The effectiveness and value of betibeglogene autotemcel for the management of transfusion-dependent beta-thalassemia

β-Thalassemia is an autosomal recessive disorder characterized by clinically significant anemia due to a genetic mutation of the HBB gene that leads to the reduced or absent synthesis of the β-globin proteins of hemoglobin. Patients with completely absent β-globin have a more severe clinical course, typically presenting in the first 6-24 months of life with severe anemia, failure to thrive, and end-organ damage.^1,2 These individuals, classified as having transfusion-dependent thalassemia (TDT), require lifelong, regular blood transfusions, typically every 2-5 weeks, and have a lower life expectancy, with the median age of death for TDT individuals in the United States being 37 years.³

Routine transfusions result in excess iron accumulation, which can cause significant health consequences of their own, including pulmonary hypertension, liver dysfunction, and cardiac manifestations. The current standard of care for these individuals includes iron chelation therapy to help prevent these complications from occurring.

Historically, hematopoietic stem cell transplantation (HSCT) has been the only curative treatment available and is typically performed only in children younger than 14 years who have a human leukocyte antigen-matched sibling donor. Less than 25% of TDT individuals have access to compatible donors, which is a limitation of using HSCT as a curative treatment.^4,5

Betibeglogne autotemcel (beti-cel, bluebird bio) is a potentially curative gene therapy for β-thalassemia that utilizes a lentiviral vector to insert a functioning version of the HBB gene into the patient’s own red blood cells. Patients must also receive myeloablative chemotherapy prior to receiving beti-cel. The US Food and Drug Administration (FDA) accepted bluebird bio’s Biologics Licensing Application of beti-cel for priority review on November 22, 2021. The FDA Advisory Committee meeting was held in early June 2022, and the date by which a regulatory decision was due was set for August 19, 2022.

The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of beti-cel. Here we present the summary of our findings and highlight the policy discussion with key stakeholders held at a public meeting of the New England Comparative Effectiveness Advisory Council (New England CEPAC) on June 17, 2022. The detailed report is available on the ICER website: https://icer.org/wp-content/uploads/2021/11/ICER_Beta-Thalassemia_Final-Report_071922.pdf.

Summary of Findings

CLINICAL EFFECTIVENESS

The evidence informing this review was derived from 2 phase 1 and 2 trials, 2 phase 3 trials, and 1 long-term follow-up study of trial participants.^6-10 Because of a manufacturing process modification following the phase 1 and 2 trials, which enhanced transduction efficiency in the phase 3 trials, evidence to inform our assessment of beti-cel was primarily derived from the 2 phase 3 trials (NorthStar-2 and -3), which enrolled 43 patients with TDT. Both NorthStar-2 and NorthStar-3 enrolled patients who were up to 50 years of age and received at least 8 transfusions per year for the last 2 years, or at least 100 mL/kg/year of packed red blood cell transfusions, and had genotypes consistent with TDT.^6,7

The prespecified primary endpoint for the trials was transfusion independence (TI), defined as weighted average hemoglobin of 9 g/dL or more without any packed red blood cell transfusions for a continuous period of at least 12 months and beginning within 12 to 24 months of beti-cel infusion. Among 41 participants infused with beti-cel from the phase 3 trials, 37 (90%) achieved TI.^11,12 Over a median follow-up of 42 months (ranges 23-88) across phase 1 and 2 and phase 3 studies, no patients who achieved TI have lost TI.¹³

In the phase 3 trials, all patients who received beti-cel and its preceding myeloablative conditioning experienced at least 1 adverse event (AE).¹⁴ Investigators deemed 2 cases of thrombocytopenia, 3 cases of abdominal pain, and 1 case each of leukopenia, neutropenia, mild thrombocytopenia, tachycardia, and pain in an extremity to be possibly related to the beti-cel infusion. There have been no deaths in patients with TDT across the beti-cel clinical development program, although serious AEs have been reported. All serious AEs were deemed likely related to myeloablative conditioning and included 5 cases of venoocclusive liver disease, stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, pyrexia, and heart failure.^13-15

Although there has been no evidence of insertional oncogenesis and no malignancies in the TDT trials of beti-cel, there have been reported cases of myelodysplastic syndrome and acute myeloid leukemia reported in gene therapy trials that have also used a lentiviral vector to treat other conditions.^16-18

LIMITATIONS OF THE CLINICAL EVIDENCE

The small sample sizes of the trials create uncertainty around the estimates of some patient-important outcomes, particularly AEs. Some serious harms are likely rare occurrences and may not be observed in small trials. Other AEs such as infertility may require more than a decade to assess. In addition to a small sample, the length of follow-up (maximum 7 years) is reassuring but leaves residual uncertainty of the longer-term durability of treatment effect. And finally, the trials lacked a control group for reasons of ethics and feasibility; therefore, there is no head-to-head comparison of beti-cel with HSCT among patients who would be eligible for both.

LONG-TERM COST-EFFECTIVENESS

We developed a decision analytic model to evaluate the cost-effectiveness of beti-cel vs standard of care (transfusions and chelation therapy) in patients with TDT who are eligible for the gene therapy. Our analysis reported results from a health care system perspective and a modified societal perspective given that patient and caregiver productivity costs are high relative to direct health care costs and that the impact of beti-cel on costs outside the health care sector is substantial. The model used a lifetime horizon, and costs and outcomes were discounted at 3% per year.

The model consisted of an upfront decision tree followed by a Markov model consisting of health states, including TD, TI, and dead. The percentage of patients achieving TI from beti-cel was based on trial data (90.2%), and the remainder of patients were assumed to remain TD over their lifetime. Redosing with beti-cel was not modeled. Given that the long-term durability of beti-cel is unknown, we assumed that starting in year 7, and each year thereafter, a small percentage of patients (0.271%) reverted to the TD health state (with half the baseline frequency of transfusions per year). Patients reverting to the TD health state remained in that state until death.

The outcomes of interest included the cost per quality-adjusted life-year (QALY) gained, cost per LY gained, cost per equal value of an LY gained (evLYG), and TD years. The base-case analysis was modeled using a payment plan that had been publicly described by the manufacturer as its goal: a full upfront payment with an outcomes-based agreement consisting of an 80% payback option for patients who do not achieve TI. Based on additional public comments by the manufacturer, we assumed that the upfront price would be $2.1 million. In accordance with the modifications to the ICER value framework for ultrarare diseases and single and short-term therapies, we conducted scenario analyses, which included a 50/50 shared savings scenario analysis in which 50% of lifetime cost offsets from beti-cel are assigned to the health care system instead of being assigned entirely to the treatment.^19,20 Full details of ICER’s cost-effectiveness analysis and model are available on ICER’s website: https://icer.org/wp-content/uploads/2021/11/ICER_Beta-Thalassemia_Final-Report_071922.pdf.

Results of the base-case analysis and the 50/50 shared savings scenario analysis are shown in Table 1 and Table 2, respectively. Beti-cel incurred additional costs but resulted in fewer TD years and more QALYs, LYs, and evLYGs. Incremental cost-effectiveness ratios approached $100,000 per QALY and evLYG from the health care system perspective. Findings from the modified societal perspective were below $50,000 per QALY or evLYG. Under the shared savings analysis, incremental cost-effectiveness ratios exceeded $200,000 per QALY and evLYG from both the health care system and modified societal perspectives.

TABLE 1.

Incremental Cost-Effectiveness Ratios for the Base Case of Beti-cel vs Standard of Care

Perspective	Cost per QALY gained, $	Cost per evLY gained, $	Cost per LY gained, $	Cost per TD year averted, $
Health care system	95,000	90,000	166,000	25,000
Modified societal	34,000	32,000	60,000	9,000

evLY = equal value life-year; QALY = quality-adjusted life-year; TD = transfusion dependent.

TABLE 2.

Scenario Analysis Results for the 50/50 Shared Savings Scenario of Beti-cel vs Standard of Care

Perspective	Cost per QALY gained, $	Cost per evLY gained, $	Cost per LY gained, $	Cost per TD year averted, $
Health care system	245,000	232,000	429,000	63,000
Modified societal	215,000	204,000	375,000	56,000

evLY = equal value life-year; QALY = quality-adjusted life-year; TD = transfusion dependent.

LIMITATIONS OF THE COST-EFFECTIVENESS MODEL

Given the heterogeneity in patient preferences around an intervention like beti-cel, we emphasize that the model-projected lifetime health gains are best interpreted only within the subpopulation of those who would first consider that the patient-related benefits of beti-cel outweigh the harms. Estimating beti-cel’s lifetime health outcomes and costs was conducted under conditions of evidence uncertainty, including the risk of death from treatment and long-term durability of treatment effect. The modeled outcomes-based risk agreement, if administered, would reduce some of the impacts of this evidence uncertainty. The cost-effectiveness findings were most sensitive to the frequency of transfusions and the cost of chelator therapy, suggesting that if the costs of standard of care were largely reduced, then beti-cel’s value would also deteriorate.

Policy Discussion

The New England CEPAC is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical and cost-effectiveness of health care interventions. The New England CEPAC comprises medical evidence experts, including practicing clinicians, methodologists, and leaders in patient engagement and advocacy. Their deliberation includes input from clinical experts and patient representatives specific to the condition under review, as well as formal comments from manufacturers and the public. A policy roundtable concludes each meeting, during which representatives from insurers and manufacturers join clinical experts and patient representatives to discuss how best to apply the findings of the evidence to clinical practice, insurance coverage, and pricing negotiations.

The ICER report on beti-cel for β thalassemia was the subject of a New England CEPAC meeting on June 17, 2022. Following the discussion, the CEPAC members deliberated on key questions raised by ICER’s report. The panel voted 12 to 0 that the evidence was adequate to demonstrate that the net health benefit of beti-cel is superior to that provided by standard clinical management.

The CEPAC panel also voted on “other potential benefits” and “contextual considerations” as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money not adequately captured in analyses of clinical and/or cost-effectiveness. They highlight several factors beyond the results of cost-effectiveness modeling that the CEPAC panel felt were particularly important for judgments of overall long-term value for money. The panel voted unanimously that beti-cel would have a major positive effect of offering a new treatment choice to patients, and the majority of the panel voted that beti-cel would have a major positive effect on patients’ and caregivers’ quality of life and their ability to achieve major life goals.

As described in ICER’s Value Assessment Framework, questions on long-term value for money are subject to a value vote when incremental cost-effectiveness ratios for the interventions of interest are between $50,000 and $175,000 per QALY in the primary base-case analysis. All panel members voted that beti-cel was either intermediate (n = 3) or high (n = 9) long-term value for money when compared with standard clinical management. Full voting items and results are shown in Table 3.

TABLE 3.

Votes on Other Benefits and Contextual Considerations for Beti-cel

When making judgments of overall long-term value for money, what is the relative priority that should be given to any effective treatment for β-thalassemia, on the basis of the following contextual considerations:
Contextual considerations	Very low priority	Low priority	Average priority	High priority	Very high priority
Acuity of need for treatment of individual patients based on short-term risk of death or progression to permanent disability	2	2	3	4	1
Magnitude of the lifetime impact on individual patients of the condition being treated	0	1	0	6	5
What are the relative effects of betibeglogene autotemcel vs standard clinical management on the following outcomes that inform judgment of the overall long-term value for money of betibeglogene autotemcel?
Potential other benefit or disadvantage	Major negative effect	Minor negative effect	No difference	Minor positive effect	Major positive effect
Patients’ ability to achieve major life goals related to education, work, or family life	0	0	0	1	11
Caregivers’ quality of life and/or ability to achieve major life goals related to education, work, or family life	0	0	0	1	11
Patients’ ability to manage and sustain treatment given the complexity of regimen	0	0	0	3	9
Society’s goal of reducing health inequities	0	0	6	5	1
A potential advantage for therapies that offer a new treatment choice with a different balance or timing of risks and benefits that may be valued by patients with different risk preferences	0	0	0	0	12

The policy roundtable discussion explored how best to translate the evidence and additional considerations into clinical practice and pricing and insurance coverage policies. The full policy recommendations can be found in the Final Evidence Report on the ICER website: https://icer.org/wp-content/uploads/2021/11/ICER_Beta-Thalassemia_Final-Report_071922.pdf. Several key policy recommendations for beti-cel are as follows: (1) All stakeholders have a responsibility to facilitate meaningful patient access to curative therapies for β-thalassemia in ways that do not exacerbate disparities. (2) Should the pricing and payment structure for beti-cel match the assumptions in this report, the treatment will meet traditional cost-effectiveness standards, and payers should therefore use the FDA label as the guide to coverage policy without seeking to unduly narrow coverage using clinical trial eligibility criteria. However, policy roundtable experts felt that it would not be unreasonable for payers to seek confirmation that patients do not have accessibility to a sibling-matched HSCT as first-line therapy. (3) Manufacturers should align prices with independent estimates of the patient-centered therapeutic value of their treatments. In the context of high-impact single or short-term therapies, transparent consideration should be given to a pricing scenario that “shares” any substantial cost-offset of treatment so that potentially large cost offsets are not used to justify exceedingly high 1-time prices.