Coagulation Factor IX FC Fusion Protein (Alprolix): Treatment Cost Comparison and Budget Impact Analysis

Transcription

1 CADTH TECHNOLOGY REVIEW Coagulation Factor IX FC Fusion Protein (Alprolix): Treatment Cost Comparison and Budget Impact Analysis Product Line: Technology Review Version: 1.0 Issue Number: 1 Publication Date: November 2015 Report Length: 15

2 Authors: Doug Coyle, Karen M. Lee Disclaimer: CADTH would like to acknowledge various participants in the development of this report: Dr. Alan Tinmouth for providing clinical expertise and feedback on the approach to the economic model; William Sheffield, Peter Saunders from the Canadian Blood Services (CBS) for their input on the scope of the project, feedback on drafts, and review of final report; and Amanda Hodgson (CADTH) for information services support. This report is prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). This report contains a comprehensive review of existing public literature, studies, materials, and other information and documentation available to CADTH at the time it was prepared. This report was produced, as part of a collaboration between CADTH and the Canadian Blood Services (CBS), to provide an economic evaluation of a new plasma product to supplement a CBS clinical evidence report. The scope of the research questions in this CADTH report was discussed in collaboration with CBS and clinical experts. Based on the scope, the clinical data needs were determined, and any gaps in the data in the CBS clinical evidence report were addressed through a systematic review. CADTH used these data to inform this report. The information in this report is intended to be used by CBS, along with the CBS evidence report, to make recommendations to the provincial and territorial ministries of health on whether to purchase and distribute the new plasma product. The information in this report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision making process nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up-to-date, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or as a result of the use (or misuse) of any information contained in or implied by the information in this report. Copyright CADTH This report may be reproduced for non-commercial purposes only provided it is not modified and appropriate credit is given to CADTH. You may not otherwise copy, modify, translate, post on a website, store electronically, republish or redistribute any material from the website in any form or by any means without the prior written permission of CADTH. About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system. Funding: CADTH receives funding from Canada s federal, provincial, and territorial governments, with the exception of Quebec. Views: CADTH takes sole responsibility for the final form and content of this report. The statements, conclusions and views expressed herein do not necessarily represent the view of Health Canada or any provincial or territorial government. Cite as: Coagulation Factor IX FC fusion protein (Alprolix): treatment cost comparison and budget impact analysis. Ottawa: CADTH; 2015 Nov. (CADTH technology review; no. 1) Contact requests@cadth.ca with inquiries about this notice or legal matters relating to CADTH services. ISSN:

3 Table of Contents ABBREVIATIONS... ii 1. BACKGROUND INFORMATION Current Treatment Options Coagulation Factor IX Fc Fusion Protein (Alprolix) Comparative Efficacy and Safety Potential for Off-Label Use Policy and Ethical Issues OBJECTIVES TREATMENT COST COMPARISON Methods Manufacturer s Base-Case Results CADTH Reanalysis BUDGET IMPACT ANALYSIS Approach Methods Estimated Number of Treated Cases Manufacturer s Estimated Budget Impact CADTH Reanalysis SUMMARY REFERENCES Tables Table 1: Assumptions Used in Cost Comparison Analysis... 4 Table 2: Cost Comparison of Alprolix and BeneFIX Based on the Manufacturer s BIA Submission... 5 Table 3: Cost Comparison of Alprolix and BeneFIX CADTH Reanalysis... 6 Table 4: Sensitivity Analysis Based on CADTH Reanalysis... 6 Table 5: Manufacturer s Estimate of Patient Numbers... 8 Table 6: Manufacturer s Estimate of Budget Impact... 8 Table 7: Manufacturer s Sensitivity Analyses... 9 Table 8: CADTH Estimate of Budget Impact... 9 Table 9: Sensitivity Analysis Based on CADTH Reanalysis CADTH TECHNOLOGY REVIEW i

4 Abbreviations BIA CADTH CBS IU budget impact analysis Canadian Agency for Drugs and Technologies in Health Canadian Blood Services international units CADTH TECHNOLOGY REVIEW ii

5 1. Background Information The current review focuses on the control and prevention of hemorrhagic bleeds and prophylaxis in patients with hemophilia B (congenital factor IX deficiency, or Christmas disease). Factor IX deficiency hemophilia is defined by the lack of factor IX blood protein, the absence of which slows down the normal clotting process. 1 It is estimated that hemophilia B affects approximately one in 50,000 people, or about 600 Canadians. 1 Hemophilia may be classified by severity, based on the percentage of factor IX circulating in the blood: severe, < 1% of normal; moderate, 1% to 5% of normal; and mild, 5% to 30% of normal. Those with severe hemophilia may experience hemorrhagic bleeds several times a month, with or without cause for bleed. Those with moderate hemophilia bleed less often, and bleeding episodes are typically the results of minor trauma (e.g., sport- or activity-based). Individuals with mild hemophilia have even fewer hemorrhagic events, which may be problematic only in cases such as surgery Current Treatment Options The main treatment option currently is short-acting recombinant coagulation factor IX (BeneFIX). It is indicated for the control and prevention of hemorrhagic episodes and routine prophylaxis in patients with hemophilia B (congenital factor IX deficiency, or Christmas disease), including control and prevention in surgical settings. 2 It is available in a number of single-use vial sizes: 250, 500, 1,000, 2,000, and 3,000 international units (IU) per vial. The Canadian Blood Services (CBS) price is $v.vv per IU. 3 In clinical studies, for routine secondary prophylaxis, the average dose for adult patients is 40 IU/kg at three- to four-day intervals. At a patient weight of 73.3 kg, the estimated average weekly cost is $5,219. An alternative, Immunine, is a purified, sterile, freeze-dried concentrate of human blood coagulation factor IX. It is available in a 500 IU vial, through CBS online order forms for hospital users Coagulation Factor IX Fc Fusion Protein (Alprolix) Coagulation factor IX Fc fusion protein (Alprolix) is a long-acting recombinant anti-hemophilic factor indicated in adults and children older than 12 years who have hemophilia B (congenital factor or Christmas disease) for: Routine prophylaxis treatment to prevent or reduce frequency of bleeding episodes Control and prevention of bleeding episodes. 5 It is available in a number of single-use vial sizes: 250, 500, 1,000, 2,000, and 3,000 IU per vial. The submitted unit cost is $v.vv per IU. 6 The recommended use is 50 IU per kg once weekly or 100 IU per kg every 10 to 14 days. At a patient weight of 73.3 kg, the estimated weekly cost is $6, Comparative Efficacy and Safety There are no clinical trials comparing coagulation factor IX products (Alprolix, BeneFIX, and/or Immunine VH). Therefore, the comparative efficacy of these blood products is unknown. The clinical experts feedback suggests similar efficacy between Alprolix and BeneFIX in terms of CADTH TECHNOLOGY REVIEW 1

6 control of bleeding. 7 The only advantage of Alprolix is a longer half-life, which may lead to fewer infusions, although the implications of this in terms of patient benefit are unclear. From a safety perspective, the opinion of the majority of the clinical experts was that there are no additional safety concerns with the use of Alprolix compared with BeneFIX, although one expert concluded that the safety was unknown. 1.4 Potential for Off-Label Use Based on the clinical experts feedback, the potential for off-label use of Alprolix is low. There is the potential for use in children (Alprolix is currently licensed only for individuals older than 12 years) and perioperatively although the numbers for the latter may be small. 1.5 Policy and Ethical Issues The policy issue relates to the new technology, which provides possible benefits in terms of a longer half-life but has no direct evidence regarding its relative efficacy in terms of control of bleeding with respect to current products. Given the lack of evidence, consideration of a premium price based on incremental effectiveness is not possible and the focus on cost neutrality in the manufacturer s submission should be the focus of any policy decision. 2. Objectives The aim of this report is to: Assess the comparative cost of coagulation factor IX Fc fusion protein (Alprolix) against recombinant coagulation factor IX (BeneFIX) in both the control and prevention of bleeding episodes Assess, from the Canadian health ministry perspective, the budgetary impact of reimbursing coagulation factor IX Fc fusion protein, over a three-year period, for prophylactic treatment of patients with hemophilia B who require prophylaxis to prevent or reduce the frequency of bleeding. Neither perioperative management of bleeding nor use in children aged 12 years or younger were considered in this analysis. CADTH TECHNOLOGY REVIEW 2

7 3. Treatment Cost Comparison 3.1 Methods The review is based on a cost comparison provided by the manufacturer as part of its submission to CBS. 8 As part of the review, the methods and assumptions of the manufacturer s analysis were assessed, and validated where possible, and any further assessment of uncertainty considered in reanalyses. The manufacturer submitted a cost comparison of coagulation factor IX Fc fusion protein and recombinant coagulation factor IX, based on the assumption of similar clinical effects and harms. It assumed that all other health care costs (such as physician visits and monitoring) would be identical between the two agents. Two patient groups were considered: Patients currently taking BeneFIX on an on-demand basis. It is assumed that a proportion of these patients who are high risk (increased number of bleeds per annum) will convert to Alprolix prophylaxis. Patients currently taking BeneFIX on a prophylaxis basis. It is assumed that a proportion of these patients will convert to Alprolix prophylaxis. Patients younger than 12 years were excluded from the analysis. Based on comments from CBS clinical experts within the briefing note, 7 BeneFIX was considered to be the most appropriate comparator for Alprolix. The average cost per dose depends on the patient s weight. Both blood products are available in single-dose vials; however, a variety of vial sizes are available and the clinical experts did not feel that wastage would be a significant issue, given the availability of various dose sizes. For both products, vials are available containing 50, 100, 200, 400, and 600 IU/mL of reconstituted product. The costs of BeneFIX and Alprolix used by the manufacturer were $XXX and $ XXX per IU, respectively. Table 1 details the assumptions made within the manufacturer s model and any revised assumptions used for the CADTH reanalysis, as well as any alternate estimates used in sensitivity analysis. CADTH TECHNOLOGY REVIEW 3

8 Table 1: Assumptions Used in Cost Comparison Analysis Parameter Manufacturer Base-Case Assumption Revised Assumption for CADTH Reanalysis Sensitivity Analysis Patient weight 73.3 kg a As manufacturer s 65 kg and 90 kg assumption Definition of on-demand patients who will switch to Alprolix 40.8 infusions per annum b 30 infusions per annum 20 infusions per annum to assess impact if lower-risk patient switches to Alprolix i Dose per infusion of on-demand 42.8 IU/kg c 42.8 IU/kg 50 IU/kg BeneFIX Annual dose of BeneFIX 5,067 IU/kg d 4,732 IU/kg 5,067 IU/kg prophylaxis Costs of blood product Not included e Not included administration Proportion of patients who convert 68% a 68% 50% and 85% to Alprolix prophylaxis treated on a weekly basis Annual dose for the weekly 2,447 IU/kg f 2,350 IU/kg 2,447 and 3,157 IU/kg prophylaxis with Alprolix regimen Annual dose for the individualized 3,157 IU/kg g 2,600 IU/kg 3,157 IU/kg interval prophylaxis with Alprolix regimen Proportion of Alprolix patients who 19.6% h 19.6% 50% i would have been treated ondemand Proportion of non high-risk ondemand 0% 0% 25% patients who will move to Alprolix on-demand Cost per IU of BeneFIX $v.vv $v.vv $v.vv BIA = budget impact analysis; CBS = Canadian Blood Services; IU = international units. a Based on phase 3 trial. 9 b Limited to high-risk patients (those who experience 20 bleeds annually, requiring 1.54 infusions per bleed, and who are administered 10 additional infusions as preventive measure prior to exercise). In the manufacturer s BIA, highrisk patients are characterized in three different ways: those requiring 40.8 infusions per annum, those requiring 30 per annum, and those experiencing 30 bleeds. c The submitted value comes from a 2001 clinical study and the true dose in the Canadian setting is unknown. 10 d The submitted value comes from a 2011 conference abstract. A 2014 manuscript that appears to be the journal article version of the conference abstract suggests a lower n annual dose of 4,732 ( ) IU/kg based on a 50 IU/kg twice-weekly regimen. 11,12 e Assumed similar. f The submitted value is stated as based on the median dose in the phase 3 trial. 9 In the phase 3 trial, the median dose is 45.2, which would lead to an annual dose of 2,350 ( ) IU per kg. g The average interval in the last three months of the phase 3 clinical trial was If a dose of 100 IU per kg were delivered every 14 days, the expected annual dose would be 2,600 (100 52/2) IU per kg. h This is based on dividing the number of forecasted Alprolix users who moved from on-demand by the total number of Alprolix users over the three-year period. i Assuming that patients with lower risk will switch to prophylaxis will also change the proportion of overall patients on prophylaxis who would have been on-demand. This is assessed by assuming 75% of on-demand patients would be in the category of potential convertors when simultaneously changing the number of infusions in this group to 20. j Revised price from CBS provided after initial analyses. CADTH TECHNOLOGY REVIEW 4

9 Analysis compared the cost per patient of Alprolix prophylaxis with on-demand use of both BeneFIX and BeneFIX prophylaxis. In addition, a weighted cost of BeneFIX was calculated based on the manufacturer s assumptions that 32% of Alprolix users would be previously ondemand users. This would allow identification of the price point for Alprolix, which would lead to no cost differences between the use of Alprolix and BeneFIX. The sensitivity analysis is presented in terms of the results of the weighted costs analysis and the required price reduction for cost neutrality. 3.2 Manufacturer s Base-Case Results Based on the manufacturer s assumptions, Alprolix prophylaxis is more costly than the use of BeneFIX on-demand (cost increase of $247,436 per patient per annum), as well as BeneFIX used as prophylaxis (cost increase of $28,365 per patient per annum). See Table 2. The price reduction required for the costs of BeneFIX and Alprolix to be equal would be 20% (a reduction of $ XXX per IU). Table 2: Cost Comparison of Alprolix and BeneFIX Based on the Manufacturer s BIA Submission Patient Group Product Price per IU ($) Patients who would be treated with BeneFIX ondemand Patients who would receive BeneFIX prophylaxis Weighted sum a Annual Dose per kg BeneFIX on-demand v.vv 1,746 vvv,vvv Average Annual Drug Cost ($) b Alprolix Cost (Savings), $ Alprolix prophylaxis v.vv 2,674 vvv,vvv 247,436 BeneFIX prophylaxis v.vv 5,067 vvv,vvv Alprolix prophylaxis v.vv 2,674 vvv,vvv 28,365 BeneFIX on-demand or prophylaxis v.vv 4,416 vvv,vvv Alprolix prophylaxis v.vv 2,674 vvv,vvv 95,048 BIA = budget impact analysis; IU = international unit. a Based on assuming 35% of Alprolix prophylaxis patients were previously on-demand BeneFIX patients. b Assuming patient weight of 73.3 kg. Source: Manufacturer s Economic Submission CADTH Reanalysis Base-Case Analysis In CADTH reanalysis, based on alternate assumptions, Alprolix prophylaxis is more costly compared with the use of BeneFIX on-demand (cost increase of $244,815 per patient per annum) and BeneFIX prophylaxis (cost increase of $17,350 per patient per annum); see Table 3. The price reduction required for the costs of BeneFIX and Alprolix to be equal would now remain 19% (a reduction of $v.vv per IU). CADTH TECHNOLOGY REVIEW 5

10 Table 3: Cost Comparison of Alprolix and BeneFIX CADTH Reanalysis Patient Group Product Price per IU ($) Patients who would be treated with BeneFIX on-demand Patients who would receive BeneFIX prophylaxis Weighted sum a Annual Dose per kg Average Annual Drug Cost ($) b Alprolix Cost (Savings), $ BeneFIX on-demand v.vv 1,284 vv,vvv Alprolix prophylaxis v.vv 2,430 vvv,vvv 244,815 BeneFIX prophylaxis v.vv 4,732 vvv,vvv Alprolix prophylaxis v.vv 2,430 vvv,vvv 17,350 BeneFIX on-demand or v.vv 4,056 vvv,vvv prophylaxis Alprolix prophylaxis v.vv 2,430 vvv,vvv 61,933 a Based on assuming 35% of Alprolix prophylaxis patients were previously on-demand BeneFIX patients. b Assuming patient weight of 73.3 kg Sensitivity Analysis Based on CADTH sensitivity analysis, the price reductions required for Alprolix to be cost neutral were relatively consistent with those reported by the manufacturer (ranging from 17% to 27%) in all scenarios, except when lower-risk on-demand patients (i.e., those who required on average 20 infusions per annum) would move to Alprolix prophylaxis. In this case, the required price reduction would be 39% a price reduction of $v.vv per IU; see Table 4. Table 4: Sensitivity Analysis Based on CADTH Reanalysis Scenario Weighted Annual Cost of BeneFIX On-demand or Prophylaxis ($) Annual Cost of Alprolix ($) Increased Annual Cost of Alprolix Prophylaxis per Patient % Price Reduction Required for Cost Neutrality (Revised $ per IU) Base case vvv,vvv vvv,vvv vv,vvv 19% (v.vv) Weight = 65 kg vvv,vvv vvv,vvv vv,vvv 19% (v.vv) Weight = 90 kg vvv,vvv vvv,vvv vv,vvv 19% (v.vv) BeneFIX on-demand patients vvv,vvv vvv,vvv vvv,vvv 39% (1.12) require 20 infusions per annum Dose per infusion of BeneFIX is vvv,vvv vvv,vvv vv,vvv 18% (v.vv) 50 IU/kg Annual dose of BeneFIX vvv,vvv vvv,vvv vv,vvv 14% (v.vv) prophylaxis = 5,067 Proportion of patients on Alprolix vvv,vvv vvv,vvv vv,vvv 20% (v.vv) prophylaxis treated weekly = 50% Proportion of patients on Alprolix vvv,vvv vvv,vvv vv,vvv 17% (v.vv) prophylaxis treated weekly = 85% Annual dose of weekly Alprolix vvv,vvv vvv,vvv vv,vvv 21% (v.vv) prophylaxis = 2,447 IU/kg Annual dose of individualized vvv,vvv vvv,vvv vv,vvv 24% (v.vv) interval Alprolix prophylaxis = 3,157 IU/kg 50% of non high-risk on-demand vvv,vvv vvv,vvv vv,vvv 27% (v.vv) patients will move to Alprolix on-demand Cost of BeneFIX is $v.vv per IU vvv,vvv vvv,vvv vv,vvv 20% (v.vv) CADTH TECHNOLOGY REVIEW 6

11 4. Budget Impact Analysis 4.1 Approach The manufacturer provided a budget impact analysis to assess the national budgetary implications of reimbursing Alprolix in Canada. 8 A prevalence-based approach was taken, using a three-year analysis time frame: Reference Year: 2014; Year 1: 2015; Year 2: 2016; Year 3: A national perspective was applied; however, Quebec was excluded from the analysis. 4.2 Methods In addition to the assumptions adopted by the manufacturer, detailed in Section 3.1 of this report, the following assumptions are required to estimate the budget impact analysis over the three-year period: The total number of hemophilia B patients in Canada will increase by 2.8% per annum. Without Alprolix, Immunine VH would be used in 10.5% of on-demand patients and 6.1% of prophylaxis patients. The unit cost of Immunine VH is $v.vv per IU. The required dosage for on-demand treatment is approximately 21% lower than with BeneFIX. The required annual dosage for prophylaxis is based on the product monograph 2,600 IU/kg. 32% of current patients are treated prophylactically. 25% of patients treated on-demand are high risk. 10% of on-demand patients will convert to Alprolix prophylaxis in Year 1, with an additional 10% in both Year 2 and Year 3. 50% of BeneFIX prophylaxis patients will convert to Alprolix prophylaxis in Year 1, with an additional 10% in both Year 2 and Year 3. 10% of Immunine prophylaxis patients will convert to Alprolix prophylaxis in Year 1, with an additional 10% in both Year 2 and Year 3. The manufacturer presented the results in terms of the estimated costs both with and without Alprolix within the base case and a range of sensitivity analyses. Scenarios considered were: Alprolix market share is increased 25% over the base-case estimate. Alprolix market share is decreased 25% over the base-case estimate. 85% of Alprolix patients will be treated with a once-weekly regimen. 50% of current patients receive prophylaxis treatment. Utilization will differ from the trial setting; specifically: o 50% of patients are following a prophylactic regimen. o 85% of Alprolix patients follow a once-weekly regimen. o 10% of moderate on-demand treated hemophilia B patients convert to Alprolix. o Annual dose will be 4,680 IU/kg for BeneFIX and 3,900 IU/kg for Immunine VH. o Annual dose for Alprolix will be 2,600 IU/kg and 2,106 IU/kg for individualized and onceweekly regimens, respectively. CADTH TECHNOLOGY REVIEW 7

12 4.3 Estimated Number of Treated Cases Table 5 details the estimated number of patients treated with BeneFIX (on-demand and prophylaxis), Immunine VH (on-demand and prophylaxis), and Alprolix from 2014 to 2017 where Alprolix is and is not covered. 13,14 Table 5: Manufacturer s Estimate of Patient Numbers Without Alprolix Low-risk on-demand patients BeneFIX Immunine High-risk on-demand patients BeneFIX Immunine Prophylaxis patients BeneFIX Immunine TOTAL With Alprolix Low-risk on-demand patients BeneFIX Immunine High-risk on-demand patients BeneFIX Immunine Prophylaxis patients BeneFIX Immunine Alprolix TOTAL Source: Manufacturer s Economic Submission Manufacturer s Estimated Budget Impact Base-Case Analysis The manufacturer estimated that the budget will increase by $971,816 in Year 1; $1,274,944 in Year 2; and $2,147,560 in Year 3 (Table 6). These figures exclude the costs of non high-risk patients treated on-demand, which is assumed to remain the same under both scenarios. For analysis to be cost neutral in Year 3, the price of Alprolix would need to be reduced by 18% to $v.vv per IU. Table 6: Manufacturer s Estimate of Budget Impact Year Total Total costs with Alprolix $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv Total costs without Alprolix $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv Incremental costs $971,816 $1,274,944 $2,147,560 $4,394,320 Source: Manufacturer s Economic Submission Sensitivity Analysis Sensitivity analysis found the three-year budget impact, ranging from $534,949 to $5,528,844 (Table 7). CADTH TECHNOLOGY REVIEW 8

13 Table 7: Manufacturer s Sensitivity Analyses Incremental Budget Impact Year Total Manufacturer s base case $vvv,vvv $v,vvv,vvv $v,vvv,vvv $4,394,320 25% increase in Alprolix market share $v,vvv,vvv $v,vvv,vvv $v,vvv,vvv $5,528,884 25% decrease in Alprolix market share $vvv,vvv $v,vvv,vvv $v,vvv,vvv $3,259,755 85% of Alprolix patients on weekly prophylaxis $vvv,vvv $vvv,vvv $v,vvv,vvv $3,570,790 50% of patients receive prophylaxis $vvv,vvv $v,vvv,vvv $v,vvv,vvv $4,907,217 Utilization differs from trial setting -$vv,vvv $vv,vvv $vvv,vvv $534,949 Source: Manufacturer s Economic Submission CADTH Reanalysis Base-Case Analysis For the CADTH reanalysis, the same revised assumptions as those in the cost comparison were adopted (Error! Reference source not found.). The incremental budget impact (cost) ssociated with Alprolix was lower than the manufacturer s estimate ($v,vvv,vvv versus $v,vvv,vvv). For analysis to be cost neutral in Year 3, the price of Alprolix would need to be reduced by 18% ($v.vv per IU). Table 8: CADTH Estimate of Budget Impact Year Total Total costs with Alprolix $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv Total costs without Alprolix $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv Incremental costs $767,231 $1,081,446 $1,798,474 $3,647, Sensitivity Analysis Sensitivity analysis adopted the same alternate assumptions utilized in the cost comparison analysis (Section 3.3.2). In addition, sensitivity analyses were conducted to assess the impact of assuming that the proportion of on-demand patients and the proportion of Immunine prophylaxis users who will convert to Alprolix prophylaxis will be as for BeneFIX prophylaxis patients (50% in Year 1, with an additional 10% in both Year 2 and Year 3) and with an additional 10% in both Year 2 and Year 3. A further sensitivity analysis assumed no use of Immunine with BeneFIX, assumed to currently have a 100% market share based on CBS current coverage. A final sensitivity analysis assumed that there would be no conversion to Alprolix for those currently receiving Immunine. The results of the sensitivity analysis suggest results are robust to all assumptions except the below (see Table 9): The use of either Alprolix prophylaxis or Alprolix on-demand for current on-demand patients at lower risk of bleeding, and The rate of adoption of Alprolix for current on-demand patients. CADTH TECHNOLOGY REVIEW 9

14 Table 9: Sensitivity Analysis Based on CADTH Reanalysis Scenario Incremental Budget Impact (Year 3) Base case $v,vvv,vvv 18% (v.vv) Weight = 65 kg $v,vvv,vvv 18% (v.vv) Weight = 90 kg $v,vvv,vvv 18% (v.vv) On-demand patients require 20 infusions per annum $v,vvv,vvv 39% (v.vv) Dose per infusion of BeneFIX on-demand is 50 IU/kg $v,vvv,vvv 17% (v.vv) Annual dose of BeneFIX prophylaxis = 5,067 $v,vvv,vvv 13% (v.vv) Proportion of patients on Alprolix prophylaxis treated $v,vvv,vvv 20% (v.vv) weekly = 50% Proportion of patients on Alprolix prophylaxis treated $v,vvv,vvv 17% (v.vv) weekly = 85% Annual dose of weekly Alprolix prophylaxis = $v,vvv,vvv 20% (v.vv) 2,447 IU/kg Annual dose of individualized interval Alprolix $v,vvv,vvv 24% (v.vv) prophylaxis = 3,157 IU/kg 50% of non high-risk on-demand patients will move to $v,vvv,vvv 35% (v.vv) Alprolix on-demand Cost of BeneFIX is $v.vv per IU $v,vvv,vvv 19% (v.vv) On-demand patients convert to Alprolix at same rate as $v,vvv,vvv 29% (v.vv) BeneFIX prophylaxis patients Immunine patients convert to Alprolix at same rate as $v,vvv,vvv 20% (v.vv) BeneFIX prophylaxis 100% current market share for BeneFIX $v,vvv,vvv 19% (v.vv) No conversion from Immunine to Alprolix $v,vvv,vvv 17% (v.vv) IU = international unit. Percentage Price Reduction Required for Cost Neutrality (Revised Cost [$] per IU) CADTH TECHNOLOGY REVIEW 10

15 5. Summary In Canada, patients with hemophilia B factor IX deficiency at high risk of bleeding are currently managed with either on-demand therapy or prophylactic treatment with either BeneFIX or Immunine, although BeneFIX is the major factor IX product currently distributed by CBS. Alprolix belongs to a new category of longer-acting recombinant factor IX products. The comparative efficacy of BeneFIX, Immunine, and Alprolix is unknown. The major advantage of Alprolix is a longer half-life, potentially leading to fewer infusions, although the clinical benefit of this to patients is unclear. Currently, BeneFIX is priced at $v.vv per IU, while Alprolix is priced at $v.vv per IU. CADTH analysis suggests that based on the assessment of uncertain parameters, the funding of Alprolix may be cost neutral if a price reduction of around $v.vv per IU (18% reduction) can be negotiated. These findings are similar to those reported by the manufacturer in its submission. This conclusion is qualified by the uncertainty regarding key assumptions relating to the adoption of Alprolix in practice. Little information is known about patient preference for Alprolix over current therapeutic options. Analysis assumes that Alprolix is of equal clinical efficacy to current therapies. If there is greater use of Alprolix in current high-risk on-demand patients, then a price reduction of 18% would not be sufficient to guarantee cost neutrality. Similarly, if there is uptake of Alprolix, either as a prophylaxis or on an on-demand basis in patients currently at lower risk of bleeding, cost neutrality would require a more substantive price reduction. Finally, if Alprolix is used in children or preoperatively, no conclusions about the cost impacts can be derived based on current evidence. CADTH TECHNOLOGY REVIEW 11

16 References 1. Canadian Hemophilia Society [Internet]. Montreal: The Society. What is hemophilia; 2015 [cited 2015 Feb 3]. Available from: 2. BeneFIX (Coagulation Factor IX (Recombinant)) [product monograph]. Kirkland (QC): Pfizer Canada Inc.; Canadian Blood Services' plasma protein products price list [CONFIDENTIAL internal document]. Ottawa: Canadian Blood Services; Canadian Blood Services. Factor concentrates & unlicensed plasma protein products order form [Internet]. Ottawa: Canadian Blood Services; [cited 2015 Feb 26]. Available from: (Brampton region example). 5. ALPROLIX (Coagulation Factor IX (Recombinant), Fc Fusion Protein): lyophilized powder for solution 250, 500, 1,000, 2,000 and 3,000 IU/vial [product monograph]. Mississauga (ON): Biogen Idec Canada Inc.; Canadian Blood Services submission: ALPROLIX, Coagulation Factor IX (Recombinant), Fc Fusion Protein. Company: Biogen Idec Canada Inc. [CONFIDENTIAL manufacturer's submission]. Mississauga (ON): Biogen Idec Canada Inc.; 2014 Apr. 7. Canadian Blood Services. Briefing note for the Product Innovation Operating Committee: New Product Selection Process (NPSP) for a new category of hemophilia B treatment product, ALPROLIX (Biogen Idec). [Ottawa]: [Canadian Blood Services]; 2014 Dec. 8. Budget impact analysis. In: Canadian Blood Services submission: ALPROLIX, Coagulation Factor IX (Recombinant), Fc Fusion Protein. Company: Biogen Idec Canada Inc. [CONFIDENTIAL manufacturer's submission]. Mississauga (ON): Biogen Idec Canada Inc.; 2014 Apr. 9. Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med Dec 12;369(24): Roth DA, Kessler CM, Pasi KJ, Rup B, Courter SG, Tubridy KL, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood Dec 15;98(13): Korth-Bradley JM, Valentino LA, Rendo P, Shafer FE, Smith L, Baumann JA, et al. Pharmacokinetic/pharmacodynamic assessment of reformulated recombinant coagulation factor IX in adults and children with severe hemophilia B [Internet]. Abstract presented at: American Society of Hematology. 53rd ASH Annual Meeting and Exposition (10-13 Dec 2011) San Diego; [cited 2015 Feb 3]. Available from: P Valentino LA, Rusen L, Elezovic I, Smith LM, Korth-Bradley JM, Rendo P. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects. Haemophilia May;20(3): Canadian Hemophilia Registry. Hemophilia B: Stats Canada-age groups [Internet]. [Toronto]: Association of Hemophilia Clinic Directors of Canada (AHCDC); 2013 May 17. [cited 2015 Feb 3]. Available from: Canadian Hemophilia Registry. Hemophilia B: hemophilia FVIII & FIX - summary by category & age <18/>=18 [Internet]. [Toronto]: Association of Hemophilia Clinic Directors of Canada (AHCDC); 2013 May 17. [cited 2015 Feb 3]. Available from: CADTH TECHNOLOGY REVIEW 12