Sickle Cell Disease: Voxelotor for Treating Hemolytic Anemia

Sickle cell disease (SCD) has prompted evidence-based recommendations for the use of voxelotor (Oxbryta) in treating hemolytic anemia in individuals aged 12 years and older. NICE develops technology appraisal guidance through a rigorous process. The recommendations in this guidance represent the view of NICE after careful consideration of the available evidence.

Health professionals are expected to take this guidance fully into account alongside the individual needs, preferences, and values of their patients. The application of the recommendations is at the discretion of health professionals and their patients and does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Sickle Cell Disease: Reporting Adverse Events and Funding Responsibilities for Treatment Implementation

All adverse events related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme. Commissioners and providers are responsible for providing the necessary funding to implement the guidance when health professionals and their patients wish to use it, in accordance with the NHS Constitution. This responsibility must be balanced with duties to eliminate unlawful discrimination, advance equality of opportunity, and reduce health inequalities.

Voxelotor, with or without hydroxycarbamide, is recommended as an option for treating hemolytic anemia caused by SCD in individuals aged 12 years and over, only if: People are ineligible for or intolerant of hydroxycarbamide, or Hydroxycarbamide alone is insufficiently effective.

Voxelotor is only recommended if the company provides it according to the commercial arrangement. This recommendation does not intend to affect treatment with voxelotor that was started in the NHS before this guidance was published. Individuals undergoing treatment outside this recommendation may continue without change to the existing funding arrangements until they and their NHS healthcare professional consider it appropriate to stop. For children or young people, this decision should be made jointly by the healthcare professional, the child or young person, and their parents or carers.

There is an unmet need for effective treatments for SCD, and health inequalities affect people with the condition. Usual treatment options for hemolytic anemia caused by SCD include hydroxycarbamide (also known as hydroxyurea) and regular blood transfusions. For this evaluation, voxelotor was positioned as a second-line treatment. This does not include everyone it is licensed for. Clinical evidence suggests that people who take voxelotor are more likely to have an increase in hemoglobin levels compared to those who receive usual treatment. Although this is likely to be beneficial, the effectiveness of voxelotor remains uncertain because the key trial was short, so the long-term benefits are unclear. Additionally, the trial population did not fully represent those who would receive second-line treatment with voxelotor in the NHS, as participants were not able to have regular blood transfusions and did not have to have already taken hydroxycarbamide.

The cost-effectiveness estimates for voxelotor are also uncertain due to unsupported assumptions in the clinical evidence. However, voxelotor has the potential to partially address some health inequalities associated with SCD and the unmet need for effective treatments. Greater uncertainty in the clinical-effectiveness estimates is accepted as a reasonable adjustment for the significant disadvantages identified for people with SCD. Thus, a higher cost-effectiveness estimate than usual could be considered acceptable. Taking these additional factors into account, the most plausible cost-effectiveness estimates are below what NICE considers an acceptable use of NHS resources, leading to the recommendation of voxelotor.

In SCD, a gene mutation causes red blood cells to become irreversibly sickle-shaped, leading to hemolysis and hemolytic anemia, resulting in low hemoglobin levels. Symptoms of hemolytic anemia in SCD include pain, fatigue, weakness, tachycardia, dizziness, and confusion. Sustained hemolytic anemia can affect the function of multiple organs, causing damage, strokes, sight loss, and other symptoms that substantially impact quality of life. The patient experts described how normal everyday activities could be challenging for individuals with hemolytic anemia, and some symptoms could lead to sickle cell crises that require multiple hospital treatments each year. This can have a considerable impact on work, education, and the lives of carers. The pain associated with SCD has a significant impact on quality of life, with constant background pain and episodes of excruciating debilitating pain. Maintaining social relationships and employment can be difficult due to complications from SCD. The clinical experts highlighted that increasing hemoglobin levels in people with hemolytic anemia would reduce hospital admissions, the risk of symptoms, and organ damage, improve mental health, and reduce time off work or education. However, this effect was not reflected in the HOPE trial.

Usual treatment for SCD includes ensuring adequate hydration, preventing infections, and treating pain, with or without hydroxycarbamide. Regular blood transfusions may also be considered. Avoiding triggers such as cold weather, stress, and physical activity is also crucial. Limited treatment options are available for SCD, and there is an unmet need for effective and well-tolerated treatment that can be taken over a lifetime. The clinical experts noted that voxelotor’s impact on fertility is unknown due to the lack of long-term data or trial data.

Sickle Cell Disease Treatment: Voxelotor Positioned as Second-Line Therapy After Hydroxycarbamide

The company positioned voxelotor as a second-line treatment after hydroxycarbamide in people who are ineligible for, intolerant of, or have insufficient response to hydroxycarbamide. The HOPE trial included individuals who had previously taken, were taking, or had

never taken hydroxycarbamide, with 64% of participants in the voxelotor arm and 63% in the placebo arm taking hydroxycarbamide at baseline. The trial excluded individuals undergoing regular blood transfusions, but the company’s model included different rates of regular transfusion therapy for each arm, leading to a misalignment with the trial population.

The comparator in the company’s cost-effectiveness analysis was established clinical management without voxelotor, defined as supportive care, hydroxycarbamide, and regular blood transfusions. Clinical experts confirmed that all individuals with SCD should be offered hydroxycarbamide as first-line treatment. However, some cannot take hydroxycarbamide or choose not to due to side effects or concerns about fertility. The committee concluded that it was important to distinguish between individuals with medical contraindications to hydroxycarbamide and those who choose not to take it for other reasons.

The HOPE trial showed that more individuals taking voxelotor had an increase in hemoglobin of at least 1 g/dl at week 24 compared to those receiving standard care, a difference that was statistically significant. This increase in hemoglobin is likely to be beneficial for individuals with SCD, as it can improve symptoms and quality of life. However, the long-term impact of voxelotor on the development of SCD complications remains uncertain. The trial did not show significant differences between voxelotor and placebo for short-term outcomes such as the rate of vaso-occlusive crises and health-related quality of life.

The company submitted a discrete event simulation model to estimate the cost-effectiveness of voxelotor compared to standard care for treating hemolytic anemia in SCD. The model was highly sensitive to the rates of regular transfusion therapy. The committee noted that the model included different rates of regular transfusion therapy at baseline for the voxelotor and standard-care arms, based on estimates from a modified Delphi panel. The committee requested scenario analyses using real-world evidence from the RETRO study to inform these rates. The RETRO study provided real-world evidence of the rates of regular transfusion therapy for individuals before and after starting treatment with voxelotor, which was considered less uncertain than expert opinion from the Delphi panel.

The HOPE trial did not show a significant difference in EQ-5D scores between the voxelotor and standard-care arms. The company used a patient journey survey of individuals with SCD to estimate the utility benefit per 1 g/dl increase in hemoglobin. The committee recognized that an increase in hemoglobin of 1 g/dl was likely to be associated with an improvement in quality of life for individuals with SCD, despite the uncertainty.

The committee’s preferred assumptions aligned with the updated company base case, except for the rates of regular transfusion therapy with standard care and voxelotor. Applying the company’s updated patient access scheme and incorporating additional flexibilities, the ICER for voxelotor compared with standard care was within the range that NICE considers an acceptable use of NHS resources for this appraisal.

The committee considered potential equality issues and the significant unmet need for effective treatments in SCD. It acknowledged that SCD is more common in certain ethnic groups that experience worse health outcomes and barriers to treatment. The committee concluded that it was willing to accept a higher cost-effectiveness estimate for voxelotor to address health inequalities, despite the considerable unresolved uncertainty.

The NICE health technology evaluations manual states that consideration of cost effectiveness is necessary but not the only basis for decision-making. The committee applied flexibility by accepting greater uncertainty around clinical-effectiveness estimates, accepting a higher cost-effectiveness estimate, and considering potential uncaptured benefits. With these considerations, voxelotor was recommended for routine use for treating hemolytic anemia caused by SCD in individuals aged 12 years and older.