OPTIMAL USE OF COAGULATION FACTORS & IMMUNOGLOBULINS MEETING
(Kreuth III)
26-27 April 2013
POSTERS
Patient Safety through an IVIg Mastered Manufacturing Process (LFB) ...... 3
Clinical trial evaluating the pharmacokinetics, efficacy and safety of a new human plasma-derived polyvalent intravenous immunoglobulin product (NewGam 10%) in patients with primary immunodeficiendy disease (PID) (Octopharma) ...... 4
BAX 111, a recombinant human von Willebrand factor drug candidate (Baxter BioScience) ...... 5
BAX 326, a recombinant human factor IX drug candidate (Baxter BioScience) ...... 6
BAX 817, a recombinant human factor VIIa drug candidate (Baxter BioScience) ...... 7
BAX 855, a PEGylated rFVIII product with prolonged half-life (Baxter BioScience) ...... 8
Clinical Development Program for BAY 94-9027, a Long-Acting PEGylated B-Domain-Deleted Recombinant Factor VIII for Patients With Hemophilia A (Bayer) ...... 9
Clinical Experience with a New Orphan Drug FACTOR X Product (BPL) ...... 10
Clinical studies with Nanogam (50 mg/ml intravenous immunoglobulin product) (Sanquin) ...... 11
Successful immune tolerance induction in patients with haemophilia A and inhibitors treated with a plasma-derived FVIII product containing von Willebrand factor: a large international, multicentre, retrospective study (Grifols) ...... 12
Open prospective trial investigating pharmaco-kinetics, tolerability and safety of a new 10% human immunoglobulin for intravenous infusion (IVIg) in patients with primary immunodeficiency disease (PID) (Biotest) ...... 13
Innovative tailored approach for traitment of von Willebrand disease wilfactin®/willfact® (LFB) ...... 14 Analytical results Fractionation process FXI andFXIIquantification in five liquidIVIgproducts Procoagulant activity by assay Elisa TGA inFXI- P atient Safety through Process IVIgMastered Manufacturing an Patient Safety Deficient plasma:comparative velocity ratios for IVIgproducts TGA: for undetectable Tegeline® andClairYg® Thrombin generation assay of11batches of Tegeline® Thrombin generation assay of5batches ofClairYg® Clinical Safety Benefits Velocity rati studyinFXIdeficient plasma in terms effect ofthromboembolic Thromboembolic effects (TEE) with Thromboembolic (TEE) effects Tegeline® Thromboembolic effects (TEE) withClairYg®Thromboembolic (TEE) effects from 2001to infrequent 2011:avery AE Roch B.,Roch Monrepos S.,DhainautF., C.,deCoupade A.,Paolantonacci A.,van C.,Sauger derMeersch Milchaski P., F. Rossi in 2010 and 2011: a very infrequentin 2010and2011:avery AE haemagglutination titres between laboratories, even whenusing This studydemonstrates upto 16-fold in variability et al. and anti reagents to standardize haemagglutination testing for anti International Collaborative Study to evaluate candidate reference the identification ofhigher titre batches define limits where these are applicable; and third, to facilitate are needed, first, to control second, to testing methodology; Appropriate reference reagents for anti-A andanti-B in IVIG a specifiedmethod, i.e. haemagglutination thedirect method. Direct haemagglutination EPassay:Direct Flow cytometry forFlow anti- cytometry ‐B in IVIg products ‐B inIVIgproducts Vox Sang. 2009Apr 27, Thorpe S.J. and O Rh(D) negativeand ORh(D) groups induced by five Specific lysis ofred bloodcells from A,B, AB Need for selection andharmonisationNeed for among fractionaters selection ontechnical assays hemagglutinins detection hemagglutinins detection significant variability Haemolysis withotherIVIG:e.g. Germany (from PEIdata) on Q1 2013 (Weber effect secondary to European alerts) effectsecondary authorities on Q12013(Weber No casesfrom Aug 2010to 2011(PSUR);Nocasesin2012;2 liquid IVIgproducts Hemolysis per kg Hemolysis per kg hemolysis 2011 hemolysis 2008 Cumula>ve Cumula>ve Haemolysis withClairYg®: infrequent avery AE 2008 2011 1000 exposed subjects : a very infrequent :avery 1000 exposed AE subjects Kiovig 10% Haemolysis with Tegeline® per in terms ofhaemolysis .%4.3% 1.9% .%1.2% 1.8% 913 19 Repor3ng rate of hemolysis with IV in Germany (PEI data) 6 A &anti Anti‐A &anti- Gamunex In total,In 40casesin16years 10% 20 ‐B Octagam 5%/10% 0.1% 0.5% ‐A 1 1
Privigen 10% 69 9 B haemagglutininsdetection Assay reproducibility for anti Sandoglobulin 1 1 Detection withFlowDetection cytometry of red bloodcells from A,B, ABandORh Sandoglobulin Privigen + 2.9% 4.7% 70 10 In ‐A anti Specific lysisSpecific (OD) procoagulant fractions) for anti- cytometry tests isrecommended (e.g. flow predictive andreproducible in- Systematically applyingthemost safety for thepatients process leadsto improved clinical steps critical inthe Mastering terms ofsafety. differencesexhibit meaningful in different IVIg preparations may used by different manufacturers, andvariousprocessesproduction toDue thecomplex methodof ClairYg®: Tegeline®: ‐B hemagglut. ‐ groups induced by five liquidIVIgproducts Conclusion Birdshot retinochoroiditis Core SPCIVIg, CIDP, MMN, Core SPCIVIg A/B HA; TGA for flow cytometric method.flow cytometric the highreproducibility ofthis (n=120) assays. all anti-A (n=162)andanti-B between highandlow QCsfor represents thesloperatios - Tegeline).Lowfigures The depleted anti-A/B ClairYg and Anti-B assays -non- (High were anti-A usedduring and Two controls Quality (QC) vitro This indicate Clinical trial evaluating the pharmacokinetics, efficacy and safety of a new human plasma-derived polyvalent intravenous immunoglobulin product (NewGam 10%) in patients with primary immunodeficiency disease (PID)
Borte M (1), Pyringer B (2), Svae TE (3) Immunologie und Infektiologie Klinik für Kinder-und Jugendmedizin Klinikum St. Georg, Leipzig, Germany (1) Clinical Research & Development Department, Octapharma Pharmazeutika Produktionsges.m.b.H, Vienna, Austria (2) Medical Science Liaison Department, Octapharma Pharmazeutika Produktionsges.m.b.H., Vienna, Austria (3)
Table 2. Pharmacokinetic details for adult full-analysis population (n=26) Table 4. Adverse events* (AEs) occurring in ≥5% of the patients during infusion or Introduction Results within 72 hours after the end of infusion, irrespective of casualty Adult patients No. of patients with AEs No. of infusions with AEs 3-weeks 4-weeks AEs NewGam 100 mg IgG/mL (10%) is the development name of a new human normal One child each was excluded from the PK and efficacy evaluations. Thus, the per- IgG total (% of patients) [n=51] (% of infusions) [n=740] immunoglobulin (IVIG) product from Octapharma. This novel high-purity glycine- protocol population in both cases comprised 50 patients. The results from the PK Mean ± standard Mean ± standard Median (range) Median (range) stabilised IVIG is manufactured using various precipitation and chromatography evaluation in these 50 subjects can be seen in Figure 1 and Table 1. The detailed IgG deviation deviation Headache 9 (17.6) 25 (3.4) techniques for the harvesting and purification of IgG, and the process comprises two total Cmax, Cmin and half-life (t1/2) values for the adult patient portfolio (n=26) can be seen C [g/L] 23.7 ± 5.9 24.2 (14.6-30.0) 17.3 ± 3.7 16.1 (12.7-26.0) max Pyrexia 7 (13.7) 8 (1.1) dedicated steps for pathogen safeguarding (solvent/detergent treatment and small- in Table 2, and the plasma IgG total trough level by infusion throughout the study for all C [g/L] 14.0 ± 2.7 14.4 (10.0-18.1) 10.0 ± 3.6 8.7 (6.8-20.6) pore nanofiltration at extreme pH). subjects (n=51) can be seen in Figure 2. There is a trend towards a shorter half-life for min Nausea 4 (7.8) 6 (0.8) the subclasses IgG3 and IgG4 than the ones demonstrated for the other two subclasses, The clinical development of this product follows the relevant guidelines issued by the t [days] 32.4 ± 12.4 32.6 (18.5-55.1) 45.1 ± 20.8 38.6 (18.7-102.8) but all the results were in the expected range and in line with the figures reported for 1/2 Fatigue 3 (5.9) 3 (0.4) European Medicines Agency [EMA/CHMP/BPWP/94033/2007.rev.2. Guideline on the other new IVIGs launched during the last decade (data not shown). clinical investigation of human normal immunoglobulin for intravenous administration Abdominal pain 3 (5.9) 3 (0.4) (IVIg). 22 July 2010.], and we hereby present the key findings from the first clinical Only one of the 50 per-protocol patients did experience a serious bacterial infection. Figure 2. Average plasma IgG total trough level for full-analysis population (n=51) *Excluding infections. trial in patients suffering from PID. The study was conducted in accordance with With altogether 49.2 patient exposure years, the result of this primary endpoint was the ‘International Conference on Harmonisation – Good Clinical Practice’, and the 0.06 SBIs/patient exposure year with a 99% confidence interval (CI) of 0.01-0.62 – see 25 Figure 3. Average (range) AE ratio by patient for eight FDA US licensed IVIGs* vs. subjects were enrolled only after a written informed consent. Table 3. Also the other efficacy parameters calculated by patient exposure year, such NewGam, representing the value 1.0 as other infections and days with use of antibiotics, absent from school or work, and The primary objective of this prospective, open-label, non-controlled, non-randomised, 20 hospitalised due to infection (see Table 3), were in line with what has been published 5.0 multicentre phase III study was to assess the efficacy of NewGam in preventing serious 3-weeks 4.5 for other IVIGs previously developed (data not shown). Based on historical data, a 4-weeks bacterial infections (SBIs). A determination of the pharmacokinetic (PK) profile and an statistical demonstration of an SBI rate per person exposure year of less than 1.0 was 15 4.0 4.0 evaluation of NewGam’s safety profile were among the secondary objectives. deemed adequate to provide substantial evidence of efficacy for the primary endpoint. 3.5 3.4 3.3 3.3 3.3 IgG [g/L] Despite the extensive product exposure, only five different adverse events (AEs) 10 3.0 2.7 2.6 2.5 2.3 occurred in more or equal than 5% of the patients during the infusion or within 72 2.3 2.0 Patient and infusion details hours after the end of infusion (irrespective of causality) – see Table 4. All of these five 5 1.9
AE ratio vs. NewGam 1.7 1.6 1.5 AEs were typically IVIG reactions. In addition to the headache, pyrexia, nausea, fatigue 1.4 1.4 1.1 1.0 and abdominal pain reactions, which occurred in connection with 0.4% to 3.4% of 1.0 0.9 The full-analysis population comprised 51 previously immunoglobulin treated 0 the infusions, two (3.9%) of the patients experienced chills during/after five infusions 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.5 0.5 patients with either common variable immunodeficiency (n=43; 84.3%) or X-linked Weeks (0.7%). The average rate of AEs reported for NewGam in this study is lower, by a factor 0.0 agammaglobulinaemia (n=8; 15.7%), and it was enrolled by four European and seven Headache Pyrexia Nausea Fatigue Abdominal pain Chills US centres. The study included 33 (64.7%) men and 18 (35.3%) women. Thirteen of at least 2, than what has been reported for some IVIGs which obtained marketing authorisations during the last ten years – see Figures 3 and 4. Table 3. Efficacy for per-protocol population (n=50) (25.5%) of the subjects were children in the age range 2-11 years, 12 (23.5%) were *Approved prescribing information for: Bivigam 10%, FlebogammaDIF 5%, FlebogammaDIF 10%, Gammagard adolescents (12-15 years) and 26 (51.0%) were adults (16-75 years). The median age Liquid/Kiovig 10%, Gammaplex 5%, Gamunex 10%, Privigen 10% and Octagam 5% (read-out March 2013). Figure 1. Average plasma IgG total for per-protocol population (n=50) Parameter All patients was 17 years (range: 2-65), and the median body weight of the patients was 61 kg (range: 13-145). The corresponding numbers for height and body mass index were Patients [n] 50 Figure 4. Average (range) AE ratio by infusion for eight FDA US licensed IVIGs vs. 163 cm (range: 90-191) and 22 kg/m2 (range: 15-52), respectively. 25 NewGam, representing the value 1.0 Patient exposure [years] 49.2 Thirty (58.8%) of the patients got the IVIG infusion every 4 weeks, whereas the 5.0 20 Max: 19.5 remaining 21 (41.2%) of the subjects were treated every 3 weeks. In total the 3-weeks Patients with serious bacterial infections [n] 1 (2.0%) 4.5 4.6 Average: 5.7
4-weeks 4.2 average duration of treatment was 360 calendar days. The administered dose 4.0 15 Serious bacterial infections [n] 3 allowed was 200-800 mg/kg per infusion day, and the actual mean dose per infusion 3.5 was 485 mg/kg. The treatment intervals and dose had to remain the same throughout Serious bacterial infections/patient exposure year [n; 99% CI] 0.06 (0.01-0.62) 3.0 IgG [g/L] the study, as long as the individual plasma IgG trough level was maintained above 10 2.5 2.5 Patients with other infections [n] 38 (76.0%) 2.3 5 g/L. One child was excluded from the efficacy evaluation after having lost two 2.1 2.0 infusion visits and was late for others, leading to plasma IgG values below the defined 1.8 5 AE ratio vs. NewGam 1.5 Other infections [n] 180 1.4 1.4 minimum trough level of 5 g/L at three visits. The PK evaluation was performed 1.3 1.1 1.0 1.1 th th 0.9 following the 9 and 7 infusion day for the 3 and 4 weeks schedules, respectively. Other infections/patient exposure year [n] 3.66 0.8 0 0.5 0.5 th 0 7 14 21 28 0.3 0.3 As from the 7 infusion the maximum allowed IVIG infusion speed was 0.08 mL/kg/min Days Patients with use of antibiotics [n] 41 (82.0%) 0.0 (equal to 480 mg/kg/hour), and all 51 (100.0%) patients experienced at least one Headache Pyrexia Nausea Fatigue Abdominal pain Chills such high-speed administration. There were altogether 740 infusions of NewGam Table 1. Median half-lives for total per-protocol population (n=50) Days with use of antibiotics [n] 4,298 performed throughout the complete study, out of which the high infusion rate was allowed in 435 (58.8%) cases. As many as 392 (53.0% of the total and 90.1% of Days with use of antibiotics/patient exposure year [n] 87.43 All patients Conclusions the allowed) infusions reached the upper rate of administration, and the total IgG total/subclass Patients absent from school or work due to infection [n] 25 (50.0%) average duration per infusion was 2.20 hours. Only two (3.9%) subjects received 3-weeks 4-weeks ■ NewGam has demonstrated a PK profile, as well as an efficacy pre-medication prior to a total of 3 treatments (0.4%). Total [days] 32.9 37.4 Days absent from school or work due to infection [n] 183 performance, equivalent to other IVIGs developed and commercialised during the last 10 years. IgG [days; 95% CI] 38.6 (28.5-47.3) 35.6 (29.5-50.0) Days absent from school or work due to infection/patient exposure year [n] 3.72 1 ■ With only a few AEs revealed both per patient and infusion, Patients hospitalised due to infection [n] 1 (2.0%) IgG2 [days; 95% CI] 38.0 (32.7-42.5) 38.3 (29.2-46.1) NewGam may display a very positive safety feature over some Days hospitalised due to infection [n] 4 of the currently licensed IVIGs. IgG3 [days; 95% CI] 26.2 (20.7-33.6) 27.3 (24.5-43.1) Days hospitalised due to infection/patient exposure year [n] 0.08 This study (www.ClinicalTrials.gov identifier: NCT01012323) will be followed by an enhanced infusion speed study (NCT01313507) in a IgG4 [days; 95% CI] 30.7 (23.7-43.0) 30.7 (25.0-36.0) subgroup of the above PID patients, and an efficacy and safety study in primary immune thrombocytopenia (NCT01349790).
XXXXXXXXXXXXXXXXXX BAX 111, a recombinant human von Willebrand factor drug candidate Baxter BioScience, Vienna, Austria
Introduction Structural and Functional Characterization Von Willebrand factor (VWF) is a multimeric adhesive glyco- Characterization of rVWF Multimer Analysis of rVWF, commercial pdVWF and VWF in Plasma 1 % agarose 2.5 % agarose protein, with a dual function in hemostasis. It mediates platelet Ratio VWF:FVIII kD VWF binding rVWF high adhesion at sites of vascular injury, which is necessary for VWF:Ag VWF:RCo VWF:RCo FVIII:C multimers capacity protein protein VWF:Ag VWF:RCo (n) Human plasma ULVWF primary hemostasis, and stabilizes factor VIII (FVIII) in the (IU/mg) (IU/mg) (IU/IU) (IU/IU) (%) Commercial rVWF 1.08 ± 0.02 ± pdVWF circulation. The pathophysiological significance of the different 183 ± 65 189 ± 42 120 ± 14 20 ± 1 (n=3) 0.28 0.002
17.9 ± 0.51 ± 0.67 ± low biological functions of this protein is demonstrated by von Haemate 8.0 ± 1.7 18 ± 2 4.7 0.10 0.13 n.a. HS n = 7 n = 11 Willebrand's disease (VWD), the most common hemorrhagic n = 12 n = 12 n = 13 07001 06002 07001 07002 06001 06001 06002 07002 Human Human plasma plasma pdVWF in house) aemate P aemate aemate P aemate ( H disorder, affecting 1% of the population. Approximately 1% of CiCoomassiestiitaining H rVWF rVWF patients with VWD have severe VWF deficiency resulting in kDa rVWF contains high and ultra-large molecular weight multimers not present in pdVWF and commercial pdVWF defective platelet adhesion, secondary FVIII deficiency, and a 250 150 Absence of ADAMTS13-mediated proteolytic fragments prolonged bleeding time. These patients can only be treated In-gel 100 Susceptibility of rVWF to ADAMTS13 visualization with polyclonal 75 anti-VWF effectively with VWF concentrates. A variety of plasma-derived low resolution (1% agarose) rADAMTS13: 1.0 U/ml high resolution (2.5% agarose) antibody concentrates (with or without FVIII) are available, and used for 50 37 the treatment of VWD. The development of a recombinant VWF rVWF 1 rVWF 3 rVWF 4 rVWF 5 rVWF 2
(rVWF), manufactured and formulated in the absence of animal Wilfactin pdVWF 1 pdVWF 3 pdVWF 2 MW marker or human plasma proteins, may increase the safety of the Haemate HS Purified rVWF is a highly concentrated product treatment of von Willebrand's disease in the management of with a physiological VWF:RCo to VWF:Ag ratio blee ding epidisodes, surgery and prophlhylax is. rVWF and purified pdVWF (control) contain a 0 0.25 0.5 1 2 5 10 30 60 0 60 0 0.25 0.5 1 2 5 10 30 60 0 60 rVWF rVWF + rADAMTS13 incubation time (min) buffer rVWF rVWF + rADAMTS13 incubation time (min) buffer plasma plasma . single band of mature monomers without protein rVWF is degraded by ADAMTS 13 upon incubation in vitro impurities Multimer size is below that of plasma VWF after only 15 seconds Multimer pattern at the 15-second time point resembles that of commercial pdVWF Production of rVWF Both commercial pdVWF products contain other Similar degradation observed in patients treated with rVWF proteins including human albumin substantially The ULMW multimers disappeared over time, similar to the disappearance in patients Recombinant VWF is co-expressed with recombinant FVIII in CHO cells. lowering their specific activity treated with DDAVP The starting material for rVWF is an intermediate of the manufacturing An ADAMTS13-specific cleavage product appeared already 15 min after administration process of the commercial rFVIII product ADVATE®. The column flow-through of the FVIII capture step, containing pro-VWF and mature VWF, is fully processed to mature VWF by recombinant furin, Key Product Characteristics and captured by an ion-exchange column. An intermediate from the rFVIII-PFM (ADVATE) manufacturing process can be used ADVATE process After DNA removal, rVWF as a source matilterial for a rVWF prodtduct CHO Cell line is solvent-detergent (SD) FVIII-VWF co-expression VWF source treated and purified by two Functional activity of rVWF shown by the binding capacity for FVIII and VWF:RCo Fermentation activity were similar to or higher than the in-house purified or commercial pdVWF Maturation by rfurin further chromatography Down-stream purification steps to a purity of more products than 95%. Fermentation rVWF has an intact multimer pattern VWF purification and concentration for rVWF and recombinant High-resolution multimer analysis demonstrated the lack of satellite bands, similar furin as well as the down- Final product formulation to endothelial- or platelet-derived human VWF stream processing is These satellite bands are formed simultaneously with the disappearance of high rFVIII rVWF performed under serum- Reconstitution free molecular-weight multimers upon incubation with ADAMTS13 Patient Patient The carbohydrate pattern of rVWF was similar to that of plasma-derived VWF with respect to terminal sialic acid, indicating an intact glycosylation
BAX 111 Clinical Study Phase 1: (ClinicalTrials.gov Identifier: NCT00816660) Phase 3: (ClinicalTrials.gov Identifier: NCT01410227) Multicenter, controlled, randomized 3-step dose escalation study Treatment of minor, moderate and major bleeding events Evaluation of pharmacokinetics, tolerability and safety in 32 VWD patients Evaluation of pharmacokinetics, tolerability and safety Study successfully completed Study planned to be completed 2013 Phase 3 Pi vot al St ud y D esi gn O vervi ew Part A Part B PK1 PK2
rVWF:rFVIII rVWF:rFVIII TREATMENT of Further TREATMENT of R bleeding episodes bleeding episodes for 1 for 6M 6M rVWF rVWF
PK1 PK2
rVWF:rFVIII rVWF:rFVIII 2 R rVWF rVWF
PK1 PK2
TREATMENT of bleeding Further TREATMENT of rVWF rVWF episodes for 6M bleeding episodes for 6M 3
Further TREATMENT of TREATMENT of bleeding episodes for 6M (rVWF 50IU/kg) bleeding episodes for 6M 4
PK50 Arm: PK assessments@ dose of 50 IU/kg VWF:RCo PK80 Arm: PK assessments@ dose of 80 IU/kg VWF:RCo
Pharmacokinetic Analysis of Phase 1 Cohort 4A Pharmacokinetics of FVIII:C in Phase 1 Cohort 4A (Type 3 VWD) VWF:RCo) Type 3 VWD: rVWF/rFVIII vs pdVWF/pdFVIII
FVIII:C* rpd
140 T1/2 [hours] 24.3 19 FVIII:C (6.5) (5.1) IU/dL . Higher FVIII levels observed in rVWF . No safety issues MRT [hours] 38.9 32.7 120 treated patients (as compared to − NhNo throm bibosis (12. 4) (7. 5) AUC o-∞ 5376 3361 pdVWF treated patients) − No inhibitors [h*U/dL] (2380) (1350) 100 . Enhanced stabilization of endogenous . Evidence for cleavage by T1/2 … Half-Life MRT … Mean Residence Time FVIII endogenous ADAMTS13 80 AUC … Area Under the Curve . Indicative for improved function in
60 secondary hemostasis . May result in in longer treatment 40 intervals and/or lower dosages
rVWF/rFVIII (38.5 IU/kg FVIII:C) 20 Presented at the pdVWF/pdFVIII (21-25 IU/kg FVIII:C) EUROPEAN SYMPOSIUM, Optimal use of The pharmacokinetic profile of rVWF seems improved 0 0 20406080100 clotting factors and immunoglobulins compared to that of pdVWF * All values are „means“, () Standard Deviation hours post-inf 26-27 April 2013, Wildbad Kreuth, Germany BAX 326, a recombinant human factor IX drug candidate Baxter BioScience, Vienna, Austria
Introduction The role of FIX in the coagulation cascade Human coagulation factor IX (FIX) is a vitamin-K-dependent coagulation factor whose absence or dysfunction XI XIa VIIa causes hemophilia B. Treatment of hemophilia B is based on replacement therapy using highly purified FIX Ca++ Ca++ TF concentrates. Baxter has developed BAX 326, a recombinant factor IX drug candidate for treating hemophilia B PL IX IXa FVIIIa patients that is produced in a CHO cell-line using a serum and protein-free fermentation technology. The Ca++ purification process avoids the use of immune-affinity chromatography and includes two viral reduction steps. PL X Xa FVa The final drug product is formulated in the absence of proteins of animal or human origin. BAX 326 resembles Ca++
commercially available rFIX in most characteristics with the exception of a significantly lower FIXa content, II IIa
which might improve standardization compared with commercial rFIX products. Fibrinogen Fibrin
Goal and current status Hemostatic potency of BAX 326 Development of a recombinant FIX molecule for treatment and FXIa-mediated activation of FIX FVIIa-mediated activation of FIX
16 Mean groups prevention of bleeding in patients with hemophilia B Mean groups 16 14 14 Expression in CHO cells 12 12 10 10 8 8 Plasma-albumin free manufacturing process Preclinical BDS (n=3) Preclinical BDS lots (n=3) 6 Preclinical FDP (n=3) 6 Preclinical FDP (n=3) Clinical BDS (n=6) Clinical BDS (n=6)
4 (U/mL)FIXa
FIXa (U/mL) FIXa 4 Clinical FDP (n=1) Clinical FDP (n=1) Pre-clinical and toxicological studies established that BAX 2 Commercial rFIX (n=3) 2 Commercial rFIX (n=3) Commercial pdFIX (n=1) Commercial pdFIX (n=1) 0 0 326 demonstrates comparability with licensed rFIX product 0 102030405060 0 102030405060 Time (min) Time (min) A pivotal global phase 1/3 clinical trial proceeds to evaluate the pharmacokinetics, efficacy, safety and immunogenicity of Peak thrombin generation Mean groups All preclinical and clinical BAX 326 lots BAX 326 350 300 were similar to each other with respect to Biologicals License Application (BLA ) under review by 250 their peak thrombin generation 200 regulatory authorities 150 Preclinical BDS (n=3) The curves obtained for three commercially Preclinical FDP (n=3) 100 Clinical BDS (n=6) Clinical FDP (n=1) available rFIX lots showed some variance 50 Commercial rFIX (n=3) Commercial pdFIX Peak thrombin(nM) 0 The peak thrombin values of the lots of 0 0.2 0.4 0.6 0.8 1 BAX 326 were somewhat below those of FIX in FIX-def. plasma (IU/mL) Key Product Characteristics the commercial rFIX Kinetics of FXIa- and FVIIa-mediated activation of rFIX was similar for all of BAX 326 Full functionality in hemostasis could be shown for BAX 326 rFIX lots for FIX activation of BAX 326 was also similar to that of a commercial rFIX and a commercial pdFIX . affinity of FIX to phospholipids - assembly of the tenase complex on a negatively charged surface . the rate of FXIa and FVIIa-mediated FIX activation - initiation Influence of FIXa content on TG capacity and amplification of the coagulation cascade TGA is sensitive to minimal amounts of FIXa. Even traces of FIXa in the FIX product . TGA - assessment of the overall hemostatic ppyotency might induce thrombin peaks. This response could could overlap with that of the test sample . Very low levels of pre-activated FIX found in BAX 326 Peak thrombin generated by rFIX spiked with a low concentration of FIXa Similar glycosylation pattern of BAX 326 and comparator A clinical BAX 326 lot was spiked with a product 350 rFIX spiked with FIXa concentration of FIXa that was equivalent to 300 Activation kinetics and affinity to phospholipid of BAX 326 250 0.02% of its FIX activity 200 This concentration led to increased peak were similar to those of commercial rFIX 150 100 Clinical FDP thrombin values compared to the non-spiked Clinical FDP spiked with 0.02% FIXa Thrombin generating capacity similar to that of comparator FIX 50 Commercial rFIX 2000 IU sample Peak thrombin(nM) products 0 0 0.2 0.4 0.6 0.8 1 The peak thrombin values for the spiked FIX in FIX-deficient plasma (IU/mL) sample were similar to those of commercial rFIX Determination of FIXa content in BAX 326 Pre-activation of FIX may occur during the purification process BAX 326: Status of Clinical Development The amount of pre-activated FIX in FIX end-product needs to be tightly controlled Immunine (pd FIX concentrate, Baxter) pre-treatment study: Detection of FIXa in FIX products with a FIXa chromogenic assay . Completed, final study report in preparation (ClinicalTrials.gov dentifier: NCT01128881) rFIX Activity FIXa Activity FIX pre-activation Batch No. (clotting assay) (chromogenic assay) (%) Pivotal Phase 1/3 Study: PK, safety and efficacy evaluation in (IU/mL) (IU/mL) PTPs>12a: (ClinicalTrials. gov Identifier: NCT01174446) Mean of BDS lots (preclinical production, n=8) 1619 0.88 0.06 . Study completed Mean of BDS lots (clinical production, n=10) 1885 0.97 0.05 Mean of preclinical FDP batches (n=4) 602 0.29 0.05 . Data presented @ ASH 2012, abstracts accepted for HTRS 2013 Mean of clinical FDP batches (n=3) 66 0.04 0.06 and ISTH 2013 Licensed rFIX product - 3 different potencies 51/96/367 0.09/0.11/0.59 0.18/0.11/0.16 Continuation Study: safety, immunogenicity and hemostatic The level of pre-activated FIX as shown as % of FIX activity was consistent in all BAX efficacy: (ClinicalTrials.gov Identifier: NCT01286779) 326 lots tested . Ongoing until BAX326 is licensed in subject’s countries Very low levels of FIXa are not likely to induce adverse events in clinical settings . > 70 subjects as of 10 April 2013 Detection of FIXa in FIX products with a sensitive FXa generation assay Surgery Study: efficacy and safety in surgical settings (major
2.0 Preclinical BDS (n=3) and minor surgeries): (ClinicalTrials.gov Identifier: NCT01507896) Preclinical FDP (n=3) Clinical BDS (n=6) Purified FVIII, FX, and PL were incubated with 1.5 Clinical FDP (n=1) . Interim report including 10 major surgeries completed, runs Commercial rFIX (n=3) Commercial pdFIX the FIX products and activation of FX was 1.0 monitored using a chromogenic FXa substrate. parallel to Continuation study, abstract accepted for ISTH 2013 FXa FXa (nM) 0.5 In this set-up, the FXa generation is solely Pediatric Study: PK, safety and efficacy evaluation in 0.0 dependent on the FIXa content present in the PTPs<12a: 0 1020304050FIX sample Time (min) . Ongoing (ClinicalTrials.gov Identifier: NCT01488994)
FIXa levels were measurable in the licensed rFIX product, and to a lesser extent in a Presented at the commercially available pdFIX, but FIXa was undetectable in BAX 326 lots EUROPEAN SYMPOSIUM, Optimal use of clotting factors and immunoglobulins 26-27 April 2013, Wildbad Kreuth, Germany BAX 817, a recombinant human factor VIIa drug candidate Baxter BioScience, Vienna, Austria
The dual role of FVIIa in the coagulation cascade Introduction II Human coagulation factor VII (FVII) is a vitamin-K-dependent protein with a molecular weight of 50 kDa. X TFPI IIa Activation of FVII occurs by a single cleavage resulting in two disulfide-linked peptide chains. The therapeutic TF VIIa Xa Va low concentration utility of rFVIIa is based on its capacity to trigger hemostasis independently from factor VIII and factor IX even of rFVIIa VII rVIIa TF-bearing Cell in the presence of inhibitors against these proteins. Baxter has developed BAX 817 a recombinant FVIIa TF dependent TF VIIa stable clot (rFVIIa) that is synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line. No materials of formation IX X human or animal origin are employed in the manufacture, purification, or formulation of the final product, thus II
reducing the risk of transmission of adventitious agents. The growth medium is a chemically defined medium, TF independent IXa VIIIa rVIIa Xa Va IIa and the downstream process does not use monoclonal antibodies for the purification of rFVIIa. Activated Platelet
Baxter’s Development Program for BAX 817 Cell-based tissue factor/FVIIa activity assay Scope: 40 Development of a recombinant FVIIa produced by a high yield CHO 40 40
expression system with an animal-component free manufacturing process 30 30 30
20 20 20 tor Xa [nM] Xa tor tor Xa [nM] Xa tor tor Xa [nM] Xa tor c c Target indication: 10 10 c 10 Fa Fa Treatment of bleeding in Fa 0 0 0 Hemophilia A and B patients 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 with inhibitors FVIIa [ng/mL] FVIIa [ng/mL] FVIIa [ng/mL]
All lots tested bound to membrane-located tissue factor comparatively well The FXa generation capacity on the TF-bearing cell surface of all preclinical and clinical Molecular structure of rFVIIa 3D model lots was in the same range as measured for the comparator lots
Key Product Characteristics Binding of BAX 817 Biochemical features were similar in all test systems between to platelet membrane and phospholipids BAX 817 and the comparator product Binding of FVIIa to dual activated platelets . Overall hemostatic potency of rFVIIa A) Black: background control - activated platelets A B without rFVIIa Thrombelastography Blue: Baxter clinical lot bound to non-activated platelets Thrombin generation assay Red: Baxter clinical lot bound to activated . TF-binding capacity of rFVIIa platelets nts [%nts of Max] u B) MtDMagenta: Des-GlarFVIIacontlbtrol boun dtd to
TF-beari ng cell li ne Co activated platelets Dual activated platelets Light blue: Baxter clinical lot bound to activated platelets . Susceptibility of rFVIIa to inhibition by TFPI DyLight488 anti-FVIIa Red: Comparator lot bound to activated (data not shown) platelets Binding of rFVIIa to phospholipid vesicles Binding to dual activated platelets . Reproducibility shown within preclinical and clinical lots were found similar in the clinical K Sample D (mean ± SD; nM) BAX 817 and the comparator lot Mean KD values of preclinical and Thrombelastography and thrombin generation assay Preclinical lots (n=4) 38 ± 3.5 clinical lots of BAX 817 ranged from Clinical lot (n=1) 44 38 to 44 nM as parameter for overall hemostatic potency K values similar to that of Comparator lots (n=4) 29 ± 2.8 D R = Time to initial fibrin Preclinical Lot 1 Preclinical Lot 2 comparator product were found 60 60 20 formation Preclinical lots 15 Clinical lots 40 40 Comparator lots 10 20 20
minutes 5 Thrombin (nM) Thrombin Thrombin (nM) Thrombin BAX 817: Status of Clinical Development 0 0 0 0 4 8 12 16 20 24 0408012004080120 Phase 1 Study: (WHO: CTRI Main ID: CTRI/2011/06/001798) Time (min) rFVIIa ( µg/mL) Time (min) . Cross-over with commercial rFVIIa at 90 µg/kg per dose K = Speed to reach a Clinical Lot 1 60 Clinical Lot 2 25 specific 60 . Dose levels: 45, 90, 180 and 270 µg/kg per dose
level of clot strength ) 20 ) M M Results: A single infusion of rFVIIa was well tolerated at all dose Preclinical lots 40 40 15 Clinical lots Comparator lots levels. PK/PD data demonstrated that BAX 817 has a similar 10 20 20 minutes 5 profile to commercial rFVIIa Thrombin (n Thrombin Thrombin (n Thrombin 0 0 0 Completed (43 subjects) 0 4 8 12 16 20 24 0 40 80 120 04080120 rFVIIa ( µg/mL ) Time (min) Time (min) Phase 3 Pivotal Study: (ClinicalTrials.gov Identifier: NCT01757405) Angle = Clot strengthening, Comparator Lot 1 Comparator Lot 2 60 . Evaluate the safety and efficacy of BAX 817 in the treatment of 50 rapidity of fibrin buildup 60 40 bleeding episodes by an on-demand regimen in hemophilia A or B 40 40 30 Preclinical lots patients with FVIII or FIX inhibitors. 20 Clinical lots degrees 20 Comparator lots 20 10 . Parallel 2 Arm: 3x90 or 1x270 µg/kg treatment regimen per bleed with Thrombin (nM) Thrombin Thrombin (nM) Thrombin 0 0 0 a 6 month treatment period per subject (home treatment) 0 4 8 12162024 0 40 80 120 0 40 80 120 rFVIIa ( µg/mL ) Time (min) Time (min) . Outcomes measured per bleeding episode through 24 hours: # doses
2 lots from preclinical, clinical and comparator lots are shown as representative results. FVIII inhibitor plasma needed, pain, mobility, subject efficacy assessments (4 point scale) was spiked with increasing concentration rFVIIa (from bottom to top: 0, 0.625, 1.25, 2.5, 5, 10 µg/mL) . Other outcomes: No significant differences between the preclinical and clinical lots in the three TEG Quality of Life, antibodies to FVII (binding and/or inhibitory) parameters R, K, and angle were observed Study started Q2/2013 (34-40 subjects planned) The preclinical and clinical lots were not significantly different to the comparator lots No statistically significant difference in dose-response of rFVIIa-mediated thrombin Presented at the generation in the FVIII inhibitor plasma between the preclinical, clinical and EUROPEAN SYMPOSIUM, Optimal use of clotting factors and immunoglobulins comparator lots 26-27 April 2013, Wildbad Kreuth, Germany BAX 855, a PEGylated rFVIII product with prolonged half-life Baxter BioScience, Vienna, Austria
Introduction Key Product Characteristics Baxter Innovations GmbH (Vienna, Austria) and Nektar Therapeutics (Huntsville AL) have developed BAX 855, a PEGylated form of Baxter’s BAX 855 is a PEGylated derivative of ADVATE™ recombinant FVIII (rFVIII) with prolonged half-life. BAX 855 can be manufactured in industrial scale, with a good Recombinant FVIII is expressed in Chinese hamster ovary cells by a batch to batch consistency plasma-/albumin-free cell culture method and is the active substance in BAX 855 retained the specific activity of FVIII, indicating that Baxter´s licensed product ADVATETM. PEGylation does not have an impact on the hemostatic Theconjtijugation process for preparing BAX 855 uses propritietary stbltable function of rFVIII PEGylation developed by Nektar Therapeutics. Similar technology has been successfully used for licensed and marketed PEGylated drug products including proteins and peptides in clinical use. After PEGylation the product is purified by use of a procedure that is based on the manufacturing process for ADVATE™. Large scale manufacturing of BAX 855 (BDS data) Spec. Act. Spec. Act. PEG degree (% of unmodified PEGylation chemistry Batch (IU/mg) (mol/mol) rFVIII sttitarting BAX 855 is a PEGylated material) Mean recombinant full-length human 6039 91 2.2 (n = 5) rFVIII for the treatment of hemophilia A SD 831 11 0.2 BAX 855 is derived from the Specific activties (ratio FVIII act./total protein) were determined by a FVIII chromogenic assay and a protein fluorescence assay in comparison with rebuffered rFVIII starting material parent, licensed rFVIII product, ADVATE™ Data show that BAX 855 can be prepared in industrial scale PEGylation is specific and highly reproducible ADVATE™ protein is PEGylated with a 20-kDa branched PEG polymer BAX 855 has a specific activity similar to that of rFVIII in ADVATE™ Amine coupling chemistry is used for PEGylation of rFVIII in BAX 855 PEGylation degrees are in the narrow range of 2 to 3 mols . Standard reaction in protein chemistry PEG / mol rFVIII . Results in specific modification Characterization of BAX 855 Manufacturing process of BAX 855 Functional characterization TM The BAX 855 manufacturing process ADVATE BAX 855 fully retained its hemostatic potency compared with ADVATE™ consists of an ion exchange chromatography Pharmacology & Toxicology step for changing the product matrix and Macaques: generally well tolerated; no adverse test-item related findings increasing the protein con-centration of full- Buffer exchange Rabbits: thrombogenicity as low as ADVATE length rFVIII. Escalating dose toxicity in macaques: no observed adverse effect level The rebuffered rFVIII is used for the (NOAEL) 1500 IU/kg (single dose) Coupling of PEG reagents chemical reaction with the PEG reagent. to rFVIII Repeated dose toxicity in rats and macaques: NOAEL 700 IU/kg The protein conjugate is purified by another • Large safety margin ion exchange chromatography, followed by Immunoggyenicity Purifi cati on b y i on exch ange an ultra/ diafilt ra tion step. chromatography (IEX) Comparative immunogenicity studies in mice and macaques revealed a The BAX 855 final drug product is formulated similar immunogenicity profile compared to ADVATE by lyophilization of the BDS supplemented Pharmacokinetics & Pharmacodynamics with formulation components without any Final UF/DF Pharmacokinetics additives of animal origin. • > 1.5x prolonged MRT (Mean Residence Time) in hemophilic mice The lyophilized product contains only rFVIII and macaques compared to ADVATE protein coupled to PEG for reconstitution Primary pharmacodynamics (efficacy) Formulation and lyophilization with sterile Water for Injection prior to • Clinically relevant prolonged (1.5x) efficacy shown in intravenous infusion . 2 hemophilia A mouse models in comparison to ADVATE
BAX 855 Clinical Study Cohort 1 Cohort 2
DMC DMC Phase 1 Study Design: (ClinicalTrials.gov Identifier: NCT01599819) n=8 DSMB n=10 DSMB Analysis/CSR
BAX 855 (PEGylated Recombinant Factor VIII): A phase 1, prospective, open Dose Dose label, cross-over, dose-escalation study in previously treated patients with 30 IU±3 ADVATE/kg 60IU±6 ADVATE/kg Followed by 30IU±3 BAX 855/kg Followed by 60IU±6 BAX 855/kg severe (FVIII < 1%) hemophilia A DSMB … Data Safety Monitoring Board
. Assess tolerability and safety post single dose treatments of BAX 855 in PTPs with severe hemophilia A . Determine the pharmacokinetic (PK) parameters of BAX 855 compared in crossover with ADVATE at the same single dose level . Evaluate the impact of anti-PEG antibodies on PK parameters . Estimate the dose necessary to maintain a factor VIII (FVIII) level of ≥ 1% for at least 5 days Presented at the EUROPEAN SYMPOSIUM, Optimal use of Phase 1 completed clotting factors and immunoglobulins 26-27 April 2013, Wildbad Kreuth, Germany Clinical Development Program for BAY 94-9027, a Long-Acting PEGylated B-Domain−Deleted Recombinant Factor VIII for Patients With Hemophilia A Susan Radke,1 René Walsch,2 Benedikt Kerschgens,2 Mel Lederman,3 Dawn Deisem,3 Bitak Bassiri,3 Anita Shah,3 Lisa A. Michaels3 1Bayer Pharma AG, Berlin, Germany; 2Bayer Pharma AG, Leverkusen, Germany; 3Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
INTRODUCTION Figure 2. Phase 1 Study Design Table 1. Main Study Objectives and Key Inclusion and Exclusion Criteria CONCLUSIONS • Factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage in Phase 1 Phase 2/3 Adult and children and adolescents with hemophilia A.1,2 Adult Study Adolescent Study Phase 3 48-h PK 168-h PK 168-h PK (NCT01184820) (NCT01580293) Pediatric Study • Phase 1 data showed that BAY 94-9027 was well rFVIII-FS First dose BAY 94-9027 Last dose BAY 94-9027 –– Prophylaxis is the standard of care for children and adolescents with severe Study objectives To assess PK, safety, To assess efficacy of BAY To evaluate PK, safety, hemophilia.3 and immunogenicity 94-9027 in prophylaxis and efficacy of BAY tolerated and had an extended elimination t½ in Single dose Multiple-dose treatment with Cohort 1: of single and multiple and treatment of bleeding 94-9027 for prophylaxis Screening Wash Wash 25 IU/kg BAY 94-9027 after rst PK over 168 h 25 IU/kg BAY 94-9027 doses of BAY 94-9027 with different infusion and treatment of (n=7) out out • Adoption of and adherence with prophylaxis is suboptimal because of challenges rFVIII-FS 16 doses – 25 IU/kg 2x/wk 25 IU/kg rFVIII-FS administered over schedules and safety and bleeding in previously patients with severe hemophilia A. 8 weeks efficacy of BAY 94-9027 treated patients with such as venous access issues in children, the time-consuming nature of prophylaxis, ≥3 days ≥3 days 8 weeks during surgery hemophilia A and a requirement for frequent infusions.4,5 Inclusion criteria • Males with severe • Males with severe • Males with severe • A phase 2/3 study of BAY 94-9027 in adults –– A longer-acting FVIII product may help overcome barriers associated with hemophilia A hemophilia A hemophilia A • Aged 18−65 years • Aged 12−65 years • Aged <12 years and adolescents is ongoing, and phase 3 prophylaxis. 48-h PK 168-h PK 168-h PK • ≥150 EDs with FVIII • ≥150 EDs with FVIII • >50 EDs with FVIII rFVIII-FS First dose BAY 94-9027 Last dose BAY 94-9027 • BAY 94-9027, a B-domain−deleted recombinant FVIII (rFVIII) that has undergone site- • Immunocompetent • Immunocompetent studies in previously treated and previously directed modification with a 60-kD polyethylene glycol (PEG) molecule (Figure 1), was Exclusion criteria • History of or current • History of or current • History of or current Cohort 2: Single dose Multiple-dose treatment with FVIII inhibitor FVIII inhibitor FVIII inhibitor Screening Wash Wash 60 IU/kg BAY 94-9027 50 IU/kg BAY 94-9027 after rst PK over 168 h untreated children with severe hemophilia A designed as a long-acting FVIII product for prophylaxis and on-demand treatment of (n=7) out out • Active hepatic disease • Bleeding disorder other • Bleeding disorder other 50 IU/kg rFVIII-FS rFVIII-FS 9 doses – 60 IU/kg 1x/wk • Abnormal renal or than hemophilia A than hemophilia A bleeds in patients with hemophilia A. ≥3 days ≥3 days 8 weeks hepatic function • Platelet count • Platelet count are forthcoming. 3 3 –– BAY 94-9027 demonstrated a prolonged half-life (t ), comparable coagulation • Bleeding disorder other <100,000/mm <100,000/mm ½ than hemophilia A activity, prolonged efficacy, and reduced immunogenicity vs unPEGylated rFVIII in PK=pharmacokinetics; rFVIII-FS=sucrose-formulated recombinant factor VIII. • Platelet count 3 • The BAY 94-9027 clinical development preclinical studies.6,7 <100,000/mm ED=exposure day; FVIII=factor VIII; PK=pharmacokinetics. • The objective of this work is to describe the BAY 94-9027 clinical development Phase 2/3 Study program will determine whether the longer t½ of program, which comprises the following studies in patients with severe hemophilia A: • This is a multicenter, partially randomized, open-label, parallel-group study being Outcomes BAY 94-9027 will allow for less frequent dosing. –– A completed phase 1 trial in adults conducted in North and South America, Europe, the Middle East, and Asia. • Key efficacy and safety outcome measures are shown in Table 2. • This study has 2 parts: –– An ongoing phase 2/3 trial in adults and adolescents that includes pharmacokinetic Table 2. Key Efficacy and Safety Outcome Measures assessments and surgeries –– Part A: on-demand and prophylactic treatment with BAY 94-9027 in 3 different dosing intervals for at least 36 weeks (Figure 3) Phase 1 Phase 2/3 Adult and –– Forthcoming phase 3 trials in previously treated and previously untreated children Adult Study Adolescent Study Phase 3 –– Part B: optional open-label, noncontrolled, single-arm study of safety and efficacy (NCT01184820) (NCT01580293) Pediatric Study REFERENCES of BAY 94-9027 in major surgery Primary clinical • PK/PD variables Part A • BAY 94-9027 efficacy 1. Aledort LM, et al. J Intern Med. 1994;236(4):391-399. Figure 1. BAY 94-9027 Structure pharmacology/efficacy (eg, FVIII recovery, • BAY 94-9027 efficacy (annualized bleeding outcomes BAY 94-9027 and (annualized bleeding events) ▪▪ Patients requiring major surgery who enrolled in part A and other patients rFVIII-FS plasma events) • PK parameters (eg, 2. Manco-Johnson MJ, et al. N Engl J Med. 2007;357(6):535-544. concentration, • PK parameters (eg, incremental recovery, meeting inclusion/exclusion criteria for part A will be included. C , AUC, AUC/D, t ) 3. Srivastava A, et al. Haemophilia. 2013;19(1):e1-e47. max ½ incremental recovery, Cmax, AUC, t½) C , AUC, t ) max ½ • Patient/caregiver 4. Blanchette VS. Haemophilia. 2010;16(suppl 5):181-188. • Patient assessment of assessment of response Figure 3. Phase 2/3 Study Design: Part A response to treatment to treatment 5. Hacker MR, et al. Haemophilia. 2001;7(4):392-396. Part B Site-speci c • Outcome of surgeries 6. Mei B, et al. Blood. 2010;116(2):270-279. Safety outcomes • Adverse events Part A • Adverse events 7. Ivens IA, et al. Blood. 2010;116(21):abstract 2214. PEGylation to • Adverse events Screen On-demand therapy (n=20) • Immunogenicity to FVIII, • Immunogenicity to FVIII, extend FVIII PEG, and BAY 94-9027 • Immunogenicity to FVIII, PEG, and BAY 94-9027 PEG, and BAY 94-9027 half-life Clinical assessment of bleeding control Part B • Quantification of blood 2 infusions per week loss in major surgery
AUC=area under the curve; AUC/D=dose-normalized area under the curve; Cmax=maximum concentration; FVIII=factor VIII; 2 infusions PD=pharmacodynamics; PEG=polyethylene glycol; PK=pharmacokinetics; rFVIII-FS=sucrose-formulated recombinant factor VIII; Disclosures Screen 1 infusion every 5 days t =half-life; t =time to reach C . per week (n=120) ½ max max SG, RW, and BK are employees of Bayer Pharma AG. ML, DD, BB, AS, and LM are employees of Bayer HealthCare Pharmaceuticals. 1 infusion every 7 days FVIII Monitoring • By chromogenic assay or one-stage coagulation assay using ellagic acid as activator. –4 0 4 10 14 20 26 32 36 weeks*
Acknowledgments *All patients who complete part A will be offered participation in an extension study to obtain observations for at least 100 total exposure days. Study funding provided by Bayer Pharma AG (Leverkusen, Germany). We would RESULTS like to thank Jane A. Phillips, PhD, from Complete Healthcare Communications, Inc., • All patients who complete part A will be offered participation in an extension study to Phase 1 Study for medical writing assistance, which was fully funded by Bayer HealthCare B-domain obtain observations for at least 100 total exposure days (EDs). Pharmaceuticals. deletion • This study is expected to enroll up to 140 patients. Patients • 14 patients were enrolled and completed the protocol (n=7 per cohort). Phase 3 Pediatric Study • The mean age was 36 years (range, 21−58 years). • This multicenter, open-label, noncontrolled study will be conducted worldwide. • Patients will be treated with BAY 94-9027 for prophylaxis and treatment of bleeds Clinical Pharmacology
for ≥50 EDs and ≥6 months; prophylaxis will be administered in 3 different dosing • BAY 94-9027 had an elimination t½ of approximately 19 hours after single and multiple
FVIII=factor VIII; PEG=polyethylene glycol. intervals (2 infusions per week, 1 infusion every 5 days, or 1 infusion every 7 days) dosing; rFVIII-FS t½ was approximately 13 hours. as selected by the investigator. • Pharmacokinetic parameters with BAY 94-9027 were similar after single and • All patients will be offered participation in an open-label extension study to obtain multiple doses. observations for at least 100 total EDs. –– Dose-proportional increases were observed in plasma concentrations • This study is expected to enroll approximately 50 patients in 2 subgroups of 25 of BAY 94-9027 at doses of 25 and 60 IU/kg. METHODS patients each (ages 6−12 years and <6 years). Safety • Previously untreated patients will be evaluated in a separate open-label, Study Design • Treatment with BAY 94-9027 was well tolerated. noncontrolled study. Phase 1 Study • No FVIII inhibitors, anti-PEG antibodies, or anti−BAY 94-9027 antibodies were • This was a multicenter, nonrandomized, open-label, parallel-group study in which Patients observed at the end of the 8-week dosing. BAY 94-9027 was administered to 2 cohorts of patients over 8 weeks in the • Main study objectives as well as key inclusion/exclusion criteria are summarized • There were no treatment-emergent adverse events (AEs) related to the study drug, United States (Figure 2). in Table 1. and there were no serious AEs related to BAY 94-9027.
Clinical Experience with a New Orphan Drug FACTOR X Product P. Fe ld man 1, J. Lloyd1, M. Norton1, S. MacDonald2, T. Aldwinckle1 and the FACTOR X inves gator group3 1 Bio Products Laboratory Ltd., Elstree, UK; 2 Department of Haematology, Addenbrooke’s Hospital, Hills Road, Cambridge, UK Introduc on Pharmacokine cs of FACTOR X in Factor X Deficiency Safety of FACTOR X in Factor X Deficiency FACTOR X is a high purity factor X concentrate developed for the treatment of hereditary factor Methods Adverse events: 6 adverse events were considered possibly related to FACTOR X: X deficiency. FACTOR X for the treatment of this very rare disease has received Orphan Drug Designa on in EU and USA. 25 IU/kg FACTOR X was administered to subjects at baseline and a repeat PK assessment. Infusion site erythema (2 cases), fa gue (2 cases), infusion site pain, back pain. Plasma samples were assayed for FX:C using the one‐stage clo ng assay at a central laboratory. None were severe or serious.
Clinical Study Design Results Inhibitors: >60 post‐dose inhibitor tests in 15 subjects have been nega ve for the FX
January 2008: parallel scien fic advice was requested from EMA and FDA to inform the Figure 3 Mean pre‐dose‐adjusted plasma concentra ons of FX:C at baseline and repeat PK assessment inhibitor screen and FX Nijmegen‐Bethesda inhibitor assay 1 FACTOR X clinical development programme. The resul ng advice from the two agencies was 0.6 Serology: No seroconversions for HAV, HBsAg, HCV, HIV or Parvovirus B19 in seven construc ve, but differed with regard to pa ent numbers and follow‐up required to secure 0.5 subjects tested at end of study marke ng authoriza on. Baseline (n = 13)
Repeat (n = 8) 0.4 Thrombogenicity: Significant inter‐pa ent variability for TAT, D‐dimer and F1+2, which are known As the clinical development for orphan drug products cannot sustain individual trials for 0.3 0.1 to be sensi ve to blood draw and sample handling technique. There was no licensing in different territories, a consolidated protocol was developed. This provided for interim and final analyses of data to sa sfy the requirements of different regulatory agencies. consistent pa ern to the results, and no clinical signs or symptoms of a 0.2
FX:C (IU/mL) FX:C (IU/mL) thrombogenic response to FACTOR X was observed.
Two clinical trials were planned to collect the data required by the two agencies: 0.1
0.01 A pharmacokine c, safety & efficacy study in 16 pa ents with severe or moderate FX 0 Considera ons from our experience 0 24487296120144 0 24 48 72 96 120 144 deficiency (basal FX:C <5 IU/dL). Time post‐dose (hours) Time post‐dose (hours) Several challenges can delay access to orphan drug products by pa ents with rare diseases: Pa ents received FACTOR X on‐demand to treat bleeding episodes for a minimum of 6 months (rou ne prophylaxis not permi ed) Clinical Trial Protocol Development Any pa ents undergoing surgery could receive FACTOR X as per the surgery study Table 1 Pharmacokine c Parameters of FACTOR X Parallel scien fic advice by EMA and FDA may differ, requiring lengthy itera ons of a consolidated
protocol to address all expecta ons. Pharmacokine c (PK) profiles at baseline and repeated a er 6 months Historical data: Any remaining requirement for an extended data set from a small pa ent group may s ll delay drug FACTOR X at the Baseline Visit PCC in healthy A surgery study in a minimum of 10 procedures in 5 pa ents with severe to mild FX deficiency volunteers¶ availability in one territory compared to another.
(basal FX:C <20 IU/dL). geometric mean CV (%) median median Inves gator Par cipa on Pa ents received FACTOR X as prophylaxis against excessive bleeding n 13 13 15 The sparse pa ent popula on needs inves gators at diverse sites, many enrolling only one pa ent. Assessment of blood loss compared to a subject without a bleeding disorder Incremental recovery The logis cal and bureaucra c burden for such a small study could discourage inves gators, given its 2.22 22.1 2.32 2.08 (IU/dL per IU/kg) dura on and follow‐up requirements. Results to date from the pharmacokine c, safety & efficacy study and surgery study are Half‐life§ presented here. Collec on of further data is ongoing. 30.9 24.8 30.0 30.7 Pa ent Recruitment (h) Market research did not fully‐reflect pa ents’ treatment regimens, so many poten al subjects were § Within the first hour post‐dose not eligible, or were unwilling to interrupt their exis ng treatment pa erns. Efficacy of FACTOR X in Trea ng Bleeds ¶ Ostermann et al. (2007) Pharmacokine cs of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb. Haemost. 98; 790‐797 Some pa ents withheld consent, due to the clinical and domes c impact of the study.
Methods Efficacy Data Acquisi on Recommended dose for replacement therapy was 25 IU/kg FACTOR X, to be repeated as Surgery with FACTOR X in Factor X Deficiency Efficacy data are dependent on unpredictable, sporadic events (treatment of bleeding episodes and necessary to achieve haemostasis. Efficacy was defined according to the number and ming of Methods surgical interven ons with product) which significantly extends the study dura on. Surgery data requires the prospec ve set‐up of inves ga on sites, an cipa ng where pa ents may doses, depending on whether it was an overt, covert or menorrhagic bleed. Infusions of FACTOR X were given to raise FX:C to 70‐90 IU/dL prior to surgery and maintain FX:C need eligible procedures (different bleeding pa erns in factor X deficiency reduces reliance on Results at >50 IU/dL un l the subject was no longer at risk of bleeding. elec ve orthopedic surgeries which are common to surgery studies in Haemophilia A or B). Eligible procedures can be lost if contracts are incomplete, while maintaining other costly sites where To date >180 bleeds in 15 subjects have been treated with FACTOR X. Of 96 bleeds included in Results no pa ent presents for surgery. the interim analysis, the majority required a single infusion of FACTOR X (Figure 1). 6 surgical procedures have taken place: 3 major and 3 minor. In an interim analysis on the first 50 assessable bleeds to be analysed, FACTOR X was rated as 5 sites have been open specifically for the surgery study over a total of 70 months (mean 14 Conclusions ‘excellent’ or ‘good’ in trea ng 96% of bleeds (Figure 2). months per site, or 17.5 site.months required per surgical procedure). FACTOR X was efficacious in treatment of 50 bleeding episodes Analysis of the remaining bleeds is on‐going and will be reported in the final analysis. Major or Inves gator’s assessment of FACTOR X was efficacious in the control of blood loss during and a er major and minor Date of surgery Descrip on of surgery Study minor FACTOR X efficacy surgical procedures Figure 1 Number of infusions of FACTOR X Figure 2 Assessment of efficacy of FACTOR X pharmacokine cs matched published data given to treat a bleed FACTOR X in trea ng a bleed December 2011 Tooth extrac on Minor Excellent PK, S&E* FACTOR X was well‐tolerated in 15 pa ents June 2012 2 x tooth extrac on Minor Excellent PK, S&E* Development and licensing of products such as FACTOR X for the treatment of very rare diseases requires the ac ve co‐opera on of sponsor, regulators, inves gators and pa ents July 2012 Knee replacement Major Excellent Surgery [3] The FACTOR X Inves gator Group: October 2012 Coronary artery bypass gra Major Excellent Surgery M.T. Alvarez, Servicio De Hematologia, Hospital Universitario La Paz, Madrid, Spain; G. Auerswald, Klinikum Bremen‐Mi e, Prof‐Hess‐Kinderklinik, Bremen, Germany; S. Aus n, St George's Haemophilia Centre, St George's Hospital, London, UK; January 2013 Knee replacement Major Excellent Surgery N. Bermejo, Servicio de Hemotologia, Unidad de Coagulacion, Hospital San Pedro de Alcantara, Caceres, Spain; M. Escobar, Gulf States Hemophilia and Thrombophilia Center, University of Texas Health Science Center, Houston, Texas, USA; March 2013 Mul ple tooth extrac on Minor Data collec on pending Surgery K. Kavakli, Department of Pediatric Hematology, School of Medicine, Ege University, Izmir, Turkey; C. Millar, Imperial College Healthcare NHS Trust, Hammersmith Hospital Haemophilia Centre, London, UK
W. Mitchell, New York Presbyterian Hospital, Weill Cornell Center, New York, NY, USA; * Pharmacokine c, safety & efficacy study A. Oner, Yuzuncu Yil University, Faculty of Medicine, Division of Pediatric Hematology, Van, Turkey; S. Pavord, Leicester Haemophilia Comprehensive Care Centre, Leicester Royal Infirmary, Leicester, UK. Presented at Kreuth III, April 2013 Clinical studies with Nanogam (50 mg/ml intravenous immunoglobulin product)
Karin Velthove PharmD PhD1, Ilona Kleine Budde PhD1, Rachel van Beem PhD1, Paul Strengers MD1
www.sanquin.nl 1 Sanquin Blood Supply Foundation, Division Plasma Products, Medical Department, Amsterdam, The Netherlands [email protected]
Sanquin Blood Supply Foundation, Amsterdam, The Netherlands collects blood and plasma, and provides blood components, cellular products, plasma derived medicinal products, and reagents. It promotes all aspects of transfusion medicine. Sanquin also performs basic and translational research in immunology, hematology, inflammation, virology and coagulation, offers specialised diagnostic services, and provides education and training.
IgG Subclass study - ongoing Parvo B19 study - ongoing SID-GBS study - ongoing Treatment in patients with recurrent infections and IgG subclass deficiency, IVIG in idiopathic cardiomyopathy and endomyocardial Parvovirus B19 Second IVIG Dose in Guillain Barré Syndrome patients with poor prognosis and/or deficient anti-polysaccharide antibody response persistence Primary objective: Primary objective: Primary objective: To assess the effectiveness of Nanogam in comparison with the prophylactic To investigate whether IVIg therapy on top of conventional heart failure may To determine whether a second IVIg dosage in GBS patients with a poor use of oral antibiotics improve cardiac systolic function as assessed by quantitative prognosis improves functional outcome after 4 weeks. Population: adults and children ≥ 5 years with IgG subclass deficiency and/or echocardiography (LVEF, LVEDD, LVESD). Population: GBS patients 12 years with indication for IVIg treatment. anti-polysaccharide antibody deficiency and with recurrent respiratory Randomization patients with poor prognosis: second IVIg course (Nanogam) Population: patients with chronic “idiopathic” cardiomyopathy despite optimal infections; n > 40 patients or placebo (Albuman 4%). N=174 (N =88 with poor diagnosis) standard heart failure treatment and a significant PVB19 viral load in their Design: Randomized, open label cross-over study; treatment period 2x12 Design: Multicentre double-blind, randomized, placebo-controlled trial (6 hearts; n=50 months, in between 3 months wash-out. month follow-up) First Patient In: Oct 2007, Last Patient Out: Feb 2014 Design: Single-centre double-blind, randomized placebo-controlled clinical First patient in: Feb 2010, Last Patient Out: 2014 Inclusion closed: November 2012 trial (6 month follow-up) January 2013: 33 poor diagnosis and randomized Investigators: members of the Dutch Inter-university Working Party for First Patient In: Nov 2009, Last Patient Out: 2014 Investigators/sponsor: Department of Neurology, Erasmus MC, Rotterdam Immune Deficiencies January 2013: 26 patients included Investigators: neurologists of 74 Dutch hospitals Sponsor: Sanquin Investigators: Department of Cardiology, Academic Hospital Maastricht In cooperation with: Sanquin Sponsor: Sanquin
TIKI study - ongoing ALL-11 IVIG study - ongoing IVIG in transplant glomerulopathy study – in preparation Treatment with or without IVIG in Kids with acute ITP Treatment study protocol of the Dutch Childhood Oncology Group for children A randomized controlled trial on the efficacy of IVIG in transplant and adolescents (1-19 year) with newly diagnosed acute lymphoblastic glomerulopathy leukemia Primary objective: Primary objective: Does prophylactic administration of IVIG reduce the Primary objective: To measure the extent to which treatment with IVIG early in the disease number of infections during the intensive treatment? To assess the effectiveness of IVIG in transplant glomerulopathy (TGP) reduces the risk of development of chronic disease in children with newly Population: Children with secondary immune deficiency in newly diagnosed Population: 34 patients (adults) with histologically proven TGP in the diagnosed acute ITP (estimate reduction in developing chronic disease Acute Lymphoblastic Leukemia (ALL); inclusion 226 children with ALL; 140 pt absence of acute humoral rejection or other glomerular pathology from 25% to about 10%) with medium risk continue after week 14 for 2 years Investigators/sponsor: Department of Transplantation, Erasmus MC, Population: Children aged 3 months -16 years, with acute ITP presented Design: Multicentre randomized controlled trial, 50% prophylactic IVIG, 50% Rotterdam to a pediatrician in one of the Dutch study centers; n=200 (6 month on demand IVIG In cooperation with: Sanquin follow-up) First Patient In: November 2012; Last Patient Out: 2017 Design: Multi-centre randomized open-label controlled study March 2013: 11 patients First Patient In: Oct 2009, Last Patient Out: 2013 Investigators: 5 Departments of Pediatric Oncology/Hematology January 2013: 130 patients included Sponsor: DCOG (Dutch Childhood Oncology Group) (=SKION) Investigators/sponsor: Wilhelmina Children’s Hospital Utrecht In Cooperation with: Sanquin In cooperation with: Sanquin
The Medical Department is, in its applied research activities, responsible for the design and conduct of clinical trials with (recently developed) plasma products. The Medical Department closely cooperates with clinical investigators in the Netherlands e.g. the Netherlands Inter-University Working Party on the Study of Immune Deficiencies and the Dutch Haemophilia Treatment Centers, and with investigators abroad.
Successful immune tolerance induction in patients with hemophilia A and inhibitors treated with a plasma-derived FVIII product containing von Willebrand factor: a large international, multicenter, retrospective study
Johannes Oldenburg1, Elena Santagostino2, Víctor Jiménez Yuste3, Margaret Heisel Kurth4 and the Investigator Participants of the ITI Study 1 Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany; 2 IRCCS - Ospedale Maggiore Policlinico, Milan, Italy; 3 Hospital La Paz, Madrid, Spain; 4 Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA
Background Methods Immune tolerance induction (ITI) is the treatment of choice to resolve Data from HA patients (FVIII <2 IU/dL) with inhibitors, from 35 centers inhibitors against FVIII in hemopohilia A patients. ITI eradicates the in Spain, Italy, Germany and the USA, who completed primary or inhibitors and subsequently induces tolerance with recovery of FVIII to rescue ITI with Fanhdi®/Alphanate® (Grifols, Barcelona Spain/LA, CA, normal levels in these patients. Some small studies suggest that VWF- US), were collected retrospectively and evaluated. Outcome was containing plasma-derived FVIII products (VWF/pd-FVIII) are more assessed using the criteria for complete/partial success and failure successful for ITI than those lacking VWF [1]. based on the 2006 International ITI Workshop Consensus [2] (Table 1). Table 1. Criteria for ITI Outcome Assessment FVIII half-life (after a Objective Inhibitor level (within FVIII recovery (with 72-h treatment-free Clinical 33 months of ITI) respect to expected) To describe the ITI outcomes in moderate to severe HA patients with washout period) Complete Success <0.6 BU >66% >6 hours No anamnesis inhibitors who have been treated with a single factor VIII/VWF Response Partial Success <5 BU <66% <6 hours concentrate as part of either a primary or rescue ITI protocol. to FVIII therapy Failure to fulfill the criteria for success within 33 months Failure <20% reduction in the inhibitor titer for any 6-month period during ITI after the first 3 months of treatment Results 1. Patient characteristics Table 5. Outcome according to inhibitor peak Titer ITI regimen Success Partial Success Failure Total • Ninety-five patients were evaluated (Spain: 26, Italy: 19, Germany: Primary 19 (73%) 5 (19%) 2 (8%) 26 17 and USA: 33) who followed ITI protocols using Fanhdi® (62 <50 BU Rescue 6 (75%) 0 (0%) 2 (25%) 8 patients) or Alphanate® (33 patients). Lost to follow up: 2 patients. Primary 6 (50%) 5 (42%) 1 (8%) 12 50‐200 BU • Seventeen patients (17.9%) were not Caucasian (10 Hispanic/Latino, Rescue 5 (36%) 5 (36%) 4 (28%) 14 3 African-American, 1 Native American, 2 Asian and 1 Arabic). Primary 4 (40%) 3 (30%) 3 (30%) 10 ≥200 BU Rescue 3 (14%) 7 (32%) 12 (54%) 22 Table 2. Patient characteristics (median and range) The data was not available for 1 rescue patient. Primary ITI (n=48) Rescue ITI (n=45) Table 6. Outcome according to titer at start of ITI Age at start of ITI (years) 3.3 (0.1‐53.2) 5.4 (0.9‐24.9) Titer ITI regimen Success Partial Success Failure Total Inhibitor peak (BU) 38 (1‐6842) 185 (8‐4505) Primary 19 (73%) 5 (19%) 2 (8%) 26 ≤10 BU Titer at start of ITI (BU) 7.1 (0‐831) 18.2 (0‐848) Rescue 6 (43%) 3 (21%) 5 (36%) 14 Primary 10 (46%) 8 (36%) 4 (18%) 22 >10BU 2. Treatment Rescue 9 (29%) 9 (29%) 13 (42%) 31 • A wide variation in treatment dose was observed (3x47 IU/kg/week – 4. Time to success and partial success 2x300 IU/kg/day) but most patients were treated with a dose ≥100 IU/kg (Table 3). A dose-outcome relationship could not be • Median time to complete tolerization was 16 months (range: 3-56) established in either primary or rescue ITI. (Figure 1) and to partial tolerization was 23 months (range: 7-52). 100 100 Table 3. Dose at the start of ITI and frequency of treatment in patients Primary ITI Primary ITI Rescue ITI Rescue ITI Primary ITI Rescue ITI 80 80 Frequency / Dose <100 IU/kg ≥100 IU/kg <100 IU/kg ≥100 IU/kg 60 60 3/day 0 0 0 2
40 40
2/day 4 10 1 2 % of patients % ofpatients 1/day 4 21 3 28 20 20 3/week 8 1 5 2 Total patients 48 43* 0 0 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 * The data of two patients were not available. Time to success (months) Time to partial success (months) 3. Outcome Figure 1. Time to ITI success (complete and partial) • Most patients achieved success, complete or partial: 41/48 (85%) in Conclusions primary ITI and 27/45 (60%) in rescue ITI (Table 4). The high success rate reported in this large study, even in patients • Outcome according to inhibitor peak and titer at start of ITI is shown ® in Tables 5 and 6 respectively. with poor prognosis, supports the effectiveness of Fanhdi and Alphanate® in both primary and rescue ITI, and should encourage Table 4. ITI outcomes in primary and rescue ITI physicians and patients to consider VWF/pd-FVIII for these patients. Success Partial Success Failure Total Primary 29 (60%) 12 (25%) 7 (15%) 48 References Rescue 15 (33%) 12 (27%) 18 (40%) 45 [1] Kurth MAH et al. Haemophilia 2008; 14:50-55 [2] Dimichele DM et al. Haemophilia 2007; 13 (Suppl 1):1 Acknowledgements: The authors thank Dr. Roser Peiró, Grifols S.A., for her support in data assessment and poster preparation.
Conflict of Interest Statement - Grifols provided a grant to support data collection. Biotest From Nature for Life Open prospective trial investigating pharmaco kinetics, tolerability and safety of a new 10% human immunoglobulin for intravenous infusion (IVlg) in patients with primary immunodeficiency disease (PID)
G. Krivan (1), Ch. Königs (2), E. 8ernatowska (3), L. Marodi (4), M. Erdös (4), A. Salama (5), R. Linde (2)
1) Oept. of Pediatric Hematology and Stern Cell Transplantation, United S1. Istvan and S1. Laszl6 Hospital, Budapest; 2) Oepartment of Pediatrics, Hemostasis and Immunodeficiency, Johann-Wolfgang-Goethe University, Frankfurt/M.; 3) Oep1. of Immunology, Children's Memorial Health Institute, Warsaw; 4) Oep1. of Infectiology and Pediatric Immunology, Medical and Health Science Center University of Oebrecen; 5) Institute for Transfusion medicine, Charite Universitätsmedizin, 8erlin.
Background Pharmacokinetics of Intratect 100g/L Tolerability of Increased Infusion Rate
Intravenous immunoglobulins are a well-established therapy in patients IgG trough levels of most patients were weil maintained above 6g/L. Overall 15 (60%) patients proceeding to part B reached an infusion with primary or secondary immunodeficiencies and recurrent infec The key pharmacokinetic parameters for Intratect 1OOg/L and Intratect speed of at least 6 mLlkg/h at 4th infusion. tions. ST090 is a highly purified 10% human IVlg (10 9 human plasma 50 g/L were shown to be comparable (Table 2). 12 patients (48%) did not reach an infusion rate of 8 mLlkg/hr for rea protein per 100 mL of solution) with a IgG subclass distribution similar Median IgG levels increased from 8g/L (pre-dose) to 17g/L (immedia sons other than intolerable AEs (investigator discretion). to that in normal serum. Its manufacturing is in general identical to the tely after infusion; Figure 1). weil established process of IntratectQ!> 50g11 including 4 virus inactivation Table 4: Tolerated infusion rate during 4th infusion of Intratect 100 g/L steps. The higher concentration offers the advantage of less volume Figure 1: Time course of totallgG and IgG subclasses and therefore shorter infusion times. (median values +/- quartiles) at 3rd infusion. Patients tolo- I Numbor 01 pationts Infusion rate rating infusion with intolerable AE TotallgG !IgG1 !IgG2 ·lgG3 1IgG4 [mLlkg/h] rate; n (%) at infusion 4 Objectives: TotallgG IgG1 IgG2 I n = 24 24 24 24 24 24 23 22 1.4 25 (100) Pharmacokinetics (PK) and safety of a 10% solution of IntratecUST090 IgG3 (Part A) and tolerability of escalating infusion rates (Part S). IgG4 2.5 24 (96) 19 18 3.0-3.1 23 (92) 17 16 4.0 21 (84) I 2 Study Design/Methodology: 15 14 13 5.0 18 (72) European multicenter trial with overall 30 PIO patients (mainly with 12 11 5.9-6.0 16 (64) CVIO), thereof 7 below 18 years. ~ 10 Cl 9 8 8.0 8 (32) 7 Participating centers: Germany (2), Hungary (2), Poland (1) 6 5 4 ~--+---+--1 3 2 At the 4th infusion, 5 patients (20%) experienced adverse events 6~ L-- ; ----, limiting the infusion rate (Table 4). All were non-serious (2x discomfort, Before End 6 hrs 24 hrs 4 d 7d 14 d 21/28 d back pain, hypothermia and infusion related reaction). No such events inf of inf , , were reported at infusion 5 or 6. Time after end of infusion No factor (age, gender, medical history) could be identified accounting 0t nd nd tn tn tn Infusion No. 1 I 2 I 3 4 5 I 6 for adverse events that led to reduction in infusion rate. Infusion Rate up to 2.0 mLlkg/h escalation individual max rate Table 2: Comparison of pharmacokinetics (totallgG, medians) PK of Intratect 100g/L (BT090) with Intratect 50g/L Tolerability of Safety & PK Conclusion escalating infusion rates
I ReportA I Intratectl!> 100 g/L Intratect C 17.7 g/L 16.2 g/L 15.5 g/L max The safety profile of Intratect 10% is comparable to that of other 10% Tma>< 3.0 h 4.1 h 4.6 h IVlgs. PartA: PIO patients received 3 infusions of 8T090 at 3- or 4-week intervals, AUCo-l 285 dayg/L 257 dayg/L 261 day g/L ast Escalation of Intratect infusion rates was tolerated in most patients. with gradual increase of infusion rates at initially 30-minute intervals 34.1 days 26.9 days 45.6 days T112 Therefore, in PIO patients an increased infusion rate that reduces the (from 0.3 to 1.4 to 2.0 mUkg/h); dosing was consistent with the pre-trial time required for administration can be considered. Every patient is standard IVlg treatment. Pharmacokinetic parameters were determined supposed to have his own maximum tolerable infusion rate, which may rd at 3 infusion(C ' t ' t , AUC for serum concentration of IgG and max max 112el differ between brands of IVlgs and may be also influenced on the other IgG subclasses 1 to 4) and maintenance of IgG trough levels Results: N= 30 All events Temp. associated Table 1 (72 hrs) n (%) n (%) Nasooharvnaitis 11 (36.7) 2 (6.7) Headache 8 (26.7 8 (26.7) Patients characteristics Bronchitis 5 16.7 0 References Oiscomfort 5 16.7 5 (16.7) Patients enrolled 30 Rhinitis 5 16.7 3 (10.0) 1) M. Scheuplein, R. Linde, O. Ounsch, U. Schauer, O. Hofmann, Ch. 2 (6.7) Gender (female/male) 9/21 ArthralOia 4 13.3 Sonnenburg, T. Klingebiel. W. Kreuz: Clinical efficacy, safety and Backoain 4 13.3 3 (10.0) pharmacokinetic properties of a novel intravenous immunoglobulin 3 (10.0) Age in years, median (range) 34.5 (10-63) I Fatiaue 4 13.3 preparation in patients with primary immunodeficiencies (PIO); Mee I Orooharvnaeal Dain 4 13.3 1 (3.3) Ouration of PIO in years, median (range) 10 (1.3-32.5) Infusion related reaction 3 10.0 3 (10.0) ting of the European Society for Immunodeficiencies (ESIO 2002): URI 3 (10.0) 0 ESID Newsletter 2002 - Supplement, Abstract T.11. Pre-study IgG trough levels (g/L), N =Number of patients who received treatment 2) W. Kreuz, M. Erdös, P. Rossi, E. Bernatowska, T. Espanol, L. Marodi: median (range) 7.68 (4.9-11) n (%) =Number and percentage of patients Temp associated adverse event: A multicentre study of efficacy and safety of Intratect, a novel occuring during infusion or wilhin 72 hours after end of infusion intravenous immunoglobulin preparation; Clin. Exp. Immuno!. 2010, Patients proceeding with Part 8 25 URI = Upper respiratory tract infeclion 161:512-517. o v Ln V co co CJ) (0 W H O 2 o f g l a s s s e a l e ( d 1 C t c V h a 0 a o l e l m i a I 0 m b I f b p r o I m I a o e l w U l t u i A o i l t o l l t w e i ( e e n m N t ≤ s V i e d n h F o ( g L o c 1 D W f V i i W T W o 0 v n a n w a s o d h n I B I o e e a n V I I a V F l i U l r I H d : o o y W k W C L O W ) v t l 0 v i o e w o n O 9 F / i s p g H o n l g N i / l : n i F A e 1 1 s c d O r s n W v F 8 b 0 a : I t o o I 2 R l r a C S n 0 V W 3 i n a ) n 2 W S l d C l n d t i d t n c e T s W I a V d a e d u o a e - b g I d n 1 o I r i a r I n ) i i I W I n f i C r d c c i n d L a a l n l ; t N a l t a o a t z s c s l n n a e t t c e g t e L e r n , e t i b d a n n F d t d v o r o a C s ® i r r n i b E d i n u i r i f r s : n o a b s s t a a n t e : R a c t n n / u a e l g r c B i d t h t v t p c a t d t t S o r i i a C i 1 n W s i A W n o o r o i o a b R e d a t a g f m n n l n r f u o l a n s l o e s p n a : t r a c A t i l t r d a i m g n e I o s p l t b r i y a o t p k g e o I L i f l e H l a n S s s s s N U , n s i r r f t t t n q t t t r L S e : a u o e h o a i e u u b . s p p D a s e n c k s f o F c i t O s s e n n a a e s s d t t a W f c d t t A d t e o a s e P i t i t F o i g r n n y u s n o f o d e a r C o r A g U r f a d f - r n V e e r n l v v L ( t - V d r d T a y I - o C t S s R V e W h h W H n V r ’ ) o ® i W e g T “ d W d e W I F h f i o n a - e w : F F O r R l F r s i e 6 l t : v h l a t C : F C h s l I A n A e i o v o t W R m t e B r o h b C o l h O u g u s r F e r . a o n t s b I 2 i r a A t e w I o v N g n i a o V N ” F n W o s a n d n n T n ( d n n s b a T W i d u f t i l d I ) a s I a m o l P , I c e a S c g i n E I 3 l o f O b A p o e l t t R b e d L t e o 5 i l I o d n v s b r o R f r a o i . o o r r a - u f e - A n r n N I l L a e i e m d n n N d o c n c o n a m W I r F x i d n o d 1 s f A n n S i d f W - e t . c W n o n 1 o A f - P s r y F a e N o M 0 O T d h n M e c d c a a r i a S e e s a a i h t x l c T n m n R c c l I o a c r o n e n n e o h c d A t L n t u y r n a t D b r o i o + I l d h g l o l r I F c t e ( W r O S v L F p N s p r O a V b o l r e ç r a f . a f r u A t t A e l a , e A , i t C t e e W e a t e e m n l n L l y F H n p o i s n c s e e t r u C r i C l A o N m t g r h e d F r b , h n z i C m U t h h O a k a l C 2 ) y n e p i c o a a e f / i e u t r O E e s t r o d ; F f l s 0 m C o e T t A T t n t o a i V e o t m l c o i d a - 2 n 1 e r e a d E i c p u e c c a e e S e W I m o h 0 n g w r a U t n g l g t t e e L n N r t z e y i f f A i a . n r r o i e R i r n i n n F e m p s t f e S i r a l l a V a o T o R i n l r r t r o S t l - c g c i ® W p l e t r l t S i p ( n g g r m s d h e f u u r P r i o r a i a e 1 / u a g O p o h i n e ( r e t I a n c t t T m C 5 g L l t g 7 t i e W a e i t i d y n d A e r e o L o p p a t l r i t 2 a t e d n o A E d m t r i e h a t - a n S r o c o n o B h i , w n T . m e a e t t e o p I t p f T R n g W r a U r T i N e r p L S r r f v l n a o T h , A l h e r a e a a i h a s p g I n o a L y 8 N L n d p i l r I e h s e a s n D n e F d a p a 0 e e e I o D d i m F 2 t e A l l 1 d t n I r s u h ° o m a m r - I A i C e A ; t C S L o w o t a V y N u a t a F T i o F i t n V J e - l r c ) c ) h b B t t C r a I 1 o R W h i e N n e f a m e l a • c c d n i r s n e s T s t o e D o o a a a h d H e r ® o l a ® n l F n u y E s e a d n s i s . s t c - : f c p d n s i / i F i i F i o s • R e s h i g n s r g V n t n u o b V A p s n o C O d h f e t ( e y W e r a r W T a r r I ) c C a o d y e f - o t p d I t , f h u a M a e I v F e ® p t e T l e A w n v s a . 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G A i f u a C p i t W n n t s A f t f 1 e r h i n X , . i . R e h a n : - o c t o S C 2 D g l a E X g a S i c R S n " l 5 C s w S c e l n o T e i C c I e e e ( o c i S I S c d e G I t I b i n s e n i A N u t 2 é ( u é n u o r m T C h g V c n r t r 0 t f a l r H é o d v t n r e w b e n g t 1 s n a e a u e h s s e ) d e 2 F d t g y s a W e s r f P i F e r r r ) v n l o s a e e 8 : a I o F f M o o W S f r b n s F W r - D a m n T 1 s a f t r ç i H e c h 1 u s c H a i a e o o t t a , e a t S i t o t h f s m i 2 i a r t J o W n e r y u H t 0 u ® g e n f h l 2 r d : 1 y t , d F n i e h s C o g 2 K 0 i . H ’ 1 e h h a w . m o c I - y 1 s n G é 2 - o o - n i p A - t m 3 t t v J e a a T c o h u u 1 A , o t r g a e , 6 n r H F n 2 l v u n J t S t n a i e , h a r a o 0 o t l ® n H t 2 e a p I y t l 1 1 M r . n n o i W t n n 0 a o 3 a X t g a 2 - c t n n W v 0 e u t i e 5 e h i 0 X e r a o i 9 n n - l n s , , t l l h 1 i n , V J e i l a u c l i 3 A B : I b e n t l I h i y n O I b r o F n a 2 I n r S L a n u n a a 3 c T o t a n d l e t - O n 2 l e d C r g M n N 8 u o F D - a , r n , T a e t 2 g i U e c i e s V o 0 r t t e r S e n i 1 I o n a m I A s a 1 I g r s s , . . l e AVRIL 2013 - Layout: Pasaya