Gene Correction in Autologous CD34+ Hematopoietic Stem Cells (HbS to HbA) to Treat Severe Sickle Cell Disease

Study Overview
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Brief Summary
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This study is a first-in-human, single-arm, open-label Phase I/II study of GPH101 in approximately 15 participants, diagnosed with severe Sickle Cell Disease. The primary objective is to evaluate safety of the treatment in this patient population, as well as preliminary efficacy and pharmacodynamic data.

Detailed Description
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Participants diagnosed with severe SCD will receive GPH101 via IV infusion following myeloablative conditioning in an autologous HSCT setting.

Official Title
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A Phase I/II Study of GPH101 in Autologous CD34+ Hematopoietic Stem Cells to Convert HbS to HbA for Treating Severe Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Genetic: GPH101 Drug Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥12 to ≤ 40 years Severe disease, as defined by having experienced at least one of the following SCD-related events despite appropriate supportive care measures: recurrent severe VOC (≥ 4 episodes in the preceding 2 years) ACS (≥ 2 episodes in the prior 2 years with at least one episode in the past year) Lansky/Karnofsky performance status of ≥ 80 Exclusion Criteria: Available 10/10 HLA-matched sibling donor Prior HSCT or gene therapy Prior or current malignancy or myeloproliferative or a significant coagulation or immunodeficiency disorder Clinically significant and active bacterial, viral, fungal or parasitic infection Pregnancy or breastfeeding in a postpartum female Presence of a chromosomal abnormality/mutation that may put the participant at an increased risk for MDS or AML per investigator's judgment

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GPH101 Drug Product<br>GPH101 Drug Product is a human autologous CRISPR-Cas9 edited and sickle mutation-corrected HSPC product. | Genetic: GPH101 Drug Product<br>* GPH101 is administered via IV infusion following a myeloablative conditioning regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who reach neutrophil engraftment |  | 42 days post-infusion | 
| Incidence rate of treatment-related mortality |  | 100 days post-infusion | 
| Incidence rate of treatment-related mortality |  | 12 months post-infusion | 
| Overall survival |  | 24 months post-infusion | 
| Frequency and severity of AEs/SAEs |  | 24 months post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neutrophil engraftment |  | through study completion, up to 24 months post-infusion | 
| Time to platelet engraftment |  | through study completion, up to 24 months post-infusion | 
| Evaluation of gene correction levels in peripheral myeloid cells |  | through study completion, up to 24 months post-infusion | 
| Evaluation of adult Hgb as a percentage of total Hgb |  | through study completion, up to 24 months post-infusion | 
| Evaluation of HbS as a percentage of total Hgb |  | through study completion, up to 24 months post-infusion | 
| Total Hgb without disease-indicated transfusion support |  | through study completion, up to 24 months post-infusion | 
| Change in annualized packed red blood cell (pRBC) transfusion requirements (volume and frequency) for SCD indications |  | through study completion, up to 24 months post-infusion | 
| Proportion of participants with complete resolution of severe vaso-occlusive crises (sVOCs) |  | over time, from 6 months to 18 months post-infusion | 
| Incidence rate of any sVOCs |  | over time, from 6 months to study completion, up to 24 months post-infusion | 
| Proportion of participants achieving HbS <50% for at least 3 months |  | through study completion, up to 24 months post-infusion | 
| Evaluation of globin chain expression compared to baseline |  | through study completion, up to 24 months post-infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease, sickle cell anemia, gene correction, gene therapy, CRISPR