Curative Therapies for Patients with Sickle Cell Disease: �A New Era

Christopher McKinney, MD

Associate Professor of Pediatrics

Director, Pediatric Sickle Cell Program

Children’s Hospital Colorado

Disclosures

• I have no conflicts of interest to disclose.

Objectives

• Discuss the genetics, pathophysiology and clinical complications of sickle cell disease
• Understand the limitations of medical management in patients with sickle cell disease
• Describe the historical development of curative strategies culminating in wider availability of these therapies
• Review the efficacy and safety data of haploidentical allogeneic transplant and autologous gene therapies.
• Preview continuing needs and future directions.

Molecular Basis of Beta Globin Disorders

Sickle Cell Disease

Kato et al, Nature Reviews Disease Primers 2018

Dworkis et al. Metabolism of Human Diseases 2014

Mortality

Advances in Sickle Cell Disease Therapies

1910

Sickle red blood cells first discovered under microscope

1951-1956

Abnormal hemoglobin structure identified in patients with SCD and DNA substitution identified

1998

Hydroxyurea approved by FDA for use in adults with SCD

2011

BABY HUG Study: Hydroxyurea improves outcomes in children

2018

L-glutamine approved by FDA;

NIH Cure Sickle Cell Initiative

2019

Voxelotor and Crizanlizumab approved by FDA

What about curative therapy?

2000

First umbilical cord blood transplant in the Western Hemisphere performed at Children’s Hospital Colorado

2023

FDA approves 2 gene therapies for SCD

1984

First patient with SCD cured by bone marrow transplant

1997

Initial study of matched sibling bone marrow transplant

2017

First patient with SCD cured by gene therapy

2018

NIH Cure Sickle Cell Initiative;

National haploidentical transplant trial opens

Allogeneic Hematopoietic Stem Cell Therapies

• Only 14% of patients with SCD have a matched-related donor
• Chance of finding a matched-unrelated donor in the sickle cell population is low
• Complications of matched-unrelated donor transplant are high
• Graft rejection/death (~1 in 3)
• Graft versus host disease (> 60%)

Haploidentical Transplantation

• Increases donor pool so 90% of patients will have a potential donor
• Reduced intensity conditioning – decreases toxicity of chemotherapy
• Post-transplant cyclophosphamide – decreases GVHD risk

Kassim et al, ASH Abstract 2023

Results

• Estimated 2-year EFS = 88%
• Estimated 2-year OS = 95%
• GVHD rates were very low
• Graft rejection – 2 patients
• Secondary graft failure – 1 patient

Kassim et al, ASH Abstract 2023

Autologous Gene Therapies

Gene Therapy Methods

Lentiviral Gene Addition

Gene Editing Technologies

Competing Strategies and Protein Products

Lentiviral Gene Insertion

• Uses altered HIV1 virus which cannot replicate to insert DNA into nucleus
• Adds beta globin gene which makes a non-sickling hemoglobin

CRISPR

• Breaks a gene which makes a protein that stops fetal hemoglobin production
• Increases fetal hemoglobin levels

Beta Globin Addition – Hb AT87Q �(Lovo-cel, Beti-cel)

• Lentiviral gene addition
• Single amino acid substitution confers anti-sickling properties to mutant beta globin
• Hb AT87Q can be measured independently using hemoglobin separation techniques
• Can be distinguished from transfused Hb A

Hb AT87Q Clinical Efficacy – SCD (Lovo-Cel)

Kanter et al, NEJM 2022

Hb AT87Q Clinical Efficacy – SCD (Lovo-Cel)

Kanter et al, NEJM 2022

Regulation of Globin Switching�Fetal Hemoglobin Induction

Wang and Thein, Nat Genet 2018

Fetal Hemoglobin Induction - SCD (Exa-Cel)

Frangoul et al, ASH Abstract 2023

Fetal Hemoglobin Induction – TDT (Exa-Cel)

Frangoul et al, ASH Abstract 2023

Potential Risks of Autologous Gene Therapies

• Most reported side effects are expected with myeloablative conditioning – cytopenias, fevers, infections, stomatitis, nausea
• Pain with mobilization
• Veno-occlusive disease of the liver due to chemotherapy and iron overload
• Myeloid malignancy
• Lovo-cel has a black box warning
• Both patients who developed myeloid malignancy were in Group A utilizing marrow harvest instead of apheresis and an older manufacturing technique
• Delayed platelet engraftment
• Neutrophil non-engraftment

Comparison of Two FDA-Approved Strategies

Open Interventional Gene Therapy Trials

Current Limitations and Unanswered Questions

Limitation

• Multiple mobilizations and collections may be needed
• Myeloablative conditioning

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• Vaso-occlusive end points of clinical trials
• Cost and resource utilization
• Limited follow up
• Narrow patient population in clinical trials

Questions

• How can we optimize stem cell collection?
• Can alkylating chemotherapy be eliminated – monoclonal antibodies? In vivo gene editing?
• What is the effect on end-organ damage and mortality?
• How do we expand access to these therapies in a sustainable way?
• What is the long-term durability of response? Long-term risks?
• What are the optimal patient characteristics? Efficacy for alternative sickle genotypes? Safety in patients with underlying comorbidities?

CHCO Pediatric Sickle Cell Program

• Only Comprehensive Sickle Cell Program in the Region
• Home of State Newborn Screening Program (CO & WY)
• > 200 pediatric patients with SCD
• 15 – 20 new diagnoses per year
• Over 40 patients have received curative therapy
• Demographics
• 92% Black
• 6% Hispanic
• 1% Middle Eastern
• 1% White

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A Milestone at CHCO

FDA Approval and Regional Qualified Treatment Center Designation

Lyfgenia – $3.1 million

Casgevy – $2.2 million

Questions