For decades, there was little to no investment in new curative treatments for sickle cell disease (SCD) despite the devasting toll the condition takes on patient health and quality of life. Allogeneic hematopoietic cell transplant (HCT) has long been the only potential cure for SCD, though it comes with risks for infection and organ damage and not all patients can find a donor. Newer treatments, like voxelotor and crizanlizumab, have been added to the therapeutic options in SCD but do not have curative potential.
Now, two investigational gene therapy treatments – specifically developed as potentially curative treatment options for SCD – are being evaluated for approval by the U.S. Food and Drug Administration.
Lovotibeglogene autotemcel (lovo-cel), a lentiviral vector gene therapy, and exagamglogene autotemcel (exa-cel), a CRISPR-Cas9 technology, have both been found to virtually eliminate vaso-occlusive crises (VOCs) and associated hospitalizations in clinical trials among patients with severe SCD who are not eligible for a HCT from a matched sibling or haploidentical donor.1,2,3 On the strength of these findings, both gene therapies appear poised for U.S. approval by the end of 2023. However, clinicians, policymakers, and patients now face thornier questions around cost, insurance coverage, and access to care.
“SCD has suffered from years of underinvestment in the research and pharmaceutical space, and the families that suffer from SCD have traditionally faced significant barriers to health care. Those two things have to be the guiding light in how we approach this,” said Chancellor Donald, MD, chair of the American Society of Hematology’s (ASH) Committee on Practice, assistant professor of medicine at Tulane University School of Medicine in New Orleans, and chief medical officer of Taking Aim at Cancer in Louisiana (TACL). Dr. Donald is urging payers and policymakers to consider patient access at the outset.
Recently, the Institute for Clinical and Economic Review (ICER), an independent research institute, evaluated these two new gene therapies and determined that they would be cost effective when priced between $1.35 million and $2.05 million per treatment.4 The actual price will be set by the individual manufacturers, and insurance coverage decisions will be made later by federal health programs and private insurers. The ICER analysis provides a starting point for the discussion on access.
ASH Clinical News spoke with Dr. Donald, ICER officials, and other experts in both SCD and gene therapy about these new therapeutic approaches, cost effectiveness, and how to make these therapies available in light of existing health disparities among patients with SCD.
A New Way to Treat SCD
Gene therapy has long held promise as a cure in SCD because of its potential to selectively target the mutations in the hemoglobin beta subunit gene (HBB) that causes the condition.
“It’s been a vision for people thinking about SCD for decades,” said Matthew Porteus, MD, PhD, a professor of pediatric stem cell transplantation at Stanford School of Medicine and a member of ASH’s Subcommittee on Emerging Gene and Cell Therapies.
Lovo-cel and exa-cel each target the beta-globin gene but use different mechanisms of action to do so. With lovo-cel, researchers transplant autologous hematopoietic stem and progenitor cells that have been transduced with a lentiviral vector encoded with a modified beta-globin gene to induce production of anti-sickling hemoglobin (Hb).5 In contrast, exa-cel relies on CRISPR-Cas9 gene editing in the hematopoietic stem and progenitor cells at the erythroid-specific enhancer region of BCL11A to reduce BCL11A expression and turn on production of fetal hemoglobin (HbF).6
In the ongoing phase I/II HGB-206 trial, lovo-cel was evaluated in adolescents and adults with severe SCD. Among 32 patients in the group C cohort, 31 patients (96%) had complete resolution of severe VOCs through 24 months of follow-up. Adverse events (AEs) were mostly related to the busulfan conditioning regimen. The median vector copy number in peripheral blood remained stable in all patients, and the total Hb level increased without transfusions, according to data presented at the 2022 ASH Annual Meeting and Exposition. There were no cases of veno-occlusive liver disease, graft failure, insertional oncogenesis, or replication-competent lentivirus, researchers reported during their presentation at the ASH meeting.1,2
In the ongoing CLIMB-111 and CLIMB-121 trials of severe SCD and transfusion-dependent beta thalassemia, exa-cel demonstrated clinically significant reductions in VOCs and reductions in hospitalizations. Among 17 patients aged 12 to 35 years with SCD who were evaluable for efficacy, 16 patients (94.1%) achieved freedom from VOCs for at least 12 consecutive months, and all patients were free from hospitalizations related to VOCs for at least 12 consecutive months, according to data presented at the annual European Hematology Association Congress in June.3
Additionally, researchers observed that increases in HbF and total Hb occurred within the first few months after treatment and were maintained. The mean proportion of edited BCL11A alleles also remained stable in bone marrow and peripheral blood. On the safety side, patients with SCD who were treated with exa-cel did not develop malignancies, and no deaths or discontinuations were determined to be related to the treatment, according to the most recent study data reported.
Trials in both therapies have provided “fantastic clinical results,” essentially freeing patients of vaso-occlusive symptoms, said Marina Cavazzana, MD, PhD, director of the Department of Biotherapy at Necker Hospital in Paris.
The side effects profiles are also encouraging based on current data, she said, with none of the ongoing clinical trials showing signs of mutagenesis because of genetic manipulation. However, long-term follow-up data will be critical.
Comparative Effectiveness, Value, and Equity
The significance of these new therapies prompted ICER to launch a review of their comparative effectiveness with standard-of-care treatments and to aim to recommend a fair price for the therapies, also called a health benefit price benchmark. While other organizations perform comparative effectiveness reviews, ICER is unique in its role of suggesting a fair price for new medicines.
“We’re hoping to either push the manufacturer to moderate the price or push the insurers to improve access, if the price is fair, or hopefully do both,” said David Rind, MD, ICER’s chief medical officer and a primary care physician at Beth Israel Deaconess Medical Center in Boston, in describing the organization’s general rationale for formulating a health benefit price benchmark.
ICER compared lovo-cel and exa-cel to each other and to the standard-of-care treatments, which it defined as supportive care, hydroxyurea, and blood transfusions. They did not compare the gene therapies to HCT from a matched sibling or haploidentical donor because those patients were excluded from the pivotal clinical trials. ICER relied on the available clinical trial data, literature on VOCs, and perspectives from patients, caregivers, researchers, and manufacturers.
Overall, ICER concluded that lovo-cel provided “at least an incremental net benefit” compared with standards of care and possibly a substantial net health benefit. They gave it a rating of B+ for “incremental or better” based on its strong clinical performance in a small number of patients weighed against the potential for severe harms from the myeloablative conditioning regimen and the uncertainty around the duration of the benefit.
Exa-cel received a rating of C++, meaning that it is in the range of “comparable to better” as compared to standard of care. The exa-cel rating was lower than for lovo-cel, Dr. Rind said, largely because the CRISPR technology is so new. ICER was unable to compare lovo-cel and exa-cel directly because of a lack of evidence.4
“We gave a slightly lower evidence rating to the CRISPR therapy than to [lovo-cel] because at the time of the report, we had fewer patients who had received therapy, and CRISPR is new and we didn’t feel like we knew as much. [Lovo-cel] is essentially identical to [Bluebird Bio’s] therapy for beta thalassemia, so we know a little bit more about it,” Dr. Rind said. “That doesn’t change the fact that we don’t know which one of these is better.”
When it came to determining a fair price for the therapies, ICER assumed identical efficacy for the two gene therapies and arrived at a range of $1.35 to $2.05 million for the therapies based on a comparison to standard of care over a lifetime. The fair price analysis considered multiple factors, including VOCs, health-related quality of life, AEs, patient productivity and caregiver costs, total life years gained, quality-adjusted life years gained, equal value of life years gained, and the total costs of the intervention.4
ICER did not issue an “access and affordability alert” for gene therapies for SCD because they estimated that initial uptake of the therapies would be slow, limiting the overall budget impact of the therapies. “What we’re hearing is that in terms of eligible patients, people wanting to get this therapy, and the availability of centers right at the beginning, probably we’re not going to see large budget impacts over the first few years of this,” Dr. Rind said. “Even at these prices, the budget impact will not cause huge disruptions.”
Though the ICER report considered the health disparities and historical discrimination faced by patients with SCD, one criticism is that their methodology does not adequately address those factors. Conventional, societal factors like lost wages and transportation costs aim to account for some of the indirect costs of illness, but they are separate from the quantification of distributional equity, explained George Goshua, MD, MSc, an assistant professor of medicine at Yale School of Medicine whose laboratory is working on distributional cost-effectiveness analysis (DCEA) – conventional cost-effectiveness analysis that incorporates equity as a quantifiable element.
Dr. Goshua and his colleagues recently performed a DCEA of gene therapy versus standard-of-care treatments to derive an equity weight threshold that could be compared to historical surveys of how much Americans value equity in the context of income inequality.7 “If we assume that we care about inequity in the care of this historically marginalized population as much as we cared about income inequality in the past, we can derive an equity weight threshold for this decision,” he said.
The researchers estimated that at $2.45 million per treatment, gene therapy would not be conventionally cost effective but would be an equitable treatment for our society. The inequity aversion parameter of 0.9 falls within (and on the lower side) of the equity scale, which ranges from 0.5 to 3, Dr. Goshua said.
Whatever price tag the manufacturers of these therapies land on, it is likely to be high and out of reach for patients without insurance coverage. But even insurance coverage – whether through Medicaid or private insurance – will not guarantee access, according to experts in sickle cell care delivery.
The process of delivery for gene therapies is long and complex, which will limit the number of centers with the appropriate expertise to provide it, said Patrick McGann, MD, PhD, director of the Lifespan Comprehensive Sickle Cell Center and an expert reviewer on the ICER report. He estimates that no more than 50 to 100 centers in the U.S. would be able to provide gene therapy for SCD at the start.
“It’s not like the floodgates will open to allow everyone with SCD to receive these therapies,” he said. “I think many centers that are able to initially deliver gene therapy will do so carefully, by treating one or two patients at a time, which is not going to scratch the surface on the more than 100,000 Americans with SCD.”
Some hospital systems may have the expertise but choose not to offer the therapy because the costs of providing the wraparound services for the procedure, such as the conditioning therapy and transfusions, are not well reimbursed by Medicaid. “It’s another disincentive for hospitals to even do this,” Dr. McGann said.
The entire process of receiving gene therapy – from screening and organ-function testing to weaning off transfusions after the procedure – is likely to take a year and involve weeks in the hospital and months away from work and daily responsibilities, Dr. McGann said. The cost and time involved is likely to limit the number of patients willing to try the therapy, especially if they are stable on current treatment, he said.
The biggest access barrier for gene therapy, though, is that most patients today do not have a source of comprehensive sickle cell care to receive existing evidence-based therapies and supportive care, Dr. Donald said. A 2020 report card on the State of Sickle Cell Disease – issued by the Sickle Cell Disease Coalition, a group established by ASH that includes providers, families, and other stakeholders – rated access to care as 5.7 out of 10. Similarly, training and professional education on SCD for health care providers was rated 6.2 out of 10.8 Numerous studies have shown that patients with SCD lack access to specialized care, face barriers to obtaining pain treatment, and have limited access to existing treatments such as hydroxyurea.9
Without that infrastructure in place, patients will not hear about gene therapies or be assessed to determine their eligibility for treatment. Even if they can receive gene therapy, comprehensive pre- and post-therapy care will be critical to achieving success with the treatment, Dr. Donald said.
For this reason, Dr. Donald and other members of the ASH Committee on Practice are calling on policymakers to approach this sickle cell therapy differently and to gather input from all stakeholders while issues of pricing, coverage, and treatment rollout are determined.
“I would not want this exploration into this type of therapy for this patient population to fail and then thwart additional attempts for years and years. My biggest concern is that there is a rollout that wasn’t thoughtful enough, and then gene therapy is deemed not to be of value, and we don’t try again for several years,” Dr. Donald said. “We have to approach this differently.”
- Walters MC, Thompson AA, Kwiatkowski JL, et al. Lovo-cel (bb1111) gene therapy for sickle cell disease: updated clinical results and investigations into two cases of anemia from Group C of the phase 1/2 HGB-206 study. Blood. 2022;140(Supple 1):26-28.
- Bluebird Bio. New data from bluebird bio’s gene therapies for transfusion-dependent beta-thalassemia and sickle cell disease presented at 64th ASH Annual Meeting. December 10, 2022. Accessed Sept. 6, 2023. https://investor.bluebirdbio.com/news-releases/news-release-details/new-data-bluebird-bios-gene-therapies-transfusion-dependent-beta.
- CRISPR Therapeutics. Positive results from pivotal trials of exa-cel for transfusion-dependent beta thalassemia and severe sickle cell disease presented at the 2023 Annual European Hematology Association (EHA) Congress. June 9, 2023. Accessed Sept. 6, 2023. https://crisprtx.com/about-us/press-releases-and-presentations/positive-results-from-pivotal-trials-of-exa-cel-for-transfusion-dependent-beta-thalassemia-and-severe-sickle-cell-disease-presented-at-the-2023-annual-european-hematology-association-eha-congress.
- Beaudoin F, Thokala P, Nikitin D, et al. Gene therapies for sickle cell disease: effectiveness and value; evidence report. Institute for Clinical and Economic Review. August 21, 2023. Accessed Sept. 6, 2023. https://icer.org/assessment/sickle-cell-disease-2023/.
- 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.
- 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.
- Goshua G, Calhoun C, Ito S, et al. Distributional cost-effectiveness of equity-enhancing gene therapy in sickle cell disease in the United States. Ann Intern Med. 2023;176(6):779-787.
- Sickle Cell Disease Coalition. State of sickle cell disease: 2020 report card. Accessed Sept. 6, 2023. http://www.scdcoalition.org/pdfs/SCD%20Report%20Card%202020.pdf.
- Lee L, Smith-Whitley K, Banks S, et al. Reducing health care disparities in sickle cell disease: a review. Public Health Rep. 2019;134(6):599-607.
- Breda L, Papp TE, Triebwasser MP, et al. In vivo hematopoietic stem cell modification by mRNA delivery. Science. 2023;381(6656):436-443.
ASH Responds to the ICER Report, Encourages Comprehensive Care
ASH is actively involved in advancing research into gene therapies while ensuring patients can access comprehensive SCD care. In mid-May, ASH submitted feedback on the ICER report to assess the comparative clinical effectiveness and value of exa-cel and lovo-cel for SCD and has continued to engage with the Centers for Medicare & Medicaid Services (CMS) about coverage for these therapies and the need for access to comprehensive care.
ASH’s comments on the ICER report highlighted the importance of access to high-quality, comprehensive care for patients with SCD, as well as the therapies that patients, in conjunction with their physicians, decide are most appropriate. The Society’s comments also encouraged ICER to better reflect the inequities this patient population faces and to consider critical factors, including other SCD therapies and intervention, the impact of pain management, and the cost associated with long-term monitoring and related data collection.
In mid-July, ICER released the revised version of this evidence report,1 which addressed several of ASH’s comments and recommendations.
Over the summer, several ASH staff members also met with leaders from CMS who are overseeing the agency’s SCD-related efforts, including the development of the Cell and Gene Therapy Access Model. The meeting addressed questions and concerns about how CMS can ensure access to gene therapies for SCD once they are approved, which is expected by the end of 2023.
1. Institute for Clinical and Economic Review. Gene therapies for sickle cell disease: evidence report. July 13, 2023. Accessed Sept. 20, 2023. https://icer.org/wp-content/uploads/2022/11/ICER_SCD_revisedreport_071323.pdf.