New horizons in sickle cell disease treatment: Promising therapies on the way

For people living with sickle cell disease, it means facing lifelong challenges marked by episodes of severe pain, fatigue, and frequent medical visits. This is because the inherited blood disorder, which is characterized by an abnormality in the protein hemoglobin, disrupts the normal function of red blood cells, causing them to become hard, sticky, and C-shaped, like a ‘sickle’, instead of smooth and round as they should be. For such a severe disease, standard-of-care sickle cell disease treatments are very much lacking and often do little to relieve symptoms.

But there is reason to be optimistic. The field has witnessed a flurry of activity in the last few years as companies successfully progress new treatment options, with gene therapy in particular revolutionizing the field. 

The success of gene therapies for sickle cell disease

November 16, 2023, marked a historic day for biotech: the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization to Vertex Pharmaceuticals and CRISPR Therapeutics’ sickle cell disease therapy, Casgevy, making it the first CRISPR-based medicine in the world to receive approval. 

Shortly afterwards, on December 8, the U.S. Food and Drug Administration (FDA) followed suit. And not only did they approve Casgevy for the treatment of sickle cell disease, but they also gave the green light to bluebird bio’s Lyfgenia, another type of gene therapy. 

Both of the therapies produced impressive results in clinical trials. Lygenia eliminated severe vaso-occlusive events for 94% of evaluable patients and eliminated all vaso-occlusive events for 88% of evaluable patients between six and 18 months post-infusion. Meanwhile, long-term follow-up data for Casgevy showed that 93% evaluable patients were free from vaso-occlusive crises for at least 12 consecutive months. 

The most groundbreaking thing about gene therapies, of course, is that they only need to be administered once and are essentially a curative treatment option. For sickle cell disease patients, this would take away the burden of having regular blood transfusions every few weeks or months for the rest of their lives. 

With Casgevy and Lyfgenia opening the doors of possibility, there are now several other candidates in clinical trials hoping to find their way to approval. The most promising of these are Editas Medicine’s Reni-cel and Beam Therapeutics’ BEAM-101. 

Reni-cel, formerly known as EDIT-301, is under investigation for the treatment of both severe sickle cell disease and transfusion-dependent beta thalassemia (another type of inherited blood disorder). The therapy consists of a patient’s CD34+ hematopoietic stem and progenitor cells that are edited using a CRISPR/Cas12a ribonucleoprotein at the gamma globin gene promoters to upregulate the gamma globin, which in turn boosts naturally occurring fetal hemoglobin – a specific type of hemoglobin found in fetuses and newborns that modulates the hematologic and clinical features of sickle cell disease. 

In December 2024, Editas reported updated clinical data for reni-cel from the phase 1/2/3 RUBY trial, showing that it was well-tolerated and continued to demonstrate a safety profile consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. Furthermore, in terms of efficacy, 27 of the 28 patients were free of vaso-occlusive events post-infusion. Treatment with reni-cel also led to early, robust increases and sustained levels of total hemoglobin and fetal hemoglobin. 

BEAM-101, meanwhile, is a base editing therapy that also uses a patient’s own CD34+ hematopoietic stem and progenitor cells, which have been edited in the promoter regions of the HBG1/2 genes and are administered via a hematopoietic stem cell transplant procedure. The therapy is designed to inhibit the transcriptional repressor BCL11A from binding to the promoter without disrupting BCL11A expression, leading to increased production of non-sickling and anti-sickling fetal hemoglobin. 

The safety and efficacy of BEAM-101 is being evaluated in an ongoing phase 1/2 study in adult patients with sickle cell disease with severe vaso-occlusive crises. Just recently, in June, Beam announced new data from the trial showing that 17 patients treated with BEAM-101 demonstrated robust and durable increases in fetal hemoglobin and reductions in sickle hemoglobin, rapid neutrophil and platelet engraftment, and normalized or improved markers of hemolysis and oxygen delivery.

The efficacy data produced by all of the aforementioned cell therapies are extremely promising for patients. The only caveat is that these types of therapies are notoriously expensive, making it challenging for patients to afford to have the therapy in the first place. The opposing argument, however, is that it is worth it because it is only a one-off cost, whereas patients could otherwise be paying for transfusions for their entire lives.

It was, therefore, a momentous occasion for sickle cell disease patients in the U.K. when the National Institute for Health and Care Excellence (NICE) recently announced that they had approved Casgevy for use on the National Health Service (NHS) at specialist NHS centres in London, Manchester and Birmingham, which will go a long way to helping many people regain control over their lives  – hopefully forever. 

Pfizer advances inclacumab and osivelotor for sickle cell disease after pulling Oxbryta from the market

Last year, Pfizer voluntarily withdrew its popular sickle cell disease treatment Oxbryta, which won approval from the FDA in 2019, from the market, citing that the drug’s overall benefit “no longer outweighs the risk” after new data showed a higher risk of deaths and complications in treated patients.

Nevertheless, this has not deterred Pfizer from pushing forward once again in the sickle cell disease field. In fact, it already has two other drugs in late-stage development: inclacumab and osivelotor. 

Inclacumab is a P-selectin inhibitor currently being tested in a phase 3 trial to determine its safety and efficacy when it comes to reducing vaso-occlusive crises. The drug works by binding to P-selectin, a cell adhesion molecule found on platelets, which prevents platelets from aggregating, in turn helping to maintain normal blood flow. Inclacumab has received both orphan and rare pediatric disease tags from the FDA for sickle cell disease.  

Pfizer’s other drug, Osivelotor, is similar to Oxbryta in that it is a sickle hemoglobin polymerization inhibitor, but it features a next-generation design that will hopefully also solve the safety issues experienced by Oxbryta. Osivelotor works by binding to hemoglobin and increasing its affinity for oxygen, stabilizing it in its oxygenated state. The idea is that if sickle cell hemoglobin is fully oxygenated, it won’t polymerize, thereby preventing red blood cell sickling and easing symptoms. The drug is currently being evaluated in a phase 2/3 trial.

Nex technologies related to sickle cell disease treatment:

• Gene Therapy for Sickle Cell Disease – Cincinnati Children’s Hospital Medical Center
• Citrulline for Treatment of Sickle Cell Crisis – University of Mississippi Medical Center
• Targeted Therapeutics for Treating Sickle Cell Disease and β-thalassemia – Henry Jackson Foundation

Other notable sickle cell disease treatments in clinical development: Sanofi’s rilzabrutinib, Fulcrum’s pociredir, and Novo’s Etavopivat

Pfizer is not the only global giant to be developing therapies for sickle cell disease; Sanofi and Novo Nordisk are also advancing their own late-stage candidates. 

Sanofi’s rilzabrutinib, which is an oral, reversible Bruton’s tyrosine kinase (BTK) inhibitor, was recently granted orphan drug designation by the FDA for sickle cell disease. According to Sanofi, the drug has the potential to be an effective new treatment for several rare immune-mediated or inflammatory diseases by working to restore immune balance via multi-immune modulation. In sickle cell disease specifically, it targets a reduction in vaso-occlusive crises. It is being tested in a phase 3 trial that is expected to enroll up to 192 sickle cell disease patients who have experienced between two and 10 vaso-occlusive crises in the previous year. The estimated completion date for the trial is 2029. 

Meanwhile, Novo gained a lead sickle cell disease asset when it acquired Forma Therapeutics in 2022. The drug, called etavopivat, is a pyruvate kinase (PK) activator – red blood cells require the PK enzyme for energy. Phase 1 data of the candidate showed a “sustained increase in hemoglobin and improvement in biomarkers of hemolysis and red blood cell health.” Furthermore, the results from 15 patients showed a trend toward decreasing vaso-occlusive crises compared to the 12 months prior to patients starting the trial. It is now being tested in a phase 3 confirmatory trial. 

Another company working on the development of a sickle cell disease drug is Fulcrum Therapeutics. The candidate, pociredir, is a small molecule polycomb repressive complex 2 (PRC2) inhibitor that is designed to induce the expression of fetal hemoglobin to compensate for the mutated hemoglobin that occurs in sickle cell disease. The drug is being tested in a phase 1b trial, which is still enrolling patients for the higher dose cohort. However, enrollment for the 12 mg dose cohort is complete, and the company said it plans to share data from this cohort in early Q3 2025.

Summary of notable clinical trials in sickle cell disease

Sickle cell disease market set for substantial growth

The candidates in this article are just a few of the most notable drugs currently in clinical development for sickle cell disease. The field as a whole, however, has been progressing rapidly in recent years. 

This can be evidenced by the sickle cell disease treatment market size, which is also rising quickly, projected to be valued at $3.2 billion in 2025 and expected to soar to approximately $8.81 billion by 2032, growing at an impressive compound annual growth rate (CAGR) of 15.69% in the forecast period. 

Having said that, the market also faces certain challenges, like high cost and limited access to advanced sickle cell disease treatments. As touched upon previously, gene therapy, as well as other advanced therapies, are expensive, which deters patients from opting for these treatments, thereby limiting the sickle cell disease treatment market demand.

Nevertheless, the overall outlook for the future of sickle cell disease treatment appears primarily optimistic – with so many candidates coming through the pipeline, there will at least be many more options for patients to choose from. The hope is that, especially with gene therapies, schemes can come into play to make these drugs more affordable and accessible, giving the chance of a better life to all sickle cell disease patients around the world.