Early observations and pilot data that first suggested a new direction
For decades, the only disease-modifying therapy for sickle cell disease was hydroxyurea. The landmark Multicenter Study of Hydroxyurea (MSH, 1995) demonstrated a 44% reduction in painful vaso-occlusive crises. Despite this evidence, hydroxyurea remained underutilised, and many patients continued to suffer from recurrent crises, organ damage, and shortened life expectancy.
Landmark RCTs and pivotal trials that established the evidence base
After two decades of hydroxyurea as the sole option, three new agents emerged in rapid succession. SUSTAIN (2017) demonstrated crizanlizumab (anti-P-selectin antibody) reduced the median annual rate of vaso-occlusive crises from 2.98 to 1.63. HOPE (2019) showed voxelotor (haemoglobin polymerisation inhibitor) increased haemoglobin by ≥1 g/dL in 51% of patients versus 7% with placebo. L-glutamine also gained approval based on crisis reduction data.
Follow-up studies, subgroup analyses, and real-world validation
In December 2023, two gene therapies received FDA approval — Casgevy (exagamglogene autotemcel), the first CRISPR-based gene therapy for any disease, and Lyfgenia (lovotibeglogene autotemcel), a lentiviral gene therapy. Both aim to functionally cure sickle cell disease by inducing fetal haemoglobin production (Casgevy via BCL11A gene editing) or introducing a modified adult haemoglobin gene (Lyfgenia). This represented a paradigm shift from disease management to potential cure.
Guidelines
Integration into clinical practice guidelines and recommendations
ASH 2020 guidelines strongly recommended hydroxyurea for all adults and children ≥9 months with SCD, regardless of disease severity. NICE endorsed crizanlizumab for crisis prevention. The gene therapy approvals prompted development of new guidelines for patient selection, conditioning regimen risk assessment, and long-term follow-up.
ASH 2020 SCD Guidelines
Strong recommendation for hydroxyurea in all SCD patients ≥9 months
Now
Current standard of care and ongoing research directions
Sickle cell disease has gone from having one drug (hydroxyurea) to multiple therapeutic options including crizanlizumab, voxelotor, and potentially curative gene therapies. Access and cost remain major barriers — gene therapy costs approximately $2-3 million per patient. Current research focuses on improving gene therapy delivery, reducing conditioning toxicity, and developing combination pharmacotherapy approaches.
Two gene therapies — Casgevy (CRISPR-based) and Lyfgenia (lentiviral) — were FDA-approved in December 2023 and offer potential functional cures by modifying the patient's own stem cells. However, they require myeloablative conditioning chemotherapy and cost approximately $2-3 million per patient.
What was the first effective drug for sickle cell disease?+
Hydroxyurea, proven in the MSH trial (1995) to reduce painful crises by 44%. It remained the only disease-modifying therapy for over 20 years until crizanlizumab, voxelotor, and L-glutamine were approved between 2017-2019.
