A Study Evaluating the Safety and Efficacy of EDIT-301 in Participants With Severe Sickle Cell Disease (RUBY)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy, safety and tolerability of treatment with EDIT-301 in adult participants with severe sickle cell disease (SCD).

Detailed Description
-----------------
This is a Phase 1/2 single-arm, open-label, multicenter study evaluating the safety and efficacy of a single unit dose of EDIT-301 for autologous hematopoietic stem cell transplant (HSCT) in subjects with severe SCD. Planned study subjects will be comprised of male and female adult subjects with severe SCD, from 18 to 50 years of age, inclusive.

Official Title
-----------------
A Phase 1/2 Study to Evaluate the Safety and Efficacy of a Single Dose of Autologous Clustered Regularly Interspaced Short Palindromic Repeats Gene-edited CD34+ Human Hematopoietic Stem and Progenitor Cells (EDIT-301) in Subjects With Severe Sickle Cell Disease

Conditions
-----------------
Sickle Cell Disease, Hemoglobinopathies

Intervention / Treatment
-----------------
* Genetic: EDIT-301


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Diagnosis of severe sickle cell disease as defined by: Documented severe SCD genotype (βS/βS, βS/β0, or βS/β+) History of at least two severe vaso-occlusive crisis events per year requiring medical attention despite hydroxyurea or other supportive care measures in the two year-period prior to provision of informed consent Karnofsky Performance Status ≥ 80 Key Exclusion Criteria: Available 10/10 HLA-matched related donor Prior HSCT or contraindications to autologous HSCT Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells (HSCs) and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients Unable to receive red blood cell (RBC) transfusion for any reason Unable or unwilling to comply with standard of care changes in background medical treatment in preparation of, during, or following HSCT, including and not limited to discontinuation of hydroxyurea, voxelotor, crizanlizumab, or L-glutamine Any history of severe cerebral vasculopathy Inadequate end organ function Advanced liver disease Any prior or current malignancy or immunodeficiency disorder Immediate family member with a known or suspected Familial Cancer Syndrome Clinically significant and active bacterial, viral, fungal, or parasitic infection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EDIT-301<br>EDIT-301 (autologous gene edited (CD)34+ hematopoietic stem cells) will be administered as a one-time intravenous infusion. | Genetic: EDIT-301<br>* Administered by IV infusion after myeloablative conditioning with busulfan.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving complete resolution of severe vaso-occlusive events (VOEs) |  | up to 2 years post EDIT-301 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete resolution of severe VOE |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in annualized rate of severe VOE by at least 90% |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in annualized rate of severe VOE by at least 75% |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in annualized rate of severe VOE by at least 50% |  | up to 2 years post EDIT-301 infusion | 
| Difference (pre-treatment vs. post-treatment) in annualized rates of severe VOEs |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in annualized rate of hospitalization for severe VOE |  | up to 2 years post EDIT-301 infusion | 
| Proportion of subjects with sustained HbF ≥ 20% (HbF/Hb) compared with pre-conditioning Baseline |  | up to 2 years post EDIT-301 infusion | 
| Proportion of subjects with mean HbF ≥ 30% (HbF/Hb) compared with pre-conditioning Baseline |  | up to 2 years post EDIT-301 infusion | 
| Proportion of subjects with mean total Hb ≥ 10 g/dL compared with Baseline |  | up to 2 years post EDIT-301 infusion | 
| Proportion of subjects with mean total Hb increase from baseline ≥ 2 g/dL |  | up to 2 years post EDIT-301 infusion | 
| Difference (pre-treatment versus post-treatment) in annualized number of units of pRBC transfused for SCD-related indications |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in HbF concentration (g/dL) |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in total Hb concentration (g/dL) |  | up to 2 years post EDIT-301 infusion | 
| Change from baseline in markers of hemolysis (reticulocyte count, indirect bilirubin, lactate dehydrogenase, haptoglobin) |  | up to 2 years post EDIT-301 infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anemia, Anemia, Sickle Cell, Anemia, Hemolytic, Congenital, Anemia, Hemolytic, Genetic Diseases, Inborn, Cell Disorders, Sickle, HbS Disease, Sickling Disorder Due to Hemoglobin S, Hematologic Diseases