Are We Finally Paying Attention to Sickle Cell Care?

SICKLE CELL TERMINOLOGY

Before getting started, let’s pause to recognize the conventions being adopted in this article namely that sickle cell is not considered a disease by most of its patient “warriors” whom it affects, but rather is considered a disorder. There is, however, no medically recognized sickle cell disorder at this time and accordingly, I will refer to it simple as sickle cell.

Similarly, the painful vaso-occlusive event that is the well documented hallmark occurrence, temporally associated with most SCD patient hospital stays, is referred to here as an episode in allyship with warrior parlance whereas it is traditionally referred to as “crisis” in academic and medical literature.

September 2025 – Sickle Cell Awareness Month

As we observe Sickle Cell Awareness Month this September, the clinical research community finds itself at an unprecedented inflection point in the treatment of sickle cell (SCD). After decades of limited therapeutic options focused primarily on symptom management, the field is witnessing a revolutionary transformation driven by breakthrough gene therapies and innovative small-molecule approaches that target the underlying pathophysiology of this devastating genetic disorder.

The Current Standard of Care

The foundation of SCD management continues to rest on a multi-modal approach combining pharmacological interventions, supportive care, and comprehensive disease monitoring. Hydroxyurea remains the cornerstone of first-line therapy globally, demonstrating its enduring clinical value since FDA approval in 1998. While traditionally recognized for increasing fetal hemoglobin production to reduce sickling, recent research has revealed multiple non-HbF related mechanisms that contribute to its therapeutic efficacy.

Hydroxyurea reduces leukocyte and platelet counts, decreases the expression of endothelial adhesion molecules CD36 and CD49d, and increases nitric oxide and cyclic nucleotide levels, which may facilitate vascular dilation. These pleiotropic effects extend beyond hemoglobin modification to address fundamental pathophysiological processes in SCD. Recent studies demonstrate that hydroxyurea reduces red blood cell reactive oxygen species, ferryl hemoglobin, and Heinz-body formation, thereby reducing membrane damage, contributing to improved erythrocyte survival independent of HbF levels. The drug’s nitric oxide donor properties activate soluble guanylyl cyclase, promoting vasodilation and potentially reducing the inflammatory cascade associated with vaso-occlusive episodes.

The myelosuppressive effects of hydroxyurea, while requiring monitoring, contribute therapeutically by reducing the elevated white blood cell counts characteristic of SCD patients, thereby decreasing cellular adhesion and reducing the inflammatory burden that contributes to vaso-occlusive pathophysiology. The full benefits of hydroxyurea therapy in SCD are multifactorial, extending beyond simple HbF induction to encompass these diverse cellular and vascular mechanisms.

Pain management protocols represent another critical component of standard care, employing a graduated approach from non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen for mild pain to opioid analgesics for severe acute episodes. The challenge lies in balancing effective pain control with the risk of opioid dependence, particularly given the chronic nature of SCD pain in many patients.

Blood transfusion therapy represents a cornerstone of both acute and chronic SCD management, with distinct approaches tailored to specific clinical scenarios. Simple red blood cell transfusions are employed for acute complications including stroke, acute chest syndrome, aplastic crisis , and severe anemia, typically aiming to increase hemoglobin levels to 9-11 g/dL. In contrast, red blood cell exchange transfusion (automated erythrocytapheresis) involves simultaneous removal of the patient’s sickle cells while replacing them with normal donor cells, maintaining stable blood volume while achieving higher percentages of normal hemoglobin. Exchange transfusion is preferred for life-threatening complications such as acute stroke, severe acute chest syndrome with hypoxemia, or multiorgan failure, as it rapidly reduces the percentage of sickle cells while avoiding hyperviscosity and volume overload.

Chronic transfusion protocols, typically administered every 3-4 weeks, serve as primary stroke prevention in high-risk pediatric patients with abnormal transcranial Doppler velocities or previous stroke history. Both simple and exchange transfusion protocols require concurrent iron chelation therapy using agents such as deferasirox, deferoxamine, or deferiprone to prevent life-threatening iron overload complications including cardiac dysfunction, hepatic fibrosis, and endocrine disorders.

Supportive measures encompass prophylactic antibiotics (particularly penicillin in pediatric patients to prevent pneumococcal sepsis due to functional asplenia), comprehensive vaccination protocols including pneumococcal, meningococcal, and Haemophilus influenzae type b vaccines, folic acid supplementation to support increased erythropoiesis, and systematic screening for organ complications. Transcranial Doppler monitoring represents a critical component of pediatric care, identifying children at high stroke risk who require primary prevention through chronic transfusion therapy or alternative interventions.

Established Modern Therapeutics

The past decade has introduced several targeted therapies that have expanded the therapeutic armamentarium beyond traditional supportive care. ENDARI (L-glutamine oral powder), approved by the FDA in 2017, represents the first amino acid-based therapy for SCD, demonstrating significant reductions in pain crises and hospitalizations in the pivotal Phase III study. The mechanism involves improved cellular energy metabolism and reduced oxidative stress through enhanced synthesis of antioxidants such as glutathione and NADH. However, L-glutamine’s regulatory approval has been geographically limited and controversial. Despite the results of the Phase 3 study and other data submitted to the EMA’s Committee for Medicinal Products for Human Use (CHMP), the CHMP maintains its initial opinion that the MAA did not demonstrate that Xyndari is effective at reducing the number of sickle cell crises or hospital visits.

The company said it would withdraw the application for Xyndari after a negative opinion from the EMA’s Committee for Medicinal Products for Human Use, which had ruled against the drug in May 2019, leading Emmaus Life Sciences to withdraw their European marketing authorization application. The UK’s NICE similarly discontinued their evaluation of L-glutamine for SCD prevention. This regulatory divergence highlights ongoing controversy about the strength of evidence supporting L-glutamine’s clinical efficacy, with European regulators requiring more robust demonstration of clinical benefit compared to the FDA’s approval standards. While L-glutamine remains available through expanded access programs in some European countries and is used in regions like Saudi Arabia with reported positive real-world outcomes, the regulatory disagreement underscores debates about the adequacy of the pivotal trial data and the clinical significance of observed benefits.

ADAKVEO (crizanlizumab-tmca), a humanized monoclonal antibody targeting P-selectin, gained FDA approval in 2019 as the first therapy specifically designed to prevent vaso-occlusive crises. However, the therapeutic landscape for crizanlizumab has become increasingly complex following regulatory setbacks in key markets. The European Commission revoked its conditional marketing authorization in August 2023 after the confirmatory STAND study failed to demonstrate the clinical benefits previously observed in the pivotal SUSTAIN trial. Subsequently, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) revoked its conditional marketing authorization in January 2024 due to lack of therapeutic efficacy, determining that the benefit-risk balance was no longer favorable.

While crizanlizumab remains approved in the United States, these regulatory actions highlight the challenges inherent in conditional approvals based on limited efficacy data and underscore the importance of robust confirmatory studies for accelerated approval pathways.

The clinical landscape experienced significant setbacks with recent regulatory actions affecting two key SCD therapies. In September 2024, Pfizer voluntarily withdrew OXBRYTA (voxelotor) globally due to safety concerns, while crizanlizumab faced regulatory revocations in Europe and the UK following failed confirmatory studies. The European Commission revoked crizanlizumab’s conditional marketing authorization in August 2023 after the STAND study failed to confirm the benefits previously seen with the drug, leading regulators to conclude that benefits no longer outweighed risks. Subsequently, the UK’s MHRA revoked its conditional marketing authorization in January 2024, determining the benefit-risk balance was no longer favorable due to lack of therapeutic efficacy. These withdrawals underscore the critical importance of robust confirmatory studies for accelerated approval pathways and highlight the ongoing challenges in SCD drug development.

Gene Therapy Revolution

The December 2023 FDA approvals of CASGEVY (exagamglogene autotemcel) and LYFGENIA (lovotibeglogene autotemcel) represent watershed moments in SCD therapeutics, introducing the first curative treatment options for eligible patients. These one-time gene therapies offer the potential to fundamentally alter the disease trajectory rather than merely managing symptoms.

CASGEVY, developed through a collaboration between Vertex Pharmaceuticals and CRISPR Therapeutics, employs CRISPR/Cas9 gene editing technology to modify patients’ own hematopoietic stem cells, enabling production of fetal hemoglobin. The pivotal trial demonstrated remarkable efficacy, with 93.5% of evaluable patients (29 of 31) achieving freedom from severe vaso-occlusive crises for at least 12 consecutive months. The therapy requires a complex treatment process involving stem cell mobilization, collection, ex vivo editing, and myeloablative conditioning before reinfusion, necessitating specialized treatment centers with extensive transplant expertise.

LYFGENIA, developed by Bluebird Bio, utilizes a lentiviral vector to introduce functional copies of a modified β-globin gene into patients’ hematopoietic stem cells. While both therapies represent transformative advances, their implementation requires careful patient selection, comprehensive informed consent processes, and long-term follow-up to monitor for potential late effects including chromosomal abnormalities and secondary malignancies.

Next-Generation Gene Editing Approaches

Beyond the currently approved CRISPR/Cas9 and lentiviral platforms, emerging gene editing technologies are advancing toward clinical application. Base editing and prime editing represent precision approaches that could potentially offer safer and more accurate genetic correction. Scientists at St. Jude Children’s Research Hospital and the Broad Institute demonstrated that prime editing can change mutated hemoglobin genes back to their normal form in SCD patient cells, which restores normal blood parameters after transplantation into mice. This approach offers the theoretical advantage of directly correcting the underlying β-globin mutation rather than inducing compensatory fetal hemoglobin production.

The University of California San Francisco (UCSF) has launched the first U.S. trial applying non-viral CRISPR-Cas9 gene-editing technology in humans to directly correct the genetic mutation that causes sickle cell, representing a potentially safer approach that avoids viral vectors entirely. CRISPR Therapeutics and BEAM Therapeutics are both pursuing strategies for in vivo editing for SCD, moving beyond current ex vivo approaches where cells are taken out of the body, edited, and reinfused.

However, these advanced editing approaches face significant developmental challenges. Several companies including Graphite Bio and Sangamo have stopped work on their respective sickle cell gene therapies, while Intellia revealed partner Novartis ended development of its genetic treatment for the blood disease, highlighting the technical and commercial hurdles in this rapidly evolving field.

Pyruvate Kinase Activators: A New Therapeutic Class

The emergence of pyruvate kinase activators represents one of the most promising developments in the current SCD pipeline. These oral small molecules target erythrocyte metabolism, addressing the fundamental energy deficits that contribute to red blood cell sickling and hemolysis.

Mitapivat, developed by Agios Pharmaceuticals, leads this therapeutic class and recently completed enrollment in the Phase III RISE UP study for patients 16 years and older. As a first-in-class oral allosteric activator of pyruvate kinase, mitapivat enhances adenosine triphosphate production while reducing 2,3-diphosphoglycerate levels in erythrocytes. The European Commission’s December 2024 designation of mitapivat as an orphan medicinal product for SCD treatment, combined with anticipated topline results in late 2025, positions this therapy for potential approval in 2026.

Etavopivat, being developed by Novo Nordisk, represents another promising pyruvate kinase activator currently in Phase II/III development. These agents offer the potential advantages of oral administration, favorable safety profiles, and mechanisms that directly address cellular energy metabolism underlying SCD pathophysiology.

Next-Generation Pipeline Developments

Pfizer’s pipeline includes two significant assets despite the OXBRYTA withdrawal. Osivelotor (GBT-601) represents a next-generation HbS polymerization inhibitor designed with improved pharmacokinetic properties compared to its predecessor. With both Orphan Drug and Rare Pediatric Disease designations, this oral therapy aims to achieve higher hemoglobin occupancy at lower doses, potentially reducing treatment burden while maintaining clinical efficacy.

Inclacumab, Pfizer’s anti-P-selectin antibody, continues development despite the discontinuation of one Phase III study due to enrollment challenges. The remaining Phase III program supports anticipated approval in 2026, offering another intravenous option for preventing vaso-occlusive episodes.

Global Treatment Disparities and Regulatory Challenges

The global SCD treatment landscape reveals significant disparities in therapeutic access, compounded by recent regulatory setbacks that highlight the complexities of accelerated approval pathways. The European Commission revoked crizanlizumab’s conditional marketing authorization in August 2023 after the STAND study results failed to confirm the benefits previously seen with the drug, with the CHMP concluding that benefits no longer outweighed risks. Subsequently, the UK’s MHRA revoked its conditional marketing authorization in January 2024 due to lack of therapeutic efficacy, determining that the benefit-risk balance was no longer favorable.

While the six major pharmaceutical markets represent the primary focus for commercial development, limited therapeutic options remain available in many regions with high SCD prevalence, particularly parts of Africa where the disease burden is greatest. The regulatory actions surrounding both crizanlizumab and voxelotor underscore the critical importance of robust confirmatory studies and comprehensive long-term safety monitoring for accelerated approval programs.

Japan presents a unique market dynamic, with extremely low SCD prevalence leading many pharmaceutical companies to forgo regulatory submissions in this market. This geographic selectivity in drug development highlights the ongoing challenges in ensuring global access to innovative therapies for rare diseases.

The Next Wave of SCD Therapeutics

Based on current market analysis, the clinical pipeline for SCD includes over 40 companies developing treatment approaches across diverse mechanisms and platforms. These emerging therapies can be categorized into distinct therapeutic modalities:

Cell and Gene Therapies (Biologics)

Advanced Gene Editing Platforms:
* CASGEVY (exagamglogene autotemcel) – Vertex/CRISPR Therapeutics (approved)
* LYFGENIA (lovotibeglogene autotemcel) – Bluebird Bio (approved)
* Prime editing approaches – direct mutation correction (preclinical)
* Base editing platforms – precision single nucleotide editing (preclinical)
* Non-viral CRISPR systems – avoiding viral vector risks (Phase I)
* CRISPR by Design – Scribe Therapeutics/Sanofi collaboration (preclinical)

Small Molecule Pharmaceuticals

Pyruvate Kinase Activators:
* Mitapivat (PYRUKYND) – Agios Pharmaceuticals (Phase III completed)
* Etavopivat – Novo Nordisk (Phase II/III)

Hemoglobin Stabilizers:
* Osivelotor (GBT-601) – Pfizer (Phase II/III)

Anti-adhesion Agents:
* Inclacumab – Pfizer (Phase III)

Fetal Hemoglobin Inducers:
* Pociredir – Fulcrum Therapeutics (Phase II)
* NDec (decitabine and tetrahydrouridine/EP101) – Novo Nordisk (Phase II)

Currently Marketed Small Molecules:
* Hydroxyurea (DROXIA) – multiple manufacturers
* L-glutamine (ENDARI) – Emmaus Life Sciences
* Crizanlizumab (ADAKVEO) – Novartis (US only, revoked in EU/UK)

This diversified pipeline reflects the field’s evolution toward precision medicine approaches targeting multiple pathophysiological pathways simultaneously.

[1] The aplastic crisis is a sudden shutdown of red blood cell production by the bone marrow, typically triggered by parvovirus B19, which leads to rapid and severe anemia. Although it affects individuals with sickle cell, it also affects other hemolytic anemias and, since it is not specific to sickle cell, is not referred to here as an “episode.”

SCD Treatment Landscape Tables

Adrian C. Wright, M.Sc.,

Adrian C. Wright, M.Sc., is a clinical research consultant and CEO of Benchmark Decision Support System, where he leads a team developing data-driven solutions to improve clinical trial representation and health equity. His expertise in sickle cell disease spans from molecular genetics research—including co-authoring transgenic sickle cell murine model work published in Nature Medicine—to current patient co-led research addressing barriers to hydroxyurea uptake in the UK.

Adrian’s clinical research credentials include past certifications by leading industry groups such as a Clinical Research Associate (ACRP) and Clinical Research Professional (SOCRA), with extensive experience monitoring trials across several therapeutic areas including Infectious Disease and Bone Marrow Transplantation–both very relevant to sickle cell. He has co-led healthcare innovation projects internationally, including designing a dialysis center in Grenada to reduce patient costs by 55%.

An active advocate in the sickle cell community, Adrian serves on organizations including the Global Gene Therapy Initiative, Sickle Cell Alliance, and Ontario Health SCD Community of Practice. He holds a Bachelors in Physiolohy and a Masters in Experimental Medicine from McGill University and was accepted into the MIT Technology Leadership Program. He combines scientific research knowledge with practical insights into treatment access challenges, making him a unique voice in translating research advances into improved patient outcomes.