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1. BackgroundThis section incorporates information and language from the 2018 ICER assessment of prophylactictreatments for hereditary angioedema (HAE).In 2018, The Institute for Clinical and Economic Review (ICER) conducted a review of lanadelumab(Takhzyro , Takeda Pharmaceutical Company, Ltd.) and two C1 inhibitors (Haegarda , CSL Behring,GmbH; and Cinryze , Takeda Pharmaceutical Company, Ltd.) for long-term prophylaxis againstacute attacks in patients with hereditary angioedema (HAE). The primary objective of this analysisis to update the prior estimation of the cost effectiveness of Takhzyro, Haegarda, and Cinryze usingrecent observational real-world evidence (RWE). This work is a pilot project to explore how ICERcan update review topics using observational RWE, with an emphasis on therapies that have beenapproved through accelerated approval pathways and are in use for over two years.HAE is a rare genetic disorder that causes painful attacks of swelling in the face, hands, feet, andstomach, as well as potentially life-threatening swelling of the throat. Most HAE is caused by adeficiency (Type I HAE) or dysfunction (Type II HAE) of a protein called C1 inhibitor (C1 esteraseinhibitor, C1-INH). Attacks can last for up to five days, and can be spontaneous or triggered bystress, medical procedures, and certain medications like oral contraceptives or ACE inhibitors.Attacks can occur rarely or as often as once every few days. Because of their severity andunpredictability, attacks can significantly reduce a patient’s functioning and ability to performactivities of daily living.The goal of HAE treatment is to reduce the duration, frequency, and severity of attacks. Ondemand treatments are used to reduce the duration and severity of a single attack. Long-termprophylactic treatments, the focus of the 2018 report1 and this update, are taken regularly toprevent attacks and reduce attack severity. ICER’s 2018 report found that long-term prophylaxiswith either of the C1 inhibitors or Takhzyro resulted in fewer acute attacks and improved quality oflife for people living with HAE, but 2018 pricing of all three treatments exceeded traditional costeffectiveness thresholds. The 2018 report identified uncertainties in the evidence and key modelassumptions that influenced the cost-effectiveness findings. One of the most consequentialuncertainties in the 2018 model was the frequency and severity of attacks at baseline amongpatients who would be prescribed prophylactic treatment. As demonstrated in the 2018 report,small differences in the assumed attack rate resulted in a wide range of cost-effectiveness results.As a first step, the 2018 economic model was assessed for inputs influential to the results that couldbe reliably and validly analyzed in an observational claims analysis. The observational RWEcontributions to cost-effectiveness updates were identified a priori in an observational claimsanalysis protocol. The primary contribution from observational RWE centers on estimating thebaseline monthly attack rate and health care resource use (i.e., severity) of attacks in individuals Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 1Return to Table of Contents

who initiated prophylactic therapy of Takhzyro, Haegarda, or Cinryze, that had a large impact on theincremental cost-effectiveness ratio in the 2018 report. Additional inputs from the observationalclaims analysis included other baseline patient characteristics (age, gender, weight), the percentageof patients who reduced Takhzyro dosing (i.e., one dose every four weeks instead of every twoweeks), and other health care resource use and unit cost estimates.The updated cost-effectiveness analysis continues to rely on the pivotal randomized controlled trial(RCT) evidence to quantify the relative reductions in attacks attributed to prophylactic treatment(i.e., treatment efficacy). Treatment effectiveness was not considered to be reliably assessed withinthe available claims data due to small sample size, limited duration of follow-up, and lack of abilityto identify an appropriate comparator due to the potential for unmeasured confounding.Therefore, real-world treatment effectiveness was explored as a descriptive pre-post analysis butdid not replace RCT treatment efficacy in the updated cost-effectiveness analysis.This report was developed specifically to pilot-test the impact of leveraging observational RWE toupdate ICER reviews of drugs initially approved through the accelerated approval pathway. Thisreport does not include an assessment of berotralstat, a recently approved prophylactic treatmentthat was not included in the 2018 Report. Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 2Return to Table of Contents

2. Methods2.1 OverviewThe primary aim of this analysis was to update our 2018 cost-effectiveness analysis of Haegarda,Cinryze, and Takhzyro for long-term prophylaxis against acute attacks in patients with HAE. Westarted with the existing 2018 report economic model, developed in Microsoft Excel, as described inthe Supplement. The update was then conducted in two phases. The first (preliminary phase),focused on incorporating new model inputs based on an updated review of the RCT literature. Thepreliminary phase literature update and supporting studies are detailed in Supplement Section A.The subsequent observational RWE phase addresses the primary aim. In the observational RWEphase, we used real-world data (RWD) analyses to provide new inputs for model assumptionsregarding baseline attack frequency and utilization costs related to severity of attack. In addition,where necessary, all unit costs from the 2018 report and 2020 US Dollars from the de novo RWEanalysis were inflated to 2021 US dollars using the Personal Consumption Expenditure (PCE) priceindex.2This two-phase update approach was taken to help make transparent the separate incrementaleffects of updating the model with new RCT evidence and with RWE. This report emphasizes theobservational RWE phase whereas the preliminary phase RCT literature update may be found in theSupplement. Consistent with the 2018 Report, the primary measure of cost effectiveness was theincremental cost per quality-adjusted life years (QALYs) gained. Equal value of life years gained(evLYG) as a measure of health gain was introduced after the 2018 Report and therefore is notfeatured within this update.2.2 Real-World Data AnalysisFull descriptions of the RWE protocol, including details of the approach used to identify patients,can be found in Supplemental Appendix B. We performed our RWE analyses using Optum’s deidentified Clinformatics Data Mart Database. This database is comprised of administrative healthclaims for members of large commercial and Medicare Advantage health plans and includesapproximately 65 million lives. These data allowed for the identification of HAE patients and thecapture of key study elements including prescription claims, costs, emergency department (ED)visits and other health care resource utilization from April 13, 2008 through March 31, 2020.Optum’s standard costs are based on algorithms that reflect the intensity of care provided,including quantity of services, relative resource costs, and the nature of utilization. Standard cost isan estimate of the allowed amount (i.e., the total cost of service) and is validated by Optum againstthe paid amount. Analyses of this database were performed within the Aetion Evidence Platform (AEP). Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 3Return to Table of Contents

In order to explore uncertainties raised in the November 2018 report,1 the real-world data (RWD)analysis had the following primary objective: to describe baseline demographic characteristics,attack rates, and attack-related medical service utilization among patients initiating treatment withTakhzyro, Haegarda, or Cinryze, identified via prescription claims. HAE attack rates were calculatedin total and by severity. Severe attacks were defined as an ED visit or hospitalization due to HAE(please see protocol for algorithms and code lists). Non-severe attacks were defined as treatmentwith on-demand therapy administered in an outpatient visit, home nurse visit, or self-administeredby the patient. Data on the duration of attacks by severity is limited, however attacks generally lastbetween two and five days.3 Thus, on-demand therapy administered by a health care professionalin an outpatient or home setting, during an ED visit, and during inpatient hospitalizations occurringwithin five days of each other were considered part of a single attack episode. Secondaryobjectives were to explore attack rates and utilization following long-term prophylaxis initiationwith Takhzyro, Haegarda, or Cinryze and to explore the percentage of Takhzyro initiators whomoved to less frequent dosing after six months attack free. All other cohort, exposure, andoutcome definitions, and statistical and sensitivity analysis were detailed in the pre-defined studyprotocol.The design, study execution, analysis, and reporting (across the report, supplement, and protocol)of this RWE study met published good practices guidelines.4 In addition, we sought public commentfrom stakeholders on the research protocol. Based on comments received from the manufacturersand clinical experts, we included descriptive information on therapies that may be associated withincreased risk of HAE attacks and added suggested limitations and interpretations to the study.2.3 Cost-Effectiveness AnalysisAll updated model assumptions and inputs are listed in Supplement Section C2 and further detailedin the model analysis plan. The key assumption related to incorporation of new RWE was thatattacks were counted through claims for attack-related prescriptions and/or ED visits orhospitalizations coded as due to HAE. Thus, all attacks were assumed to be treated. Patients mighthave experienced some form of episode but if they did not seek and receive medical care it wouldnot have been counted in our RWE analysis.In the observational RWE phase, the preliminary phase model was updated to include data from thede novo RWE claims analysis. Supplement Section C2 presents a comparison of model inputs thatwere updated for this effort versus the inputs used in the 2018 assessment. A complete listing of alloriginal model inputs can be found in the 2018 Final Report.1 We performed both one-way andprobabilistic sensitivity analyses according to standard methodologies in the field. Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 4Return to Table of Contents

3. Results3.1 Observational RWE FindingsAs shown in Supplement Table B1, during the 12-year timespan covered by the RWE analysis, 158patients initiated prophylactic treatment with Cinryze (49.4%), Haegarda (24.0%), or Takhzyro(26.6%).In the six months prior to initiation of prophylaxis therapy, 136 of these 158 patients (86%) hadevidence of at least one attack episode (note: attacks occurring within five days of each other wereconsidered part of a single attack episode). Out of 1,783 total attack episodes observed for allpatients in the six months prior to initiation of prophylaxis therapy, 5.7% were severe, and 94.3%were non-severe (Table 3.1).On average, the 158 patients had 1.88 HAE attacks per month prior to initiation of prophylaxistherapy.Table 3.1. Baseline HAE Attack Rates over Six MonthsSevere HAE attack episodesNon-severe HAE attack episodesTotal attacks (severe and non-severe)AttacksN (%)102 (5.7%)1,681 (94.3%)1,783 (100%)Mean Attack Rate(per Patient per Month)0.111.771.88Supplement Section C4 provides details on the results of sensitivity analyses of attack rates andother utilization, cost, and exploratory analyses. Sensitivity analyses were conducted varying thedefinition of HAE attacks. Data on the precise timing of self-administered treatment is notavailable. Rather, the number of treatments administered was estimated from pharmacydispensing data, including date and quantity dispensed, and dosing guidelines. In estimating thenumber of self-treated attacks, we assumed, based on clinical guidelines, that patients would haveon-demand treatment on hand to treat up to two attacks. These two on-hand doses weresubtracted out in the calculation of self-administered doses in the primary analysis. In sensitivityanalysis, each prescription dose was counted as an attack. This increased the non-severe attacks to1,871 and total attacks to 1,973 and resulted in 2.08 attacks per patient per month.In the primary analysis we treated attack-related visits within five days of each other to be part ofthe same attack. In sensitivity analyses, we reduced the assumed attack duration to two days andthen to one day, treating events on distinct days as separate attacks in the one-day durationanalysis. Estimated attack rates increased to 1.90 and 1.96 in these analyses, respectively. Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 5Return to Table of Contents

For non-severe episodes the most common on-demand therapy used was Firazyr, used in 61.0% ofepisodes, followed by Berinert (19.6%). Of 102 severe attack episodes, 19 (18.6%) included ahospitalization. The average cost per ED visit was 2,940 and average cost per hospitalization was 20,957 (2021 USD). An analysis of Takhzyro initiators suggested that 48% (20/42) reduced dosingto every four weeks. Although not used in the cost-effectiveness analysis updates, descriptiveanalyses of severe attack rates pre versus post prophylaxis initiation suggested a post period meansevere attack rate of 0.0389 severe attack episodes per patient per month (vs. 0.1076 in the preperiod).3.2 Observational RWE Updated Cost-Effectiveness FindingsKey results of the RWE analysis which were used in the observational RWE updated costeffectiveness model included baseline attack rate, unit costs for health care resource use,distribution of attack severity, market share for on-demand drugs, and proportion of Takhzyropatients who switch to every four week dosing (Supplement Tables C3 – C9). Table 3.2 presents theobservational RWE update results on discounted costs and outcomes for prophylaxis and noprophylaxis.Table 3.2. Results for the Observational RWE Update Base Case for HAE Prophylaxis Compared tono ProphylaxisTreatmentProphylaxisDrug Cost*Total Cost*AttacksQALYsLife YearsNo prophylaxis 0 6,780,000 92618.0023.30Haegarda 12,890,000 13,950,000 14818.5323.31Cinryze 13,520,000 16,880,000 45818.3323.30Takhzyro 12,660,000 13,490,000 11418.5423.31QALY: quality-adjusted life year*Results rounded to the nearest 1,000; Results rounded to the nearest 10,000 when over 1 million.With the inclusion of RWE alongside the other model inputs, long-term prophylaxis continued toresult in a lower number of acute attacks, higher costs, and higher QALYs compared to no long-termprophylaxis, but with fewer QALYs gained than the prior base-case analyses. The influence of thesenew model assumptions on cost effectiveness was dramatic, increasing the incremental costeffectiveness ratios for all drugs to figures above 10 million per QALY gained (Table 3.3). Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 6Return to Table of Contents

Table 3.3. Comparison of 2018 and Observational RWE Update Base-Case Results for HAEProphylaxis versus no Prophylaxis2018 ReportObservational RWE UpdateCost per QALY gainedCost per QALY gainedCinryze 5,950,000 30,070,000Haegarda 328,000 13,430,000Takhzyro 1,110,000 12,370,000QALY: quality-adjusted life year*Results rounded to the nearest 1,000; Results rounded to the nearest 10,000 when over 1 million. Note: Dueto ratio properties of incremental cost-effectiveness ratios, results can become extreme with small denominators.TreatmentSensitivity analysis, scenario analysis, and threshold analysis for the Observational RWE Phaseupdates are presented in Supplement Section C4.The incremental contribution of key inputs to the difference in the cost-effectiveness ratiosbetween the original 2018 report, the preliminary phase update, and the observational RWE phaseupdate is presented in Table 3.4 below. The first row presents the incremental cost per QALY ofprophylaxis compared with no prophylaxis from the 2018 evaluation. The second row presents theresults of the preliminary phase updates (Supplement Tables C10 and C11). Each subsequent rowbuilds upon the previous with the addition of another group of RWE inputs. More detailed tablesby drug are provided in Supplement Tables C26, C27, and C28.Table 3.4. Impact of RWE Update on Incremental Cost per QALYIncremental Cost per QALYHaegardaCinryze 328,000 5,954,000Takhzyro2018 evaluation base-case results 1,108,000Preliminary phase literature update 461,000 7,060,000 1,280,000resultsObservational RWE Update StepsHaegardaCinryzeTakhzyro1. Proportion on Takhzyro that switch toN/AN/A 199,000every 4-week dosing2. Baseline attack rate 10,390,000 24,280,000 10,010,0003. Population and clinical parameters* 13,790,000 30,360,000 12,730,0004. Cost parameters† 13,430,000 30,070,000 12,370,000Final RWE Update Results 13,430,000 30,070,000 12,370,000QALY: quality-adjusted life year, RWE: real-world evidence* Population parameters, pretreatment attack severity, treatment pathway (proportion of mild and moderateattacks treated with home self-administration, home nurse, or outpatient; proportion of severe attacks whichresult in hospitalization, hospitalization resource utilization mortality)† Direct cost of emergency department visits and hospitalization, cost of administration, market shares of ondemand drugs Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportPage 7Return to Table of Contents

3.3 New Health Benefit Price Benchmarks Based on ObservationalRWE UpdateAs shown in Table 3.5 below, based on the Observational RWE Phase updates, all the HAEprophylaxis agents would need to be priced significantly lower than the current list prices to reachhealth-benefit price benchmarks (HBPBs). Discounts needed to reach cost-effectiveness thresholdsare more substantial than those suggested in the original 2018 report.Table 3.5. Observational RWE Update HBPBs for HAE Prophylactic TherapiesAnnualWACPrice toAchieve 100,000 perQALY 247,669 139,742 218,858*Haegarda 536,694Cinryze 548,563Takhzyro 461,611*QALY: quality-adjusted life year*Considers proportion with dose reductionPrice toAchieve 150,000 perQALY 248,779 140,550 219,844* Institute for Clinical and Economic Review, 2021HAE RWE Update - ReportDiscount from ListPrice to ReachThreshold PricesDiscounts from ListPrice to Reach 2018Report Threshold Prices53.6% to 53.9%74.5% to 75.4%52.4% to 52.6%27.7% to 28.2%59.7% to 60.0%33.7% to 34.2%Page 8Return to Table of Contents

4. DiscussionThe goal of this update to the 2018 ICER report on prophylactic treatments for HAE was to evaluatethe impact of integrat

Institute for Clinical and Economic Review, 2021 Page v HAE RWE Update - Report List of Acronyms and Abbreviations Used in this Report ACE Angiotensin-converting enzyme AE Adverse event AEP Aetion Evidence Platform AHRQ Agency for Healthcare Research and Quality ARB Angiotensin II receptor blocker ASP Average sales price CDC Centers for Disease Control and Prevention