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June 19 is marked as World Sickle Cell Awareness Day, granting the opportunity to reflect on the current state of treatment, access, equity, and more that impacts patients living with sickle cell disease.
At the end of 2023, patients with sickle cell disease (SCD) gained 2 new, potentially curative options for their debilitating blood disorder, but these gene therapies still present a number of challenges, including logistics, access, and cost.
World Sickle Cell Awareness Day was officially established on June 19, 2009.1 Each year, observing this day grants opportunities to further educate the public understanding of SCD and shed light on the innovations, challenges, and barriers that clinicians, patients, families, and caregivers face in their efforts to mitigate the detrimental effects of this rare blood disorder.
In the last year, the FDA approved 2 novel gene therapies designed to dramatically alter the natural history of SCD. On December 8, 2023, the approval of exagamglogene autotemcel (exa-cel; Casgevy) and lovotibeglogene autotemcel (lovo-cel; Lyfgenia) marked a significant advancement in the treatment of SCD as the first cell-based gene therapies indicated for patients 12 years and up.2
Exa-cel was developed for patients with SCD who experience recurring, painful episodes known as vaso-occlusive crises (VOCs). For exa-cel, the FDA approved its first treatment that employs clustered regularly interspaced palindromic repeats (CRISPR)/Cas9, a technology capable of editing the genome of dysfunctional cells. This process targets a patient’s hematopoietic stem cells, essentially splicing part of the DNA and either removing, adding, or replacing the malfunctioning DNA at this juncture.
Subsequently, the patient undergoes a transplant to return the newly altered, functioning stem cells to their bone marrow, where they hopefully multiply and manufacture more fetal hemoglobin (HbF). For patients enduring SCD, higher concentrations of HbF have been associated with reduced mortality, morbidity, and less severe symptoms as it facilitates the circulation of more oxygen and hinders the sickling of red blood cells.2,3
On the other hand, lovo-cel is a cell-based therapy that utilizes a lentiviral vector to address a patient’s history of VOCs.2 This process modifies a patient’s hematopoietic stem cells to make HbAT87Q. HbAT87Q is a form of hemoglobin procured from gene therapy to resemble the function of hemoglobin A (HbA), produced naturally in healthy individuals without SCD. With this modification, red blood cells have a reduced risk of occluding and sickling. In the same process, the exa-cel includes lovo-cel requires an infusion to facilitate the hematopoietic stem cell transplant.
After the collection of a patient’s stem cells, each patient must undergo high-dose chemotherapy (myeloablative conditioning) to effectively rid the bone marrow of other cells in preparation for the transplant.
“These 2 gene therapy treatments represent the newest of a relatively small number of FDA-approved therapies for SCD (adding to hydroxyurea, L-glutamine, voxeletor, and crianlizumab), which represents progress, of course, but also highlights limited options for those who do not respond to or have access to these approved therapies,” Marc Walters, MD, University of California, San Francisco, expressed to The American Journal of Managed Care® (AJMC®) in an email interview. “This emphasizes a strong need for research to develop broader, effective, safe therapies in SCD. The full impact of the availability of the FDA approvals for lovo-cel and exa-cel is too early to judge, but access to the treatments should be monitored closely, and if barriers are identified, these will need to be addressed.”
In May of 2024, phase 3 trial results supporting the use of exa-cel were published in The New England Journal of Medicine.3 Throughout an SCD cohort of 44 patients between the ages of 12 and 35, exa-cel infusion was administered to eradicate VOC events for 12 consecutive months. Add the end of the study period, 30 patients had completed sufficient follow-ups, and 97% (n = 29) had achieved the anticipated year-long freedom from VOC events (95% CI, 83-100; P < .001). Furthermore, Frangoul et al observed all 30 of these patients avoided VOC-related hospitalization during those 12 months (100%; 95% CI, 88-100; P < .001). Notably, no graft failures occurred, nor did cancers develop throughout this process. Each patient experienced an adverse event following their infusion of exa-cel; however, the investigators saw these events as more closely linked to the pre-infusion regimen patients underwent rather than a direct consequence of exa-cel. Among the most prevalent, stomatitis (experienced by 55% of patients), febrile neutropenia (48%), reduced platelet count (48%), and reduced appetite (41%) were listed.
As a part of an ongoing, long-term study, patients who receive exa-cal or lovo-cel will continue to be monitored to assess these products’ safety and lasting efficacy.2
“In the words of a sickle cell warrior who received one of the approved gene therapy treatments during a pre-approval clinical trial,” Walters further commented, “he predicted that these treatments will be transformative. It is his hope that the life he lived with illness and pain should be replaced by a new reality, which is the institution of this treatment early in the life of a person with sickle cell disease so that they will not have to experience the same complications he experienced. I think it is important to emphasize the experiences of those who have received a gene therapy treatment and share their opinions.”
At the time of Frangoul et al’s publication, The New York Times reported that the first commercial patient with SCD—Kendrick, a 12-year-old boy from Washington, DC—was beginning treatment with lovo-cel at Children’s National Hospital in Washington.4 The process requires extensive dedication but holds curative potential. Collecting and modifying the patient’s stem cells can take months, especially if the first retrieval (which can take upwards of 8 hours) does not yield enough viable stem cells, and more collections are needed. The Times reported that due to the time-consuming nature of this process, bluebird bio—which produces lovo-cel—estimated that it only 85 to 105 patients can receive treatment in the first year; other medical centers have even less capacity for gene therapy patients due to the intensive and expert care it requires.
Although the commercial use of these medications has the potential to transform the lives of patients with SCD, gene therapy is accompanied by its own challenges. “In meeting with patients and participating in town hall meetings in the community, there is a great deal of concern about infertility after high-dose chemotherapy that precedes the gene therapy and about the risk of leukemia and other cancers after the treatment. Both need to be addressed during the decision-making process,” Walters detailed. “The other challenge, of course, is the intensive therapy itself and the cost, not so much for the gene therapy product that is borne by the insurer, but the cost to family and lost time needed to support a person through the treatment. Without resources and a family to support through the treatment, gene therapy is not really an option to pursue.” The Times noted that the current price listed for lovo-cel is $3.1 million, making it one of the costliest treatments on the market.4
Kendrick’s physicians noted another pressing challenge that comes with gene therapy: hematopoietic stem cell collection. Part of the reason this process is so lengthy is due to the weeks-long tests and protocols necessary to ensure the safety, purity, and potency of an individual’s sample. And, as they mention, there is the possibility that a patient will have to start the process over again if their sample is not sufficient.
The sheer number of stem cells that can be collected from a patient largely designates the course of treatment and success of gene therapy. To address this treatment obstacle, BioLineRx, and St Jude Children’s Research Hospital will be collaborating to investigate the safety and efficacy of motixafortide (Aphexda)5—a selective C-X-C motif chemokine receptor 4 inhibitor designed to encourage hematopoietic stem cell mobilization.6
This phase 1 study, SCDSTEMM (NCT06442761), is set to begin enrollment in the coming months.5 Other methods to initiate stem cell mobilization, Maia reported, may contribute to severe adverse events or fail to gather enough stem cells necessary for treatments like exa-cel and lovo-cel. Motixafortide, which has been approved for multiple myeloma, blocks the stem cells’ CXCR4 receptor, which keeps them from staying put in one’s bone marrow, effectively forcing their migration into the bloodstream. When the study officially begins, 12 adult patients with SCD will be included to assess the drug’s tolerability as researchers quantify the stem cells available for retrieval. This cohort will be split into 2 parts: Part A participants will feature 6 patients undergoing a single-dose therapy, and Part B will include the remaining 6 patients with 2-days’ worth of daily dosing. Pending successful results, motixafortide’s indication for SCD holds the potential to increase the treatment options and access afforded to patients with SCD.
A groundbreaking initiative by the Biden-Harris Administration has designated SCD as the first focus of the Cell and Gene Therapy Access Model. This model, set to begin in 2025, aims to facilitate access to new gene therapy treatments for Medicaid-insured individuals with SCD. However, as Regina Hartfield, president and CEO of the Sickle Cell Disease Association of America (SCDAA), noted in an email interview with AJMC®, ensuring that patients can access and afford these treatments is crucial.
The SCDAA is actively collaborating with the Center for Medicare and Medicaid Innovation to refine the model, advocating for comprehensive coverage of the services required before, during, and after treatment. The community awaits further details on how states will implement this model and ensure equitable access to these life-changing therapies.
“SCDAA is hopeful that the Cell and Gene Therapy (CGT) Model will allow for individuals living with SCD insured by Medicaid to access the 2 new gene therapy products if they are eligible and choose to pursue this course of treatment,” Hartfield added. More information about the model will be released this summer and will describe how states ensure individuals pursuing a gene therapy will have access to and adequate coverage of the other services they will need both pre- and posttreatment, he explained.
“SCDAA also feels that it is critical that we do not let the excitement of these approvals overshadow the need to ensure that high-quality care is available to those living with SCD who are not eligible for, are unable to access or choose not to pursue gene therapy, and we must continue to invest in research to find other treatments and potential cures for all those not eligible for these two new therapies,” Hartfield said.
In the US, newborn screening for SCD only began within the last 50 years and wasn’t widely adopted until 19867 Even with this progress, the transition to adult care presents significant challenges. Adult programs for SCD are often underresourced, leading many patients to rely on emergency care rather than regular, preventive treatment.8 This dependence on the emergency department (ED) results in a staggering $3 billion annual burden on the US health care system.
Additionally, decades of mistrust in the health care system have left many African American patients with SCD at a significant disadvantage. Socioeconomic disparities often mean that these individuals lack insurance and the financial resources necessary for long-term disease management. This situation is compounded by discrimination in hospital settings, where African American patients seeking emergency care for severe pain face biases that can hinder their treatment.
In one interview with HCPLive, expert hematologist Titilope Fasipe, MD, PhD, assistant professor, Department of Pediatrics, Texas Children's Cancer & Hematology Centers, Baylor College of Medicine, shared her experience of discrimination when she sought emergency care for a VOC as a patient herself.9
Another challenge faced by those with SCD care is blood transfusion therapy.8 Patients frequently require transfusions to alleviate symptoms, and these are most effective when the blood comes from donors of similar ethnic backgrounds. However, there is a significant challenge: the majority of blood donors are Caucasian, while those most in need of these transfusions are African American. This disparity can lead to antigen mismatches and the development of antibodies, complicating treatment.
Addressing these barriers to SCD care has become a priority as awareness increases. According to Hartfield, the past year has marked a significant era of advancement and advocacy for the SCD community. With renewed governmental attention and a surge in legislative activities, the landscape of care and treatment for SCD is evolving.
“Both the (Biden-Harris) Administration and Congress are paying more attention to the disease and are recognizing some of the challenges this community faces,” she wrote to AJMC®. “In September 2023, CMS announced its Sickle Cell Disease Action Plan and since then has engaged with the community through a roundtable event.”10
While SCD has historically been underrepresented in health care discussions and policy-making, Harfield said the conversation is shifting toward action.
“There are also currently 3 active sickle cell disease–specific pieces of legislation in the 118th Congress. SCDAA is hopeful that the Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act (H.R. 3884/S.1852), bipartisan legislation introduced by Representatives Danny Davis and Michael Burgess and Senators Cory Booker and Tim Scott, reauthorizing HRSA’s [Health Resources and Services Administration] Sickle Cell Disease Treatment Demonstration Program from 2024 through 2028, will pass this Congress. In the past year, the bill has passed out of committee in both the House and Senate.”11
Right now, multiple pieces of legislation are under consideration in the 118th Congress, each aiming to enhance access to care and support for individuals with SCD:
The SCDAA has been diligently advocating for these bills, engaging lawmakers, and gaining additional co-sponsors during its annual Hill Day in May. The passage of these bills would mark a significant step forward in securing better care and support for the SCD community.
While the approval of gene therapies offers hope for a potential cure, significant challenges remain in making these treatments accessible to all. Hartfield and Edward Donnell Ivy, MD, MPH, the association's vice chief medical officer, highlight the key developments and the path ahead for improving the lives of individuals with SCD.
“For those who are eligible and choose to pursue gene therapy, we must ensure these individuals are able to access the services needed to successfully receive these treatments—this includes a lengthy eligibility, evaluation, and preparative regimen, and an extended hospital stay, and much more,” Hartfield explained.
Understanding the complex process and evaluating whether gene therapy is the right choice requires clear, accessible information. Trusted organizations like the SCDAA and health care providers play vital roles in this educational effort.
“Helping the sickle cell warrior community understand the new therapy will not be enough,” Ivy stated. “We also need to help frontline sickle cell providers that treat sickle cell warriors to understand the therapy and position those providers to give evidence-informed information to the sickle cell community. Those frontline providers are often the first source of information for many of the patients and can help patients access new and emerging therapies. We need to help these frontline workers understand which patients are the best candidates for these therapies and the next steps that need to be taken by both the provider and the patient to move them into the system to receive the therapy.”
According to Ivy, strategies for increasing the accessibility of gene and cell therapy for those with SCD are crucial. Without those, the advancement of medicine itself falls short of addressing gaps in care for this community.
"As you may be aware, these therapies are in the millions of dollars per treatment per patient," he said. "We will need to explore payment models that can help to ensure that the financial barriers are not a limiting factor to this therapy being available to the sickle cell community. Fortunately, CMS announced that they will be working on a payment model for these new therapies and will be rolling out the model for states to join the effort later in the year."
The new payment models that CMS is developing are anticipated to be rolled out before the end of this year. Then, the sickle cell community will need to work with CMS and the US to get states to enroll in the payment models and provide access for patients.
"The pharmaceutical companies that are providing these therapies are in the process of building out the infrastructure and capacity to be able to offer these new therapies," Ivy continued. "This includes working with medical centers to meet the requirements for administering these therapies to patients."
References
1. World Sickle Cell Day. Sickle Cell 101. Updated 2023. Accessed June 17, 2024. https://www.sc101.org/sicklepedia/world-sickle-cell-day/
2. FDA approves first gene therapies to treat patients with sickle cell disease. News release. FDA. December 8, 2023. Accessed June 5, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
3. Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662. doi:10.1056/NEJMoa2309676
4. Kolata G. First patient begins newly approved sickle cell gene therapy. NY Times. Updated May 7, 2024. Accessed June 7, 2024. https://www.nytimes.com/2024/05/06/health/sickle-cell-cure-first.html?searchResultPosition=1
5. Maia M. Study to test motixafortide stem cell mobilization for SCD gene therapies. Sickle Cell Disease News. June 6, 2024. Accessed June 7, 2024. https://sicklecellanemianews.com/news/study-test-motixafortide-stem-cell-mobilization-sickle-cell-gene-therapies/
6. Hoy SM. Motixafortide: First approval. Drugs. 2023;83(17):1635-1643. doi: 10.1007/s40265-023-01962-w
7. Minkovitz CS, Grason H, Ruderman M, Casella JF. Newborn Screening Programs and Sickle Cell Disease: A Public Health Services and Systems Approach. Am J Prev Med. 2016;51(1 Suppl 1):S39-S47. doi:10.1016/j.amepre.2016.02.019
8. Sundd P. Addressing the healthcare challenges and disparities among sickle cell disease patients. Versiti Blood Research Institute Articles. December 14, 2023. https://versiti.org/versiti-blood-research-institute/articles/2023/addressing-the-healthcare-challenges-and-disparities-among-sickle-cell-disease-patients
9. Grossi G. Titilope Fasipe, MD, PhD: Understanding sickle Cell disease complications. HCPLive. October 22, 2021. https://www.hcplive.com/view/titilope-fasipe-understanding-sickle-cell-disease-complications
10. CMS Sickle Cell Disease Action Plan. cms.gov. September 2023. Accessed June 2024. https://www.cms.gov/files/document/sickle-cell-disease-action-plan.pdf
11. H.R.3884 - Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act of 2023. congress.gov. Accessed June 18, 2024. https://www.congress.gov/bill/118th-congress/house-bill/3884
12. S.1423 - Sickle Cell Care Expansion Act of 2023. congress.gov. Accessed June 18, 2024. https://www.congress.gov/bill/118th-congress/senate-bill/1423
13. H.R.7432 - Sickle Cell Disease Comprehensive Care Act. congress.gov. Accessed June 18, 2024. https://www.congress.gov/bill/118th-congress/house-bill/7432
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