Sickle Cell Disease in 2024: One Step Forward and Two Steps Back

A year ago, the sickle cell disease (SCD) community celebrated a major milestone — the first regulatory approval of gene therapy in the United States. This success was achieved through years of preclinical studies, culminating in largely successful clinical trials (relying on brave and committed patients, families, and providers) that demonstrated a greater than 90% reduction in vaso-occlusive pain events.^1,2 

So where are we now? The list prices of the gene therapy products lovotibeglogene autotemcel and exagamglogene autotemcel are $3.1 million and $2.2 million, respectively, which does not include cost for hospital stays, red cell exchanges, myeloablative conditioning, and fertility preservation (if desired). Given the 100,000 individuals living with SCD in the United States and the current uptake rate based on production capacity, costs, and risks of therapy, the impact of gene therapy for SCD is likely to be limited to a few fortunate individuals in the near future. We question the fairness of these costs, which will be mostly borne by public insurance programs (Medicaid and Medicare), considering that much of the foundational knowledge that led to these breakthrough therapies was funded via public dollars from the National Institutes of Health.^3-5  As reported in October 2024 in The New York Times, approximately 30 people with SCD are in various stages of gene therapy to date, including 12-year-old Kendric Cromer, the first patient to receive gene therapy off-study.⁶  Mr. Cromer’s experience highlighted the need for more patient-centric education about mucositis from myeloablative busulfan conditioning, a difficult and seldom emphasized feature of gene therapy.

In the previous issue of The Hematologist, a breakthrough multicenter phase II trial of haploidentical stem cell transplant (haploSCT) for SCD using non-myeloablative conditioning was outlined.⁷  Strengths of this trial include the large sample size (70 adults and children with SCD), inclusion of people with serious comorbidities such as stroke, an encouraging 94% two-year overall survival, 100% donor chimerism in adults, and an acceptable 10% rate of graft-versus-host disease. This rate of engraftment is a huge improvement compared to prior non-myeloablative regimens. Limitations include higher rates of graft failure in children below age 18 and lack of data on pain events, quality of life, and sustained fertility. Nevertheless, this trial showed the potential for haploSCT to become a dominant transformative therapy for young adults living with SCD, especially for individuals with cerebrovascular disease or residing in lower-resourced settings, given the cost disparity between haploSCT ($100,000+, albeit with significant stem cell transplant infrastructure) and gene therapy. Thus, this is our nominee for the year’s best achievement.

This year also witnessed two major setbacks in treatment for SCD. Hydroxyurea was initially approved in 1998 in the U.S. after a landmark phase III study demonstrated reduction in pain events and acute chest syndrome (study terminated early for overwhelming benefit).⁸  Further benefits in prolonged life expectancy and delayed end-organ damage were confirmed in long-term, albeit piecemeal, follow-up.^9,10  After a nearly 20-year hiatus, three new drugs for SCD were approved in the U.S. — L-glutamine (2017), crizanlizumab (2019), and voxelotor (2019). Buried under the exuberant celebration of the U.S. regulatory approval for gene therapy at the ASH 2023 Annual Meeting was the phase III STAND trial outcomes for crizanlizumab, which showed no benefit in pain events at two different dose levels of crizanlizumab compared to placebo.¹¹  This was in stark contrast to the phase II data showing a reduction in pain events compared to placebo (on which U.S. Food and Drug Administration approval was based),¹²  leading to revocation of approval in Europe. While no new safety concerns were uncovered, this study has injected significant therapeutic uncertainty into the benefit of crizanlizumab for SCD.

On September 25, 2024, Pfizer, the manufacturer of voxelotor, an antisickling agent for SCD, announced the immediate withdrawal of the medication from the market. The press release cited unpublished clinical data suggesting an “imbalance in vaso-occlusive crises and fatal events” and stated that the “overall benefit of OXBRYTA [voxelotor] no longer outweighs the risk in the approved sickle cell patient population.”¹³  No further details were shared, with these findings in sharp contrast to the phase III trial showing an improvement in anemia (but not pain events).^14,15  Unfortunately, no guidance on transitioning off the medication was provided, nor was compassionate use offered for the minority of patients (e.g., un-transfusable individuals) who benefited from the therapy. The ensuing turmoil negatively affected patients on voxelotor, and the sudden withdrawal led to clinicians around the country scrambling for alternatives while simultaneously sharing ad hoc best practices to avoid rebound hemolysis. The effects of this are still being felt two months later, putting stress on the fragile relationships between patients, practitioners, and the pharmaceutical industry — a necessary component in developing new therapies for SCD.

Where do we go from here? We must examine the process for drug approvals in SCD, beginning with a focus on finding a consensus and/or composite endpoint as well as the number of patients tested to establish efficacy. No current symptom or biomarker alone fully captures the spectrum of symptom and disease activity in SCD. Acute pain episodes, the most widely used endpoint, are inherently subjective and may not be the most appropriate reflection of other features of pathophysiologic damage, such as hemolysis.¹⁶  Accounting for chronic pain, which afflicts the majority of adults with SCD in high-income countries such as the U.S., must be considered in trial design. We should also consider carefully structured and ethical partnerships with high-prevalence, lower-resource settings to fully evaluate novel therapies. Lastly, we must examine long-term, post-approval, real-world outcomes, ideally with a multisite data registry such as the Globin Research Network for Data and Discovery, to ensure that subtle problems (and benefits!) can be uncovered. Registries have long since been informatively employed in other lifespan disorders such as cystic fibrosis and hemophilia, so why not SCD? Without these steps, we will find ourselves yet again losing out on promising therapies for SCD.