. By reducing the number of sickle-shaped red blood cells, hydroxyurea helps reduce the frequency of painful attacks and other complications associated with the disease. During these painful attacks, deformed red blood cells block small blood vessels, leading to intense pain and organ damage. These treatments help prevent the risks associated with the disease, but also entail transfusion-related risks (immunological response that may prevent the necessary transfusion). The only curative treatment to date is a bone marrow transplant from a compatible sibling donor. Bone marrow contains stem cells capable of producing blood cells (red blood cells, white blood cells and platelets) throughout an individual's life. Unfortunately, this treatment is only available for 25% of patients, and is associated with significant immunological complications caused by the white blood cells present in the graft (graft-versus-host disease) or risk of rejection (if partially compatible donor). The aim of this study is to treat patients with severe sickle cell disease with a new experimental gene therapy treatment. This is a new therapeutic approach for patients without a compatible donor, and patients will be followed for 2 years.
Interventions
GENETICDREAM01 drug product
Each patient will receive a single IV infusion of DREAM01, autologous CD34+ stem cells transduced with βAS3m/miR7m lentiviral vector
DRUGanti-inflammatory therapy
Patient will receive anti-inflammatory therapy if necessary
Sponsors
Assistance Publique - Hôpitaux de Paris
Imagine Institute
URC-CIC Paris Descartes Necker Cochin
Association Française contre les Myopathies (AFM), Paris
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Age 12 - 35 years * Acceptation of myelogram (bone marrow aspiration) * Diagnosis of HbSS by Hb electrophoresis and genetic analysis to analyse the alpha locus * Clinical history or ongoing evidence of severe sickle cell anemia with one OR more of the following clinical complications demonstrating disease severity: * At least 3 vaso-occlusive crises requiring hospitalization, under hydroxyurea or transfusion, within 2 years prior to enrolment * One severe acute chest syndrome (ACS) hospitalized in the intensive care unit * At least 2 episodes of ACS, including one under HU. * Acute priapism (at least 2 episodes \>3h in the preceding year or in the year prior to the start of a regular transfusion program), OR stuttering priapism ≥ 1 by week under sickle cell treatment (HU, transfusion or phlebotomy). * Tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph without pulmonary hypertension confirmed by right heart catheterization (mPAP\>\<25mmHg) * Failed hydroxyurea (HU) therapy, OR Inadequate clinical response to HU, defined as any one of the following outcomes, while on HU for at least 3 months: 2 or more acute sickle pain crisis requiring hospitalization, requirement of transfusion to maintain Hb \>6.0g/dL, an episode of ACS despite adequate supportive care measures * Karnovsky/Lansky performance score ≥ 60% * Sexually active patients must be willing to use an acceptable method of double-barrier contraception for at least 12 months post-infusion (beyond 12 months at the discretion of the investigator) * Procedure for obtaining consent (adults, dependent minors, to give their consent) * Affiliation to social security
Exclusion criteria
* Existence of a matched sibling donor * Based on myelogram, the presence of chromosomal (detected by karyotyping) or molecular abnormalities (detected by NGS) and retained dangerous by the Hemato-Oncology referent and validated during a specific multidisciplinary concerted meeting * Hematologic evaluation: Leukopenia (WBC \<3,000/µL) or neutropenia (ANC \<1,000/µL) or thrombocytopenia (platelet count \<100,000/µL) within 90 days prior to mobilization or harvest (not due to an erythrapheresis procedure or possible acute viral infection) * PT/INR or PTT \>1.5 times the upper limit of normal (ULN) or clinically significant bleeding disorder * Two alpha deletions (risk of alpha-thalassemia after gene therapy) * Hypersensitivity to the active substances of the administered drugs (plerixafor, busulfan, anti-inflammatory therapy) or to any of their excipients * Patients who have already been treated with gene therapy Evaluations within 6 months prior to screening visit: * ALT or AST \>3 times ULN * Severe liver iron overload evaluated by MRI (\>15mg Fe/g dry weight or \>270umol Fe/g dry weight) or liver cirrhosis suspicion on echography or elastometry or CT scan or MRI AND confirmed by histology * Measured GFR \<60ml/min/1.73 m² * Cardiac evaluation: LVEF \<40% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities * Stroke with significant CNS sequelae i.e., Rankin \>2 * Specific sickle cell disease cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) OR transcranial doppler ultrasound with or without Moya-moya WITH an indication of chronic transfusion program (target HbS\<30%) * Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO less than 60% at steady state * Confirmed pulmonary hypertension defined by a right heart catheterization (PAPm \>25 mmHg). Right heart catheterization is required if tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph OR \>2.5m/s with an abnormal Brain Natriuretic Peptide dosage or an important decrease in transcutaneous Hb O2 saturation during the 6 minutes' walk test. * Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV or parvovirus B19, based on positive blood PCR. * Pregnancy or breastfeeding in a postpartum female * Any current cancer or prior history of a malignant disease, with the exception of curatively treated non-melanoma skin cancer * Immediate family member with an established or suspected Familial Cancer Syndrome * Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study * Patients who failed previous HSCT * Any clinically significant active infection * Participation in another clinical study with an investigational drug within 30 days of screening * Any condition, based on perspective of the medical monitor and treating investigator, which may lead to increased safety risk or inability to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neutrophil recovery | within the 24 months following IV infusion of DREAM01 | Neutrophil recovery defined as the first of three consecutive days with an ANC of \> 500/µL |
| Platelet recovery | within the 24 months following IV infusion of DREAM01 | Platelet recovery defined as the first of three consecutive days with a platelet count of \> 20.000/µL sustained without platelet transfusion for at least seven days |
| In vivo engraftment (neutrophils and platelets) | every 3 months between 3 to 24 months following IV infusion of DREAM01 | hematopoietic reconstitution after IV infusion of the drug product |
| Adverse event | within the 24 months following IV infusion of DREAM01 | Adverse event will be measured using CTCAE |
| Transplant-related mortality (TRM) | within 100 days following IV infusion of DREAM01 | Transplant-related mortality |
| All-cause mortality | Up to the 24 months following IV infusion of DREAM01 | Mortality |
| Efficacy of DREAM01 | between 3 and 15 months following IV infusion of DREAM01 | absence of vaso-occlusive events (VOE) in patients who have discontinued the transfusion program or/and hydroxyurea |
| Efficacy of anti-inflammatory therapy | within the 3 months following administration of anti-inflammatory therapy | Decrease of HSPCs inflammation assessed through a reduction of the score and/or the number of inflammatory pathways (among the 6 pathways established) by transcriptomic analysis on HSPCs between inclusion and after 3 months of anti-inflammatory therapy treatment before infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized rate of VOE | Up to the 24 months following IV infusion of DREAM01 | Proportion of subjects with reduction in annualized rate of VOE at the time of analysis from baseline by at least 90% up to 24 months after DREAM01 infusion |
| Transfusion requirement | Up to the 24 months following IV infusion of DREAM01 | Number of transfusion requirement |
| Change in number of units of RBCs transfused | Up to the 24 months following IV infusion of DREAM01 | change in number of units of RBCs transfused for SCD-related indications over time |
| Percentage of HbAS3 | Up to the 24 months following IV infusion of DREAM01 | Measure of HbAS3 |
| Percentage of HbS | Up to the 24 months following IV infusion of DREAM01 | Measure of Measure of HbS |
| Quantification of the transgene copy number (VCN) | Up to the 24 months following IV infusion of DREAM01 | Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells |
| Rate of hemolysis | Up to the 24 months following IV infusion of DREAM01 | Biological parameters that reflect hemolysis : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO |
| Rate of anemia | Up to the 24 months following IV infusion of DREAM01 | Biological parameters that reflect anemia : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO |
| Changes in brain function | Up to the 24 months following IV infusion of DREAM01 | Occurrence of ischemic lesions, vascular stenosis, aneurysm assessed using cervical doppler ultrasound and cerebral MRI |
| Changes in ocular function | Up to the 24 months following IV infusion of DREAM01 | Assessed Using Fundus examination |
| Changes in cardiac function | Up to the 24 months following IV infusion of DREAM01 | evaluated through electrocardiographic (ECG) assessment |
| Changes in the occurrence of left ventricular ejection fraction [LVEF] right and left atrial | Up to the 24 months following IV infusion of DREAM01 | Occurrence of left ventricular ejection fraction \[LVEF\], right and left atrial, left assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Changes in left ventricular size | Up to the 24 months following IV infusion of DREAM01 | Changes in left ventricular size assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Changes in left ventricular wall thickness | Up to the 24 months following IV infusion of DREAM01 | Changes in the left ventricular wall thickness assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Changes in systolic pulmonary artery pressure [sPAP] | Up to the 24 months following IV infusion of DREAM01 | Changes in systolic pulmonary artery pressure \[sPAP\], assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Changes in tricuspid regurgitation velocity [TRV] | Up to the 24 months following IV infusion of DREAM01 | Changes in tricuspid regurgitation velocity \[TRV\] assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Changes in E/A ratio | Up to the 24 months following IV infusion of DREAM01 | Changes in of E/A ratio assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Change in serum electrolyte panel | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in serum creatinine | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in estimated glomerular filtration rate (eGFR) | Up to the 24 months following IV infusion of DREAM01 | Renal function assessed through estimated glomerular filtration rate (eGFR) calculated using CKD-EPI equation |
| Change in urinary microalbumin | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in protein excretion | Up to the 24 months following IV infusion of DREAM01 | — |
| Changes in hepatic function | Up to the 24 months following IV infusion of DREAM01 | Description of hepatic morphology assessed through abdominal ultrasound |
| Change in diffusing capacity for carbon monoxide (DLCO) | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in vital capacity (VC) | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in residual volume (RV) | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in FEV1/FVC ratio (Tiffeneau index) | Up to the 24 months following IV infusion of DREAM01 | — |
| Changes in bone metabolism | Up to the 24 months following IV infusion of DREAM01 | Assessed through Osteodensitometry, osteoarticular MRI |
| Changes in muscular function | Up to the 24 months following IV infusion of DREAM01 | Assessed through physical capacity testing |
| Occurrence of iron overload | Up to the 24 months following IV infusion of DREAM01 | Efficacy |
| Fertility evaluation | Up to the 24 months following IV infusion of DREAM01 | Safety |
| Walk ability | Up to the 24 months following IV infusion of DREAM01 | 6-minute walk-test |
| Jump | Up to the 24 months following IV infusion of DREAM01 | Vertical jump test : The jump height will be recorded using video analysis software. The average height of the 3 jumps will be calculated |
| Cardiopulmonary capacity | Up to the 24 months following IV infusion of DREAM01 | Cardiopulmonary exercise test, using the Cardio Pulmonary Exercise Test |
| Physical ability | Up to the 24 months following IV infusion of DREAM01 | Physical ability questionnaire, using the Global physical activity questionnaire (GPAQ) (16 items) developed by WHO |
| Quality of life Evaluation : patient health | Up to the 24 months following IV infusion of DREAM01 | Medical Outcomes Study Short Form 36 SF-36 .The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health |
| Quality of life Evaluation : fatigue | Up to the 24 months following IV infusion of DREAM01 | FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale) FACIT-Fatigue is a 13-item self-report scale that assesses fatigue and its effect on daily activities and function. |
| Quality of life Evaluation : physical, mental, and social health | Up to the 24 months following IV infusion of DREAM01 | PROMIS (Patient-Reported Outcomes Measurement Information System) PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. |
| Health-realted Quality of life Evaluation | Up to the 24 months following IV infusion of DREAM01 | Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales PedsQL is a modular system that assesses health-related quality of life in healthy and ill children and adolescents. It combines generic core scales and disease-specific modules into one measurement system. |
| Change in urinary creatinine | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in hepatic function | Up to the 24 months following IV infusion of DREAM01 | Occurrence of fibrosis and cirrhosis assessed through Liver elastography |
| Changes in creatinine clearence | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in liver enzyme AST | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in liver enzyme ALT | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in liver enzyme GGT | Up to the 24 months following IV infusion of DREAM01 | — |
| Changes in in liver enzyme ALP | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in total bilirubin | Up to the 24 months following IV infusion of DREAM01 | — |
| Change in unconjugated (free) bilirubin | Up to the 24 months following IV infusion of DREAM01 | — |
Countries
France
Contacts
CONTACTMarina CAVAZZANA, MD, PhD
CONTACTNelly BRIAND, PhD
STUDY_DIRECTORElisa MAGRIN, PhD
Department of Biotherapy, Necker-Enfants Malades Hospital
Outcome results
None listed