What are the newest disease-modifying treatments approved for sickle cell disease?

New Disease-Modifying Treatments for Sickle Cell Disease

The newest FDA-approved disease-modifying treatments for sickle cell disease include L-glutamine (Endari, 2017), crizanlizumab (Adakveo, 2019), voxelotor (Oxbryta, 2019, though subsequently withdrawn in 2024), and most recently, two gene therapies: exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia), both approved in 2023-2024 for patients ≥12 years of age. 1, 2, 3

FDA-Approved Pharmacologic Therapies

Established First-Line Therapy

• Hydroxyurea remains the cornerstone and benchmark for all disease-modifying therapy in SCD, with proven 40-50% reduction in pain crises, acute chest syndrome, hospitalizations, and up to 40% reduction in mortality 4, 5, 6
• Should be offered to every child with HbSS or Sβ0-thalassemia starting at 9 months of age, even without clinical symptoms 1

Newer Adjunctive Agents

L-Glutamine (Endari)

• FDA-approved for reducing pain events in patients with SCD
• Works by reducing oxidative damage and preventing cell sickling
• Can be used alone or in combination with hydroxyurea 1, 3, 7

Crizanlizumab (Adakveo)

• Anti-P-selectin monoclonal antibody that reduces vaso-occlusive crises
• Prevents adhesion of sickled cells to blood vessel walls
• Shown to reduce frequency of pain crises and hospitalizations 3, 7, 5

Voxelotor (Oxbryta)

• Hemoglobin oxygen-affinity modulator that improves hemoglobin levels and reduces hemolytic anemia
• Important caveat: While initially approved in 2019, voxelotor was voluntarily withdrawn from the market in 2024 due to regulatory concerns, highlighting the ongoing challenges in translating biological mechanisms into sustained clinical benefits 8, 3, 7

Curative Therapies

Hematopoietic Stem Cell Transplantation (HSCT)

• Remains the established curative option with >90% disease-free survival when using HLA-matched sibling donors 9, 1
• Best outcomes occur when performed before age 16 years 1
• The ASH 2021 guidelines suggest performing HSCT at an earlier age rather than older age when an indication exists 9
• Only 18% of patients have a matched sibling donor available 10
• Alternative donors (haploidentical, matched unrelated) are increasingly used but carry higher risks of graft rejection and graft-versus-host disease 10, 9

Gene Therapies (Most Recent Approvals)

Exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia)

• First gene therapies approved for SCD in patients ≥12 years of age 2, 3
• Represent potentially curative one-time treatments
• Three approaches under investigation: gene addition, gene correction, and gene editing 1
• Major limitation: Extremely high cost limits accessibility, even in developed countries 11, 6
• Long-term efficacy and stroke prevention data are still being collected 2

Clinical Decision Algorithm

For all patients with SCD:

1. Start hydroxyurea at 9 months for HbSS or Sβ0-thalassemia (first-line) 1
2. Monitor CBC and reticulocyte count every 1-3 months for myelosuppression 1

For inadequate response to hydroxyurea:

• Add L-glutamine for pain crisis reduction 3, 7
• Consider crizanlizumab for recurrent vaso-occlusive crises 7, 5
• Evaluate for chronic transfusion therapy if stroke risk or recurrent severe complications 1

For curative intent:

• **If HLA-matched sibling available and age <16 years**: Strongly consider HSCT (>95% disease-free survival) 10, 9, 1
• If age ≥12 years without matched donor: Discuss gene therapy options, acknowledging cost barriers 2, 3
• If alternative donor available: Weigh risks of GVHD, rejection, and infertility against disease severity 10, 9

Important Caveats

Combination therapy will likely be required for optimal outcomes given the limited efficacy of individual agents 8, 5. No single therapy provides complete protection across the lifespan 8.

Common pitfall: Delaying HSCT discussion until severe organ damage occurs. The ASH guidelines emphasize earlier transplantation before development of SCD-related organ damage, as outcomes are significantly better 9. However, severe chronic GVHD has been described in heavily-transfused end-stage adult patients 10.

Access disparity: Despite therapeutic advances, hydroxyurea remains the most accessible and cost-effective disease-modifying treatment globally, while gene therapies remain prohibitively expensive and inaccessible to most patients, even in developed countries 11, 6, 12.

Regulatory uncertainty: The withdrawal of voxelotor underscores that initial FDA approval does not guarantee sustained clinical benefit, emphasizing the need for ongoing post-market surveillance 8.