Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia

Evidence-based recommendations on alirocumab (Praluent) for treating primary hypercholesterolaemia or mixed dyslipidaemia in adults.

# Recommendations
Alirocumab is recommended as an option for treating primary hypercholesterolaemia or mixed dyslipidaemia, only if:
Lowdensity lipoprotein concentrations are persistently above the thresholds specified in table 1 despite maximal tolerated lipidlowering therapy. That is, either the maximum dose has been reached or further titration is limited by intolerance (as defined in NICE's guideline on familial hypercholesterolaemia: identification and management).
The company provides alirocumab with the discount agreed in the patient access scheme.

# Table 1 Lowdensity lipoprotein cholesterol concentrations above which alirocumab is recommended
Without CVD
With CVD
High risk of CVD
Very high risk of CVD
Primary nonfamilial hypercholesterolaemia or mixed dyslipidaemia
Not recommended at any LDLC concentration
Recommended only if LDLC concentration is persistently above 4.0 mmol/l
Recommended only if LDLC concentration is persistently above 3.5 mmol/l
Primary heterozygousfamilial hypercholesterolaemia
Recommended only if LDLC concentration is persistently above 5.0 mmol/l
Recommended only if LDLC concentration is persistently above 3.5 mmol/l
High risk of cardiovascular disease is defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation), coronary or other arterial revascularisation procedures, coronary heart disease, ischaemic stroke, peripheral arterial disease.
Very high risk of cardiovascular disease is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (that is, polyvascular disease).
Abbreviations: CVD, cardiovascular disease; LDLC, lowdensity lipoprotein cholesterol.
This guidance is not intended to affect the position of patients whose treatment with alirocumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology
Alirocumab (Praluent, Sanofi) is a monoclonal antibody that targets proprotein convertase subtilisin/kextin type 9 (PCSK9). It stops lowdensity lipoprotein receptors in the liver from degrading, helping to lower levels of lowdensity lipoprotein cholesterol (LDLC) in the blood. Alirocumab has a marketing authorisation in the UK for 'adults with primary hypercholesterolaemia (heterozygousfamilial and nonfamilial) or mixed dyslipidaemia, as an adjunct to diet:
in combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDLC goals with the maximum tolerated dose of a statin or
alone or in combination with other lipidlowering therapies in patients who are statinintolerant, or for whom a statin is contraindicated.'Alirocumab is given by subcutaneous injection. The recommended dose is either 75 mg or 150 mg every 2 weeks. In January 2021, the licensed dosage was updated to include another option of 300 mg every 4 weeks (monthly).
Common reported adverse reactions include local injection site reactions, upper respiratory tract signs and symptoms, and pruritus. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Alirocumab costs 168 for a 75 mg or 150 mg singleuse prefilled pen (excluding VAT; MIMS, January 2016). The annual cost of treatment per patient is 4,383 for 75 mg or 150 mg every 2 weeks. The company has agreed a patient access scheme with the Department of Health that will provide a simple discount to the list price of alirocumab with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee considered evidence submitted by Sanofi and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.

# Clinical effectiveness
The company presented evidence of the clinical effectiveness of alirocumab from 10 trials: ODYSSEY HIGH FH, FH I and II, LONGTERM, COMBO I and II, OPTIONS I and II, MONO and ALTERNATIVE. The trials were from the ODYSSEY programme, which evaluated alirocumab as an addon to maximally tolerated dose statins with or without other lipidmodifying therapies (LMT) including ezetimibe.

## Clinical trials
ODYSSEY HIGH FH was a randomised, doubleblind study in 107 people with heterozygousfamilial hypercholesterolaemia whose LDLC levels were not adequately controlled with a maximally tolerated, stable, daily dose of statin with or without other LMT. Patients were randomised in a 2:1 ratio to either alirocumab 150 mg or placebo. The difference in mean percent change from baseline in LDLC level at 24 weeks was 39.1% (p<0.0001) with alirocumab compared with placebo.
ODYSSEY FH I was a randomised, doubleblind, study in 486 people with heterozygousfamilial hypercholesterolaemia whose LDLC levels were not adequately controlled with a maximally tolerated, stable, daily dose of statin with or without other LMT. Patients were randomised in a 2:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) or placebo. The difference in mean percent change from baseline in LDLC level at 24 weeks (with possible uptitration) was 57.9% (p<0.0001) with alirocumab compared with placebo.
ODYSSEY FH II was a randomised, doubleblind study in 249 people with heterozygousfamilial hypercholesterolaemia whose LDLC levels were not adequately controlled with a maximally tolerated, stable, daily dose of statin with or without other LMT. Patients were randomised in a 2:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) or placebo. The difference in mean percent change from baseline in LDLC level at 24 weeks (with possible uptitration) was 51.4% (p<0.0001) with alirocumab compared with placebo.
ODYSSEY COMBO I was a randomised, doubleblind study in 316 people with hypercholesterolaemia and established coronary heart disease or coronary heart disease risk equivalents whose LDLC levels were not adequately controlled with a maximally tolerated daily dose of statin with or without other LMT. Patients were randomised in a 2:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) or placebo. The difference in mean percent change from baseline in LDLC level at 24 weeks was 45.9% (p<0.0001) with alirocumab compared with placebo.
ODYSSEY COMBO II was a randomised, doubleblind, ezetimibecontrolled, doubledummy study in 720 people with hypercholesterolaemia and established coronary heart disease or coronary heart disease risk equivalents whose LDLC levels were not adequately controlled with a maximally tolerated daily dose of statin. Patients were randomised in a 2:1 ratio to either alirocumab (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) or ezetimibe 10 mg. The difference in mean percent change from baseline in LDLC level at 24 weeks was 29.8% (p<0.0001) with alirocumab compared with ezetimibe.
ODYSSEY LONGTERM was a randomised, doubleblind study in 2,341 people with nonfamilial hypercholesterolaemia or established coronary heart disease/coronary heart disease risk equivalent, or people with heterozygousfamilial hypercholesterolaemia with or without coronary heart disease/coronary heart disease risk equivalents whose LDLC levels were not adequately controlled with a maximally tolerated daily dose of statin with or without other LMT. Patients were randomised in a 2:1 ratio to either alirocumab 150 mg or placebo. The difference in mean percent change from baseline in LDLC level at 24 weeks was 61.9% (p<0.0001) with alirocumab compared with placebo.
ODYSSEY OPTIONS I was a randomised, doubleblind study in 355 people with nonfamilial hypercholesterolaemia or heterozygousfamilial hypercholesterolaemia and a history of coronary heart disease, risk of cardiovascular disease or diabetes with target organ damage, whose LDLC levels were not adequately controlled with atorvastatin 20 mg to 40 mg. Patients on a baseline regimen of atorvastatin 20 mg were randomised in a 1:1:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) with atorvastatin 20 mg, atorvastatin 40 mg, or atorvastatin 20 mg with ezetimibe 10 mg. Patients on a baseline regimen of atorvastatin 40 mg were randomised in a 1:1:1:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) with atorvastatin 40 mg, atorvastatin 80 mg, atorvastatin 40 mg with ezetimibe 10 mg, or rosuvastatin 40 mg. For patients having atorvastatin 20 mg, the difference in mean percent change from baseline in LDLC level at 24 weeks (with possible uptitration) was 39.1% (p<0.0001) with alirocumab and statin (atorvastatin 20 mg) compared with statin (atorvastatin 40 mg) alone. The difference in mean percent change from baseline in LDLC level was 23.6% (p<0.0001) with alirocumab with statin (atorvastatin 20 mg) compared with ezetimibe with statin (atorvastatin 20 mg). For patients on atorvastatin 40 mg at baseline, the difference in mean percent change from baseline in LDLC level at 24 weeks (with possible uptitration) was 49.2% (p<0.0001) with alirocumab and statin (atorvastatin 40 mg) compared with statin (atorvastatin 80 mg) alone. The difference in mean percent change from baseline in LDLC level was 32.6% (p<0.0001) with alirocumab and statin (atorvastatin 40 mg) compared with statin alone (rosuvastatin 40 mg). The difference in mean percent change from baseline in LDLC level was 31.4% (p<0.0001) with alirocumab with statin (atorvastatin 40 mg) compared with ezetimibe with statin (atorvastatin 40 mg).
ODYSSEY OPTIONS II was a randomised, doubleblind study in 305 people with nonfamilial hypercholesterolaemia or heterozygousfamilial hypercholesterolaemia and a history of coronary heart disease, risk of cardiovascular disease, or diabetes with target organ damage whose LDLC levels were not adequately controlled with rosuvastatin 10 mg to 20 mg. Patients on a baseline regimen of rosuvastatin 10 mg were randomised in a 1:1:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) with rosuvastatin 10 mg, rosuvastatin 20 mg, or rosuvastatin 10 mg with ezetimibe 10 mg. Patients on a baseline regimen of rosuvastatin 20 mg were randomised in a 1:1:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) with rosuvastatin 20 mg, rosuvastatin 40 mg, or rosuvastatin 20 mg with ezetimibe 10 mg. For patients having rosuvastatin 10 mg at baseline, the difference in mean percent change from baseline in LDLC level at 24 weeks (with possible uptitration) was 34.2% (p<0.0001) with alirocumab and statin (rosuvastatin 10 mg) compared with statin (rosuvastatin 20 mg) alone. The difference in mean percent change from baseline in LDLC level (with possible uptitration) was 36.2% (p<0.0001) with alirocumab and statin (rosuvastatin 10 mg) compared with ezetimibe and statin (rosuvastatin 10 mg). For patients on rosuvastatin 20 mg at baseline, the difference in mean percent change from baseline in LDLC level at 24 weeks (with possible uptitration) was 20.3% (p=0.0453) with alirocumab and statin (rosuvastatin 20 mg) compared with statin (rosuvastatin 40 mg) alone. The difference in mean percent change from baseline in LDLC level was 25.3% (p=0.0136) with alirocumab with statin (rosuvastatin 20 mg) compared with ezetimibe with statin (rosuvastatin 20 mg).
ODYSSEY ALTERNATIVE was a randomised, doubleblind, ezetimibecontrolled, doubledummy study in 361 people with people with nonfamilial hypercholesterolaemia or heterozygousfamilial hypercholesterolaemia with a moderate, high or very high cardiovascular risk and a history of intolerance to statin. Patients were randomised in a 2:2:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels), ezetimibe 10 mg or atorvastatin 20 mg. The difference in mean percent change from baseline in LDLC level was 30.4% (p<0.0001) with alirocumab compared with ezetimibe.
ODYSSEY MONO was a randomised, ezetimibecontrolled, doubleblind study in 103 people with hypercholesterolaemia with a moderate cardiovascular risk. Patients were randomised in a 1:1 ratio to either alirocumab 75 mg (with uptitration to alirocumab 150 mg at 12 weeks based on LDLC levels) or ezetimibe 10 mg. The difference in mean percent change from baseline in LDLC level at week 24 (with possible uptitration) was 31.6% (p<0.0001) with alirocumab compared with ezetimibe.

## Metaanalyses
The company undertook metaanalyses of individual patient data for the mean percent change from baseline in calculated LDLC levels (ontreatment) using a fixedeffects model. In these analyses, alirocumab (with or without statins) was compared with a statin or ezetimibe (with or without statin). The metaanalyses showed:
The difference in mean percent change from baseline in LDLC level at 12 weeks was approximately 49.3% with alirocumab 75 mg with statin compared with placebo with statin.
The difference in mean percent change from baseline in LDLC level at 24 weeks ranged from 54.1% to 56.1% with alirocumab 75 mg (with possible uptitration to 150 mg) with statin compared with placebo with statin.
The difference in mean percent change from baseline in LDLC level at 24 weeks was 62.5% with alirocumab 150 mg with statin compared with placebo with statin.
The difference in mean percent change from baseline in LDLC level at 12 weeks ranged from 27.2% to 33.1% with alirocumab 75 mg with or without statin compared with ezetimibe with or without statin.
The difference in mean percent change from baseline in LDLC level at 24 weeks ranged from 29.9% to 35.1% with alirocumab 75 mg (with possible uptitration to 150 mg) with or without statin compared with ezetimibe with or without statin.
The company also provided information from an independent metaanalysis of PCSK9 inhibitors (Navarese et al.). This showed a difference in mean percent change from baseline in LDLC level of 47.49% (95% confidence interval  69.64 to 25.35) and reduced allcause mortality and cardiovascular mortality with PCSK9 antibodies compared with control. The company stated that a large randomised controlled trial exploring the occurrence of cardiovascular events of alirocumab compared with placebo is expected to report in 2018.

## Adverse effects of treatment
The company provided safety information based on combined phase II and phase III studies. The company stated that the rate of treatmentemergent adverse events (including serious adverse events) was similar between the alirocumab and control arms. It stated that there was no difference in the safety profile observed between alirocumab 75 mg and 150 mg. It also stated that discontinuation due to general allergic adverse events was infrequent but occurred in a higher percentage of the people having alirocumab.
The company estimated the risk of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischaemic stroke, or unstable angina requiring hospitalisation) by pooling phase III ODYSSEY trial data. The analysis showed a lower risk of a major adverse cardiovascular event with alirocumab compared with control (hazard ratio  0.81; 95% CI 0.52 to 1.25), although this was not statistically significant. A posthoc analysis from LONGTERM also showed a lower risk of major adverse cardiac events with alirocumab compared with placebo (HR 0.52; 95% CI 0.31 to 0.90).

## ERG's comments
The ERG noted that evolocumab was not considered to be a relevant comparator by the company because it was still under assessment by NICE. It noted that there were no headtohead trials of alirocumab compared with evolocumab.
The ERG stated that although it had identified missing terms in the company's search strategy which may have affected its overall sensitivity, it generally considered the company's searches to be fit for purpose.
The ERG noted that the LDLC reduction with alirocumab compared with control was rapid and persistent throughout followup.

# Cost effectiveness
The company presented basecase costeffectiveness analyses for alirocumab, either as an adjunct to statin with ezetimibe or with ezetimibe alone, in 4 populations:
People with heterozygousfamilial hypercholesterolaemia for primary prevention (referred to as the primary prevention  population).
People with heterozygousfamilial hypercholesterolaemia for secondary prevention (referred to as the secondary prevention  population).
People with nonfamilial hypercholesterolaemia and highrisk cardiovascular disease (CVD). This includes people with a history of:
acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation)
coronary or other arterial revascularisation procedures
coronary heart disease
ischaemic stroke
peripheral arterial disease.
People with nonfamilial hypercholesterolemia and a very high risk of CVD. These are people with recurrent cardiovascular events or polyvascular disease (referred to as the recurrent events/polyvascular disease  population). This includes people with recurrent cardiovascular events, or cardiovascular events in more than 1 vascular bed.

## Model structure
The company submitted a Markov model based on the modelling approaches developed for NICE guidelines on lipid modification and familial hypercholesterolaemia, and technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia, ticagrelor for the treatment of acute coronary syndromes and rivaroxaban for preventing adverse outcomes after acute management of acute coronary syndrome. The cycle length was 1 year and a half cycle correction was applied. An annual discount rate of 3.5% was applied to costs and health effects. The model had a lifetime time horizon and was conducted from a NHS and personal social services perspective.
The company's model consisted of 12 mutually exclusive health states:
initial health states: stable, 01 years following an acute coronary syndrome event, 12 years following an acute coronary syndrome event
types of events: nonfatal acute coronary syndrome including myocardial infarction and unstable angina requiring hospitalisation, nonfatal ischaemic stroke, and elective revascularisation
postevent health states: post nonfatal acute coronary syndrome (01 years, 12 years and stable coronary heart disease; that is, more than 2 years after an acute coronary syndrome event), post nonfatal ischaemic stroke (01 years, 12 years and stable ischaemic stroke; that is, more than 2 years following ischaemic stroke) and stable elective revascularisation.The model also consisted of health states for cardiovascular death and noncardiovascular death. Costs and outcomes were compared between identical cohorts of people on alirocumab and comparators.
The baseline characteristics (age, sex, percentage of patients with diabetes and minimum LDLC level) for each population were informed by UK data from the Health Improvement Network (THIN) database, patient characteristics from ODYSSEY trials and the UK National Familial Hypercholesterolaemia audit.
For heterozygousfamilial hypercholesterolaemia, the starting age was 50 years for primary prevention and 60 years for secondary prevention. The baseline LDLC level was 2.59 mmol/l, 50% of the cohort were men, 7% of the primary prevention cohort had diabetes and 26% of the secondary prevention cohort had diabetes.
For highrisk cardiovascular disease, the starting age was 65 years and the baseline LDLC level was 3.36 mmol/l. Around 60% of the cohort were men and 23% had diabetes.
For recurrent events/polyvascular disease, the starting age was 65 years and the baseline LDLC level was 2.59 mmol/l. Around 60% of the cohort were men and 30% had diabetes.
The baseline probabilities of cardiovascular death in all postacute coronary syndrome and postischaemic stroke health states were adjusted to account for the higher risk of future events associated with recurrence of cardiovascular events.

## Treatment, clinical variables and parameters
Alirocumab was given in line with its marketing authorisation. The patient population was modelled according to severity of hypercholesterolaemia (by baseline LDLC levels) before starting treatment. Baseline cardiovascular risk (calculated using THIN data) was adjusted by LDLC level using a loglinear relationship between the absolute LDLC observed in statin studies and cardiovascular events using the Cholesterol Treatment Trialists' Collaboration (CTTC) metaanalysis of statins. The company used the difference in mean percent change of alirocumab compared with alternatives based on estimates from specific clinical trials and metaanalyses. The model assumed that the relative reduction in LDLC for alirocumab was constant across all subgroups.
In the absence of cardiovascular events data from the clinical trials for alirocumab, the company used LDLC reduction as a surrogate to link to cardiovascular events. In its basecase analysis, the company chose the Navarese metaanalysis of 24 randomised controlled trials (n=10,159) to provide the rate at which the risk of a cardiovascular event declines with a reduction in LDLC levels. This was because it preferred estimates from PCSK9 inhibitor studies rather than estimates from statin studies (such as CTTC), because they better reflected the population who will have alirocumab. By assuming a loglinear relationship between LDLC levels and cardiovascular events, the company estimated the risk reduction for cardiovascular mortality as rate ratios (RRs): 0.64 per 1.0 mmol/l reduction in LDLC rate (95% CI 0.40 to 1.04) and 0.64 for myocardial infarction (95% CI 0.43 to 0.96). The risk reduction for coronary revascularisation and ischaemic stroke was assumed to be the same as other nonfatal cardiovascular events.

## Transition probabilities
Transition probabilities were based on KaplanMeier analyses from an observational retrospective cohort analysis using the THIN database of people with established cardiovascular disease, diabetes, familial hypercholesterolaemia or chronic kidney disease. This was used to calculate 1year cardiovascular risk probabilities. Transition probabilities for the primary prevention (heterozygousfamilial) population were based on the Dutch lipid criteria for people with heterozygousfamilial hypercholesterolaemia, because the patient characteristics from THIN were not representative of this population. For the secondary prevention (heterozygousfamilial) population (see section 3.19), some patient characteristics (such as rate of diabetes and age) were different from known prevalence. To address this, the company used data from Mohrschladt (2003) in its basecase analysis for this population.
Noncardiovascular death probabilities in the model increased in accordance with age and sex using UK life tables. Probability of cardiovascular events also increased with age, in line with published data.

## Utility values
Ageadjusted utility values for the primary prevention (heterozygousfamilial) population were calculated using Health Survey for England (HSE) data for people with no history of cardiovascular disease, multiplied by the disutility associated with cardiovascular events taken from Ara and Brazier (2010). Baseline utilities in the model were as follows: nonfatal myocardial infarction 0.765, unstable angina 0.765, acute coronary syndrome 0.765, ischaemic stroke 0.775.
Ageadjusted utility values for the secondary prevention (heterozygousfamilial), highrisk cardiovascular disease and recurrent events/polyvascular disease (nonfamilial) populations were calculated using HSE data for people with no history of cardiovascular disease, multiplied by the disutility values associated with a coronary cardiovascular health state (cardiovascular event more than 1 year ago) taken from Ara and Brazier 2010. Utility multipliers in the model were: primary prevention of heterozygousfamilial hypercholesterolaemia 1 (assumed), secondary prevention of heterozygousfamilial hypercholesterolaemia 0.924, acute coronary syndrome (0 to 12 months) 0.765, history of ischaemic stroke 0.822, acute coronary syndrome (13 to 24 months) 0.924, coronary heart disease 0.924, peripheral arterial disease 0.924, and polyvascular 0.854. Disutilities for further cardiovascular events in the model were applied to the secondary prevention (heterozygousfamilial) population baseline utilities.

## Costs
Initial costs of treatment for hypercholesterolaemia and cardiovascular events were based on the cost of hospitalisation, followup care and medication. Drug acquisition costs for the comparators were taken from the January 2015 edition of the British National Formulary. The cost of the background therapy was weighted by the proportion of the cohort using the statin sources from market research data. The cost of alirocumab incorporated the patient access scheme.
Health state costs were based on the NICE guideline on lipid modification and costs for the first 3 years after a cardiovascular event were taken from the British national formulary, the NHS Drug Tariff, NHS reference costs, PSSRU unit costs, and the NICE guideline on stroke rehabilitation in adults. The costs for each health state were as follows:
nonfatal myocardial infarction: 3,337 (incremental cost years 2 and 3: 788)
unstable angina: 3,313 (incremental cost years 2 and 3: 385)
acute coronary syndrome: 3,329 (incremental cost years 2 and 3: 654)
revascularisation: 3,802
ischaemic stroke: 4,092 (incremental cost years 2 and 3: 155)
cardiovascular death: 1,174
noncardiovascular death: 0.

## ERG comments
The ERG stated that in terms of face validity, the company's model structure and transition probabilities were plausible. However, the ERG noted that the company's model omitted the transient ischaemic attack and stable angina health states and that it had limited capacity to capture multiple cardiovascular event histories. It also stated that the company omitted treatmentemergent adverse events from the model. The ERG also noted that the secondary prevention (heterozygousfamilial) population (see section 3.19) using Mohrschladt had a higher cardiovascular risk compared with data from THIN. It was unable to verify the most appropriate risk without another external data source. The ERG believed that the company's use of THIN for cardiovascular event and transition probabilities was appropriate because QRISK2 risk estimates were not valid for the high cardiovascular risk population.
Although the ERG accepted the company's decision to use an LDLC threshold of 3.36 mmol/l for people with highrisk cardiovascular disease, it noted that Jameson et al. reported a mean LDLC of 2.13 mmol/l in people with cardiovascular disease having atorvastatin in primary care in the UK. It also noted that a large proportion of people in THIN were having lowintensity statins and may not have been on optimal statin treatment. The ERG stated that the mean baseline LDLC levels used by the company may not have been applicable to people having maximally tolerated statins and that it considered the company's mean LDLC levels to be uncertain.
The ERG had several comments about the company's assumptions used to scale the estimated effect of alirocumab to cardiovascular events:
It was satisfied with the company's approach to estimate the LDLC reduction with alirocumab compared with placebo.
The ERG noted that the company assumed there is a linear/loglinear relationship between LDLC and cardiovascular events as demonstrated by CTTC. It noted that the estimated relative reduction in cardiovascular events from Navarese was greater than estimates from CTTC. The ERG also noted that the estimates from Navarese were based on a smaller number of events reported in shorter trials with fewer patients compared with CTTC.
The ERG noted that the company used all the trials used to estimate the mean reduction with LDLC from the Navarese analysis, instead of only the trials used to estimate the HRs for specific cardiovascular events. In its response to clarification, the company provided estimates of LDLC reduction using trials only informing the HRs for myocardial infarction and cardiovascular death; an LDLC reduction of 1 mmol/l resulted in HRs of 0.58 for cardiovascular death and 0.68 for myocardial infarction. The ERG considered these values to be more relevant.
The ERG noted that the company's estimated HR for myocardial infarction events was used for ischaemic stroke and coronary revascularisation events. The ERG stated this was a controversial assumption, because other studies (such as CTTC) show that a reduction in LDLC levels may have less of an effect on ischaemic stroke risk than on acute coronary syndrome risk.
The ERG stated that the company assumed 100% treatment continuation and compliance over the entire time horizon. It noted that the high compliance was in line with ODYSSEY (approximately 98%) and that the assumption was consistent with the NICE guideline on lipid modification and the technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia.
The ERG stated that the company's health state utility values were calculated and implemented appropriately. However, it had several comments on the costs used in the model:
The company's model only captured costs for the first 6 months after a cardiovascular event in the first year, and so did not capture followup for the second half of the first year.
Followup costs for cardiovascular events were incurred for up to 3 years after the event. The ERG considered this to be conservative and possibly unrealistic, considering the need for ongoing social care and medical attention.
The costs for the stroke and poststroke health states were low and inconsistent with costs applied in previous technology appraisals.
The ERG was unclear how the cost of revascularisation was estimated.
The company's submission mentioned that alirocumab will be continued in secondary care via a sponsored homecare service.

# Company's results and sensitivity analysis
The company's incremental costeffectiveness ratios (ICERs) for all comparisons, populations and sensitivity analyses incorporated the patient access scheme for alirocumab, as do all ICERs in this document (see tables 1 to 4).
In the primary prevention (heterozygousfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER was 36,793 per qualityadjusted life year (QALY) gained (incremental costs 52,256; incremental QALYs 1.42). For alirocumab and a statin compared with ezetimibe and a statin, the ICER was 48,193 per QALY gained (incremental costs 45,962; incremental QALYs 0.95).
In the secondary prevention (heterozygousfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER was 16,896 per QALY gained (incremental costs 39,306; incremental QALYs 2.33). For alirocumab and a statin compared with ezetimibe and a statin, the ICER was 20,352 per QALY gained (incremental costs 34,632; incremental QALYs 1.70). Using baseline risk data from THIN instead of Mohrschladt (2003) the ICER was 19,060 per QALY gained (incremental costs 40,733; incremental QALYs 2.14) for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe.
In the highrisk cardiovascular disease (nonfamilial) population, for alirocumab and a statin compared with a statin alone, the ICER was 19,751 per QALY gained (incremental costs 34,684; incremental QALYs 1.76). For alirocumab and a statin compared with ezetimibe and a statin, the ICER was 24,175 per QALY gained (incremental costs 31,195; incremental QALYs 1.29). In the highrisk cardiovascular disease (nonfamilial) population who cannot have statins, the ICER for alirocumab and ezetimibe compared with ezetimibe alone was 17,256 per QALY gained (incremental costs 35,146; incremental QALYs 2.04). For alirocumab alone compared with ezetimibe alone the ICER was 17,295 per QALY gained (incremental costs 30,829; incremental QALYs 1.78).
In the recurrent events/polyvascular disease (nonfamilial) population, for alirocumab and a statin compared with a statin alone, the ICER was 19,447 per QALY gained (incremental costs 31,953; incremental QALYs 1.64). For alirocumab and a statin compared with ezetimibe and a statin, the ICER was 23,078 per QALY gained (incremental costs 28,781; incremental QALYs 1.25). For the recurrent events/polyvascular disease (nonfamilial) population who cannot have statins, the ICER for alirocumab and ezetimibe compared with ezetimibe alone was 13,669 per QALY gained (incremental costs 32,798; incremental QALYs 2.40). For alirocumab alone compared with ezetimibe alone, the ICER was 13,469 per QALY gained (incremental costs 28,820; incremental QALYs 2.14)

## Sensitivity analyses
The company undertook a number of probabilistic sensitivity analyses, stating that the uncertainty in the results reflected the wide confidence intervals from preliminary PCSK9 inhibitor outcomes data.
For the primary prevention (heterozygousfamilial) population, the probability of alirocumab and a statin plus ezetimibe being cost effective compared with a statin and ezetimibe was between 15% and 36% (for a maximum ICER of 20,000 to 30,000 per QALY gained).
For the secondary prevention (heterozygousfamilial) population, the probability of alirocumab and a statin plus ezetimibe being cost effective compared with a statin and ezetimibe was between 56% and 79% (for a maximum ICER of 20,000 to 30,000 per QALY gained).
For the highrisk cardiovascular disease (nonfamilial) population, the probability of alirocumab and a statin being cost effective compared with a statin alone was between 46% and 78% (for a maximum ICER of 20,000 to 30,000 per QALY gained).
For the recurrent events/polyvascular disease (nonfamilial) population, the probability of alirocumab and a statin being cost effective compared with a statin alone was between 49% and 80% (for a maximum ICER of 20,000 to 30,000 per QALY gained).
The company also undertook deterministic sensitivity analyses to explore the upper and lower bounds of the confidence interval or by varying selected inputs by an arbitrary 20%. The ICERs for all populations were most sensitive to changes in the relationship of LDLC level to cardiovascular events and annual cardiovascular risk.

## Subgroup and scenario analyses
The company conducted subgroup analyses by LDLC level:
In the primary prevention (heterozygousfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER decreased from 36,793 per QALY gained at a threshold of 2.59 mmol/l to 28,923 per QALY gained at a threshold of 4.13 mmol/l.
In the secondary prevention (heterozygousfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER decreased from 16,896 per QALY gained at a threshold of 2.59 mmol/l to 14,242 per QALY gained at a threshold of 4.13 mmol/l.
In the highrisk cardiovascular disease (nonfamilial) population, for alirocumab and a statin compared with a statin alone, the ICER decreased from 25,287 per QALY gained at a threshold of 2.59 mmol/l to 16,043 per QALY gained at a threshold of 4.13 mmol/l.
In the recurrent events/polyvascular (nonfamilial) disease population, for alirocumab and a statin compared with a statin alone, the ICER decreased from 19,447 per QALY gained at a threshold of 2.59 mmol/l to 12,606 per QALY gained at a threshold of 4.13 mmol/l.
The company conducted a range of scenario analyses:
Increasing the discontinuation rate from 0% to 3% and 8% led to a modest increase in the ICERs for all populations.
Changing the cost and benefit discount rates from 3.5% to 0 or 5% substantially changed the ICERs in all populations.
Reducing the treatment duration from lifetime to 1 to 5 years had a modest impact on the ICERs in all populations.
Decreasing the time horizon from lifetime to 5 or 10 years substantially increased the ICERs in all populations.
Using a different source to link LDLC reduction to cardiovascular relative risk instead of Navarese changed the ICERs in all populations:
using relative risks from CTTC instead of Navarese increased the ICERs by approximately 16,000 to 24,700 per QALY gained
using relative risks from pooled phase III trials instead of Navarese increased the ICERs by approximately 8,800 to 15,700 per QALY gained
using relative risks from LONGTERM instead of Navarese increased the ICERs by approximately 2,400 to 4,100 per QALY gained.
Using a different adjustment to baseline cardiovascular risk had a modest impact on the ICERs in all populations.
Using utility values from ODYSSEY instead of Ara 2010 significantly decreased ICERs in all populations.
Changing the treatment strategy from uptitration to 100% use of alirocumab 75 mg or 150 mg had a modest impact on the ICERs in all populations.

# ERG's exploratory analyses
The ERG undertook exploratory analyses for all comparators and populations, making 7 changes to the company's model. It presented ICERs for both Navarese and CTTC metaanalyses to show the uncertainty in the relationship between LDLC reduction and cardiovascular events. In summary, the ERG's exploratory analyses:
applied annual postcardiovascular event costs (such as care for stroke) over the entire modelled time horizon (lifetime) instead of 3 years
applied followup costs to the second half of first year costs following a cardiovascular event
applied an updated cost of 8,618 for stroke and an annual care cost for stroke of 1,769
used only trials informing the hazard ratios in Navarese instead of all trials, applying rate ratios of 0.67 per 1 mmol/l reduction for myocardial infarction and 0.58 per 1 mmol/l reduction in cardiovascular death
applied a rate ratio of 0.79 per 1 mmol/l reduction in LDLC for ischaemic stroke based on results from CTTC, instead of assuming the same rate ratio of 0.64 per 1 mmol/l reduction
applied an annual discontinuation rate of 8% instead of 0% so that it is consistent with discontinuation observed in ODYSSEY and LONGTERM
applied the effects of ezetimibe on LDLC reduction using rate ratios from CTTC.
In summary, the ERG's exploratory analyses showed only modest changes to the basecase ICERs for all comparisons in all populations using Navarese to estimate the relationship between LDLC and cardiovascular events. Using CTTC to estimate the relationship between LDLC and cardiovascular events substantially increased the ICERs for all comparisons in all populations. All these ICERs were in excess of 20,000 per QALY gained.

## Table 2 ERG exploratory analyses: deterministic basecase and additional comparison ICERs for the primary prevention (heterozygousfamilial) population (cost per QALY), including PAS
Company's base case with rate ratios from Navarese
Company's scenario analysis with ratios from CTTC
ERG scenario with rate ratios from Navarese
ERG scenario with rate ratios from CTTC
Alirocumab + statins + ezetimibe vs statins + ezetimibe
People who cannot tolerate statinsAlirocumab +ezetimibe vs ezetimibe
Comparison with ezetimibeAlirocumab + statins vs ezetimibe + statins

## Table 3 ERG exploratory analyses: deterministic basecase and additional comparison ICERs for the secondary prevention (heterozygousfamilial) population (cost per QALY) including PAS
Company's base case with rate ratios from Navarese
Company's scenario analysis with ratios from CTTC
ERG scenario with rate ratios from Navarese
ERG scenario with rate ratios from CTTC
Alirocumab + statins + ezetimibe vs statins + ezetimibe
People who cannot tolerate statinsAlirocumab +ezetimibe vs ezetimibe
Comparison with ezetimibeAlirocumab + statins vs ezetimibe + statins

## Table 4 ERG exploratory analyses: deterministic basecase and additional comparison ICERs for the highrisk CVD (nonfamilial) population (cost per QALY), including PAS
Company's base case with rate ratios from Navarese
Company's scenario analysis with ratios from CTTC
ERG scenario with rate ratios from Navarese
ERG scenario with rate ratios from CTTC
Alirocumab + statins vs statins
People who cannot tolerate statinsAlirocumab +ezetimibe vs ezetimibe
Comparison with ezetimibeAlirocumab + statins vs ezetimibe + statins
People who cannot tolerate statins comparison with ezetimibeAlirocumab vs ezetimibe

## Table 5 ERG exploratory analyses: deterministic basecase and additional comparison ICERs for the recurrent events/polyvascular disease (nonfamilial) population (cost per QALY), including PAS
Company's base case with rate ratios from Navarese
Company's scenario analysis with ratios from CTTC
ERG scenario with rate ratios from Navarese
ERG scenario with rate ratios from CTTC
Alirocumab + statins vs statins
People who cannot tolerate statinsAlirocumab + ezetimibe vs ezetimibe
Comparison with ezetimibeAlirocumab + statins vs ezetimibe + statins
People who cannot tolerate statins comparison with ezetimibealirocumab vs ezetimibe

# Company's new evidence in response to consultation
In response to the appraisal consultation document, in which alirocumab was not recommended for primary hypercholesterolaemia (heterozygousfamilial and nonfamilial) or mixed dyslipidaemia, the company was permitted to submit revised costeffectiveness analyses which included a change to the patient access scheme for alirocumab. The company also incorporated the committee's preferred assumptions outlined in the appraisal consultation document and provided comparisons for alirocumab in combination with ezetimibe and statin compared with ezetimibe and statin.
In the primary prevention (heterozygousfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER was 45,004 per QALY gained (incremental costs 16,773; incremental QALYs 0.37) for people with an LDLC above 3 mmol/l and 37,228 per QALY gained (incremental costs 16,531; incremental QALYs 0.44) for people with an LDLC above 4 mmol/l.
In the secondary prevention (heterozygousfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER was 22,600 per QALY gained (incremental costs 13,368; incremental QALYs 0.59) for people with an LDLC above 3 mmol/l and 19,973 per QALY gained (incremental costs 13,092; incremental QALYs 0.66) for people with an LDLC above 4 mmol/l.
In the highrisk CVD (nonfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER was 35,899 per QALY gained (incremental costs 13,556; incremental QALYs 0.38) for people with an LDLC above 3 mmol/l and 24,835 per QALY gained (incremental costs 13,012; incremental QALYs 0.52) for people with an LDLC above 4 mmol/l.
In the recurrent events/polyvascular disease (nonfamilial) population, for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe, the ICER was 27,644 per QALY gained (incremental costs 12,255; incremental QALYs 0.44) for people with an LDLC above 3 mmol/l and 19,291 per QALY gained (incremental costs 11,588; incremental QALYs 0.60) for people with an LDLC above 4 mmol/l.
The company conducted new subgroup analyses using different rate ratios from the CTTC metaanalysis for the relationship between LDLC levels and cardiovascular outcomes:
Using CTTC rate ratios as applied in NICE technology appraisal guidance on ezetimibe reduced the ICERs by between 1,000 to 2,400 per QALY gained for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe.
Using CTTC rate ratios as applied in the NICE technology appraisal of evolocumab reduced the ICERs by between 3,800 and 9,700 per QALY gained for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe.

## ERG comments
The ERG stated that the company's new evidence was consistent with the committee's preferred modelling assumptions.
The ERG agreed with the company's assertion that the rate ratios used to estimate the relationship between LDLC levels and cardiovascular outcomes for alirocumab were different from the rate ratios used in the NICE technology appraisals of ezetimibe and evolocumab. It noted that:
The rate ratios used in the NICE technology appraisal of evolocumab were derived from 5 trials of more intensive statin treatment compared with less intensive statin treatment using the CTTC metaanalysis from 2010.
The rate ratios used in the NICE technology appraisal of ezetimibe were derived from trials of statins compared with control using the CTTC metaanalysis from 2010.
The rate ratios used in the NICE technology appraisal of alirocumab were derived from 27 trials of both more intensive statin treatment compared with less intensive statin treatment, and trials of statins compared with control using the CTTC metaanalysis from 2012.

# ERG's revised exploratory analyses
The ERG undertook revised exploratory analyses to estimate the LDLC level at which the ICER falls below a maximum acceptable ICER of 30,000 per QALY gained. In summary, the baseline LDLC levels for an ICER below 30,000 per QALY gained ranged from approximately 3.5 mmol/l for the recurrent events/polyvascular (nonfamilial) disease population to approximately 6.1 mmol/l for the primary prevention (heterozygousfamilial) population (see table 6).

## Table 6 ERG's revised exploratory analysis: LDLC level (mmol/l) when the ICER is below 30,000 per QALY gained for alirocumab with ezetimibe plus statin compared with ezetimibe with statin, including patient access scheme
Population
Mean baseline LDLC (mmol/l) for ICER 30,000 per QALY gained
Primary prevention (heterozygousfamilial) population
Secondary prevention (heterozygousfamilial) population
Highrisk cardiovascular disease (nonfamilial)
Recurrent events/polyvascular (nonfamilial) disease
Abbreviations: ICER, incremental costeffectiveness ratio; LDLC, lowdensity lipoprotein cholesterol; QALY, qualityadjusted life year.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of alirocumab, having considered evidence on the nature of primary hypercholesterolaemia and mixed dyslipidaemia and the value placed on the benefits of alirocumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee heard from the patient experts about the nature of the condition and their experience with treatment. It heard that people with familial hypercholesterolaemia have a lifetime risk of cardiovascular events and their quality of life is adversely affected by the need to be on treatment throughout their life. The committee noted that some people taking statins for hypercholesterolaemia can experience side effects such as muscle and joint pain that can disrupt daily activities and reduce quality of life. It heard from the clinical and patient experts that although lowdensity lipoprotein (LDL) apheresis is an alternative treatment option for people with very severe hypercholesterolaemia, it is not available in all areas and is not a sustainable therapy because it requires lengthy attendance at a clinic every 2 weeks and time to recover from the procedure. The committee concluded that the current treatment options for hypercholesterolaemia or mixed dyslipidaemia may not be sufficient in all cases, and that alternative treatment options are desirable.
The committee discussed the marketing authorisation for alirocumab and how alirocumab might be used in practice. The committee was aware that alirocumab has a marketing authorisation for use in adults with primary hypercholesterolaemia (heterozygousfamilial and nonfamilial) or mixed dyslipidaemia (see section 2.1), and understood that 5 clinical groups of people can be distinguished within the marketing authorisation for treating primary hypercholesterolaemia:
A primary prevention nonfamilial hypercholesterolaemia group.
A secondary prevention nonfamilial group of people with established cardiovascular disease, who have previously had a cardiovascular event (the highrisk cardiovascular disease  population). This group included people with nonfamilial hypercholesterolaemia with a history of:
acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation)
coronary or other arterial revascularisation procedures
coronary heart disease
ischaemic stroke
peripheral arterial disease.
A subgroup of people from the highrisk group who have had more than 1 previous cardiovascular event or who have polyvascular disease (referred to as the recurrent events/polyvascular disease  population). This group included people with nonfamilial hypercholesterolaemia with recurrent cardiovascular events, or cardiovascular events in more than 1 vascular bed.
A primary prevention heterozygousfamilial hypercholesterolaemia group (the primary prevention  population)
A secondary prevention heterozygousfamilial hypercholesterolaemia group (the secondary prevention  population). This group included people with heterozygousfamilial hypercholesterolaemia with a history of:
acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation)
coronary or other arterial revascularisation procedures
coronary heart disease
ischaemic stroke
peripheral arterial disease.The committee considered that these groups broadly corresponded to those defined in the company submission. It noted that the homozygousfamilial hypercholesterolaemia population is not within the marketing authorisation for alirocumab (see section 2.1). It also noted that the company did not present any evidence for people with nonfamilial hypercholesterolemia without a history of cardiovascular disease (primary prevention) and therefore, agreed that it could not make recommendations for this population. The committee noted that the 4 groups defined by the company were within the marketing authorisation, and concluded that the company's subgroups were appropriately defined and relevant for its decisionmaking.
The committee discussed whether alirocumab would be used for treating mixed dyslipidaemia. It noted that although the marketing authorisation and the final scope for alirocumab included people with mixed dyslipidaemia, the company did not present any separate evidence for this population. The committee was aware that people with mixed dyslipidaemia also have higher LDLC levels, and heard from the clinical experts that treatment for mixed dyslipidaemia is partly determined by LDLC level. The committee was aware that people with heterozygousfamilial hypercholesterolaemia are considered to be at high risk of CVD not only because of the high LDLC concentrations, but also because of the lifelong exposure to such concentrations. The committee understood from the clinical experts that although alirocumab was likely to mainly be used for primary hypercholesterolaemia in clinical practice, it may also be used for treating mixed dyslipidaemia when LDLC levels remain persistently high.
The committee considered the current treatment options and comparators for people with hypercholesterolaemia. The committee heard from the clinical experts that a maximally tolerated dose of statins is the main treatment option for familial and nonfamilial hypercholesterolaemia (as described in NICE's guidelines on familial hypercholesterolaemia and lipid modification), but that a minority of people cannot have statins. It understood that common side effects such as fibromyalgia and headache contribute to intolerance and discontinuation of statin therapy. The committee was also aware that NICE's technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia recommends ezetimibe monotherapy as an option to treat primary hypercholesterolaemia when statin treatment is insufficient. The committee concluded that a maximally tolerated dose of statins with ezetimibe was the main treatment option and therefore was an appropriate comparator for alirocumab in this appraisal.
The committee discussed statin therapy for treating hypercholesterolaemia. It was aware that the marketing authorisation stated that alirocumab should be used in combination with a statin or with a statin and other lipidlowering therapies in patients unable to reach LDLC goals with the maximum tolerated dose of statin, or alone or in combination with other lipidlowering therapies in patients who cannot have a statin or for whom a statin is contraindicated (see section 2.1). The committee heard from the clinical expert that although up to approximately 23% of people with primary hypercholesterolemia were currently reported to be intolerant to statins, the true rate was likely to be between 0.5% to 3.0% of the population because there were no clear diagnostic criteria for statin intolerance. The committee acknowledged that there is no universally accepted definition of intolerance to statins, but was aware of the definition of intolerance used in NICE's guideline on familial hypercholesterolaemia. It agreed that some people could be misidentified as intolerant to statins and that the true size of the population that cannot take statins was relatively small compared to the wider population covered by the marketing authorisation. The committee was aware that there may also be people in whom statins are contraindicated. It was aware that these people have the same unmet clinical need as those who cannot tolerate statins and that there is no biologically plausible reason for the alirocumab to work differently in these people. The committee was aware that the populations in the company's new evidence (see section 3.48) were defined by the LDLC level at which treatment with alirocumab should be started. The committee was aware that people who cannot take statins have higher than average LDLC levels, and would therefore meet the LDLC levels needed to start treatment with alirocumab for people who can take statins. The committee concluded that it was not necessary to make separate recommendations for people who cannot take statins.
The committee discussed the place of lipoprotein apheresis in managing primary hypercholesterolaemia, noting that this was not included as a comparator in the final scope for this appraisal. The committee noted from consultation comments that apheresis is not only costly and onerous for the patient, but also difficult to access because only a few centres offer it. The committee further heard from the clinical expert that lipoprotein apheresis would be considered for people with heterozygousfamilial hypercholesterolaemia whose LDLC level remains above 5.0 mmol/l or decreases by less than 40% when taking maximally tolerable doses of combined drug therapy. The committee concluded that treatments that avoid the need for apheresis would be welcomed.
The committee heard from the clinical expert that alirocumab should only be used when LDLC levels are persistently high despite lipidlowering therapy. The committee recalled that statins with or without ezetimibe are the main treatment for primary hypercholesterolaemia, but that some people may be misidentified as being unable to take statins (see section 4.5) which may make subsequent treatments less cost effective. Because of this, the committee emphasised that its recommendations for alirocumab should only apply when the maximum tolerated lipidlowering therapy has failed. It clarified that this meant that either when the maximum dose has been reached or when further titration is limited by intolerance (as defined in NICE's guideline on familial hypercholesterolaemia: identification and management).

# Clinical effectiveness
The committee considered the clinicaleffectiveness evidence for alirocumab. It agreed that the trials included patients whose characteristics reflected those with hypercholesterolaemia seen in clinical practice in England, and that the results could be generalised to clinical practice. It noted that in people with hypercholesterolaemia, alirocumab statistically significantly reduced LDLC levels from baseline at 24 weeks by 39% to 62% compared with placebo, 24% to 36% compared with ezetimibe, and 20% to 49% compared with a statin. The committee heard from the clinical expert that PCSK9 inhibitors could reduce LDLC by up to 60% compared with placebo and that the treatment would have a sustained benefit, especially for people with familial hypercholesterolaemia. It also noted the ERG's comments that alirocumab was shown to have a similar safety profile to control groups. The committee concluded that alirocumab is clinically effective in reducing LDLC levels when compared with placebo, ezetimibe or statins in people with hypercholesterolaemia.
The committee discussed the effect of alirocumab on cardiovascular events in people with hypercholesterolaemia. It noted that the trials mainly reported surrogate end points (especially LDLC) and were not powered to measure cardiovascular outcomes, which the committee considered to be an important limitation of the evidence base. The committee noted that the company provided information about the relationship between LDLC and cardiovascular events from the Navarese metaanalyses of PCSK9 inhibitor trials. The committee heard from the clinical expert that the currently accepted relationship between LDLC and cardiovascular events is based on a Cholesterol Treatment Trialists' Collaboration (CTTC) metaanalysis of statin trials. It understood that the CTTC metaanalysis included trials that had long followup periods, were designed to measure cardiovascular outcomes, had a large number of patients and many observed events. In contrast, the Navarese metaanalysis of PCSK9 inhibitors included trials with shorter followup periods, fewer patients and fewer events. The committee also discussed the company's new evidence submitted in response to the appraisal consultation document, which used the CTTC metaanalysis. The company stated that although NICE's technology appraisals for ezetimibe and evolocumab used the CTTC metaanalysis, it had used the most conservative estimate of the relationship between LDLC and cardiovascular outcomes in its own modelling for alirocumab. The committee heard from the ERG that this estimate was taken from the most recent update of the CTTC metaanalysis, which included more trials and patients than the older metaanalysis used in the other NICE technology appraisals. Therefore, the committee concluded that the most appropriate evidence to assess this relationship was from the most recent update of the CTTC metaanalysis.

# Cost effectiveness
The committee considered the structure of the company's model. It noted that the model was consistent with the approaches for hypercholesterolaemia developed for related NICE guidance. Although the structure omitted the transient ischaemic attack and stable angina health states, the ERG considered these limitations to be conservative assumptions and considered the model to be of good quality with an appropriate structure. The committee concluded that the company's approach to modelling and the model structure was a reasonable basis for its decisionmaking.
The committee considered the baseline characteristics, risks and the transition probabilities used by the company. The committee understood that they were based on relevant realworld data from the Health Improvement Network (THIN) database, and noted the ERG's comment that there was good agreement with mediumterm survival for the highrisk cardiovascular disease and recurrent events/polyvascular disease (nonfamilial) populations. The committee therefore agreed that using data from THIN for these populations was appropriate. It understood that the company checked the face validity of baseline characteristics with known prevalence. It was aware that the company acknowledged that the baseline characteristics based on THIN were different from the known prevalence for the primary and secondary prevention (heterozygousfamilial) populations. Therefore, the committee accepted the company's approach using the Dutch lipid criteria with THIN instead of THIN alone, to identify people for the primary prevention (heterozygousfamilial) population because the baseline characteristics were considered more realistic. The committee noted the company's belief that the patient characteristics for the secondary prevention (heterozygousfamilial) population using the Dutch lipid criteria with THIN still lacked face validity, because they were different from known prevalence. The committee noted that the company used an alternative source (Mohrschladt) for this population and that this resulted in a composite annual baseline cardiovascular risk twice as high when compared with data from THIN. Although the ERG was unable to verify whether this alternative source was appropriate, the committee agreed that on balance, given that the patient characteristics from a realworld dataset (THIN) were different from known prevalence, it was appropriate to use Mohrschladt for the secondary prevention (heterozygousfamilial) population. The committee concluded that the baseline characteristics, risks and transition probabilities used in the company's model were acceptable for its decisionmaking.
The committee considered the incremental costeffectiveness ratios (ICERs) per qualityadjusted life year (QALY) for each group separately (as defined in section 4.2). It considered the ICERs from the company's new evidence in response to the appraisal consultation document, and noted that they incorporated both a revised patient access scheme and the committee's preferred assumptions as outlined in the appraisal consultation document.
The committee discussed how the company defined subgroups by LDLC level for each population in its new evidence. The committee recognised that using subgroups based on LDLC levels at which treatment should be started (that is, threshold LDLC levels) was consistent with both suggestions from consultation comments received in response to the appraisal consultation document and the committee's approach in previous technology appraisals. However, the committee recognised that the threshold LDLC levels were calculated as an average and would therefore include some people in whom alirocumab was most beneficial and cost effective (that is, people at relatively high baseline LDLC levels) as well as people in whom alirocumab was less beneficial and cost effective (that is people, at relatively low baseline LDLC levels). Therefore, the committee agreed that the LDLC levels in the company's new evidence may not be representative of the threshold at which alirocumab would be cost effective for all patients in the subgroup. The committee then noted that the ERG's revised exploratory analysis identified the LDLC level at which the ICER could be within the range normally considered to be a costeffective use of NHS resources (using a maximum acceptable ICER of less than 30,000 per QALY gained). The committee concluded that the company's approach was clinically plausible and consistent with other NICE technology appraisals for hypercholesterolaemia, and that the ERG's revised exploratory analysis could be used to more accurately identify the LDLC level at which the ICER would be within the range normally considered to be a costeffective use of NHS resources.

## Nonfamilial hypercholesterolaemia (primary prevention) population
The committee noted that the company did not submit evidence for people with nonfamilial hypercholesterolaemia without a history of cardiovascular disease (see section 4.2). Because of this, the committee concluded that alirocumab in combination with other lipidlowering therapies had not been shown to be a costeffective use of NHS resources for treating nonfamilial hypercholesterolaemia in adults without a history of cardiovascular disease and did not recommend alirocumab for this group.

## Nonfamilial hypercholesterolaemia highrisk cardiovascular disease (secondary prevention) population
In this population, the ICERs to be considered for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe were between 24,800 and 44,300 per QALY gained. Applying the ERG's revised exploratory analysis showed that the ICER for alirocumab in combination with other lipidlowering therapies compared with other lipidlowering therapies alone would be below 30,000 per QALY gained at an LDLC level of 4.1 mmol/l. The committee agreed that alirocumab in combination with other lipidlowering therapies could be considered a costeffective use of NHS resources compared with lipidlowering therapies alone for treating primary nonfamilial hypercholesterolaemia in adults with a high risk of cardiovascular disease and persistent LDLC levels of at least 4.0 mmol/l despite having the maximum tolerated lipidlowering therapy, and recommended it for this group.

## Nonfamilial hypercholesterolaemia recurrent events/polyvascular disease (secondary prevention) population
In this population, the ICERs to be considered for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe were between 19,300 and 34,000 per QALY gained. Applying the ERG's revised exploratory analysis showed that the ICER would be below 30,000 per QALY gained at an LDLC level of 3.5 mmol/l. The committee agreed that alirocumab in combination with other lipidlowering therapies could be considered a costeffective use of NHS resources compared with lipidlowering therapies alone for treating primary nonfamilial hypercholesterolaemia in adults with a very high risk of cardiovascular disease and persistent LDLC levels of at least 3.5 mmol/l despite having the maximum tolerated lipidlowering therapy, and recommended it for this group.

## Heterozygousfamilial hypercholesterolaemia (primary prevention)
In this population, the ICERs to be considered for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe were between 37,000 and 50,000 per QALY gained. The committee noted that all of these ICERs were above the maximum acceptable ICER normally considered to represent a costeffective use of NHS resources (20,000 to 30,000 per QALY gained). Although no ICERs were available for LDLC levels above 4 mmol/l, the committee noted that, in general, the ICERs tended to decrease as the LDLC level threshold for treatment increased. Therefore, it agreed that at higher LDLC levels (above 4 mmol/l) the ICER for alirocumab could plausibly approach the range normally considered to be a costeffective use of NHS resources. The committee also recalled that the ICERs for specific LDLC level thresholds for treatment could include a cohort of people in whom alirocumab would not be cost effective (see section 4.13). The committee noted that the ERG's revised exploratory analysis showed the ICER would be below 30,000 per QALY gained at an LDLC level of 6.1 mmol/l, and agreed that this was most likely the LDLC level at which the ICER would be within the range normally considered to be a costeffective use of NHS resources. The committee also noted that people with hypercholesterolaemia with an LDLC level above 5.0 mmol/l would be eligible for apheresis; it recalled its conclusion that treatments that avoid the need for apheresis would be welcomed (see section 4.6), but was aware that the company's model did not incorporate the cost and disutility associated with apheresis, which could reduce the resulting ICER. The committee concluded that despite the high ICERs, alirocumab in combination with other lipidlowering therapies could plausibly be considered a costeffective use of NHS resources compared with other lipidlowering therapies alone for treating heterozygousfamilial hypercholesterolaemia in adults without a history of cardiovascular disease and persistent LDLC levels of at least 5.0 mmol/l despite having the maximum tolerated lipidlowering therapy, and recommended it for this group.

## Heterozygousfamilial hypercholesterolaemia (secondary prevention)
In this population, the ICERs to be considered for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe were between 20,000 and 24,000 per QALY gained. Applying the ERG's revised exploratory analysis showed that the ICER for alirocumab in combination with other lipidlowering therapies compared with other lipidlowering therapies alone would be below 30,000 per QALY gained at an LDLC level of 4.0 mmol/l. The committee considered consultation comments that indicated that people with heterozygousfamilial hypercholesterolaemia with a history of cardiovascular disease had a lifelong risk of future cardiovascular events. It also noted consultation comments suggesting that treatment with alirocumab should be started at an LDLC level of 3 mmol/l, or at 4.0 mmol/l pending further evidence from cardiovascular outcome studies. The committee accepted that alirocumab would be beneficial for people with a lifelong risk of cardiovascular events in this population group. The committee also considered consultation comments suggesting that an LDLC level above 4 mmol/l to start treatment would exclude some people at high risk of cardiovascular disease. Having accepted that a minimum LDLC level of 4 mmol/l may exclude a small group of people, the committee agreed that a lower LDLC level of 3.5 mmol/l for starting treatment would be more appropriate than 4.0 mmol/l. On balance, the committee concluded that alirocumab in combination with other lipidlowering therapies could be considered a costeffective use of NHS resources compared with other lipidlowering therapies for treating heterozygousfamilial hypercholesterolaemia in adults with a history of cardiovascular disease and persistent LDLC levels of at least 3.5 mmol/l despite having the maximum tolerated lipidlowering therapy, and recommended it for this group.

## Mixed dyslipidaemia
The committee was aware that the company's model did not include people with mixed dyslipidaemia. It discussed whether its recommendations for primary hypercholesterolaemia could be generalised to mixed dyslipidaemia. The committee recalled that people with mixed dyslipidaemia also have elevated LDLC concentrations, and that treatment for mixed dyslipidaemia is partly determined by the LDLC concentration (see section 4.3). The committee understood that unlike people with nonfamilial hypercholesterolemia, people with heterozygousfamilial hypercholesterolaemia are at high risk of cardiovascular disease not only because of the high LDLC concentrations, but also because of the lifelong exposure to such concentrations. Therefore, the committee concluded that the recommendations for people with mixed dyslipidaemia should be the same as the recommendations for people with nonfamilial hypercholesterolaemia.
The committee discussed whether the ICERs presented accurately reflect the cost of alirocumab to the NHS. It understood that the actual discount received by the NHS may be less than the percentage discount offered in the patient access scheme. This is because people may move from secondary to primary care after several years, and simple discounts do not apply when drugs are prescribed through GP's FP10 prescriptions. The committee considered that the subgroups for which alirocumab is recommended have severe hypercholesterolaemia and a high risk of CVD, so treatment should continue in secondary care where simple patient access schemes apply. The committee concluded that the discounted patient access scheme price of alirocumab would be consistently applied for all people for whom alirocumab is recommended.
The committee discussed whether alirocumab could be considered innovative, and noted that clinical and patient experts thought it to be an innovative drug. The committee acknowledged that alirocumab was one of the first in a new class of drugs with a novel mechanism of action. Even so, it concluded that there was no evidence of additional gains in healthrelated quality of life over those already included in the QALY calculations, and that there was no need to change its conclusions on that basis.
The committee considered a potential equality issue raised by a patient and professional organisation that the incidence of familial hypercholesterolaemia could be higher in people of Ashkenazi Jewish origin. The committee concluded that its recommendations for alirocumab would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently.
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 appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.

# Summary of appraisal committee's key conclusions
TA393
Appraisal title: alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia
Section
Key conclusion
Alirocumab is recommended as an option for treating primary hypercholesterolaemia or mixed dyslipidaemia, only if:
Lowdensity lipoprotein concentrations (LDLC) are persistently above the thresholds specified in table 1 despite maximal tolerated lipidlowering therapy. That is, either the maximum dose has been reached or further titration is limited by intolerance.
The company provides alirocumab with the discount agreed in the patient access scheme.
In summary, alirocumab in combination with other lipidlowering therapies:
is not recommended for treating nonfamilial hypercholesterolaemia or mixed dyslipidaemia in adults without a history of cardiovascular disease
is recommended treating primary nonfamilial hypercholesterolaemia or mixed dyslipidaemia in adults with a high risk of cardiovascular disease and persistent LDLC levels of at least 4.0 mmol/l despite having the maximum tolerated lipidlowering therapy
is recommended for treating primary nonfamilial hypercholesterolaemia or mixed dyslipidaemia in adults with a very high risk of cardiovascular disease and persistent LDLC levels of at least 3.5 mmol/l despite having the maximum tolerated lipidlowering therapy
is recommended for treating heterozygousfamilial hypercholesterolaemia in adults without a history of cardiovascular disease and persistent LDLC levels of at least 5.0 mmol/l despite having the maximum tolerated lipidlowering therapy
is recommended for treating heterozygousfamilial hypercholesterolaemia in adults with a history of cardiovascular disease and persistent LDLC levels of at least 3.5 mmol/l despite having the maximum tolerated lipidlowering therapy.
, 4.14 to 4.18
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee concluded that the current treatment options for hypercholesterolaemia may not be sufficient in all cases, and that alternative treatment options are desirable.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The committee acknowledged that alirocumab was one of the first in a new class of drugs with a novel mechanism of action. The committee concluded that alirocumab is clinically effective in reducing LDLC levels when compared with placebo, ezetimibe or statins in people with hypercholesterolaemia.
There was no evidence of additional gains in healthrelated quality of life over those already included in the qualityoflife (QALY) calculations.
What is the position of the treatment in the pathway of care for the condition?
The committee concluded that a maximally tolerated dose of statins with ezetimibe was the main treatment option and appropriate comparator for hypercholesterolaemia (heterozygousfamilial and nonfamilial).
Adverse reactions
The committee noted that alirocumab was shown to have a similar safety profile to control groups.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that the trials mainly reported surrogate end points (especially LDLC) and were not powered to measure cardiovascular outcomes.
Relevance to general clinical practice in the NHS
The committee concluded that the current treatment options for hypercholesterolaemia may not be sufficient in all cases, and that alternative treatment options are desirable.
Uncertainties generated by the evidence
The committee noted that the trials mainly reported surrogate end points (especially LDLC) and were not powered to measure cardiovascular outcomes, which the committee considered to be an important limitation of the evidence base.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee heard from the clinical expert that PCSK9 inhibitors could reduce LDLC by up to 60% compared with placebo and that the treatment would have a sustained benefit especially for people with familial hypercholesterolaemia.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee noted that in people with hypercholesterolaemia, alirocumab statistically significantly reduced LDLC levels from baseline at 24 weeks by 39% to 62% compared with placebo, 24% to 36% compared with ezetimibe, and 20% to 49% compared with a statin.
Evidence for cost effectiveness
Availability and nature of evidence
The committee concluded that the company's model was acceptable for its decisionmaking.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee concluded that the most appropriate evidence to assess this relationship between LDLC and cardiovascular outcomes was from the most recent update of the CTTC metaanalysis.
The committee noted that the company incorporated both a revised patient access scheme and the committee's preferred assumptions as outlined in the appraisal consultation document.
Incorporation of healthrelated qualityoflife benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
There was no evidence of additional gains in healthrelated quality of life over those already included in the QALY calculations.
Are there specific groups of people for whom the technology is particularly cost effective?
The committee accepted that alirocumab would be beneficial for people with a lifelong risk of cardiovascular events in the heterozygousfamilial hypercholesterolaemia (secondary prevention) population.
What are the key drivers of cost effectiveness?
The committee was aware that using different rate ratios for the relationship between LDLC levels and cardiovascular outcomes could impact on the cost effectiveness of alirocumab.
The committee agreed that the LDLC levels in the company's new evidence may not be representative of the threshold at which alirocumab would be cost effective for all patients in the subgroup.
Most likely costeffectiveness estimate (given as an ICER)
For the nonfamilial hypercholesterolaemia (primary prevention) population:
the company did not submit evidence for this population.
For the nonfamilial hypercholesterolaemia highrisk cardiovascular disease (secondary prevention) population:
between 24,800 and 44,300 per QALY gained for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe
the ICER would be below 30,000 per QALY gained at an LDLC level of 4.1 mmol/l.
For the nonfamilial hypercholesterolaemia recurrent events/polyvascular disease (secondary prevention) population:
between 19,300 and 34,000 per QALY gained for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe
the ICER would be below 30,000 per QALY gained at an LDLC level of 3.5 mmol/l.
For the heterozygousfamilial hypercholesterolaemia (primary prevention) population:
between 37,000 and 50,000 per QALY gained. Considered for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe
the ICER would be below 30,000 per QALY gained at an LDLC level of 6.1 mmol/l.
For the heterozygousfamilial hypercholesterolaemia (secondary prevention) population:
between 20,000 and 24,000 per QALY gained for alirocumab and a statin plus ezetimibe compared with a statin and ezetimibe
the ICER would be below 30,000 per QALY gained at an LDLC level of 4.0 mmol/l.
to 4.18
Additional factors taken into account
Patient access schemes
The company has agreed a patient access scheme with the Department of Health.
Endoflife considerations
Not applicable.
Equalities considerations and social value judgements
The following potential equality issues were identified during the scoping process:
Inequality of access to LDLapheresis due to high set up costs for treatment and few established centres with appropriate expertise.
Injection only treatment which will exclude people who will not accept injection based therapies, including many from ethnic minority groups.
The potential equality issues identified during the scoping process have been noted by the committee. None of these issues related to protected characteristics, as defined by the Equalities Act, and so were not considered equality issues.
The following potential equality issue was identified during the consultation:
The incidence of familial hypercholesterolaemia could be higher in people of Ashkenazi Jewish origin.
The committee concluded that its recommendations for alirocumab would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently.

# Recommendations for research
The committee was aware that an ongoing randomised controlled trial exploring the occurrence of cardiovascular events of alirocumab compared with placebo are available is expected in 2018. The committee agreed that this trial would give useful data on the direct effect of alirocumab on cardiovascular disease.