Expanded eligibility for emerging therapies in sickle cell disease in the <scp>UK</scp> – crizanlizumab and voxelotor (2022)

Sickle cell disease (SCD) is one of the most common inherited conditions worldwide. It is characterised by the deformation of deoxygenated red blood cells into a rigid, sickle shape. This leads to vaso-occlusion, causing pain, tissue damage and chronic haemolytic anaemia. Management of SCD patients in the UK largely relies on transfusion therapy, hydroxycarbamide (hydroxyurea) and supportive care. Recently, there has been progress in developing novel treatments for SCD that target specific aspects of its pathophysiology.1 Crizanlizumab, an inhibitor of the cellular adhesion molecule P-selectin, has been shown to reduce the frequency of vaso-occlusive crises (VOC) in patients aged ≥16 in a randomised, placebo-controlled phase 2 trial (SUSTAIN).2 Voxelotor is an HbS polymerisation inhibitor and showed increased haemoglobin levels with reduced markers of haemolysis in a phase 3 trial (HOPE).3 There has been considerable interest from our patients regarding their eligibility for access to these new therapies. We assessed SCD patients from two Haemoglobinopathy Coordinating Centres (HCCs), University Hospitals Bristol and Weston NHS Foundation Trust (UHBristol) and Oxford University Hospitals NHS Foundation Trust (OxfordUH), against the eligibility criteria used in the SUSTAIN2 and HOPE3 trials to answer this question. These data were presented at the BSH Annual Scientific Meeting 2021.4 We subsequently validated our findings in a larger SCD population in Guy's and St Thomas' NHS Foundation Trust (Guy'sSTT). Since our study, crizanlizumab has been approved by the UK licensing authority National institute for Health and Care Excellence (NICE) and will be available for eligible patients in England soon.5 Crizanlizumab is accessible for SCD patients aged 16 and over via a Managed Access Agreement (MAA).5 The patient must have had two reported VOCs in the previous 12 months. The key difference is that the VOC may have taken place at home or in hospital, whereas in SUSTAIN2 it had to result in a medical facility visit. These broadened eligibility criteria mean more SCD patients will be eligible than we had originally calculated with the trial criteria. Records for patients with trial-eligible sickle cell disorders in each HCC were assessed. In UHBristol and OxfordUH, the period studied was 01 October 2019 to 30 Spetember 2020 and in Guy'sSTT the period was 01 April 2020 to 31 March 2021. Emergency presentations coded as related to a VOC were included. Electronic patient records and laboratory systems were reviewed for the inclusion and exclusion criteria from the HOPE and SUSTAIN trials to determine eligibility (Table 1). SCD genotype: HbSS, HbSC, HbSβ0 or HbSβ+ VOC: 1–10 per year Age: 12–65 years oldb b Over 18s only in UHBristol and OxfordUH data; over 16s only in Guy'sSTT data. Hb: 60–105 g/L If on hydroxycarbamide dose should be stable for at least 3 months SCD genotype: HbSS, HbSC, HbSβ0 or HbSβ+ VOC: 2–10 per year Age: 16–65 years oldb b Over 18s only in UHBristol and OxfordUH data; over 16s only in Guy'sSTT data. If on EPO, on for 6 months and dose stable for 3 months If on hydroxycarbamide, on for 6 months and dose stable for 3 months Male, female of non-childbearing potential, or female compliant with appropriate birth control methodsc c Not considered in Guy'sSTT analysis. Patients on regular transfusions Transfusion in past 60 daysc c Not considered in Guy'sSTT analysis. Comorbidities (hepatic dysfunction, ALT >4× ULN; severe renal dysfunction; malignancy within 2 years, unstable cardiac or pulmonary disease) Hb: <40 g/L Patients on regular transfusions HbA > 20% of total Hbc c Not considered in Guy'sSTT analysis. Planned exchange transfusion Comorbidities (active and unstable cardiovascular, neurologic, endocrine, hepatic, or renal disorders clearly unrelated to SCD; malignancy within 5 years). Results of the analysis of the UHBristol/OxfordUH SCD patient cohort according to the stringent trial criteria are shown in Table 2. These show that, out of 158 patients with eligible sickle cell disorders, there were only 17 patients (10.8%) for whom one of these therapies would be available if trial criteria were used. Only 7 (4.4%) would be eligible for both therapies, eight (5.1%) for voxelotor only, and two (1.3%) for crizanlizumab only. In the Guy'sSTT patient cohort, similar numbers are shown with only 97 of 817 patients (11.9%) being eligible under trial criteria for either therapy; 5.4% were eligible for both, 4.8% for voxelotor and 1.7% eligible for crizanlizumab. The most common reason for ineligibility according to the trial eligibility criteria was an insufficient annual rate of VOCs. SCD patients with no VOC in 12 months as defined by trial criteria were ineligible for either therapy; 47.5% in the UHBristol/OxfordUH cohort and 73.9% in the Guy'sSTT cohort. A further 2.3% of the Guy'sSTT cohort would have been excluded due to over 10 VOCs/year. Similarly, regular transfusion therapy would be the second most common exclusion trial criterion, applying to 18.4% of the UHBristol/OxfordUH cohort and 7.7% of the Guy'sSTT cohort (Table S1). In the recent NICE approval for crizanlizumab, transfusion therapy is not an exclusion criterion.5 In this study we have identified that a small percentage of SCD patients would be eligible for crizanlizumab and/or voxelotor if treatment is restricted to those who meet the trial criteria. This was tested in a small patient population (UHBristol/OxfordUH) and thereafter validated in a larger patient cohort (Guy'sSTT). We hypothesise that taking all patients together; this should represent an accurate estimate for the national SCD population. The main reason why our UK patient population would not have been eligible for crizanlizumab under the restrictive trial criteria is an insufficient number of documented VOCs per year. There are several reasons why these may be underreported. Firstly, time periods coincide with the Covid-19 pandemic. It is likely that a significant number of patients managed their VOC at home rather than presenting to acute services. In addition, in the Guy'sSTT cohort, VOCs were determined by clinical coding of attendances, which includes further scope for error, as telephone calls to an advice line will not be captured, visits may not be recorded and thus missed, or coded incorrectly. Based on this information, and the data on UK sickle cell patient numbers derived from the National Haemoglobinopathy Registry (NHR) Annual Data Report 2019/2020,6 the potential number of patients in England who would qualify for these treatments according to trial criteria can be estimated. There were 11 555 patients with SCD, of which 11 166 (96.6%) were HbSS, HbSβ0, HbSβ+ or HbSC. Therefore, an estimated 536 patients would qualify for voxelotor only (4.8%), 190 for crizanlizumab only (1.7%), 603 for both (5.4%) and 1329 for either based on the Guy'sSTT qualifying proportions. Taking into account the broader NICE approval criteria for crizanlizumab it is likely that 1.7% is an underestimation. We are aiming to monitor the uptake of patients commencing on crizanlizumab in England prospectively via the NHR. After both crizanlizumab and voxelotor had been approved by the Food and Drug Administration (FDA) (November 2019),7, 8, crizanlizumab received conditional marketing authorisation by the European Marketing Authority (EMA) in October 20209 and was recommended by NICE in October 2021.5 The broader eligibility criteria under the MAA mean more patients will be eligible than we had calculated. Accurate enumeration of sickle cell crises managed at home will be challenging. We therefore aim to collect this information prospectively. Voxelotor is under review by the EMA and NICE,10, 11 with licensed indications that are likewise less restrictive than those in the HOPE trial. Limitations of our study are that our data included only those aged over 16 (Guy'sSTT) or 18 (UHBristol/OxfordUH), while the trial criteria for voxelotor included patients aged 12 and over. Additionally, while the patients identified may be eligible for new therapies, uptake and adherence will require careful counselling and monitoring. Our study has shown that only a small percentage of patients meet trial criteria for crizanlizumab and voxelotor. Wider approvals are required to ensure benefit for sickle-cell-disease patients. The criteria in the MAA approval will ensure that more patients than we have predicted will soon have a choice of novel therapies available to them to improve clinical outcomes. Collection of real-life efficacy data in this cohort of sickle cell patients is crucial to confirm positive outcomes and improved quality of life. Sona M. Vora, Stephen Boyd, Nicholas Denny and Elizabeth Jackson contributed to data collection. Sona M. Vora and Stephen Boyd analysed the data and wrote the manuscript. Sanne Lugthart, Jo Howard and Noemi B. A. Roy reviewed the manuscript and supervised data collection. Sanne Lugthart designed the study. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.