PHARMA DEVELOPMENT DIGEST HEMOPHILIA A

PHARMA DEVELOPMENT DIGEST HEMOPHILIA A Reprint from PDD Hematology April 2017 ANDERSON CONSULTING GROUP

Overview Greylock Pharma Development Digest is a surveillance service designed for pharmaceutical industry vendors. It therefore provides an industry perspective, as it is this perspective that is of most value to vendors. The information contained herein is primarily gathered and summarized from industry press releases, literature and announcements and is not designed to provide a balanced perspective. The Publisher does not assume any legal liability or responsibility for the accuracy, completeness, or usefulness of the information supplied herein, nor any opinion expressed. The Publisher, its agents, and employees will not be liable for any loss or damage arising directly or indirectly from the possession, publication, use of, or reliance on information obtained from this report. It is provided in good faith without express or implied warranty. Reference to any specific commercial product or service does not imply endorsement or recommendation by the Publisher. The report is divided into two parts: Top Line Data Section: The topline data is organized by company and provides a quick review of product specifics including; company name, generic and brand name (only product name is listed for devices), indication, the date and regulatory status of the product indication (in the European Union, United States), and a brief timeline of significant regulatory and research events from 2013 forward. Entries are color coded: (Darker shade of green indicates a potential blockbuster. Darker shade of yellow indicates impending regulatory approval within six months). PRODUCT OVERVIEW Green: Entries in dark green indicate an approved product with a large revenue potential. Light green entries are for approved products with a lower revenue potential. Yellow: All product entries are yellow until they are approved either in the EU or in the US. There are three shades of yellow: the palest yellow indicates that there is only clinical trial activity associated with a product; once there is regulatory activity then it becomes a darker yellow; the darkest indicates a positive CHMP or FDA advisory committee positive opinion indicating approval is imminent. Red: A negative clinical trial result or regulatory event has occurred. Product Detail Section: This information is organized by company and provides a detailed description of the product, including indication data for prescription drugs, and a more detailed timeline of research and regulatory events from 2013 forward. Greylock Pharma Development Digest. All rights reserved. Neither this publication nor any part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of Greylock Press LLC. Greylock Pharma Development Digest is a registered trademark of Greylock Press, LLC. ISSN 2471-2795 Contact Information: info@greylockpress.com 2

Glossary Term CMMS NCD EMA APP EMA CE EMA CHMP EMA COMP EMA DCP EMA MAA FDA ACR FDA APP FDA BLA FDA BTD FDA CRL FDA FTD FDA HDE FDA IDE Definition United States (US) Centers for Medicare & Medicaid Services National Coverage Determination Approved by the European Medicines Agency for marketing within the European Union. The EMA Conformité Européene Mark indicates that a medical device complies with all of the safety requirements established by the European Union. The CE Mark is required to market a medical device within the European Union. The EMA Committee for Medicinal Products is the European equivalent of the Food and Drug Administration Advisory Committee. A positive opinion from the CHMP is the second step in the approval process. The EMA Committee for Orphan Medicinal Products adopts a positive opinion recommending a pharmaceutical for orphan drug status. EMA Decentralized Procedure allows companies to obtain the simultaneous authorization of a pharmaceutical in more than one EU country if it has not yet been authorized in any EU country and it does not fall within the mandatory scope of the centralized procedure. European Medicines Agency Marketing Authorization Application. This is the first step in obtaining authorization to market a pharmaceutical within the European Union. Food and Drug Administration Advisory Committee Recommendation drugs and devices must first be recommended by the advisory committee before final approval by the FDA. Approved by the FDA to be marketed within the United States A Biologics License Application is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce and begins the drug approval process in the US. Breakthrough Therapy Designation is granted when a new drug is intended to treat a serious or life-threatening disease and data indicates that the new drug provides substantial benefits over existing therapy. A Complete Response Letter is issued when the FDA requires additional information in the review of an application. Fast Track Designation is granted when a drug offers unmet medical needs for life-threatening conditions. The goal is to grant approval within six months of this designation. The Humanitarian Device Exemption is the device version of the orphan drug designation and is granted to devices designed to treat rare diseases. The Investigation Device Exemption is granted to equipment manufacturers prior to marketing authorization. IDE allows companies to test the product in a limited clinical settings prior to full approval. 3 GLOSSARY

Term Definition FDA IND FDA NDA FDA ODD FDA PMA FDA PRD FDA QIPD FDA snda UK NICE ASCO ASH CR ESH ESMO JCO ORR OR OS PFS r/r An Investigational New Drug application is filed when a pharmaceutical company wishes to transport unapproved drugs across state lines for the purposes of conducting multi-state clinical trials. A New Drug Application begins the process of FDA review of a new drug. Orphan Drug Designation is granted for therapies in rare diseases (less than 200,000 cases). A Pre-Market Approval application is the first step in the regulatory process for medical devices and allows manufacturers to test the device in a number of medical centers. FDA Priority Review Designation. This designation is given to investigational compounds that treat serious conditions for which current therapy is inadequate or where a new drug offers a significant potential advancement. PRD means that the FDA will attempt to take action within 6 months of receipt of the application. QIDP status provides priority review and a five-year extension of market exclusivity following product approval in the United States. A Supplemental New Drug Application is submitted by a pharmaceutical company for any changes in packaging, labeling, dosages, ingredients, or new indications to an already approved pharmaceutical product. The England and Wales National Institute for Health Care Excellence (NICE). NICE looks at pharmaco-economic data and makes recommendations on use of drugs based on a NICE cost/benefit analysis. NICE recommendation occur after a product has been approved by the EMA and the UK drug approval authorities. Common Abbreviations American Society of Clinical Oncology Annual Meeting American Society of Hematology Complete Response Rate European Society of Hematology European Society of Clinical Oncology Annual Meeting Journal of Clinical Oncology Objective Response Rate Overall Response Rate Overall Survival Rate Progression-free Survival Relapsed/Refractory GLOSSARY 4

Table of Contents Topline Data Pages 6-8 Detail Data Alnylam/Genzyme: fitusiran (ALN-AT3) Page 9 Bayer: BAY 81-8973, damoctocog, octocog Page 10 Biogen: rfviiifc (Elocta) Page 11 BioMarin: BMN270 Page 12 CSL: factor rviii Afstyla Novo Nordisk: NovoSeven Page 13 Roche: emicizumab Page 14 Shire/Baxalta: Advate Page 15 Shire/Baxalta :Adynovate, BAX 817 Page 16 Shire/Baxalta: OBI-1 Page 17 TABLE OF CONTENTS Product Revenues Page 18 Chart Page 19 5

Company Alnylam/ Genzyme Pg 9 Brand Generic Name n/a fitusiran ALN-AT3 US Status FDA ODD EU Status EMA COMP Other Country Status Event Timeline 17 Feb: Ph 1 study presented at EAHAD 16 Dec: Interim data from Ph 2 OLE study presented at ASH 16 Jul: Ph 1c study results presented at WFH 15 Dec: Ph 1 study data presented at ASH 15 Jun: Ph 1 study presented at ISTH 15 Jan: Ph 1 study presented at GCC 14 Dec: Ph 1 study presented at ASH 14 Aug: EMA COMP for and hem B 14 May: Topline data from a Ph 1 study presented at WFH TOPLINE DATA Bayer Pg 10 Kovaltry BAY 81-8973 FDA APP EMA APP CA: APP 16 Mar: Approved in Japan for 16 Mar: FDA APP for 16 Feb: EMA APP for prophylaxis 16 Feb: Approved in Canada for 15 Dec: EMA CHMP for 15 Jun: MAA for in Japan 14 Dec: Submission of an FDA BLA for 14 Dec: EMA MAA for Bayer Pg 10 n/a damoctocog 14 May: PROJECT presented at WFH Bayer Pg 10 Kogenate FS Kogenate Octocog FDA APP EMA APP CA: APP Hem A 14 Dec: SPINART study published in Blood 14 May: FDA APP for in adults Biogen Pg 11 Eloctate Elocta rfviiifc FDA APP EMA APP CA: APP 16 Dec: Ph 3 longitudinal data presented at ASH 15 Dec: Post hoc analysis of ASPIRE presented at ASH 15 Nov: EMA APP for 15 Sep EMA CHMP positive opinion for 15 Aug: ASPIRE study published in Haemophilia 14 Oct: EMA MAA for 14 Jun: FDA APP for 14 Apr: Topline data for Kids A-LONG released 6

Company BioMarin Pg 12 CSL Behring Pg 13 Brand Generic Name n/a BMN270 Afstyla rfviii US Status FDA ODD FDA APP EU Status EMA COMP EMA APP Other Country Status CA: APP Event Timeline 17 Feb: EMA PRIME for 16 Jul: Ph 1 study results presented at WFH 16 Mar: EMA COMP for severe 16 Mar: FDA ODD 17 Jan: EMA APP for 16 Dec: Approved in Canada for 16 Nov: EMA CHMP for 16 Aug: Ph 1/3 study published in Blood 16 Jul: Ph 3 study presented at WFH 16 May: FDA APP for adult and pediatric 15 Dec: EMA MAA for 15 Jul: FDA BLA for 15 Jun: Ph 3 AFFINITY study presented at ISTH TOPLINE DATA Novo Nordisk Pg 13 NovoSeven rfviia FDA APP, hem B EMA APP, GLT CA: APP Hem A, hem B 16 Dec SMART-7 study presented at ASH Roche Pg 14 n/a ACE910 emicizumab FDA BTD JP: ODD 16 Dec: Topline Ph 3 HAVEN-1 data released 16 Aug: Japan ODD for 16 Jul: Ph 1/2 study results presented at WFH 16 May: Ph 1 study published in NEJM 15 Sep: FDA BTD for 15 Jun: ACE002JP presented at ISTH 14 Dec: Ph 1 study presented at ASH Shire/Baxalta Pg 15 Advate FDA APP EMA APP 14 Apr: FDA APP BAXJECT III system 14 Feb: AHEAD study presented at EAHAD 7

Company Shire/Baxalta Pg 16 Brand Generic Name Adynovate Adynovi Advate PEGylated (Bax 855) US Status FDA APP EU Status EMA MAA Other Country Status CA: APP JP: APP Event Timeline 16 Dec: FDA APP for pediatric use 16 Dec: Approved in Canada for 16 Jul: Ph 3 study results presented at WFH 16 Apr: APP in Japan 16 Mar: EMA MAA for 16 Feb: FDA sbla for children <12 years and in surgical settings 15 Dec: Topline date from a Ph 3 study released 15 Nov: FDA APP for 15 Jul: A Ph 2/3 study published in Blood 15 Feb: Ph 3 study presented at EHAD 14 Dec: FDA BLA for 14 Aug: Topline Ph 3 results released TOPLINE DATA Shire/Baxalta Pg 16 n/a BAX 817 15 Mar: Results from Ph 3 study released Shire/Baxalta Pg 18 Obizur OBI-1 FDA APP EMA APP CA: APP 2015 15 Nov: EMA APP for acquired 15 Oct: Canadian APP for acquired 15 Jul: EMA CHMP for acquired 14 Oct: FDA APP for acquired in adults 8

Product Alnylam/ Genzyme fitusiran ALN-AT3 Research and Regulatory Timeline Detail Product Description: Fitusiran (ALN-AT3) is a subcutaneous RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia. AT is a protein expressed in the liver that acts as an anti-coagulant by inactivating factor Xa and thrombin. RNA interference (RNAi) is a new biological therapeutic approach. RNAi is a natural process of gene silencing. RNAi silences specific mrnas thus preventing disease-causing proteins from being made. Class: RNAi AT Treatments (approved or in clinical trial): hemophilia A () hemophilia B (hem B) 2017 Feb: Exploratory results from a Phase 1 study designed to evaluate the safety and efficacy of fitusiran in and hem B was presented at the European Association of Haemophilia and Allied Disorders (EAHAD) congress. The analysis showed that breakthrough bleeds were effectively managed with replacement factors or bypassing agents, with no thromboembolic events. 2016 Dec: A Phase 2 OLE study including 16 or B patients without inhibitors was presented at the ASH meeting. All patients were previously enrolled in a fitusiran Phase 1 study. In the Phase 2 OLE study, fitusiran was administered oncemonthly at two fixed dose levels, 50 mg and 80 mg. Both dose levels achieved mean AT (antithrombin III) lowering of approximately 80% and mean increases in thrombin generation levels approaching the lower end of the range observed in normal healthy individuals in Part A of the Phase 1 study. 2016 Jul: Topline data from a Phase 1 (Part C) study was presented at the World Federation of Hemostasis Congress (WFH). Part C evaluated fitusiran at dosages ranging from 225 mcg/kg to 1800 mcg/kg in & B. Fitusiran achieved dosedependent lowering of antithrombin (AT). 2015 Dec: A Phase 1 study was presented at ASH. The study showed fitusiran reduced AT by 88% and resulted in an 85% reduction in median estimated annualized bleeding rates. 2015 Jun: Data from a Phase 1 study was presented at ISTH. The study results showed that ALN-AT3 achieved knockdown of AT of up to 86% in and B patients. The knockdown was highly durable, lasting up to two months after the last dose. 2015 Jan: Data from a Phase 1 study was presented at GCC. The study results showed up to a 70% knockdown of AT and resulted in a thrombin increase of 334% with a marked improvement in blood clotting. 2014 Dec: Data from a Phase 1 study was presented at ASH. The study showed up to a 57% knockdown of AT (antithrombin III) in hemophilia patients with the effects lasting for about 60 days. 2014 Aug: EMA COMP received for and B. 2014 May: Topline data from a Phase 1 study was presented at WFH. The data showed that a single dose of ALN-AT3 resulted in a 28% to 32% knockdown of AT levels, which was statistically significant compared with placebo. PRODUCT DETAIL ALNYLAM 9

Product Bayer Kovaltry Bayer damoctocog BAY 94-9027 Bayer EU: Kogenate US: Kogenate FS Research and Regulatory Timeline Detail Product Description: BAY 81-8973 (Kovaltry) is a full-length recombinant factor VIII (rfviii) compound for the treatment of hemophilia A ()in both children and adults. BAY 81-8973 has demonstrated efficacy as a prophylaxis 2 to 3 times a week. Class: rfviii Treatments (approved or in clinical trial): 2016 Mar: Approved in Japan for the treatment of. 2016 Mar: FDA APP received for the treatment of in children and adults. 2016 Feb: EMA APP received for use as prophylaxis in children and adults with. 2016 Feb: Approved in Canada for the treatment of. 2015 Dec: EMA CHMP positive opinion received for treatment and prophylaxis in children and adults with (the average length of time from EMA CHMP to approval in the EU for hematology products listed in PDD is 3 months). 2015 Jun: Bayer submitted an application for marketing authorization for the treatment of in Japan. 2014 Dec: FDA BLA submission for prophylaxis in adults and children. 2014 Dec: EMA MAA for use as prophylaxis of in children and adults. Product Description: Damoctocog is a site-specific PEGylated recombinant factor VIII (rfviii). It is intended to slow down the clearance of factor VIII from the blood stream, thus extending its plasma half-life. Class: rfviii Treatments (approved or in clinical trial): 2014 May: The Phase 3 PROJECT study was presented at WFH. PROJECT studied previously treated adults and adolescents with severe. The study met its primary endpoint of protection from bleeds with fewer infusions. Product Description: Octocog (Kogenate) alpha is a recombinant factor VIII (rviii) compound. It is approved for prophylaxis of bleeding in adults and children with. It is approved in over 90 countries including the US and the EU for prophylaxis of bleeding. Class: rfviii Treatments (approved or in clinical trial): 2014 Dec: The Phase 3 SPINART study was published in Blood. The SPINART study looked at the efficacy of secondary prophylaxis vs on-demand therapy with octocog in patients with severe hem a. The study showed that the prophylaxis cohort had less pain, were more active, and had better treatment outcomes than the on-demand cohort. 2014 May: FDA APP received for use as routine prophylaxis in adults with. PRODUCT DETAIL BAYER 10

Product Biogen EU: Elocta US: Eloctate Research and Regulatory Timeline Detail Product Description: Alprolix, an rfixfc, is a long-acting recombinant clotting factor IX developed using Biogen s new monomeric Fc fusion technology. The new technology makes use of a naturally occurring pathway that delays the destruction of factor IX consequently leading to a longer circulating half-life. This should reduce the treatment burden for hem B patients. Class: rfix Treatments (approved or in clinical trial): hem B 2017 Mar: Thrombosis and Haemostatis (T&H) published interim results from the B-YOND extension study that evaluated the long-term efficacy of Alprolix as prophylactic therapy in previously-treated severe hem B patients. The overall median annualized bleeding rate (ABR) at the time of the B-YOND interim data cut was 2.3 for adult/adolescent participants in both the weekly and individualized prophylaxis treatment groups, and 2.4 for those in the modified prophylaxis study arm. Participants receiving on-demand therapy, or treatment when a bleeding episode occurred, had a median ABR of 11.3. 2016 Dec: Updated longitudinal safety and efficacy findings from Phase 3 and extension studies were presented at the ASH meeting. The presentations show low target joint annual bleeding rates and effective target joint resolution in pediatric, adolescent and adult patients on long-term prophylaxis with Eloctate. Target joints occur when patients experience frequent bleeds in the same joint, leading to chronic joint disease. An 18% improvement in hemophilia-related quality of life measures was seen in adolescents and adults who experienced target joint resolution with Eloctate prophylactic treatment compared with baseline measurements. 2016 May: EMA APP received for on-demand and prophylaxis treatment of hem B. 2016 Feb: EMA CHMP positive opinion received for the treatment of hem B (the average length of time from EMA CHMP to approval in the EU for hematology products listed in PDD is 3 months). 2015 Dec: A post-hoc analysis of the B-LONG study was presented at ASH. The analysis showed that patients taking Alprolix prophylactically had reduced frequency of bleeding episodes overall and in target joints. 2015 Aug: Results from the B-YOND extension study were presented at the NHF meeting. The study showed that people with severe hem B who were treated with Alprolix with one to two prophylaxis regimens experienced low bleeding rates for up to two years. 2015 Jun: EMA MAA for the treatment of hem B (the average length of time from submission to approval in the EU for hematology products listed in PDD is 16 months). 2015 Feb: Topline results for the Phase 3 Kids B-LONG study were released. The study focused on children under 12 with severe hem B who were given an once-weekly prophylaxis dosing of Alprolix. The study showed that Alprolix was welltolerated, achieved low bleeding rates, and no inhibitors were detected. PRODUCT DETAIL BIOGEN 11

Product BioMarin BMN270 Research and Regulatory Timeline Detail Product Description: BMN270 is a gene therapy AAV5 factor VIII vector, designed to restore factor VIII in hemophilia A. Gene therapy works by inserting a functional gene, containing a DNA sequence, which acts as a delivery mechanism providing a functional gene to the cells. The cells then use the functional gene to produce functional factor VIII. Class: AAV5 FVIII Treatments (approved or in clinical trial): 2017 Feb: EMA PRIME designation granted for the treatment of patients with. 2016 Jul: A Phase 1 proof-of-concept study was presented at the World Federation of Hemophilia (WFH) Congress. BMN270 lifted Factor VII levels above 50%. 2016 Mar: EMA COMP for the treatment of severe. 2016 Mar: FDA ODD received for the treatment of. PRODUCT DETAIL BIOMARIN 12

Product CSL Behring Afstyla Novo Nordisk NovoSeven Research and Regulatory Timeline Detail Product Description: Recombinant factor VIII (Afstyla) single-chain is a recombinant Factor VIII. The stability of rfviii single-chain provides a longer half-life and reduces frequency of dosing. The rviii single-chain also has an affinity for von Willebrand factor which plays a role in the drug s stability and integrity in the blood stream. Class: rfviii Treatments (approved or in clinical trial): hemophilia A () 2017 Jan: EMA APP received for the treatment of children and adults with hemophilia A. 2016 Dec: Approved in Canada for the treatment of. 2016 Nov: EMA CHMP positive opinion received for the treatment of. 2016 Aug: Blood published a Phase 1/3 study that evaluated the safety and efficacy of Afstyla on-demand with routine prophylaxis or surgical prophylaxis in patients with severe. The study met its primary endpoint of low median overall annualized bleeding rate in the prophylaxis arm and excellent efficacy in surgery and controlled bleeding events. 2016 Jul: A Phase 3 study that evaluated the efficacy of Afstyla as prophylaxis in was presented at the World Federation Hematology (WFH). The study showed that Afstyla was effective across different treatment intervals. 2016 May: FDA APP for use as routine prophylaxis in adult and pediatric patients. 2015 Dec: EMA MAA for the treatment of (the average length of time from EMA submission to approval in the EU for hematology products listed in PDD is 15 months). 2015 Jul: FDA BLA for the treatment of (the average length of time from FDA submission to approval in the US for hematology products listed in PDD is 6 months). 2015 Jun: The Phase 3 AFFINITY study was presented at ISTH. The study compared rfviii single-chain with octocog alpha as a prophylaxis in patients. rfviii single-chain had improved pharmacokinetic parameters compared with octocog and lead to a low annualized spontaneous bleeding rate. Product Description: NovoSeven is a recombinant activated factor VII (rfviia) and is indicated for the treatment of spontaneous and surgical bleedings in hemophilia A or B patients with inhibitors, acquired hemophilia, congenital FVII deficiency and Glanzmann s thrombasthenia. Class: rfiia Treatments (approved or in clinical trial):, hem B, Glanzmann s thrombasthenia (GLT) 2016 Dec: The prospective, post-authorization, single-arm, multinational, multi-center, non-interventional SMART-7 study investigating the safety and effectiveness of NovoSeven in & B patients with inhibitors was presented at the American Society of Hematology (ASH) meeting. NovoSeven resolved 96.5% of bleeds when initiated within one hour of bleeding onset. PRODUCT DETAIL CSL 13

Product Roche ACE 910 emicizumab Research and Regulatory Timeline Detail Product Description: Emicizumab (ACE 910) is a bispecific monoclonal antibody designed to bind factors IXa and X, thus mimicking the function of factor VIII. ACE910 is designed to promote blood coagulation in hemophilia A () patients. It acts regardless of whether the patient has developed inhibitors to factor VIII, and is not expected to lead to the formation of inhibitors. Class: factor VIII Treatments (approved or in clinical trial): 2016 Dec: Topline results from the Phase 3 HAVEN-1 study comparing emicizumab prophylaxis with placebo in treatmentexperienced patients with hemophilia A and inhibitors to factor VIII was released. The study met its primary endpoint, significantly reducing number of bleeds over time. 2016 Aug: Japan ODD for patients who have developed FVIII inhibitors. 2016 Jul: An update from a Phase 1/2 study was presented at the World Federation of Hematology (WFH) Congress. The study demonstrated prophylactic efficacy in Japanese patients with with and without Factor VIII inhibitors. 2016 May: NEJM published a Phase 1 study that evaluated the efficacy and safety of emicizumab as prophylaxis in Japanese patients with or without FVIII inhibitors. The study demonstrated a clinically acceptable safety profile and potential for prevention of bleeding in patients with and without FVIII inhibitors. 2015 Sep: FDA BTD received for prophylactic treatment in patients 12 years who have developed factor VIII inhibitors. 2015 Jun: The Phase 1/2 ACE002JP study was presented at ISTH. The study evaluated the prophylactic efficacy and safety of ACE 910 in Japanese patients both with and without FVIII inhibitors. ACE 910 demonstrated prophylactic efficacy regardless of the presence of FVIII inhibitors. 2014 Dec: A Phase 1 study that evaluated the efficacy and safety of emicizumab as prophylaxis in Japanese patients with or without FVIII inhibitors was presented at ASH. The study demonstrated a clinically acceptable safety profile and potential for prevention of bleeding in patients with and without FVIII inhibitors. PRODUCT DETAIL ROCHE 14

Product Shire/ Baxalta Advate Research and Regulatory Timeline Detail Product Description: ADVATE is a recombinant antihemophilic factor plasma/albumin-free method derived from the FVIII gene. It is to control and prevent bleeding in adults and children with hemophilia A (). It is also indicated for routine prophylaxis to prevent or reduce bleeding episodes in adults and children with. Class: rfviii Treatments (approved or in clinical trial): 2014 Apr: FDA APP received for the new BAXJECT III reconstitution system for Advate. PRODUCT DETAIL SHIRE 15

Product Shire/Baxalta EU: Adynovi US: Adynovate Shire/Baxalta Bax 817 Research and Regulatory Timeline Detail Product Description: Adynovate is built on the full-length Advate molecule. Advate is a recombinant antihemophilic factor plasma/albumin-free method derived from the factor VIII (FVIII) gene. Adynovate combines Advate with PEGylation technology designed to extend the amount of FVIII available for use by the body. Class: rfviii Treatment (approved or in clinical trial): hemophilia A () 2016 Dec: FDA APP received for the treatment of pediatric patients aged >12 years and for use in surgical settings for both adult and pediatric patients. 2016 Dec: Approved in Canada for the treatment of. 2016 Jul: A Phase 3 study was presented at the World Federation of Hematology (WFH) Congress. The study evaluated the safety and efficacy of twice-weekly prophylactic Adynovate to control bleeding in previously-treated children. The study met its endpoint with 40% of patients experiencing no bleeding. 2016 Apr: Approved in Japan for the treatment of. 2016 Mar: EMA MAA for the treatment of pediatric, adult, and for use during surgery (the average length of time from EMA MAA submission to approval in the EU for hematology products listed in PDD is 16 months). 2016 Feb: FDA sbla for use in children aged <12 years with and for use in surgical settings (the average length of time from FDA BLA submission to approval in the US for hematology products listed in PDD is 7 months). 2015 Dec: Topline data from an uncontrolled Phase 3 study was released. The study was designed to measure the safety and efficacy of Adynovate in previously treated patients with severe aged <12 years as prophylaxis and for the treatment of bleeding episodes. The study met its primary endpoints as no patients developed antibodies to Adynovate and no treatment-related adverse events were reported. 2015 Nov: FDA APP received for the treatment of. 2015 Jul: A Phase 2/3 study was published in Blood. The study compared twice weekly prophylaxis treatment with ondemand treatment in previously treated patients aged 12-65 years with. The study met its primary endpoint of prevention of bleeding episodes achieving a 95% reduction in annualized bleed rate (ABR). 2015 Feb: A Phase 3 study was presented at EHAD. The study evaluated the efficacy of BAX 855 as prophylaxis for bleeding in treatment-experienced patients aged >12 years. The prophylaxis cohort achieved a 95% reduction in annualized bleed rate (ABR) compared with on-demand therapy. 2014 Dec: FDA BLA for for treatment of. 2014 Aug: Topline results from a Phase 3 study showed that BAX 855 achieved a 95% reduction in ABR when administered as a twice-weekly prophylaxis compared with on-demand treatment. Product Description: BAX 817 is an investigational recombinant factor VIIa (rfviia) treatment for people with hemophilia A () or hemophilia B (hem B). Factor VIIa is one of the several proteins that causes blood to clot. Class: rfviii Treatments (approved or in clinical trial): & B 2015 Mar: Baxter announced positive results from a prospective open-label Phase 3 study. The study was designed to assess the safety and efficacy of Bax 817 in adult male patients with or hem B and who have developed inhibitors. The trial met its primary endpoint of successful resolution of acute bleeding of on-demand treatment at 12 hours. PRODUCT DETAIL SHIRE 16

Product Research and Regulatory Timeline Detail Shire/Baxalta Obizur Product Description: OBI-1 (Obizur) is a porcine factor VIII (pdfviii) which is effective in achieving hemostatic VIII levels in patients who have developed inhibitors to human recombinant factor VIII (rfviii). Patients do not appear to develop inhibitors to pdfviii and it appears to be effective in acquired hemophilia A (). Class: pffviii Treatments (approved or in clinical trial): acquired 2015 Nov: EMA APP received for the treatment of bleeding episodes in adults with acquired caused by antibodies to FVIII. 2015 Oct: Canadian APP received for the treatment of bleeding episodes in adults with acquired caused by antibodies to FVIII. 2015 Jul: EMA CHMP positive opinion received for the treatment of bleeding episodes in adults with acquired caused by antibodies to FVIII. 2014 Oct: FDA APP received for the treatment of bleeding episodes in adults with acquired. PRODUCT DETAIL SHIRE 17

Drug or Device ($mil) Advate/Adynovate Eloctate Kogenate Novo Seven 2016 Q4 905 (US410) 149 (US126) 302 (US111) 2016 Q3 884 (US428) 132 (US110) 332 (US116) 2016 Q2 959 (US409) 125 (US 110) 311 (US 97) 2016 Q1 843 (US417) 108 (US 99) 340 (US 110) 2016 2015 2014 3591 (US1664) 513 (US445) 1224 (US414) 2840 (US1339) 2984 (US1281) 320 58 1247 1231 357 357 357 357 1424 n/a n/a GLOBAL REVENUE (US$ MIL) Notes: 1) All revenues are recorded in US Dollars, some companies report their revenues in currencies other than US Dollars, in the event that a company reports in a currency other than dollars, the reported figures are converted to USD as at the exchange rate on the last day of the reporting period. 2) All figures come from unaudited quarterly reports filed to stockholders. Therefore, the quarterly totals may not equal the annual total. 3) Green indicates growth (in US Dollars) red indicates contracting sales. 4) If data is not available, it is indicated by n/a. 0 indicates no sales for the period. 5) Top number represents global sales, numbers in parenthesis (US66) represent sales within the United States. If there are no numbers in parenthesis, than only global data is provided. 18

# of events 11 10 9 8 7 6 5 Events Chronicled in PDD Q2 2014 Q1 2017 Regulatory Phase 3 Phase 2 Phase 1 Qtr. Sales (Advate/Adynovate, Eloctate, Kogenate, Novo Seven) 66 events recorded Global Sales (mil $) 2200 2000 1800 1600 1400 1200 1000 HEMOPHILIA A: METRICS 4 800 3 600 2 400 1 200 0 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 2014 2015 2016 2017 19