ICER Says Gene Therapies For Sickle Cell Likely To Improve Lives, But Points To Uncertainties
Executive Summary
The drug pricing watchdog said improvement to patients’ quality and length of life from lovo-cel and exa-cel were likely, but noted ongoing uncertainty around durability and toxicity concerns.
With the US Food and Drug Administration likely to soon have two applications for gene therapies to treat sickle cell disease (SCD) on its plate, the Institute for Clinical and Economic Review (ICER) is assuming a price of $2m with potential outcomes-based reimbursement agreements for each while emphasizing the need to balance their potential to improve patient’s lives with ongoing uncertainty about their durability as well as concerns about adverse events, particularly from myeloablative conditioning.
The drug pricing watchdog released the draft evidence report on 12 April for the two therapies, bluebird bio’s lentiviral vector-based lovotibeglogene autotemcel (lovo-cel) and Vertex Pharmaceuticals Incorporated and CRISPR Therapeutics AG’s CRISPR/Cas9 gene editing-based exagamglogene autotemcel (exa-cel), which are in stiff competition to reach the market.
The public comment period is open until 9 May, and there will be an “early insights” webinar on 24 April. ICER said there is only very limited data on exa-cel in the public domain, with more expected to emerge in the coming weeks, and so it postponed the publication of its evidence report to 13 June and will have its virtual public meeting on 27 July.
Vertex/CRISPR said 3 April that they completed their rolling biologics license application submission to the FDA for exa-cel. (Also see "Vertex/CRISPR Are First To US FDA With A CRISPR Gene-Editing Therapy For Sickle Cell Disease" - Scrip, 3 Apr, 2023.) Bluebird had expected to file the week before Vertex/CRISPR, but it said 29 March that it had to delay those plans by at least a few weeks due to a product comparability analysis, though it sought to reassure investors that it was still on track to launch lovo-cel in early 2024. (Also see "Investors Take Flight After Bluebird Bio’s Sickle Cell Delay" - Scrip, 30 Mar, 2023.)
Balancing Outcomes With Unclear Durability, Adverse Events
The report assumed a “placeholder” list price of $2m each for lovo-cel and exa-cel, based on analyst estimates and pending greater clarity about its price from bluebird and Vertex/CRISPR as well as on the potential for outcomes-based agreements. In that sense, it is somewhat reminiscent of ICER’s report for bluebird’s gene therapy Zynteglo (betibeglogene autotemcel) in transfusion-dependent beta-thalassemia (TDT), which at the time of its release in June 2022 assumed a list price of $2.1m while pulling back from an earlier recommendation to reimburse the cost in five annual payments, in favor of a single upfront payment linked to an outcomes-based agreement. (Also see "Bluebird Could Find US Tailwind For Zynteglo After ICER Report" - Scrip, 2 Jun, 2022.)
Ultimately, when the FDA approved Zynteglo two months later, bluebird set the list price at $2.8m, with an outcomes-based agreement whereby the company would reimburse payers for up to 80% of the gene therapy’s cost if a patient failed to achieve transfusion independence within a defined period. (Also see "Bluebird’s Zynteglo Approval Kicks Off Commercial Operations" - Scrip, 17 Aug, 2022.)
A key difference between TDT and SCD is that while TDT is rare in the US, SCD is estimated to affect about 100,000 people, with economic costs estimated at around $2.98bn per year, a figure that does not factor in personal economic burdens as well as significant effects on patients’ quality of life, according to ICER.
Based on the assumed $2m placeholder price, ICER’s report calculated that for the health care system, that would translate into $211,000 per quality-adjusted life year (QALY) gained, $186,000 per equal-value life year (evLY) gained or $15,900 per vaso-occlusive crisis (VOC) averted. From a modified societal perspective, those figures would be $180,000, $158,000 and $13,500, respectively.
Overall, ICER gave lovo-cel a B+ or “incremental or better” rating compared with standard-of-care therapy – such as hydroxyurea, chronic blood transfusions, pain medication and iron chelation – particularly among patients with severe SCD, noting it was necessary to balance the marked improvement seen in a small number of such patients with “the potentially severe harms” of myeloablative conditioning and uncertainty around the duration of benefit.
Exa-cel got a C++ or “comparable or better” rating due to similar concerns and because CRISPR/Cas9 is newer than lentiviral gene therapy. But there was insufficient evidence to compare the two gene therapies against each other.
“Although uncertainties about durability and harm remain, both lovo-cel and exa-cel are likely to substantially improve quality and length of life,” the report says. “Ultimately, cost effectiveness will depend on the actual prices for these therapies.”
The most frequent potential harms stem from myeloablative conditioning, which relies on the drug busulfan. In particular, the drug carries the long-term risk of causing infertility, which in turn may deter use of the gene therapies, particularly among younger children, though for older patients sperm banking and ova collection are an option. (Also see "Busulfan-Induced Infertility May Deter Some Pediatric Patients From Bluebird, Other Gene Therapies" - Scrip, 19 Dec, 2022.) To that end, researchers have sought to develop alternatives to busulfan, such as CD117-targeting agents. (Also see "Jasper Data Show Potential Promise For Anti-CD117 Conditioning Agent" - Scrip, 3 Jan, 2023.)
While less prevalent, there have also been concerns about hematological malignancies in patients receiving lentiviral vector-based gene therapies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In August 2021, the FDA placed the development program for bluebird’s Skysona (elivaldogene autotemcel) in cerebral adrenoleukodystrophy (CALD) on clinical hold due to three boys in the trial program developing MDS believed to result from insertion of the viral vector.
Skysona’s label includes a black box warning about the risk of hematologic malignancies. (Also see "Bluebird Confident In Financial Runway For Skysona Launch" - Scrip, 19 Sep, 2022.) Zynteglo raised similar concerns, but two patients who had anemia initially suspected to result from MDS turned out to have developed it due to having alpha-thalassemia trait, and further investigation also alleviated concerns about AML that led bluebird to voluntarily suspend marketing of Zynteglo in the European Economic Area, prior to pulling it from the EEA market amid an impasse over pricing and reimbursement. (Also see "Busulfan-Induced Infertility May Deter Some Pediatric Patients From Bluebird, Other Gene Therapies" - Scrip, 19 Dec, 2022.)