Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia

3.1 The clinical experts stated that the aim of treatment is to lower, and reduce long-term exposure to, low-density lipoprotein cholesterol (LDL-C) and that statins are the first treatment offered. The clinical experts explained that if people's LDL-C levels remain too high, then ezetimibe may also be offered and, if they are eligible, alirocumab and evolocumab are also options. The patient expert explained that people with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia are at increased risk of cardiovascular events and that the conditions are treated inconsistently across the NHS. They highlighted that it can be difficult to access testing for high cholesterol and that treatments like alirocumab and evolocumab are only offered to people with higher levels of LDL-C. They added that a large proportion of people who are eligible for these treatments are not referred to secondary care to have them. The clinical and patient experts also highlighted that many people do not receive testing for heterozygous familial hypercholesterolaemia. The patient expert stated that inclisiran offers a twice-yearly treatment option, compared with more frequent dosing of currently available treatments, and this would likely increase treatment adherence. The clinical experts explained that it is difficult to reach LDL-C target levels with currently available oral treatments (statins and ezetimibe). The committee concluded that people with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia would welcome a new treatment option.

3.2 The NICE scope outlined 3 separate positions for inclisiran in the treatment pathway:

3.3 The company proposes that inclisiran would be given by a healthcare professional in a primary care setting. After an initial dose, it would be given again after 3 months and then twice a year. The committee was aware that other currently available treatments, such as alirocumab and evolocumab, are usually prescribed in secondary care. The clinical experts stated that the primary care setting could be appropriate, although it would need some changes in how the condition is currently managed. The committee noted that, in general, the responses to technical engagement from professional organisations supported the use of inclisiran in a primary care setting. These responses also noted that primary care can be used to identify and provide treatment for people who would be eligible for inclisiran. The committee noted that there were some concerns in submissions received surrounding the implementation of inclisiran in a primary care setting but noted that the Accelerated Access Collaborative and NHS England had plans to support the implementation of inclisiran within a primary care setting. The committee was also aware of an ongoing implementation research project (SPIRIT) that aims to assess the feasibility of delivering inclisiran within a primary care setting in England. The committee noted that this trial was due to complete in 2022 and considered that it could provide some relevant information on how inclisiran can be delivered in a primary care setting. The committee accepted that inclisiran is likely to be used in a primary care setting.

3.4 The marketing authorisation for inclisiran does not specify a minimum LDL-C level before beginning treatment. The company presented analysis by 3 populations:

3.5 NICE technology appraisal guidance recommends ezetimibe, alirocumab and evolocumab as treatment options in the same part of the treatment pathway as inclisiran (see section 3.2). The company did not consider ezetimibe to be a relevant comparator. Instead, the company included a small amount of ezetimibe use as part of standard of care, based on the ORION clinical trial programme (see section 3.7), and did not include the efficacy of ezetimibe as estimated by the network meta-analysis (NMA; see section 3.8). The company highlighted that ezetimibe use in the NHS was low and that NICE's guideline on cardiovascular disease: risk assessment and reduction includes ezetimibe only as an option and not a required pathway step before further treatment. The ERG believed that ezetimibe should be a distinct comparator and their base case used the efficacy from the company's NMA for ezetimibe, rather than comparing with the company's definition of standard of care, which was assumed to provide no reduction in baseline LDL-C (see section 3.2). The ERG had been informed by its clinical experts that if LDL-C is too high after maximum tolerated statins, then there is a clinical decision to either switch to rosuvastatin (another statin, which is not yet generic) or add ezetimibe. The ERG also highlighted that, unlike for treatment with alirocumab or evolocumab, there are no minimum LDL-C thresholds needed for treatment with ezetimibe (see section 3.6). It also noted that ezetimibe is now available as a generic treatment, which means its cost is low, and highlighted that ezetimibe was considered a relevant comparator in each of NICE's previous technology appraisals in this condition. The ERG also highlighted that hypercholesterolemia is undertreated, and this applies to all treatments. The committee agreed with the ERG that ezetimibe should be considered as a relevant comparator. The committee also agreed that it would not eliminate the company's definition of standard of care from its decision-making, noting that this was a mix of predominately maximum tolerated statins, with low amounts of ezetimibe use (but did not include the efficacy of ezetimibe as estimated by the NMA), as in the ORION trials. The committee concluded that the appropriate comparators are ezetimibe, alirocumab, evolocumab and maximum tolerated statins (when inclisiran is given in combination with statins).

3.6 The committee noted that the populations in the company submission included people with a minimum LDL-C level of 2.6 mmol/l (see section 3.4). Therefore, a proportion of people would be eligible for alirocumab or evolocumab based on recommendations in NICE's technology appraisal guidance on alirocumab and evolocumab. This includes people in:

3.7 The clinical trial evidence in the company submission came from 3 randomised 18-month trials comparing inclisiran with placebo:

3.8 Because the ORION trials only included a placebo comparator, the company undertook NMAs to indirectly compare inclisiran with alirocumab, evolocumab and ezetimibe. The company produced 3 NMAs for different populations, based on a common placebo comparator:

3.9 The completed ORION clinical trials (see section 3.7) were unable to provide enough data on the effectiveness of inclisiran in reducing cardiovascular events and mortality. This was because the follow up of 18 months was not long enough to provide these outcomes. The company used the reduction in LDL-C from the indirect treatment comparison (see section 3.8) to estimate the assumed reduction in cardiovascular events. The company used the Cholesterol Treatment Trialist Collaboration (CTT) meta-analyses, which reported change in cardiovascular event risk per 1 mmol/l reduction in LDL-C by statin use. The ERG agreed that these analyses were appropriate and noted that earlier versions of this source were used in past NICE technology appraisals in this disease area (NICE technology appraisal guidance on ezetimibe, alirocumab, evolocumab and bempedoic acid with ezetimibe). The committee expressed a concern that the link between changes in LDL-C levels and cardiovascular outcomes used in the company model, may not be appropriate for inclisiran because the mechanism of action is different to that of statins. The clinical experts stated that the CTT meta-analyses were appropriate and that a similar relationship between LDL-C lowering and a reduction in cardiovascular event risk as seen with statin use could be expected with inclisiran. The committee was aware that longer-term trial evidence was available for alirocumab (ODYSSEY OUTCOMES) and evolocumab (FOURIER) but noted that the follow-up period of these trials may not have been long enough to estimate the full effect on cardiovascular outcomes. The committee also noted that the ODYSSEY OUTCOMES trial was restricted to people who had had a recent cardiovascular event. The committee was also aware that an ongoing UK clinical trial, ORION-4, would provide outcome data on cardiovascular events with a median follow up of 5 years for inclisiran compared with placebo in people who have already had a cardiovascular event. The committee noted, however, that this trial would not report until 2026. The company explained that a global clinical trial with a similar design was in development. The company also confirmed that it is planning a clinical trial (ORION‑17) to collect data on cardiovascular outcomes of inclisiran compared with placebo, in people who have not experienced a cardiovascular event. The committee considered that the lack of data on inclisiran's effect on cardiovascular outcomes was a key uncertainty in the appraisal and was a major driver of the cost-effectiveness results. The committee concluded that the effect of inclisiran on cardiovascular event risk is uncertain as there is a lack of long-term evidence.

3.10 The company's economic model assumed that the treatment effect as estimated by the NMA at 24 weeks (see section 3.8) would be maintained at the same level over a lifetime. The company stated that this assumption was based on previous NICE technology appraisals of alirocumab and evolocumab in the same condition. The ERG noted that given the lack of long-term trial evidence beyond 18 months to support this assumption, the company could have provided a scenario in which inclisiran's effectiveness is assumed to reduce over time. The clinical experts stated that inclisiran would likely be used over the course of a lifetime, as LDL-C levels would be expected to return to baseline if discontinued. The company highlighted that the assumption of no treatment discontinuation was also based on previous NICE technology appraisals of alirocumab and evolocumab and stated that the treatment discontinuation rate for inclisiran in the ORION clinical trials was low (annual discontinuation rate of 1.7% in ORION-9 and 3.2% in ORION-10 and ORION-11). The committee noted that there was a lack of long-term data for inclisiran to support this assumption. The committee concluded that assumptions of no waning of treatment effect and no treatment discontinuation may be appropriate but add uncertainty.

3.11 The company highlighted that inclisiran was the first cholesterol-lowering small interfering RNA (siRNA) and has the potential to be a step change in how the condition is managed. The company, clinical and patient experts highlighted that treatment with inclisiran had the potential to increase treatment adherence, because of its twice-yearly dosing schedule (see section 3.1). The committee considered the potential additional benefits inclisiran might provide but concluded that there was no evidence of additional gains in health-related quality of life over those already included in the quality-adjusted life year (QALY) calculations. The committee concluded that inclisiran is innovative, however all relevant benefits are likely to be captured in the QALY calculations.

3.12 The ERG's base-case analyses included ezetimibe as a separate comparator and also included comparisons with maximum tolerated statins. Therefore, it differed from the company's base case, which included a small amount of ezetimibe use as part of standard care (see section 3.5). The committee was aware that the ERG's base-case analyses was otherwise the same as the company's. This included using the company's NMA estimate for treatment efficacy (see section 3.8) and no treatment waning or treatment discontinuation (see section 3.10). The committee concluded that it preferred the ERG base case but would take the company analyses into account in its decision making.

3.13 NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee also needs to be increasingly certain of the cost effectiveness of a technology as the impact of its adoption on NHS resources increases and may need more robust evidence for technologies that are expected to have a larger impact. Therefore, because of the high level of uncertainty in the clinical and economic evidence, primarily caused by the lack of outcome data on inclisiran's effect on cardiovascular events (see section 3.9), the NMA clinical effectiveness estimates (see section 3.8) and long-term treatment effects and discontinuation assumptions (see section 3.10), the committee agreed that an acceptable ICER would be no higher than £20,000 per QALY gained or above £30,000 per QALY lost when considering each of the population groups and their respective LDL-C ranges (see section 3.6).

3.14 The cost-effectiveness results for the secondary prevention population who are eligible for alirocumab or evolocumab were assessed by calculating net monetary benefit. This was because inclisiran was estimated to provide marginally fewer incremental QALYs compared with alirocumab or evolocumab (see section 3.8). The incremental net monetary benefit of inclisiran was compared with alirocumab or evolocumab, at threshold values of £30,000 saved per QALY lost using the committee preferred assumptions (see section 3.12 and section 3.13). This resulted in a positive incremental net monetary benefit at that threshold value, meaning that the amount of lost QALYs associated with inclisiran compared with alirocumab or evolocumab was acceptable when considering the differences in costs between these treatments. The committee considered that net monetary benefit was appropriate for decision making as it was likely that any differences in QALYs between inclisiran and alirocumab or evolocumab are small. This confirmed that inclisiran is cost effective compared with alirocumab and evolocumab in the following secondary prevention populations in which alirocumab and evolocumab are available:

3.15 Using the committee's preferred assumptions (see section 3.12) the most plausible ICERs for inclisiran compared with ezetimibe or maximum tolerated statins for the secondary prevention population who are not eligible for alirocumab or evolocumab (see section 3.6), were likely to be around or below £20,000 per QALY gained in pairwise and fully incremental analysis. Therefore, the committee concluded that inclisiran is cost effective in this population. Because of the confidential discount for inclisiran, the exact ICERs cannot be reported here.

3.16 Using the committee's preferred assumptions (see section 3.12) the most plausible ICERs for inclisiran in the primary prevention with elevated risk population and an LDL-C of at least 2.6 mmol/l, were likely to be above £20,000 per QALY gained. This was based on considering comparisons with ezetimibe or maximum tolerated statins in pairwise and fully incremental analysis. Therefore, the committee concluded that inclisiran is not cost effective in the primary prevention population with elevated risk.

3.17 The committee considered that the cost-effectiveness estimates were highly uncertain for the primary prevention with elevated risk population. The committee highlighted that smaller numbers from ORION-11 informed the cost-effectiveness estimates for this population (see section 3.9). The committee also noted that the budget impact for inclisiran was estimated to be high in the primary prevention population. The committee was aware that NICE's guide to the methods of technology appraisal notes, in general, that the committee will want to be increasingly certain of the cost effectiveness of a technology as the impact of its adoption on NHS resources increases. The committee was also aware that the company is developing a UK clinical trial (ORION-17) to evaluate the effect of inclisiran compared with placebo on cardiovascular outcomes in people who have not had a cardiovascular event. The committee therefore recommended that inclisiran is used only in the context of research in this population.

3.18 Using the committee's preferred assumptions (see section 3.12) the most plausible ICERs for the primary prevention with heterozygous familial hypercholesterolaemia populations were as follows:

3.19 The committee considered that the cost-effectiveness estimates were highly uncertain for the primary prevention with heterozygous familial hypercholesterolaemia population. The committee also noted that many people do not receive testing for heterozygous familial hypercholesterolaemia. This means cases may either be missed or classified as other population groups (see section 3.1 and section 3.4). The committee was also aware that the company is developing a UK clinical trial (ORION-17) to evaluate the effect of inclisiran compared with placebo on cardiovascular outcomes in people who have not had a cardiovascular event. The committee therefore recommended that inclisiran is used only in the context of research in this population.

3.20 A number of potential equality issues were raised during the appraisal. These included the higher prevalence of cardiovascular conditions in more deprived areas and in some specific populations (such as minority ethnic groups or people with severe mental health conditions or learning disabilities). The committee also heard that the treatments provided could vary across the NHS depending on region and availability of specialist care, and that there may be difficulties in accessing treatment for older people. The committee concluded that its recommendations for inclisiran would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently. The committee also considered that further evidence should be collected to assess whether the implementation of inclisiran into the treatment pathway would reduce health inequalities in this condition (see section 5.4).

3.21 The committee was concerned that there was a lack of long-term data on cardiovascular outcomes from the clinical trials that compared inclisiran with placebo. However, it noted that ongoing clinical trials would provide more data on these outcomes. The cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for inclisiran, represent a cost-effective use of NHS resources for adults with a history of cardiovascular events and persistent LDL-C levels of at least 2.6 mmol/l despite having the maximum tolerated lipid-lowering therapy. The committee therefore concluded that inclisiran is recommended for this group.

3.22 The cost-effectiveness results for both the primary prevention with elevated risk, and primary prevention with heterozygous familial hypercholesterolaemia were highly uncertain and the ICERs for these populations were likely above £20,000 per QALY gained. The committee considered that inclisiran had the potential to be cost effective in these populations. Based on the information it had heard about ORION-17, it considered that it was likely that the research needed would be commissioned and successfully report, and that its potential value to the NHS would likely represent good value in the context of limited research resources. It therefore recommended inclisiran only in the context of research in this group.