New Gene Therapies Offer Hope to Patients with Sickle Cell Disease
All the way home from school, Talia's mind buzzed with excitement about the fun she would have with her friends after getting off the bus. As soon as they reached their stop, the group headed to the neighborhood park to shoot some baskets. Amidst the laughter and games, Talia suddenly found herself struggling to breathe and overwhelmed by fatigue. Despite her eagerness, just ten minutes at the park was all she could manage before her energy waned. At 12 years old and in the sixth grade, Talia faces more challenges than her peers – she has sickle cell disease (SCD). This condition limits her from engaging in physically demanding activities, casting a shadow on her dreams of playing professional basketball. With a heavy heart, she made her way back home, those dreams feeling more distant than ever.
Children across the United States and globally share Talia's experience, harboring dreams of sports or simply living a "normal" life, yet the harsh reality of SCD often shatters these aspirations. As they grow into adulthood, even securing steady employment can be a daunting challenge. However, a ray of hope shines with the recent FDA approval of Casgevy and Lyfgenia, groundbreaking gene therapies for sickle cell disease. These one-time treatments hold the promise of opening doors previously thought closed to patients with SCD, offering them new opportunities and a chance at a life unencumbered by the disease's limitations.
Who is Affected?
In the United States, around 100,000 individuals live with Sickle Cell Disease (SCD). Most of these cases, approximately 93%, occur in individuals of Black or African American ancestry. However, SCD also impacts other ethnicities: Hispanic Americans represent about 5% of cases, while those of Southern European, Middle Eastern, and Asian Indian heritage comprise the remaining 2%.
Origins & Early Treatments
The discovery of Sickle Cell Disease (SCD) in Western medicine dates back to 1910, with a Chicago physician's description of "sickle-shaped" red blood cells. The cause, identified in 1957 as a genetic mutation for abnormal hemoglobin, is believed to have originated in Africa as a defense against malaria. Treatment initially focused on blood transfusions in the 1960s, with the first SCD-specific medication, hydroxyurea, gaining FDA approval in 1998.
Impacts of the Condition
Individuals with SCD possess a mutated hemoglobin gene, causing their red blood cells to take on a sickle or crescent shape. These cells, less efficient in oxygen transport and shorter-lived than normal cells, lead to anemia and fatigue due to rapid cell death. This heightened cell turnover results in jaundice from increased bilirubin levels. Moreover, these rigid, sticky cells often clump and obstruct blood flow in smaller vessels, causing vaso-occlusive crises (VOCs) characterized by severe pain, especially in the chest, arms, and legs. Such crises can manifest as acute chest syndrome, mimicking pneumonia, and are life-threatening. Stroke is another severe complication, resulting from blocked blood flow to the brain.
Emergency care and hospitalizations are frequently necessary for managing VOCs and providing pain relief, leading to higher healthcare utilization among SCD patients. This has unfortunately led to the misconception of these patients as "drug seekers," a label that overlooks the intense, often unbearable pain they endure. SCD affects almost every major organ, causing increased risk of infections, kidney and bone damage, eye problems and sometimes multiple organ failure. Tragically, the median age of death for SCD patients is around 43 years old.
Current Treatments
Hydroxyurea as Standard of Care:
Early Use: Off-label use of Hydrea (hydroxyurea) [WAC $420/yr] for SCD began in the early 1990s, initially approved for some cancers.
FDA Approval for SCD: Droxia (hydroxyurea) [WAC $2069/yr] was FDA-approved in 1998 for adult SCD treatment.
Pediatric Studies and Usage: Studies in 2003 confirmed its safety and efficacy for children and infants as young as 9 months. This led to widespread off-label use and prescribing of compounded hydroxyurea suspensions for young patients.
Siklos for Pediatrics: Approved in 2017 for patients 2 years and older, Siklos tablets [WAC $60,898/yr] dissolve in water for easy pediatric administration.
Additional FDA-Approved Medications:
Endari: Approved in 2017 for patients 5 years and older, this powdered l-glutamine formulation [WAC $48,454/yr] has been shown to reduce VOC frequency and hospitalization rates.
Oxbryta: An oral agent approved in 2019 for children aged 4 and older [WAC $139,047/yr]. Increases hemoglobin levels, with ongoing trials to confirm clinical outcome improvements.
Adakveo: An intravenous treatment administered monthly in medical facilities, approved in 2019 [WAC $117,741/yr]. Its effectiveness in reducing VOC frequency is currently under review following recent phase III study results.
Limited Curative Interventions
SCD treatment options are limited, with hematopoietic stem cell transplantation (HSCT) being the only established cure. However, HSCT is not widely accessible. It requires a matched related sibling donor, often unavailable to patients. Additionally, HSCT carries significant risks and is ideally performed in children at high risk for severe SCD before complications develop. Despite its decades-long use, only about 1,200 HSCT transplants for SCD have been carried out to date.
This highlights the urgent need for additional, potentially curative therapies for a condition identified over a century ago in the U.S. The recent approval of two gene therapies offer hope for significant improvements in the lives of those affected by SCD.
Gene Therapies Bring Hope
On December 8, 2023, the FDA approved Casgevy and Lyfgenia, the first gene therapies for treating SCD in patients 12 years and older with a history of recurrent VOCs. While both target the same patient population, their distinct methodologies will influence treatment choice.
Each therapy involves harvesting and genetically modifying the patient’s own stem cells before a one-time infusion. High-dose chemotherapy is administered before this infusion to eliminate the patient’s mutated stem cells, making way for the modified cells.
Casgevy ($2.2 million for the one-time therapy), developed by Vertex Pharmaceuticals and CRISPR Therapeutics, uses CRISPR/Cas9 genome editing to increase fetal hemoglobin levels in red blood cells, reducing sickling. Clinical trials indicated a 93% success rate in patients being free from VOCs over 12 consecutive months in a 24-month period.
Lyfgenia ($3.3 million for the one-time therapy), by bluebird bio, employs a lentiviral vector for genetic modification. It produces red blood cells with modified hemoglobin less prone to sickling. Clinical trials showed 88% of patients experiencing complete resolution of VOEs 6 to 18 months post-infusion. However, Lyfgenia's trials also reported occurrences of blood cancer, leading to a black box warning for lifelong hematologic malignancy monitoring for patients who receive this therapy.
Navigating the Cost of Gene Therapies: Alternative Payment Models
The groundbreaking gene therapies for SCD come with steep price tags, presenting financial challenges for healthcare payers. While these therapies are one-time treatments, the cumulative cost of treating a significant number of patients is daunting. Unlike treatments for rare conditions like hemophilia or Spinal Muscular Atrophy, which affect fewer individuals, SCD has a much wider impact, with about 16,000 patients in the U.S. potentially eligible for these therapies. This poses a particular challenge for state budgets, as estimates suggest that two-thirds of SCD patients are on government health insurance, primarily Medicaid.
Recognizing this financial burden, manufacturers have introduced alternative payment models in recent years. These include outcomes-based models, where a portion of the total cost is paid upfront, followed by additional payments only if the treatment continues to be effective. Another model involves manufacturers offering refunds for a part of the cost if the treatment ceases to benefit the patient within a certain period.
Bluebird Bio, for instance, has secured outcomes-based reimbursement contracts with various payers, covering 200M lives in the U.S. This model, based on hospitalizations related to VOCs up to three years post-infusion of Lyfgenia, alongside Bluebird’s extensive network of payers, providers, and qualified treatment centers, supports the premium pricing of Lyfgenia.
However, Vertex Pharmaceuticals has yet to announce a similar outcomes-based or alternative payment model for Casgevy. They have, though, secured an agreement with Synergie Medication Collective, a medication contracting organization founded by Blue Cross and Blue Shield affiliates, covering approximately 100 million patients commercially, to provide access to Casgevy.
These innovative payment approaches are crucial in making these life-altering treatments accessible, ensuring that financial constraints do not hinder patient care.
Immeasurable Benefits
Although the extreme high cost of gene therapies for SCD can be justified by the offset in medical costs resulting from reduced hospitalizations, decreased need for costly medications and transfusions over time, it is nearly impossible (yet necessary from a societal financial perspective) to put a price on the potential for improved quality of life and ability to live longer. Although the durability of these gene therapies is still in question due to the limited amount of clinical trial data, patients are finding hope in the potential for a transformative impact on their lives. Patients, providers, and healthcare payers have all been anticipating this potential cure for SCD and hopefully many patients will be able to benefit from them in the not-too-distant future.
By Jason Peterson, RPh, Clinical Pharmacist at Nuwae
Sources:
American Red Cross. History of Sickle Cell Disease. Available at: https://www.redcrossblood.org/donate-blood/blood-types/diversity/african-american-blood-donors/history-of-sickle-cell-disease.html (Accessed 2024 January 3)
Ashorobi D, Naha K, Bhatt R. Hematopoietic Stem Cell Transplantation in Sickle Cell Disease. 2023 Jul 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30860750.
Beaudoin F, Thokala P, Nikitin D, Campbell J, Spackman E, McKenna A, Pearson SD, Rind DM. Gene Therapies for Sickle Cell Disease: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, April 12, 2023. https://icer.org/assessment/sickle-cell-disease-2023/.
Centers for Disease Control and Prevention. Data & Statistics on Sickle Cell Disease. Available at: https://www.cdc.gov/ncbddd/sicklecell/data.html (Accessed 2024 January 3).
U.S. Food and Drug Administration. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease (Accessed 2024 January 3).