Coagulation Factor IX (Recombinant), Albumin Fusion Protein

Transcription

1 IDELVION Product Monograph Instructions for Use The IDELVION Product Monograph is presented as an interactive PDF. To locate information quickly and easily, click the appropriate section within the Table of Contents or use the navigation buttons on the bottom of each page. Select this icon to move forward one page. Select this icon to move backward one page. Select this icon to go to the last page you were on. Select this icon to go to the Table of Contents. CSL Behring is committed to protecting the privacy of all individuals it deals with. Additional information on how CSL Behring safeguards your privacy can be found at or can be provided in hard copy upon request. IDELVION is manufactured by CSL Behring AG and distributed by CSL Behring LLC. IDELVION is a trademark of CSL Behring Limited. Mix2Vial is a trademark of West Pharmaceutical Services, Inc., or a subsidiary thereof. All other products are registered trademarks or trademarks of their respective companies. CSL Behring GmbH P.O. Box Marburg, Germany Phone: Fax: CSL Behring LLC [date] 9442XXXX

2 Table of Contents To locate information quickly and easily, click the appropriate section within the Table of Contents. List of Tables and Figures List of Abbreviations Preface CSL Behring: A Leader in Coagulation Therapy 1 Haemophilia B 1.1 Overview 1.2 Haemostasis 1.3 Coagulation Cascade 1.4 Current Therapies 2 IDELVION 2.1 Overview 2.2 Method of Action 2.3 Dosing and Administration 2.4 Packaging and Vial Sizes 2.5 Storage 2.6 Reconstitution 3 IDELVION Manufacturing Safety 3.1 Overview 3.2 IDELVION Manufacturing Process 3.3 Virus Safety 4 PROLONG 9-FP Clinical Trial Programme 4.1 Overview 4.2 Preclinical Trials 4.3 Phase I Safety and PK Trial 4.4 Phase I/II Safety and Efficacy Trial 4.5 Phase II/III Safety and Efficacy Trial 4.6 Pooled PK in Adults and Adolescents with Severe Haemophilia B 4.7 Phase III Safety, PK, and Efficacy Trial in Paediatric Patients 4.8 Phase III Surgical Substudy 4.9 Phase IIIb Safety and Efficacy Extension Study 5 Safety Profile 5.1 Overview 5.2 Adverse Events/Adverse Drug Reactions 5.3 Factor IX Class Warnings 6 Conclusions IDELVION Product Information References Please see essential information for IDELVION. 3 4

3 List of Tables and Figures List of Abbreviations List of Tables AE adverse event PK pharmacokinetics Table 1: CSL Behring a history of innovative milestones in bleeding disorders AR adverse reaction PUPs previously untreated patients Table 2: Severity levels of haemophilia AsBR annualised spontaneous bleeding rate QOL quality of life Table 3: Dosing guide for control and prevention of bleeding episodes and for use in surgery AUC area under the curve rfix recombinant factor IX Table 4: Table 5: Table 6: Table 7: Table 8: Table 9: Patient population for phase I safety and PK trial PK parameters after a single dose of IDELVION or previous FIX products, according to noncompartmental analysis Bleeding rate reduction in prophylaxis patients Summary of FIX activity PK parameters after 50 IU/kg of IDELVION and 50 IU/kg of previous FIX product (PK population) Annualised spontaneous bleeding rate (AsBR) (primary efficacy population) Annualised bleeding rates of 7-, 10- and 14-day prophylaxis regimens Table 10: PK parameters for patients ( 12 years) with severe haemophilia B (<1% FIX) following a single injection of IDELVION 50 IU/kg Table 11: Summary of FIX PK parameters after administration of IDELVION or previous FIX product in paediatric patients Table 12: Annualised bleeding rates during prophylaxis treatment with IDELVION (efficacy population) Table 13: Adverse reactions during uncontrolled open-label clinical trials with IDELVION CHO CL C max dl EMA FDA FV FVII FVIII FIX FX FXI FXII FXIIIa Chinese hamster ovary clearance maximum concentration deciliter European Medicines Agency Food and Drug Administration (US) factor V factor VII factor VIII factor IX factor X factor XI factor XII activated factor XIII rix-fp SD TF t 1/2 ULN VWD VWF recombinant fusion protein linking coagulation factor IX with albumin standard deviation tissue factor half-life upper limit of normal von Willebrand disease von Willebrand factor List of Figures Figure 1: Coagulation cascade Figure 2: Fusion of rfix with recombinant albumin via cleavable peptide linkage and activation Figure 3: Summary of IDELVION clinical trial programme Figure 4: Linear plot of baseline-corrected FIX activity level after the injection of 50 IU/kg of IDELVION or previous FIX product Figure 5: Baseline-corrected FIX activity following IDELVION 25 IU/kg injection compared with prior FIX 50 IU/kg (data from phase I and phase I/II studies) Figure 6: Study design for phase II/III trial (adults) Figure 7: Mean (SD) baseline-uncorrected plasma FIX activity time profiles after administration of single injection of 25 and 50 IU/kg IDELVION (PK population) h HBV HCV HIV IR IU IV kg pd pdfix hour hepatitis B virus hepatitis C virus human immunodeficiency virus incremental recovery international unit intravenous kilogram plasma derived plasma-derived factor IX Figure 8: Mean (SD) baseline-uncorrected plasma FIX activity time profiles after administration of single injection of 25 and 50 IU/kg IDELVION and 50 IU/kg of previous FIX product (semi-log plot) (PK population) Figure 9: Mean (SD) baseline-uncorrected plasma FIX activity time profiles after 50 IU/kg dose of IDELVION and previous FIX product, stratified by age group (linear plot) (PK population) Please see essential information for IDELVION. 5 6

4 Preface CSL Behring: A Leader in Coagulation Therapy CSL Behring is a world leader in the plasma protein biopharmaceuticals industry. For over a century (Table 1), CSL Behring has been committed to manufacturing and marketing safe and effective therapies that treat a wide range of rare and serious bleeding disorders, including von Willebrand disease (VWD) and haemophilia A and B. CSL Behring s dedication to this therapeutic category began in 1946 when they became the first fractionator of human plasma proteins, and progressed as the company developed its portfolio of treatments for coagulation disorders. Today, this legacy of innovation continues with IDELVION, a long-acting recombinant factor IX (rfix) product. rfix is fused to recombinant albumin, extending its half-life and giving haemophilia B patients the freedom and peace of mind to enjoy active lives while also being protected from bleeds. IDELVION is indicated for the treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX [FIX] deficiency, and can be used in all age groups. 1 Table 1: CSL Behring a history of innovative milestones in bleeding disorders 1901 Emil von Behring becomes the first Nobel laureate in Physiology or Medicine for his work on serum therapies Emil von Behring creates Behringwerke to produce antisera and vaccines Behringwerke becomes the first fractionator of plasma proteins in Europe ZLB produces the first pasteurised plasma protein solution Behringwerke introduces the world s first pasteurised factor VIII therapy (predecessor of Haemate HS/Haemate P) for the treatment of haemophilia A Haemate HS/Haemate P (human plasma coagulation factor VIII/VWF complex) is additionally approved for the treatment of patients with VWD with FVIII deficiency Humate-P is approved by the US Food and Drug Administration (FDA) for the prevention and control of haemorrhagic episodes in patients with haemophilia A Mononine (highly purified FIX monoclonal antibody) is approved by the FDA for treatment of haemophilia B Humate-P is approved by the FDA for the treatment of patients with VWD BIOSTATE (high-purity human coagulation FVIII/VWF complex) is launched in Australia for the treatment of haemophilia A The company completes the acquisition of Aventis Behring, combining it with ZLB Bioplasma to create ZLB Behring. Mononine (human coagulation FIX concentrate) is approved by the EMA to treat 2004 haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe, spontaneous haemorrhage ZLB Behring introduces the Mix2Vial alternate transfer device, a new way to reconstitute products Haemate P and Humate-P become available in the United States and the European Union (EU) with smaller diluents, thus shortening injection time ZLB Behring changes name to CSL Behring BIOSTATE is approved in Australia for the treatment of VWD VONCENTO (human coagulation FVIII/VWF complex) is approved by the European Medicines Agency (EMA) for the treatment of haemophilia A and VWD. a 2016 IDELVION, the first haemophilia B therapy to bind recombinant FIX (rfix) to recombinant albumin, is approved for treatment of haemophilia B by the FDA and EMA. Today CSL Behring continues to build on its legacy of innovation. a VONCENTO is a registered European trade name for commercially supplied BIOSTATE. Please see essential information for IDELVION. 7 8

5 1 Haemophilia B Section Highlights Haemophilia B is a congenital X-linked bleeding disorder caused by a deficiency of coagulation factor IX (FIX) 2 The severity of haemophilia B is based on the amount of FIX missing from a person s blood 2 The recommended treatment for patients with haemophilia B is replacement of FIX with either a rfix or plasma-derived product at least 2 or 3 times weekly 3,4 There is a need for a rfix product with an enhanced pharmacokinetic (PK) profile that allows the frequency of dosing to be decreased, thus improving the quality of life (QOL) of patients with haemophilia B 5 Table 2: Severity levels of haemophilia 4,10,11 Level Normal factor activity in blood International units (IU) per milliliter (ml) of whole blood Normal range 50%-150% IU Mild haemophilia >5% to <40% >0.05 to <0.40 IU Moderate haemophilia 1%-5% IU Severe haemophilia <1% <0.01 IU 1.1 Overview Haemophilia B is a congenital X-linked (sexlinked) bleeding disorder caused by a deficit of coagulation FIX. 4 FIX is a protein necessary for the efficient coagulation of blood. A deficiency of this coagulation factor can lead to frequent spontaneous bleeding events and bleeding following an injury. 2,6 Haemophilia B is the second most common type of haemophilia; its incidence is around 3.75 in 100,000 males worldwide. 7 However, in around 30% of cases, haemophilia B is not inherited but is caused by a spontaneous gene mutation. 2,8 Clinical manifestations of haemophilia B depend on the severity of FIX deficiency. 2 People with haemophilia B experience poor wound healing and increased bleeding times with injuries and surgeries. 2,6 Spontaneous or traumatic bleeding associated with haemorrhage in the joint or muscle spaces of elbows, knees, and ankles may also occur. 9 Permanent joint damage (arthropathy) may result if there is recurrent bleeding in the same location. 9 Classification The severity of haemophilia B is based on the amount of FIX missing from a person s blood. FIX plasma levels normally range from 50% to 150% (Table 2). 2,10 When FIX activity levels fall below 50%, the patient s symptoms can be characterised. 2 People with mild haemophilia usually bleed only as a result of surgery or major injury. 2 In most cases, mild haemophilia is not diagnosed until an injury or surgery results in prolonged bleeding. 2 People with moderate haemophilia experience prolonged bleeding after surgery, an injury, or dental work. Bleeds usually occur about once a month, although spontaneous bleeding is rare. 10 People with severe haemophilia usually bleed frequently into their muscles or joints. They may bleed 1 to 2 times per week, and bleeding is often spontaneous. 10 As a consequence of continuous bleeding into the joints, haemophilic arthropathy develops. Arthropathy not only impairs joint function but also may be related to increased bleeding frequency. Avoidance of chronic arthropathy is key in haemophilia treatment and can generally be achieved through prophylaxis Haemostasis Haemostasis is the process initiated by the body to control the flow of blood after vascular injury. First, blood flow is reduced to the injured area by vasoconstriction, the narrowing of blood vessels through contraction of the muscular vessel wall. 13 In primary haemostasis, platelets become activated by thrombin and aggregate at the site of injury, forming a temporary loose platelet plug. 14 Platelets bind to the collagen exposed on endothelial cell surfaces directly or mediated by von Willebrand factor (VWF). 14 In secondary haemostasis, a fibrin mesh (clot) forms and entraps the plug, ensuring its stability. 14 The stable and durable fibrin clot is the result of interplay between coagulation factors including factor VIII (FVIII) and FIX. 15 Please see essential information for IDELVION. 9 10

6 1 Haemophilia B (cont d) 1.3 Coagulation Cascade Previously the coagulation cascade was divided into the intrinsic and extrinsic pathways; however, this model was inconsistent with clinical observations and did not fully explain the process of haemostasis in vivo More recently a new model has been developed, which consists of overlapping stages (Figure 1) as follows: Initiation: A break in the vessel wall exposes cells expressing tissue factor (TF) to components of the coagulation cascade in blood. Platelets adhere to collagen at the site of injury. During the initiation phase TF binds to factor VII (FVII) which results in the activation of FIX. Small amounts of thrombin are produced during this stage, which activate the amplification phase Amplification: Thrombin produced from the initiation phase promotes platelet activation and adhesion. Thrombin activates factor FVIII, which is released from VWF. Thrombin also activates factor XI (FXI) and factor V (FV). By the end of this stage, everything is in place for large-scale thrombin generation in the propagation phase. 15,17,19 Propagation: In the propagation phase platelets adhere to and aggregate at the site of injury and provide the surface for the tenase complex to form, which consists of activated FVIII and activated FIX (FIXa) and is essential for effective coagulation. The tenase complex activates fator X (FX), which forms the prothrombinase complex with activated FV and generates large amounts of thrombin. The thrombin produced cleaves fibrinogen to produce fibrin, which forms the mesh of the clot. Thrombin activates factor XIII (FXIIIa), which is necessary for stabilisation. 17,19 Stabilization: FXIIIa covalently cross-links adjacent chains of fibrin monomers to stabilise the fibrin clot and make it insoluble. 20 Figure 1: Coagulation cascade Current Therapies Plasma versus recombinant concentrates The goal of haemophilia B treatment is to minimise potential haemorrhagic episodes and reduce disabling joint and tissue damage (haemophilic arthropathy). The recommended treatment for patients with haemophilia B is replacement of FIX with either rfix or a plasma-derived (pd) product. 4 Treatment can be given on-demand, to treat individual bleeding episodes, or at regular intervals with the aim of preventing bleeding episodes (prophylactic therapy). For patients with severe haemophilia B, prophylactic therapy is recommended. 22 Prior to 1960, the only therapy available for the treatment of hereditary bleeding disorders, such as haemophilia B, was the transfusion of human plasma. In the 1970s, highly purified pdfix concentrates were developed to improve the efficacy and efficiency of FIX levels. However, as combinations of factors, including FIX, were used at this time, thrombotic events were observed. Later these thrombotic events were avoided by using pure pdfix concentrates. Then, during the 1980s and 90s, as awareness increased of blood-based diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), CSL Behring incorporated pasteurisation as part of its safety and manufacturing process, virtually eliminating virus transmission for its pd products. 23,24 Around this time, the first rfix product (BeneFIX ) was introduced. While rfix products offer advantages compared with pd concentrates, therapeutic challenges still exist. 5 For instance, more international units (IUs) of rfix are required than of a purified pdfix, such as Mononine, because rfix has a substantially reduced in vivo recovery. 25 In addition, because the half-life of FIX is short (18-34 hours), in patients receiving prophylactic therapy, administration of FIX replacement products is recommended at least 2 to 3 times per week to achieve a significant reduction in bleeding episodes. 22 The need for regular intravenous (IV) injections often results in adherence issues, manifesting as reduced compliance. 3 The need for longer-acting agents There is a significant treatment burden associated with frequent administration of rfix products in patients with haemophilia B. 5 Current research is focused on decreasing the frequency of rfix injections by improving the PK profile in particular, prolonging terminal half-life (t ½ ) and improving other parameters such as area under the curve (AUC), clearance (CL) and incremental recovery (IR). 5 This improved profile decreases the frequency of FIX injections, prevents bleeding episodes, and improves the QOL of patients with haemophilia B. 26 Please see essential information for IDELVION

7 2 IDELVION Section Highlights IDELVION is a recombinant fusion protein linking rfix with recombinant albumin via a cleavable peptide linker 1 IDELVION demonstrates an improved PK profile compared with rfix and pdfix, with a prolonged terminal half-life, increased AUC, reduced clearance, and enhanced systemic exposure 1,27,29,30,32 IDELVION is administered as an IV injection for on-demand, prophylactic, or perioperative treatment and is suitable for use in all age groups 1 Figure 2: Fusion of rfix with recombinant albumin via cleavable peptide linkage and activation 3 rfix ralbumin FXIa or FVIIa/TF + + Activated rfix 2.1 Overview IDELVION is a novel long-acting rfix indicated for the treatment and prophylaxis of bleeding in patients with haemophilia B and can be used in all age groups. 1 IDELVION uses albumin fusion protein technology to genetically fuse recombinant albumin to rfix via a cleavable linker. 1 The cleavable linker connecting rfix and recombinant albumin is derived from the activation peptide in native FIX. 1 IDELVION remains intact in circulation until FIX is activated, whereupon recombinant albumin is cleaved off, only releasing activated FIX when needed for coagulation. 1 Its novel structure allows IDELVION to effectively treat and prevent bleeding in patients with haemophilia B by replacing the missing FIX needed for haemostasis, using less-frequent dosing than regular-acting FIX products. 1, Method of Action IDELVION is a purified protein produced by recombinant DNA technology, generated by the genetic fusion of recombinant albumin to rfix. The protein is produced as a single recombinant protein, ensuring product homogeneity by avoiding chemical conjugation. This molecular design enables the protein to provide FIX activity when required for haemostasis and demonstrates an extended half-life, increased AUC, reduced CL, and enhanced systemic exposure compared with regular-acting FIX products. 1,28 This improved PK profile is achieved by the fusion of rfix to recombinant albumin. Albumin is a natural and abundant carrier protein in plasma and is inherently inert to the immune system. In addition, albumin has a long half-life of about 20 days and its metabolism is well characterised, making it an ideal fusion partner for extending the half-life of FIX. 1,29 Albumin is connected to rfix via a short C-terminal cleavable linker that is derived from the activation peptide in native FIX. 3 When IDELVION is administered it remains in the circulation until it is activated, in the same way that native FIX is activated. Upon activation, recombinant albumin is cleaved off, releasing activated FIX (FIXa) only when it is necessary for coagulation. 1,28 All that separates FIXa derived from IDELVION from wild-type FIXa, is the short C-terminal linker fragment (Figure 2). 3 Adapted with permission from Metzner HJ, Weimer T, Kronthaler U, et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009;102: Dosing and Administration IDELVION dosing and duration of treatment is dependent on the severity of the FIX deficiency, the location and extent of the bleeding, and the patient s clinical condition. 1 The initial dose of IDELVION and the frequency of administration must be assessed on an individual basis for clinical effectiveness. 1 IDELVION is administered as an IV injection for on-demand or prophylactic treatment and perioperative management. 1 Prophylaxis dosing For long-term prophylaxis, the usual doses are 35 to 50 IU/kg once weekly. Some patients who are well controlled on a once-weekly regimen might be treated with up to 75 IU/kg on an interval of 10 or 14 days. 1 On-demand dosing On-demand treatment is the administration of IDELVION at the beginning of a bleed. The amount to be administered and the frequency of administration should be oriented to the clinical effectiveness in the individual case. Calculation of the appropriate dose of FIX is based on the finding that IDELVION at 1 IU/kg of body weight increases the circulating level of FIX by an average of 1.3 IU/dL in patients 12 years of age and by 1.0 IU/dL in patients <12 years of age. 1 The required dose is determined using 2 formulas: Required dose (IU) = body weight (kg) desired FIX increase (% of normal or IU/dL) [reciprocal of observed recovery (IU/kg per IU/dL)] 1 Expected FIX increase (IU/dL or % of normal) = dose (IU) recovery (IU/dL per IU/kg)/ bodyweight (kg) 1 Patients 12 years of age An IR of 1.3 IU/dL per 1 IU/kg requires a dose determined as follows: 1 Dose (IU) = body weight (kg) desired FIX increase (IU/dL) 0.77 dl/kg Patients <12 years of age An IR of 1 IU/dL per 1 IU/kg requires a dose determined as follows: 1 Dose (IU) = body weight (kg) desired FIX increase (IU/dL) 1 dl/kg Please see essential information for IDELVION

8 2 IDELVION (cont d) Dosing for bleeding episodes and surgery Table 3 lists the IDELVION dosing guidelines for control and prevention of bleeding episodes and for use in major and minor surgical procedures. 2.4 Packaging and Vial Sizes IDELVION is available as single-dose vials of 4 different doses: 1 Table 3: Dosing guide for control and prevention of bleeding episodes and for use in surgery 1 Degree of haemorrhage/type of surgical procedure FIX level required (%) (IU/dL) Frequency of doses (h)/duration of therapy (d) Haemorrhage Minor or moderate haemarthrosis, muscle bleeding (except iliopsoas), or oral bleeding Single dose should be sufficient for majority of bleeds. Maintenance dose after hours if there is further evidence of bleeding. Major Life-threatening haemorrhages; deep muscle bleeding, including iliopsoas Minor Surgery Including uncomplicated tooth extraction (initial level) Repeat every hours for the first week, and then maintenance dose weekly until bleeding stops and healing is achieved. Single dose may be sufficient for majority of minor surgeries. If needed, maintenance dose can be provided after hours until bleeding stops and healing is achieved. 250 IU Store at 2 25 C for 24 months 500 IU Store at 2 25 C for 24 months Major Surgery (initial level) Repeat every hours for the first week, and then maintenance dose 1 2 times per week until bleeding stops and healing is achieved. Previously untreated patients Method of administration The safety and efficacy of IDELVION have not yet been established in previously untreated patients (PUPs). 1 Geriatric patients IDELVION is administered via IV injection. The reconstituted solution should be injected slowly intravenously at a rate comfortable for the patient up to a maximum of 5 ml/min IU Store at 2 25 C for 36 months 2000 IU Store at 2 25 C for 36 months The dosing regimen has not been determined in clinical studies for patients >65 years of age. Images do not represent actual packs or vials. Please see essential information for IDELVION

9 2 IDELVION (cont d) 3 IDELVION Manufacturing Safety 2.5 Storage IDELVION should not be stored above 25 C. Do not freeze. Keep vials in the outer carton in order to protect from light. 1 The shelf life is 24 months for IDELVION 250 IU and 500 IU, and 36 months for 1000 IU and 2000 IU. 1 After reconstitution, the chemical and physical in-use stability has been demonstrated for 8 hours at 2 25 C. 1 From a microbiological point of view, the product should be used immediately 1 If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user Reconstitution Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial (device pack). For injection of IDELVION, only the provided administration sets should be used because treatment failure can occur as a consequence of factor IX adsorption to the internal surface of some injection equipment. Care should be taken that no blood enters the syringe filled with product, as there is a risk that the blood could coagulate in the syringe and fibrin clots could therefore be administered to the patient. The IDELVION solution must not be diluted. The reconstituted solution should be administered by slow intravenous injection. The rate of administration should be determined by the patient s comfort level, up to a maximum of 5 ml/min. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Withdrawal and application 1. Open the Mix2Vial by peeling off the lid. Do not remove the Mix2Vial from the blister package! 2. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper. 3. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set. 4. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial. 5. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully counterclockwise into two pieces. Discard the solvent vial with the blue Mix2Vial adapter attached. 6. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake. 7. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the product vial. 8. While keeping the syringe plunger pressed, turn the system upside down and draw the solution into the syringe by pulling the plunger back slowly. 9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counterclockwise. Section Highlights IDELVION is manufactured using a highly controlled, multistep process 30 The manufacturing process includes numerous controls and tests to ensure product safety Overview IDELVION is manufactured in a state-of-the-art facility in Marburg, Germany, under controlled conditions. The facility utilises a multistep manufacturing process that includes numerous in-process tests and controls that ensure the quality and safety of the final product IDELVION Manufacturing Process The active ingredient of IDELVION is secreted by a genetically engineered Chinese hamster ovary (CHO) cell line into a chemically defined cell culture that is free of animal-derived materials. IDELVION is then purified via chromatography, and concentrated and incubated in the presence of a solvent/detergent reagent. This is the first dedicated step to inactivate any potential viral contaminants. 30 The product undergoes a second dedicated step of nanofiltration to further eliminate potential viral contaminants and is then diluted to produce the final bulk solution. 30 This is aseptically filled into sterile glass vials, lyophilised, and then sealed Virus Safety In the manufacturing process the virus safety of IDELVION is ensured by the combination of virus testing of the expression system, exclusion of animal components in media used in the cell culture process, and the incorporation of 3 virus removal/inactivation steps of chromatography, solvent/detergent, and nanofiltration. 30 Please see essential information for IDELVION

10 4 PROLONG 9-FP Clinical Trial Programme Section Highlights In preclinical and phase I trials, IDELVION demonstrated an excellent safety profile and an improved PK profile over other currently marketed FIX replacement products (pdfix, rfix) 29,31,32 The PROLONG 9-FP clinical trial programme evaluated the PK profile, safety, and efficacy of IDELVION for on-demand, prophylactic, and perioperative treatment of bleeding in adult and paediatric patients with severe haemophilia B 30,33 In the PROLONG 9-FP clinical trial programme, IDELVION demonstrated: 30 An improved PK profile compared with regular-acting FIX replacement products (rfix, pdfix) 29,32 A favourable safety profile 27,29,30,32,34,35 A reduction in annualised spontaneous bleeding rate (AsBR) compared with on-demand treatment 27,34 Maintenance of haemostasis during and after surgery Overview The PK, safety, and efficacy of IDELVION were evaluated in preclinical and clinical trials. Preclinical IDELVION studies showed a significantly extended terminal half-life, increased AUC, and reduced CL compared with rfix in a variety of animal models. IDELVION also significantly increased the in vivo recovery of IDELVION compared with rfix. 3,31 The PROLONG 9-FP clinical trial programme is designed to determine the PK profile, safety, and efficacy of IDELVION in adult and paediatric patients with haemophilia B. The programme includes 5 open-label, prospective clinical studies (N=107 patients) (Figure 3). 30,33 In a phase I clinical trial (n=25), IDELVION demonstrated an improved PK profile over a marketed rfix product. 32 Mean half-life of IDELVION was 92 hours; over 5 times longer than that of rfix. Additionally, IDELVION showed approximately 44% higher IR, more than 7-fold larger AUC, and more than 7-fold slower CL compared with rfix products taken by patients previously. 32 A phase I/II clinical trial of IDELVION (n=17) also found favourable PK results, with mean FIX trough activity levels of 5.6 and 2.9 IU/dL at day 7 and day 14, respectively. 34 Mean half-life was about 95 hours, which is comparable with phase I trial PK results. 32 This trial also demonstrated the clinical efficacy of IDELVION. 34 All bleeding events were successfully treated with 1 or 2 injections of IDELVION. Additionally, the mean weekly consumption of IDELVION was reduced compared with the previous FIX product use. In a phase II/III clinical trial (n=63), IDELVION showed an improved PK profile over standard marketed FIX products (pdfix, rfix); compared to rfix, IDELVION demonstrated an approximately 52% higher IR, 4.3-fold longer half-life, 5.1-fold larger AUC, and 81% decrease in CL. 30 IDELVION was associated with lower AsBR compared to on-demand treatment and lower consumption compared with previously used FIX products. In a phase III clinical trial (n=27) in children, IDELVION showed an improved PK profile over previous FIX treatment, with a ~5-fold longer half-life, and an 80% decrease in clearance. 30 Weekly prophylaxis resulted in a median AsBR of zero and weekly consumption was lower than with previously used FIX products. 30 In a surgical substudy of patients participating in the two phase III studies or the phase III extension study who required major or minor non-emergency surgery, the haemostatic response of IDELVION was rated by investigators as excellent (n=17) or good (n=4) for all surgeries, and a single dose of rix-fp was sufficient to maintain haemostasis during 20 of 21 surgeries. 36 The favourable safety and PK profile of IDELVION supports a prophylactic dosing regimen of once every 14 days for patients with haemophilia B. 27 This less-frequent dosing may improve adherence and enhance QOL for patients with haemophilia B. 3,5 Figure 3: Summary of IDELVION clinical trial programme 30,33 Phase I Safety and PK Phase I/II PK, safety, and efficacy Phase II/III Pivotal PK, safety, and efficacy Surgery substudy Phase III Paediatric PK, safety, and efficacy Surgery substudy Phase IIIb Extension Safety and efficacy Surgery substudy Completed (NCT ) Completed (NCT ) Completed July 2014 (NCT ) Completed October 2014 (NCT ) Ongoing since January 2014 (NCT ) Please see essential information for IDELVION

11 4 PROLONG 9-FP Clinical Trial Programme (cont d) 4.2 Preclinical Trials Preclinical studies were conducted to compare the PK properties of IDELVION and rfix in mice, rats, and rabbits. In these studies, IDELVION demonstrated: Increased in vivo recovery vs rfix (rats, 47.1% vs 27.6%; rabbits, 73.4% vs 46.7%) 3 Extended terminal half-life vs rfix (rats, 24.1 h vs 5.13 h; rabbits, 36.2 h vs 9.14 h) 3 Increased AUC vs rfix (rats, 8.16 h IU/mL vs 1.76 h IU/mL; rabbits, 33.4 h IU/mL vs 4.65 h IU/mL) 3 Other studies were conducted to further compare the PK characteristics of IDELVION and rfix in FIX-deficient dogs. In these studies, IDELVION showed: Higher recovery rate vs rfix (43% vs 23%) 31 Prolonged t 1/2 vs rfix (51.9 h vs 33.6 h) 31 Increased AUC vs rfix (41.5 h IU/mL vs 9.7 h IU/mL) 31 Lower CL rate vs rfix (2.41 ml/h/kg vs ml/h/kg) 31 The favourable PK profile of IDELVION demonstrated in these studies was explored further in phase I, II, and III in-human studies. 4.3 Phase I Safety and PK Trial Safety and PK study of IDELVION in patients with haemophilia B Study design 29,32 This first phase I in-human study conducted with IDELVION was a prospective, multicentre, openlabel, dose-escalation study designed to evaluate the safety and PK of IDELVION in 25 patients with haemophilia B (Table 4). Safety arm: Patients received 25 IU/kg, 50 IU/kg or 75 IU/kg of IDELVION, which were given to each dosing group sequentially and dosing of the next cohort began following a review of safety data at 28 days. IDELVION was administered to patients in their nonbleeding state. There was a washout period of at least 4 days from the last administration of the prior FIX product and a washout period of at least 14 days between doses of IDELVION. Patients were tested for inhibitors to FIX on day 28. PK arm: PK evaluation was performed following a single dose of 25 IU/kg, 50 IU/kg or 75 IU/kg IDELVION Patients who received 50 IU/kg IDELVION were given 50 IU/kg of their prior FIX product before or after administration of IDELVION, with a minimum washout period of 4 days after injection of prior FIX product or a minimum of 14 days after IDELVION injection. All bleeding events during the study were treated with prior FIX product. Table 4: Patient population for phase I safety and PK trial 29,a IDELVION pdfix or rfix 25 IU/kg 50 IU/kg 75 IU/kg 50 IU/kg n (%) n (%) n (%) n (%) Total n (%) Patients enrolled Analysis populations Safety population 9 (100.0) 14 (100.0) 9 (100.0) 15 (100.0) 25 (100.0) PK population 7 (77.8) 13 (92.9) 8 (88.9) 12 (80.0) 22 (88.0) Completed study 9 (100.0) 14 (100.0) 9 (100.0) 15 (100.0) 25 (100.0) a Patients were permitted to participate in up to 2 IDELVION dosing cohorts, and a washout period of at least 14 days between doses was required. Seven patients participated in more than 1 arm as follows: 3 patients participated in the 25-IU/kg and 50-IU/kg arms, 3 patients participated in the 50-IU/kg and 75-IU/kg arms, and 1 patient participated in the 25-IU/kg and 75-IU/kg arms. The safety population included all patients exposed to IDELVION. Patients were included in the PK analysis if they had more than 1 postdose PK sample drawn with no sample quality issues as reported by the central laboratory and who did not receive any FIX product for the treatment of a bleed during the PK sampling period. Republished with permission of American Society of Hematology, from Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rix-fp) in hemophilia B patients. Santagostino E, et al. Blood 120(12): , 2012; permission conveyed through Copyright Clearance Center, Inc. Study endpoints 29,32 The primary endpoint was: Safety of IDELVION up to 28 days post administration. Safety assessments included: Frequency of adverse events (AEs) Occurrence of inhibitors to FIX Antibody development against IDELVION Local tolerability The secondary endpoints were: Evaluation of PK parameters after a single IV injection of IDELVION 50 IU/kg, compared with 50 IU/kg of a previous FIX product (rfix or pdfix) Additional evaluation of PK parameters of IDELVION 25 IU/kg and 75 IU/kg Please see essential information for IDELVION

12 4 PROLONG 9-FP Clinical Trial Programme (cont d) Results Safety 29,32 IDELVION was well tolerated in all patients No hypersensitivity reactions, inhibitors to FIX or antibodies to IDELVION developed in any of the patients who received IDELVION therapy There were no clinical signs or symptoms of thrombosis associated with IDELVION therapy Pharmacokinetics 29,32 Mean half-life of IDELVION in the 50 IU/kg dose group was hours, and was >5.8 times longer than that of the patients prior pdfix product (14.5 h) and 5.3 times longer than that of rfix (17 h) (Table 5) 29,32 After administration of IDELVION 50 IU/kg, trough FIX activity levels remained above 5% for as long as 14 days (Figure 4) 32 IR of IDELVION was 29% higher than that of pdfix and 44% higher than that of rfix 29 IDELVION showed a >7-fold larger AUC and slower CL compared with rfix and a >6-fold larger AUC and slower CL than pdfix 29 Table 5: PK parameters after a single dose of IDELVION and previous FIX products, according to noncompartmental analysis 29 Parameter (unit) baseline-corrected AUC 0-inf, h IU/dL 25 IU/kg (n=7) rix-fp 50 IU/kg (n=13) 75 IU/kg (n=8) rfix (n=8) Previous FIX pdfix (n=4) Mean SD C max, IU/dL Mean SD IR, IU/dL per IU/kg Mean SD Half-life, h Mean SD CL, ml/h per kg Mean SD Figure 4: Linear plot of baseline-corrected FIX activity level after the injection of 50 IU/kg of IDELVION or previous FIX product 29,32 FIX Activity (IU/dL) IU/kg IDELVION (n=13) 50 IU/kg rfix (n=8) 50 IU/kg pdfix (n=4) 5% FIX activity Time (hours) Republished with permission of American Society of Hematology, from Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rix-fp) in hemophilia B patients. Santagostino E, et al. Blood 120(12): , 2012; permission conveyed through Copyright Clearance Center, Inc. 4.4 Phase I/II Safety and Efficacy Trial Safety, efficacy and PK study of IDELVION in patients with haemophilia B Study design 34,35 This was a prospective, multicentre, open-label study designed to evaluate the safety, efficacy, and PK profile of IDELVION for the control and prevention of bleeding episodes in 17 patients who had previously received factor replacement therapy for haemophilia B. 5 % PK evaluation period 34,35 Patients were given a dose of 25 IU/kg of IDELVION and then underwent PK evaluation over a 10- to 14-day period. C max =maximum concentration. Republished with permission of American Society of Hematology, from Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rix-fp) in hemophilia B patients. Santagostino E, et al. Blood 120(12): , 2012; permission conveyed through Copyright Clearance Center, Inc. Please see essential information for IDELVION

13 4 PROLONG 9-FP Clinical Trial Programme (cont d) Treatment period 34,35 On-demand group (in Bulgaria): 4 patients then received IDELVION 25 IU/kg as needed for bleeding episodes over a 20-week period, with monthly visits Prophylactic group (in Israel): 13 patients received IDELVION IU/kg with incremental increases to 50 and 75 IU/kg, according to the patient s requirements, for up to 44 weeks Inclusion criteria 34,35 Males, 12 to 65 years of age, with FIX activity level 2%, who had received FIX products for >150 exposure days Platelet count 100,000/μL; CD4 count 200/mm 3 ; liver enzymes <5 times the upper limit of normal (ULN); creatinine level <2 times ULN On-demand patients had at least 2 bleeds per month on average during the previous 3 6 months No history of FIX inhibitors or detectable FIX inhibitors at screening Study endpoints 34,35 The primary endpoints were: Frequency of treatment-related AEs Number of patients who developed inhibitors to FIX Number of patients who developed antibodies to IDELVION The secondary endpoints were: AUC t 1/2 of single dose of IDELVION IR of IDELVION CL of single dose of IDELVION Breakthrough bleeding events in patients receiving prophylactic treatment with IDELVION Number of injections to achieve haemostasis in on-demand treatment group Results Safety 34,35 IDELVION demonstrated a favourable safety profile and was well tolerated when administered as weekly prophylaxis or as on-demand treatment at doses between 25 and 75 IU/kg. None of the 46 (43 mild, 3 moderate) AEs reported were deemed to be related to IDELVION treatment There were no hypersensitivity reactions, development of FIX inhibitors or treatmentemergent antibodies to IDELVION Efficacy 34 All 13 prophylaxis patients were successfully maintained on a weekly IDELVION treatment regimen throughout the study Patients who switched from prophylaxis with a previous FIX product to weekly prophylaxis with IDELVION experienced a significant reduction in mean weekly FIX consumption Patients who switched from on-demand treatment to weekly prophylaxis (Table 6) experienced a: 95% reduction in mean annualised spontaneous bleeds 83% reduction in mean annualised total bleeds All bleeding events were treated successfully with 1 or 2 injections of IDELVION 95.3% of bleeds were treated with a single injection of IDELVION Pharmacokinetics 34,35 At a dose of 25 IU/kg, IDELVION treatment increased FIX activity above 30% Mean FIX activity level of IDELVION 25 IU/kg was 4.4% on day 7 (Figure 5) Mean half-life was 95 hours Table 6: Bleeding rate reduction in prophylaxis patients 30,a Spontaneous bleeds median (min, max) Traumatic bleeds median (min, max) Total bleeds median (min, max) Previous on-demand treatment (n=3) 35 (15, 45) 15 (5, 15) 50 (30, 50) IDELVION weekly prophylaxis (n=3) 1.3 (0, 3.4) 4.5 (0, 12.7) 7.9 (0, 14) Mean bleeding reduction 95% fewer bleeds 50% fewer bleeds 83% fewer bleeds a Values for total, spontaneous, and traumatic bleeding episodes are the annualised bleeding rate per patient for bleeding episodes reported during the study (i.e., prophylaxis, treatment) and the total number of episodes reported during the 12 months before study entry (i.e., previous on-demand treatment). Figure 5: Baseline-corrected FIX activity following IDELVION 25 IU/kg injection compared with prior FIX 50 IU/kg (data from phase I and phase I/II studies) 35 FIX Activity (IU/dL) Day 7 4.4% 168 Time (hours) 25 IU/kg IDELVION (n=13) 50 IU/kg rfix (n=8) 50 IU/kg pdfix (n=4) 5% trough Reprinted from Thromb Res 13(Suppl 2), Martinowitz U & Lubetsky A. Phase I/II, open-label, multicenter, safety, efficacy and PK study of recombinant coagulation factor IX albumin fusion protein (rix-fp) in subjects with hemophilia B. S11 S14., Copyright 2013, with permission from Elsevier. 5 % Please see essential information for IDELVION

14 4 PROLONG 9-FP Clinical Trial Programme (cont d) 4.5 Phase II/III Safety and Efficacy Trial Safety and efficacy study of IDELVION in adult patients with haemophilia B Study design 27 This prospective, open-label study was designed to evaluate the safety, PK, and efficacy of IDELVION as both routine prophylaxis and on-demand treatment for the control and prevention of bleeding episodes in patients aged 12 to 65 years with severe (FIX activity 2%) haemophilia B (Figure 6). Sixty-three patients were enrolled: prophylaxis arm, n=40; on-demand arm, n=23. Prophylaxis arm (Arm 1): The initial 7-day prophylaxis regimen of Arm 1 lasted 26 weeks. Patients received a weekly dose of IU/kg IDELVION, as decided by the treating physician. Following the 7-day regimen, patients could be switched to a 10- or 14-day dosing interval at a dose of 75 IU/kg, provided that they had maintained a dose of 40 IU/kg once weekly to switch to the 14-day dosing interval or 50 IU/kg once weekly to switch to the 10-day interval, and had a lack of spontaneous bleeding episodes in the 4 weeks prior to the switch. The dose could be adjusted based on the treating physician s assessment. On-demand arm (Arm 2): Patients received on-demand dosing with IDELVION for 26 weeks. Thereafter, patients were switched to a weekly prophylactic regimen with IU/kg IDELVION for the remainder of the study. All bleeding episodes were treated with IDELVION at doses between IU/kg, as decided by the treating physician. PK arm: Subjects who had not already undergone PK analysis of IDELVION in a previous study participated in a 14-day PK evaluation of 25 or 50 IU/kg IDELVION at the start of the study. A subset of patients also underwent a PK evaluation of their previous FIX product and a second PK evaluation of 50 IU/kg IDELVION after 26 weeks of 7-day prophylaxis treatment. Figure 6: Study design for phase II/III trial (adults) 27 rix-fp PK (14 days) Inclusion criteria 27 Switch Arm 1 Arm 2 Once-weekly prophylaxis ~6 months On-demand ~6 months 6 months Switch Switch 7-, 10- and 14-day prophylaxis ~6 months Once-weekly prophylaxis ~6 months 12 months (End of study) Extension Study Males, 12 to 65 years of age, severe haemophilia B (FIX activity level, 2%), who had received FIX products for >150 exposure days No confirmed prior history or family history of FIX inhibitor formation and no confirmed detectable inhibitors On-demand patients only: Minimum of 2 spontaneous (nontrauma-induced) bleeding episodes per month over past 3 6 months Willingness to switch to a prophylactic regimen Please see essential information for IDELVION

15 4 PROLONG 9-FP Clinical Trial Programme (cont d) Exclusion criteria 27,30 Known hypersensitivity to any FIX product/ hamster protein Known congenital/acquired coagulation disorder other than FIX deficiency Low platelet count or kidney or liver dysfunction HIV-positive patients with CD4 count <200/mm 3 Evidence of thrombosis, life-threatening bleeding episode, or major surgical intervention within 4 months before dosing on day 1 Study endpoints 27 The primary endpoints were: Efficacy of IDELVION in preventing bleeding episodes (prophylaxis) versus on-demand treatment Safety of IDELVION with respect to development of inhibitors to FIX The secondary endpoints were: PK of single dose of IDELVION Haemostatic efficacy of IDELVION for prevention and treatment of bleeding episodes Overall safety of IDELVION, including frequency of AEs and development of antibodies to IDELVION Results Safety 27,30 IDELVION was shown to be well tolerated across both treatment arms. Fifty-four (85.7%) of the 63 patients experienced 347 treatmentemergent AEs during the study. However, only 2 (3.2%) of the 63 patients experienced an AE that led to study drug withdrawal. One patient who experienced headache and eczema (assessed by investigator as related to IDELVION ) withdrew from the study Another patient had an injection-related reaction that led to study drug withdrawal No inhibitors to IDELVION were detected, and the majority of AEs were mild to moderate in severity. The most common treatmentemergent AEs ( 5% of patients) in either treatment arm were: Nasopharyngitis Headache Arthralgia Influenza Pharmacokinetics 27,30 Overall, IDELVION 50 IU/kg demonstrated an improved PK profile over standard marketed FIX products (pdfix, rfix) (Table 7) IDELVION 50 IU/kg compared with rfix demonstrated: 30 Approximately 52% higher IR 4.3-fold longer half-life 5.1-fold larger AUC 81% decrease in CL Please see essential information for IDELVION

16 4 PROLONG 9-FP Clinical Trial Programme (cont d) Table 7: Summary of FIX activity PK parameters after 50 IU/kg of IDELVION and 50 IU/kg of previous FIX product (PK population) 30 Figure 7: Mean (SD) baseline-uncorrected plasma FIX activity time profiles after administration of single injection of 25 and 50 IU/kg IDELVION (PK population) 27 Parameter (unit) IDELVION 50 IU/kg (n=46) 50 IU/kg rfix (N=8) Treatment, Dose Mean (CV%) d Previous FIX 50 IU/kg pdfix (N=4) Total (N=12) IR, a IU/dL per IU/kg 1.27 (23.9) (18.1) 1.27 (25.3) (30.6) C max, IU/dL 63.9 (23.4) 41.7 (18.0) 63.7 (25.3) 49.1 (30.5) AUC 0-inf, h IU/dL 7176 (29.5) 1396 (34.5) 1408 (27.0) 1400 (30.5) CL, b ml/h per kg (33.5) (38.2) (26.4) 3.93 (33.5) Vss, b dl/kg 1.03 (18.7) (23.0) (17.9) 1.18 (29.0) t 1/2, h (21.8) 24.2 (19.7) 17.0 (20.3) 21.6 (25.5) MRT, c h (19.5) 35.3 (20.6) 24.4 (16.1) 31.3 (26.1) a Incremental recovery (IU/dL)/(IU/kg) is defined as maximum (peak) FIX activity (IU/dL) recorded 30 minutes after injection, per dose of (IU/kg) injection. b Clearance and volume of distribution at steady state (Vss) are normalised for body weight. c MRT=mean residence time. d CV%=percent coefficient of variation. Note: All values are baseline-uncorrected, with the exception of IR and C max, which are presented as baseline-corrected. At a 26-week PK assessment, there were no changes in PK parameters for IDELVION 50 IU/kg 27 After single-dose administration of IDELVION 50 IU/kg, mean FIX activity remained above 5% through day 14 (Figures 7 and 8) 27 Plasma FIX Activity (IU/dL) Time (hours) 25 IU/kg IDELVION (n=6) 50 IU/kg IDELVION (n=46) 5 IU/dL trough Republished with permission of American Society of Hematology, from Long-acting recombinant coagulation factor IX albumin fusion protein (rix-fp) in hemophilia B: results of a phase 3 trial. Santagostino E, et al. Blood 127(14), 2016; permission conveyed through Copyright Clearance Center, Inc. Figure 8: Mean (SD) baseline-uncorrected plasma FIX activity time profiles after administration of single injection of 50 IU/kg IDELVION and 50 IU/kg of previous FIX product (matched-pair plot of patients with PK assessments for both IDELVION and previous FIX) 27 Plasma FIX Activity (IU/dL) IU/kg IDELVION (n=12) 50 IU/kg previous FIX (n=12) 5 IU/dL trough Time (hours) Republished with permission of American Society of Hematology, from Long-acting recombinant coagulation factor IX albumin fusion protein (rix-fp) in hemophilia B: results of a phase 3 trial. Santagostino E, et al. Blood 127(14), 2016; permission conveyed through Copyright Clearance Center, Inc. Please see essential information for IDELVION