Migalastat for treating Fabry disease

The committee understood that Fabry disease is a serious and progressive condition that causes a variety of symptoms and can greatly affect quality of life. It heard from patient experts that Fabry disease can cause significant disability and that people with the disease are likely to need a carer. The committee also understood that Fabry disease is a heterogeneous condition. The activity of the enzyme affected by Fabry disease (alpha-galactosidase A; alpha‑gal A) varies depending on the mutation; some mutations lead to reduced enzyme activity and others produce a non-functional enzyme or no enzyme at all. The committee concluded that Fabry disease is a serious condition with a major effect on quality of life.

The committee discussed the current treatment of Fabry disease. It understood that enzyme replacement therapy (ERT) with agalsidase alfa or agalsidase beta has been the standard of care since 2001. The committee heard that ERT can provide important clinical benefits and gave some people dramatic health improvements, slowing progressive organ damage. The committee was aware that the dose of agalsidase beta may be reduced when the condition is stable, although the effectiveness of this unlicensed dose is not fully established and practice varies between centres. The clinical experts noted in particular that because Fabry disease is progressive, it may be difficult to define 'stability', and clinicians and people with the disease are often reluctant to risk symptoms worsening and progressive organ damage. The committee understood that ERT has a number of limitations. These include an inconvenient dosing schedule every 2 weeks causing variation in enzyme levels, risk of infusion-related reactions and infections and the possibility of developing antibodies against treatment. The clinical experts suggested that there is also the theoretical possibility of limited penetration of ERT into key tissues. They advised that the decision about which ERT to use is usually made by the patient because there is no clear clinical difference between the 2 therapies apart from infusion time and risk of infusion-related reactions. The details of each therapy are explained to the person, who may also seek advice from family members already having treatment. People on ERT have the option of switching between the 2 therapies if needed. The committee concluded that ERT is an established treatment but there are still some unmet needs for people with Fabry disease.

The clinical experts explained that there are specific criteria for starting ERT for Fabry disease, primarily based on evidence of early clinical signs of kidney, heart or brain involvement. The committee was aware that the starting criteria for ERT for Fabry disease are described in the UK adult Fabry disease standard operating procedures (Hughes et al. 2013). Most men and roughly half of women have disease that meets these criteria when diagnosed. Of those whose disease does not meet the criteria at diagnosis, around 10% each year will progress to needing treatment. The clinical experts envisaged using the same starting criteria for migalastat. The decision about which treatment to use, migalastat or ERT, would be made by the clinician and the patient. The committee concluded that migalastat could be offered as an alternative to ERT and that no major changes to the current clinical pathway for Fabry disease would be needed.

The committee discussed how migalastat would be used in clinical practice. It heard from the clinical experts that they would expect migalastat to be an option for people with amenable mutations whose disease meets the existing starting criteria for ERT treatment. The committee understood that the UK adults Fabry disease standard operating procedure (Hughes et al. 2013) recommends that people with classical Fabry disease start ERT at diagnosis, and people with non‑classical Fabry disease start ERT when disease symptoms have an impact on quality of life or there is evidence of renal disease, cardiac disease, neurovascular disease or gastrointestinal symptoms. The clinical experts stated that similar criteria would be used to determine when patients might start migalastat and the committee considered that this approach was reasonable and consistent with the evidence it had seen. Stopping criteria for ERT include worsening of pain, deterioration of glomerular filtration rate or proteinuria, worsening heart failure symptoms and new presentation of clinically significant neurovascular disease. The patient experts noted that people with Fabry disease were very interested in a potential new treatment, and recognised the benefits of a more convenient oral option, but would make a careful decision about which treatment would be best for them, taking into account clinical effectiveness, their experience with ERT and convenience.

The committee noted that the company presented evidence from 2 randomised clinical trials, ATTRACT and FACETS, and from 2 open‑label extension studies. The company stated that migalastat was comparable in effectiveness to ERT and the clinical experts gave their opinion that migalastat was at least as good as ERT. However, the committee considered that the company's clinical effectiveness evidence had considerable weaknesses. It noted that the trials had enrolled small populations, were short in relation to disease progression, and did not collect sufficient data to formally establish the clinical equivalence of migalastat and ERT. The committee noted that the pre-specified criteria for comparability of migalastat and ERT were met, but it had some reservations about the interpretation of these. The company also presented some optimistic results for renal, cardiac and composite clinical outcomes and health-related quality of life. The clinical experts advised that people on migalastat had similar renal outcomes to those on ERT and that some cardiac outcomes appeared to improve with time spent on migalastat. People on migalastat reported that pain and gastrointestinal symptoms were manageable. The committee concluded that, despite some important uncertainties in the clinical evidence, migalastat may provide similar outcomes to ERT.

The committee considered that migalastat could offer additional benefits compared with ERT infusion because it is an oral treatment. The clinical and patient experts explained that ERT infusions every 2 weeks can have a major impact on a person's home and work life. An oral treatment would allow people with Fabry disease freedom from these frequent infusions. The committee recognised that oral treatment is more convenient than an infusion every 2 weeks. However, it acknowledged that there might be some concerns about whether people would fully adhere to treatment. In particular, it heard that adherence may be difficult in some young people and people who have had a stroke, for example. It also heard that there is a need to fast before and after taking migalastat. The committee was reassured by the clinical and patient experts that people with Fabry disease would be very motivated to continue treatment to avoid symptoms returning, but considered that it would be important to provide support to help people adhere to the treatment regimen. The committee was further reassured that the company was taking steps to support adherence. The committee concluded that an oral treatment would allow people with Fabry disease much more freedom.

The committee heard from the clinical experts that migalastat would be discussed as an option for treatment at the same time as ERT. Improvements in LVMi suggest that migalastat might be more beneficial in people with cardiac complications, but that they would not want to restrict the treatment to a particular group. The committee concluded that migalastat would likely be offered as an option to all people for whom treatment is suitable.

Migalastat is only suitable for people with specific amenable mutations. The company advised that there was variability in the in-vitro response to migalastat according to mutation, but only mutations for which migalastat produced substantial increases in enzyme activity were judged amenable. Migalastat does not work in people who have mutations that do not produce any alpha‑gal A. The committee was advised that the heterogeneity of Fabry disease would lead to some variation in results for individual people.

The committee heard that people have genetic testing when diagnosed, or when a close family member is diagnosed, as part of established practice in the NHS. The results of these tests can be checked against the migalastat amenability table. The company explained that any unknown mutations would be tested for amenability at no cost to the NHS. The committee concluded that this approach was acceptable and did not expect this testing to have any additional resource implications for the NHS. The committee understood that its recommendations would apply only to people with amenable mutations, consistent with migalastat's marketing authorisation.

Although the ATTRACT results met the pre-specified criteria for comparability between migalastat and ERT, the committee concluded that the evidence for overall clinical effectiveness of migalastat is uncertain and advised that more long-term data are needed. The committee therefore recommended that the company, treatment centres and NHS England should collect further evidence on the effectiveness of migalastat compared with ERT, particularly on the long-term benefits of treatment.

The committee heard details of the estimated 5‑year budget impact for migalastat. It was aware that the company had proposed a patient access scheme in which migalastat would be available with a discount. It was also aware that agalsidase alfa and agalsidase beta are available in the NHS with discounts. The results of the budget impact analysis, the migalastat patient access scheme discount and the ERT discounts are confidential and cannot be reported here. The committee concluded that the budget impact analysis showed that migalastat would be associated with savings for the NHS, compared with ERT.

The committee noted that the budget impact analysis was based on the company's estimate that migalastat might be considered for 142 people in England. This estimate was based on the prevalence of Fabry disease, the proportion of people diagnosed, the proportion of diagnosed people having treatment with ERT, and the prevalence of amenable mutations. The committee recalled that the clinical experts would consider migalastat for people whose disease meets the existing starting criteria for ERT treatment (see section 5.3). The estimate was considered reasonable by the clinical experts. Although new mutations are being added to the migalastat amenability table, the experts stated that the proportion of people for whom migalastat was suitable was unlikely to change substantially. The committee concluded that the company's estimate for the number of people for whom migalastat would be considered was reasonable.

The committee accepted the estimated net budget impact for migalastat based on the current prices of migalastat, agalsidase alfa and agalsidase beta. However, it noted that the results were highly sensitive to these prices. The committee highlighted that the prices of agalsidase alfa and agalsidase beta, and therefore the net budget impact for migalastat, may change if the national tenders for these drugs were renegotiated.

The committee noted that the company presented a cost–consequence analysis based on a Markov model. The committee considered that the company's approach and the structure of the model were generally reasonable, after discussion with the clinical and patient experts. The committee noted that the evidence review group (ERG) commented on a number of limitations in the company's model, and presented exploratory analyses to address these limitations. The main assumption in the model was clinical equivalence between migalastat and ERT. The committee recalled that the available evidence was consistent with this assumption (see sections 5.4 to 5.10) and therefore concluded that it was reasonable. However, the committee noted that the evidence was limited and uncertain, particularly for long-term outcomes.

The committee noted that the company used average weight from the general population to calculate the doses of ERT needed for treatment. This was questioned by the ERG, who commented that the average weight of people included in the clinical trials was low. However, the clinical experts considered that the average body weight of people with Fabry disease is not much different to that of the general population. The committee therefore concluded that the most appropriate body weights to use in the model were uncertain.

The committee noted that the company modelled the effect of disease complications on quality of life using disutilities. These disutilities were the same for end-stage renal disease, stroke and heart complications. The ERG had concerns about this, because they are very different conditions in terms of their effects on quality of life. The patient and clinical experts emphasised that each of these complications has a major effect on quality of life. The committee concluded that there were uncertainties about the disutilities for disease complications.

The committee noted that the infusion disutility had a substantial impact on incremental quality-adjusted life years (QALYs). The ERG stated that this disutility lacked face validity and was higher than the disutility for developing disease complications. The ERG reduced the infusion disutility by 50% in its preferred analysis. The committee recalled that patient and clinical experts stated that the oral administration of migalastat is a major advantage of this treatment, and that changing to an oral drug from an infusion could have substantial benefits. The committee accepted that oral delivery is an improvement compared with infusion. But it questioned the size of the disutility, noting that having an infusion was unlikely to reduce health-related quality of life to the same extent as developing a new disease complication. The committee concluded that it is plausible that migalastat is associated with more health benefits than ERT as a result of its more convenient administration, but the ERG's estimates were more likely than the company's estimates. Even then, the size of the benefit is highly uncertain because of the limited evidence. The results of the company's economic model showed that migalastat is associated with an incremental QALY gain of 0.98 compared with ERT. When the infusion disutility was decreased by 50% in the ERG's preferred analysis, the incremental QALYs reduced to 0.34 compared with ERT.

The committee noted the ERG's comment that the background mortality data used in the model produced an unexpectedly high life expectancy (83.4 years) for people with Fabry disease. It also noted that the model did not allow for people developing end-stage renal disease to stop treatment with migalastat.

The committee noted that ERG scenario 6 (when migalastat is stopped because of end-stage renal disease) was inappropriate because the clinical experts advised that some of these people would resume ERT, leading to both additional costs and additional benefits. Therefore, the true impact of people stopping migalastat because of end-stage renal disease would be much smaller than suggested by this scenario analysis. The committee concluded that the company and ERG scenario analyses show a range of possibilities, the majority of which are consistent with the evidence.

The committee discussed the total and incremental costs associated with migalastat, taking into account the patient access scheme for migalastat and the discounts for ERT. These results are commercial in confidence and cannot be reported here. The committee was aware that in the company base case and the ERG preferred analysis, migalastat was associated with lower costs than ERT. The committee concluded that the overall results were highly uncertain but consistent with migalastat providing additional health benefits at a lower cost compared with ERT, but the size of any additional benefits was highly uncertain.

The committee noted that the value of migalastat has only been assessed compared with ERT, and therefore migalastat should only be recommended for people with Fabry disease for whom ERT would otherwise be offered. It considered that this was appropriate, given the scope for the evaluation and the established use of ERT in current clinical practice. However, the committee emphasised that because NICE has not evaluated ERT, the benefits and value for money of ERT have not been formally considered. It therefore considered that, by extension, the benefits and value for money of migalastat were uncertain. The committee heard from NHS England that there was evidence to suggest that ERT may not provide value for money and therefore NHS England supported the need for an evaluation of all disease-modifying treatments for Fabry disease. The committee decided that its conclusions on the value for money of migalastat were appropriate given the current evidence and clinical practice, but that they would need to be reconsidered if ERT was no longer available in routine practice. It further concluded that a complete evaluation of the costs and benefits of ERT for Fabry disease would be valuable, and requested that NHS England considers doing such an evaluation.

The committee noted that there were a number of limitations of ERT because it is an infusion. As an oral therapy, migalastat may help to address some of these limitations and so have additional benefits beyond direct health benefits. The company presented infusion disutilities to capture this. Additional savings from the reduced need for homecare were also captured in the model.

The committee noted concerns that the once every other day dosage of migalastat could lead to low adherence, particularly for example for people with neurological problems because of stroke. The patient expert explained that symptoms of the disease return within 1 week of stopping treatment, which is likely to help adherence. For people who need extra support, the clinical experts explained that a mobile phone reminder app and other strategies can be used with the help of expert centre staff.

The committee acknowledged that Fabry disease is a serious condition that has severe effects on the lives of people with the condition, as well as their families and carers. It considered the evidence suggesting that migalastat has comparable effectiveness to ERT, and heard the experiences of the patient and clinical experts. It concluded that the evidence had considerable limitations but, on balance, migalastat was likely to provide similar benefits to ERT. The committee understood that migalastat may have additional benefits because it is taken orally rather than as an infusion. The committee considered that the company's economic model was broadly appropriate and that the ERG's exploratory analyses presented a range of possibilities that were consistent with the evidence. It concluded that migalastat provides the additional health benefits of an oral therapy at a lower cost compared with ERT, but that the clinical effectiveness evidence was highly uncertain. The committee accepted that, in the context of current clinical practice, the value of migalastat compared with ERT had been shown, although it noted that NICE has not evaluated ERT. The committee concluded that the case for national commissioning of migalastat is supported when used as an option for treating Fabry disease in people over 16 for whom ERT would otherwise be offered. It also concluded that further evidence on both the long-term effectiveness of migalastat and a full evaluation of the costs and benefits of ERT for Fabry disease would be valuable.

The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this evaluation. It therefore concluded that the PPRS payment mechanism was not relevant in considering the value for money of the technology in this evaluation.