Key Considerations for Implementing CRISPR/Cas9 Therapy in Health Systems

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In December 2023, the FDA approved the first 2 curative cell-based gene therapy agents for sickle cell disease in patients 12 years and older: exagamglogene autotemcel (exa-cel; Casgevy; Vertex Pharmaceuticals Incorporated) and lovotibeglogene autotemcel (lovo-cel; Lyfgenia; bluebird bio, Inc). Exa-cel is also the first cell-based therapy using the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) technology (CRISPR/Cas 9) to treat genetic diseases, marking the beginning of commercializing this gene editing technique. Invented by American scientist Jennifer Doudna, PhD, and French scientist Emmanuelle Charpentier, PhD, this CRISPR/Cas 9 technique allows precise DNA editing in human, animals, and plants, whereby small sections of DNA can be deleted, modified, and/or added. For their work, Doudna and Charpentier were awarded the 2020 Nobel Prize in Chemistry.¹

Sickle cell disease is caused by a single base-pair gene mutation on chromosome 11, which leads to amino acid replacement of the hydrophilic glutamic acid with hydrophobic amino acid valine in the β-globin. This mutation causes the formation of abnormal hemoglobin S (Hgb S), which aggregates and causes the red blood cells to become sickle shaped instead of the normal disc shape. This change leads to shorter red blood cell survival time, accumulation of red blood cells, and reduced oxygen transport within the body, which can result in severe pain, anemia, stroke, and multiorgan damage.^2,3

Patients with sickle cell disease need frequent blood transfusions and hydroxyurea for disease management. The accumulation of red blood cells and restricted blood flow may also cause vaso-occlusive crisis (VOC), which an require additional hospitalization. The lifespan for patients with sickle cell disease is approximately 52.6 years, compared with the average life expectancy for men of 73.5 years globally and 79.3 years in the United States.^3,4

The only curative treatment prior to the approval of exa-cel and lovo-cel was bone marrow transplant (BMT). However, less than 20% of all patients with sickle cell disease can find matching donors. In addition, BMT comes with its own risks, such as graft-vs-host disease, graft failure, organ damage, and infections. Patients also need lifelong immunosuppressants if the stem cells for transplant come from a donor.⁵

In addition, sickle cell disease poses significant financial burdens on patients, families, and the health care systems, as patients often need frequent blood transfusions, emergency department visits, and hospital admissions to manage severe VOC. The unmet need is great for both improved quality of life and extended life expectancy. There are approximately 100,000 patients diagnosed with sickle cell disease in the United States.⁴

Sickle cell disease, which can affect children from a very young age, is a monogenic disorder, making it an ideal candidate for gene editing treatment. Because fetal hemoglobin does not cause red blood cell sickling in newborn babies, young infants with sickle cell disease are asymptomatic. As the babies grow older, adult hemoglobin (β-globin) concentrations increase, causing sickle cell disease–related issues.⁵ The approval of exa-cel and lovo-cel generated great excitement in the health care industry because they are the first curative agents for this painful and debilitating illness. The wholesale acquisition cost for 1 course of exa-cel is $2.2 million vs $3.1 million for 1 course of lovo-cel.⁶ Given the innovative nature and high cost of these therapies, health care leaders should develop strategies to balance best clinical outcome and financial sustainability.

The manufacturers of both agents will conduct long-term follow-up posttreatment studies to further evaluate the efficacy and safety of these therapies. The CLIMB SCD-121 trial (NCT03745287) for exa-cel and the HGB-206 trial (NCT02140554) for lovo-cel are ongoing.

Exa-cel uses the CRISPR/Cas9 system to diminish the BCL11A gene expression for β-globin and reactivate the production of fetal hemoglobin (γ-globin), increasing the production of γ-globin; γ-globin does not cause the hemoglobin polymerization and red blood cell sickling, which induces VOC and other related illnesses. Exa-cel is indicated for sickle cell disease and transfusion-dependent β-thalassemia (TDT) due to Hgb S. The result is a reduction of the amount of abnormal Hgb S production, thereby curing sickle cell disease and TDT. This scientific breakthrough therapy can lower morbidity and mortality in patients with sickle cell disease and TDT.^5,7

CLIMB SCD-121 is a global multicenter, single-arm, open-label, phase 3 trial studying the safety and efficacy of exa-cel. It reported a 96.7% treatment response at the end of a 24-month follow-up, with 29 of the 30 patients achieving 12 months of freedom from severe VOC. Further, 100% (30 patients) were free of hospitalization due to severe VOC for 12 consecutive months. The trial reported no incidence of hematologic malignancy, non-target gene editing, treated graft failure, or graft rejection. The adverse effects (AEs) reported were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia, headache, and itching. Additionally, no fatality was reported in CLIMB SCD-121, and no black box warning is in the FDA approval package.⁷

HGB-206 reported an 88% VOC-free rate. The VOC-free time in study participants ranged from 6 months to 18 months. The common AEs noted in the trial were stomatitis; low levels of platelets, white blood cells, and red blood cells; and febrile neutropenia; however, 2 cases of hematologic malignancy and patient death were reported. A black box warning was added for hematologic malignancy for the lovo-cel package insert. However, no association between lovo-cel and the insertional oncogenesis was reported by the primary investigators. Patients who received lovo-cel will receive long-term monitoring for hematologic malignancies, according to the FDA approval letter. The FDA also requested a 15-year posttreatment prospective study to assess the risks of secondary malignancies.^8-10

Based on currently available data, exa-cel seems to be a slightly safer, more effective, and lower-cost option. However, long-term efficacy and safety data are forthcoming.

The exa-cel treatment involves at least 8 weeks of red blood cell transfusion to reduce the Hgb S level to less than 30% and to achieve total hemoglobin level at 11 g/dL. The hematopoietic stem cell mobilization treatment can then be administered, followed by apheresis, to collect CD34+ cells. The harvested cells will then undergo genetic modification by the CRISPR/Cas9 system, as described previously. Full myeloablation is necessary prior to the infusion of edited cells.

Patients must be admitted into a hospital for this process and the final infusion of modified cells. Therefore, all treatment centers must undergo a rigorous certification process to ensure that the center can provide appropriate care for these patients at each step in the treatment protocol. Facilities with well-established BMT programs may be ideal candidates, as they have well-trained pharmacy, nursing, and quality leadership teams, as well as mature cellular therapy program policies and procedures. Because exa-cel is approved for patients 12 years or older with sickle cell disease and TDT, facilities that plan to be certified to offer this treatment must be able to care for pediatric patients as young as 12 years.

As noted earlier, a single course of exa-cel costs $2.2 million, and payer coverage can be complicated. Medicaid coverage varies state by state; for patients with Medicare, exa-cel may qualify for new technology add-on payments. This is welcome news, given the ultrahigh cost and the innovative nature of this treatment.

Hospital charges will need to cover pretreatment infusions and posttreatment hospitalization; thus, the actual cost of the treatment may exceed the initial $2.2 million cost. For this reason, it may be beneficial for health care facilities to provide this treatment in hospital-owned infusion centers, thereby maximizing 340B program benefits. However, there has been no confirmation of 340B price availability as of the date this article was written.

The postinfusion hospital stay can also be costly, and coverage can be complex for different payers. There is general coding and billing information provided on the manufacturer’s website for frontline providers to reference. The most common diagnoses would be under D57, sickle cell disorders. However, the specific modifiers and other information needed for each payer may vary. The International Statistical Classification of Diseases, Tenth Revision (ICD-10) code for inpatient stay may be considered under the cell mobilization, cell collection, and conditioning category. The exa-cel administration ICD-10 Procedure Coding System codes are XW133J8 and XW143J8.^11-13

Exa-cel represents the first wave of the CRISPR/Cas9 technology–based therapy, with other CRISPR/Cas9-related treatments for other disease states underway. There are 61 clinical trials registered at ClinicalTrials.gov that are associated with CRISPR/Cas9-based therapies. In these trials, researchers are investigating these therapies for cancer, diabetes, heart diseases, and rare diseases.¹⁴

CRISPR/Cas9 technology is likely to revolutionize precision medicine. To prepare for these therapies, health care leaders must develop and implement innovative methodologies to optimize the clinical benefit of this new treatment option while maintaining health system financial sustainability.

References

1. The Nobel Prize in Chemistry 2020. Press release. Nobelprize.org. October 7, 2020. Accessed February 25, 2024. https://www.nobelprize.org/prizes/chemistry/2020/press-release/

2. Ceglie G, Lecis M, Canciani G, Algeri M, Frati G. Genome editing for sickle cell disease: still time to correct? Front Pediatr. 2023;11:1249275. doi:10.3389/fped.2023.1249275

3. Ma L, Yang S, Peng Q, Zhang J, Zhang J. CRISPR/Cas9-based gene-editing technology for sickle cell disease. Gene. 2023;874:147480. doi:10.1016/j.gene.2023.147480

4. Jiao B, Johnson KM, Ramsey SD, Bender MA, Devine B, Basu A. Long-term survival with sickle cell disease: a nationwide cohort study of Medicare and Medicaid beneficiaries. Blood Adv. 2023;7(13):3276-3283. doi:10.1182/bloodadvances.2022009202

5. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384(3):252-260. doi:10.1056/NEJMoa2031054

6. Pagliarulo N. Pricey new gene therapies for sickle cell pose access test. BioPharma Dive. Published December 8, 2023. Accessed February 9, 2024. https://www.biopharmadive.com/news/crispr-sickle-cell-price-millions-gene-therapy-vertex-bluebird/702066/

7. Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. Presented at: 65th Annual American Society of Hematology Meeting & Exposition; December 9-12, 2023; San Diego, CA.

8. bluebird bio details plans for the commercial launch of Lyfgenia gene therapy for patients ages 12 and older with sickle cell disease and a history of vaso-occlusive events. Press release. bluebird bio, Inc. December 8, 2023. Accessed January 4, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-details-plans-commercial-launch-lyfgeniatm-gene

9. Lyfgenia FDA approval. bluebird bio, Inc. December 8, 2023. Accessed January 4, 2024. https://investor.bluebirdbio.com/static-files/654a8ff5-eba5-49e2-80ec-47ead0cfebb4

10. Kanter J, Thompson AA, Pierciey FJ Jr, et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98(1):11-22. doi:10.1002/ajh.26741

11. Madigan V, Zhang F, Dahlman JE. Drug delivery systems for CRISPR-based genome editors. Nat Rev Drug Discov. 2023;22(11):875-894. doi:10.1038/s41573-023-00762-x

12. CMS. ICD-10-CM tabular list of diseases and injuries. CMS; 2010. Accessed November 29, 2023. https://www.cms.gov/medicare/coding/icd10/downloads/6_i10tab2010.pdf

13. FY 2024 IPPS proposed rule home page: table 6A-new diagnosis codes. CMS. Updated May 8, 2023. Accessed November 29, 2023. https://www.cms.gov/medicare/payment/prospective-payment-systems/acute-inpatient-pps/fy-2024-ipps-proposed-rule-home-page

14. The National Library of Medicine. ClinicalTrials.gov. Accessed February 27, 2024. https://clinicaltrials.gov/search?cond=CRISPR