Allergy‘
`v.70, no. 10 (Oct. 2015)
`General CO“
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`Volume 70 - Number 10 0 October 2015
`
`EUROPEAN JOURNAL OF ALLERGY
`AND CLINICAL IMMUNOLOGY
`
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`Page 1 of 14
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`CSL EXHIBIT 1077
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`EUROPEAN JOURNAL OF ALLERGY
`AND CLINICAL IMMUNOLOGY
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`The cover image depicts: Molecular characterization of tree pollen allergens. From Asam C. Hoier H, Wolf M, Aglas L, Wallner M. Tree pollen allergens—an
`update from a molecular perspective. Allergy 2015; 70: 1201-1211.
`
`This mate ri al was copied
`atthe NLIvI and may be
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`Page 2 of 14
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`

`

`EUROPEAN JOURNAL OF ALLERGY
`AND CLINICAL IMMUNOLOGY
`
`
`
`CONTENTS
`
`Volume 70 - Number 10 - October 2015
`
`NEWS AND
`
`1193
`
`COMMENTARIES
`
`Consensus communication on early peanut introduction and the prevention
`of peanut allergy in high-risk infants
`primaryContributors:, D. M. Fleischer, S. Sicherer, M. Greenhawt, D. Campbell,
`E. Chan, A. Muraro, S. Halken, Y. Katz, M. Ebisawa, L. Eicnen, H. Sampson, H. Sampson,
`G. Lack, G. Du Toit, G. Roberts, H. Bahnson, M. Feeney, J. Hourihane, J. Spergel,
`M. Young, A. As'aad, K. Allen. S. Prescott, S. Kapur, H. Saito, |. Agache. C. A. Akdis.
`H. Arshad, K. Beyer, A. Dubois, P. Elgenmann, M. Fernandez—Rivas, K. Grimshaw,
`K. Hoffman—Sommergruber, A. Host, S. Lau, L. O'Mahony, C. Mills, N. Papadopoulos,
`C. Venter, N. Agmon-Levin, A. Kessel, R. Antaya, B. Drolet and L. Rosenwasser
`
`Subject J3 {boy‘right Laws
`
`REVIEW ARTICLES
`
`Angioedema induced by cardiovascular drugs: new players join old friends
`M. Bas, J. Greve, U. Strassen, F. Khosravani, T. K. Hoffmann and G. Kojda
`
`Tree pollen—allergens an update from a molecular perspective
`C. Asam. H. Hofer. M. Wolf, L. Aglas and M. Wallner
`
`POSITION PAPER
`
`Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI
`position statement
`L. Ansley, M. Bonini, L. Delgado, 8. Del Giacco, G. Du Toit, M. Khaitov, M. Kurowski,
`J. H. Hull, A. Moreira and P. J. Robson—Ansley
`
`ORIGINAL ARTICLES
`
`Experimental Allergy And Immunology
`1222
`
`Poor association of allergen-specific antibody, T- and B-cell responses
`revealed with recombinant allergens and a CFSE dilution-based assay
`J. Eckl-Dorna. R. Campana. R. Valenta and V. Niederberger
`
`Urinary 11B-PGF20L and N-methyl histamine correlate with bone marrow
`biopsy findings in mast cell disorders
`R. Divekar and J. Butterfield
`
`Ara h 2 and Ara 6 are the best predictors 0! severe peanut allergy: a
`double-blind placebo-controlled study
`A. K. Kukkonen, A. S. Pelkonen, S. Makinen—Kiljunen. H. Voutilainen and M. J. Mékela
`
`Allergic sensitization is associated with inadequate antioxidant responses in
`mice and men
`
`L. Utsch, C. Folisi, J. H. Akkerdaas, A. Logiantara, M. A. Van De Pol, J. S. Van Der Zee,
`E. J. M. Krop, R. Lutter, R. Van Ree and L. S. Van Rijt
`
`MPLA shows attenuated pro-inflammatory properties and diminished capacity
`to activate mast cells in comparison with LPS
`5. Schlllke, A. Flaczyk. L. Vogel, N. Gaudenzio, I. Angers, B. Lb‘schner, S. Wolfheimer,
`I. Spreitzer, S. Qureshi, M. Tsai, S. Galli, S. Vieths and S. Scheurer
`
`Intrinsic properties of germinal center-derived B cells promote their enhanced
`class switching to lgE
`F. Ramadani, N. Upton, P. Hobson, Y.— C. Chan, D. Mzinza, H. Bowen, C. Kerridge,
`B. J. Sutton, D. miFeeM—Iiedii'lasisfiiedld
`at the NLM and may be
`
`Page 3 of 14
`
`

`

`Childhood asthma is associated with mutations and gene expression
`differences of ORMDL genes that can interact
`A. A. Toncheva, D. P. Potaczek, M. Schedel, S. W. Gersting, 5. Michel, N. Krajnov,
`V. D. Gaertner, J. M. Klingbeil, T. lltig, A. Franke, C. Winkler, J. M. Hohlfetd, C. Vogelberg,
`A. Von berg. A. Bufe, A. Heinzmann, 0. Laub, E. Rietschet, B. Simma. J. Genuneit,
`A. C. Muntau and M. Kabesch
`
`Subject USCopyrighL Laws
`
`Farm exposures are associated with lower percentage of circulating myeloid
`dendritic cell subtype 2 at age 6
`M.- V. Martikainen, H. Keari‘o, A. Karvonen, P. C, Schr‘dder, H. Renz, V. Kaulek,
`J.— C. Dalphin. E. Von Mutius, B. Schaub, J. Pekkanen, M.- R. Hirvonen and M. Roponen
`
`Epidemiology And Genetics
`
`Association between adult atopic dermatitis, cardiovascular disease, and
`increased heart attacks in three population-based studies
`J. I. Sitverberg
`
`Airway Diseases
`
`eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers
`GWAS-identitied asthma genes
`X. Li, A. T. Hastie, G. A. Hawkins, W. C. Moore, E. J. Ampleford, J. Milosevic, H. Li,
`W. W. Busse, S. C. Erzurum, N. Kaminski, S. E. Wenzel, D. A. Meyers and E. R. Bleecker
`
`Immunodeficiencies
`
`Phase II study results of a replacement therapy for hereditary angioedema
`with subcutaneous C1-inhibitor concentrate
`
`B. L. Zuraw, M. Cicardi, H. J. Longhurst, J. A. Bernstein, H. H. Li, M. Magerl, |. Martinez—
`Saguer, S. M. M. Rehman, P. Staubach, H. Feuersenger, R. Parasrampuria, J. Sidhu,
`J. EdeLman and T. Craig
`
`Diagnostic test allergens used for in viva diagnosis of allergic diseases are at
`risk: a European Perspective
`L. Klimek, H. J. Hoffmann, H. Renz, P. Demoly, T. Werfel, P. M. Matricardi, A. Muraro,
`P. Schmid-Grendelmeier, V. Cardona and N. G. Papadopoulos
`
`Diagnostic use of recombinant Tha p 2 in the allergy to Thaumetopoea
`pityocampa
`A.
`|. Rodriguez—Mahitto, N. Carballeda-Sangiao, J. M. Vega, J. C. Garcia-Ortiz, A. Roques,
`I. Moneo and M. Gonzalez-Munoz
`
`T helper 2 response in allergic bronchopulmonary aspergillosis is not driven
`by specific Aspergillus antigens
`H. Jolink, R. de Boer, L. N. A. Willems, J. T. van Dissel, J. H. F. FaIkenburg and
`M. H. M. Heemskerk
`
`Bee venom enhances the differentiation of human regulatory T cells
`I. Caramalho, A. Meto, E. Pedro, M. M. P. Barbosa, R. M. M. Victorino, M. C. Pereira Santos
`and A. E. Sousa
`
`Prevalence of celiac disease in patients with severe food allergy
`R. Pillon, F. Ziberna, L. Badina. A. Ventura, G. Longo, S. Ouagtia, L. De Leo, S. Vatta,
`S. Martelossi, G. Patano, T. Not and I. Berti
`
`
`
`BRIEF
`
`COMMUNICATIONS
`
`CORRESPONDENCE
`
`The influence of childhood traffic-related air pollution exposure on asthma,
`allergy and sensitization
`E. Fuertes and J. Heinrich
`This material was-{spied
`attire NLMand may he
`
`Page 4 of 14
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`

`

`concentrate
`
`B. L. Zuraw1, M. Cicardiz, H. J. Longhurst3, J. A. Bernstein‘, H. H. Li5, M. Magerle, |. Martinez-8a uer7,
`S. M. Magiehmans, P. Staubachg, H. Feuersengerw, R. Parasrampuria”, J. Sidhun, J. Edelman1 &
`T. Craig
`
`1Department of Medicine, University of California, San Diego, La Jolla, CA, USA; 2Department of internal Medicine, Universita degli Studi di
`Milano, Ospedale L. Sacco, Milan, ltaiy; 3Department of Immunology, Barts Health NHS Trust, London, UK; “Department of Imrnunology/
`Allergy, University of Cincinnati College of Medicine, Cincinnati, OH; 5lnstitute for Asthma and Allergy, Chevy Chase, MD, USA; 6Charité,
`Universitétsmedizin Berlin, Berlin; 7HZRM Haemophilia Centre Rhine Main, Morfelden—Walldorf. Germany: 8Toledo institute Asthma and Allergy
`Center, Toledo, OH, USA; 9University Medical Center, Mainz; 10CSL Behring GmbH, Marburg, Germany; HCSL Behring, King of Prussia, PA.
`USA; 12CSL Limited, Parkville, Vic., Australia; 13Departments of Medicine and Pediatrics, Penn State University, Hershey, PA. USA
`
`To cite this article: Zuraw BL, Cicardi M, Longhurst HJ, Bernstein JA, Li HH, Magerl M, Martincszagucr I, Rehman SMM, Staubach P, Feuersenger H,
`Parasrampuria Ft, Sidhu J, Edelman J, Craig T. Phase II study results oi a replacement
`therapy for hereditary angioedema with subcutaneous Ci—inhibitor
`concentrate. Allorgy20l5; 70: 131971328.
`
`
`
`Keywords
`Berincrt; Ci—csterase inhibitor; hereditary
`angioedema; long—term prophylaxis; subcuta—
`neous treatment.
`
`Abstract
`
`Subject Uiflopyright Laws
`
`inhibitor deficiency
`(HAE) due to C1
`Background: Hereditary angioedema
`manifests as recurrent swelling attacks that can be disabling and sometimes fatal.
`Long‘term prophylaxis with twice-weekly intravenous injections of plasma-derived
`Cl-inhibitor (pdCl-INH) has been established as an effective treatment. Subcutane-
`ous (SC) administration ot‘pdCl-INH has not been studied in patients with HAE.
`Methods: This open-label, dose—ranging, crossover study (COMPACT Phase II) was
`conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500,
`3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks
`each. The mean trough plasma levels of Cl-INH functional activity, Cl-INH and C4
`antigen levels during Week 4, and overall safety and tolerability were evaluated. The
`primary outcome was model-derived steadystate trough Cl—INH functional activity.
`Results: After SC CSL830 administration, a dose-dependent increase in trough func-
`tional Cl-INH activity was observed. Cl-INI—i and C4 levels both increased. The
`two highest dose groups (3000 and 6000 IU) achieved constant Cl—INH activity lev-
`els above 40% values, a threshold that was assumed to provide clinical protection
`against angioedema attacks. Compared with intravenous injection, pdCl-INH SC
`injection with CSL830 showed a lower pcak-to-trough ratio and more consistent
`exposures. All doses were well tolerated. Mild-to-modcrate local site reactions were
`noted with pain and swelling being the most common adverse event.
`Conclusions: Subcutaneous volume-reduced CSL830 was well tolerated and led to
`a dose—dependent increase in physiologically relevant functional Cl-INH plasma
`levels. A clinical otitcomc study of SC CSL830 in patients with HAE warrants
`further investigation.
`
`Abbreviations
`
`Correspondence
`Bruce L. Zuraw, MD, Department of Medi-
`cine, University of California, San Diego,
`9500 Gilman Dr., Mail Code 0732, La Jolla,
`CA 92093—0732, USA.
`Tel.: +1 858 822 6597
`Fax: +1 858 642 379i
`E-mail: bzuraw@ucsd,edu
`
`ClinicalTrialsgov identifier: NCT01576523.
`
`Accepted for publication 22 May 2015
`
`DOI:10.1 i l l/all.12658
`
`Edited by: Werner Aberer
`
`AE, adverse event; AUCw ,,, area under the plasma concentrationetime curve over a dosing interval; Cl-INH, Ct»inh‘ibitor; CW, average Cl-
`iNH functional activity over dosing interval; CI, confidence interval; CL. clearance; CLss, steady—state clearance; Cmax, maximum drug
`concentration in plasma; CSL830, volume-reduced C1-iNH concentrate; F, bioavailability; HAE, hereditary angioedema due to Cl
`inhibitor
`deficiency; IU, international unit; lV, intravenous; Ka, absorption rate constant; kDa, kiloDalton; pd, plasma-derived; PD, pharmacodynamicc
`PK, pharmacokinetic; pnf. pasteurized, nanofiltered; SC, subcutaneous; SD, standard deviation; tvz, half-life; TEAE, treatment-emergent
`adverse event; U, unit; V, volume of distribution; V55, steady-state volume of distribution; WT, body weight.
`
`Allergy 70 (2015) 1319—1328 © 2015 The Authors. Allergy Published by John Wiley 84 Sons Ltd,
`This is an open access article under the terms of the Creative Commons AttributionrNonCornmcrcialNcDorivs License, which permits use and
`distribution in any medium, provided the original work is properly cited, tmigse‘éstgpfgcmegiagfld no modifications or adaptations are made.
`at the FILM and may be
`
`Page 5 of 14
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`

`

`Subcutaneous C1-INH replacement for HAE
`
`Zuraw et al.
`
`
`
`Hereditary angioedema (HAE) is a rare autosomal dominant
`disease caused by C1 inhibitor deficiency and is associated
`with significant morbidity and mortality (14), which has been
`substantially reduced with the advent of effective on-demand
`therapies (5). However, patients continue to have impaired
`quality of life and in seine cases require hospitalization for an-
`gioedema attacks. To minimize the number and severity of
`attacks, many patients choose to use prophylactic treatment,
`Consensus guidelines conclude that long-term prophylaxis is
`appropriate for HAE patients with frequent attacks or who do
`not achieve sufficient benefit from Oil-demand treatment (4, 6e
`1 1). Before 2009, the most commonly utilized prophylactic drugs
`were anabolic androgens and to a lesser extent antifibrinolytics,
`Subsequently, long-term prophylaxis with Cl inhibitor concen—
`trates (Cl-INH) has become available and found to be safe and
`effective (12). The concept of routine prophylaxis with continu-
`ous intravenous Cl-lNH is based on correcting the deficiency of
`Cl-INH activity,
`the fundamental abnormality in HAE. The
`efficacy of this approach was shown in two placebo—controlled
`studies;
`the efficacy of a vapor-heated Cl-INH concentrate
`(25 U/kg body weight) was established for long-term prophy-
`laxis in patients who did not respond adequately to androgcns
`or antifibrinolytics (13), and the Cl-INH concentrate (Cinryzc,
`1000 IU twice a week) demonstrated a reduction in the number
`of HAE attacks (12). However, none of the previous studies on
`CI-INH replacement
`therapy were specifically designed to
`achieve a constant level of biologically relevant activity Cl-INII
`levels. Thus, most patients on intravenous Cl-lNH long-term
`prophylaxis continue to experience breakthrough attacks, likely
`related to the relatively short period of time that functional
`Cl-INH plasma levels remain near the normal range (13).
`levels
`Theoretically, maintaining plasma Cl-INH functional
`above a certain threshold should prevent all attacks. However,
`this threshold value has not yet been defined. Hereditary angioe—
`dema is diagnosed based on functional Cl-lNH levels <50% of
`normal, but patients typically have Cl-INH functional
`levels
`<40% of normal (14, 15). Enhanced activation of the complement
`system has been observed with Cl-INH functional levels <38%
`of normal, suggesting a critical
`threshold of Cl-INH function
`(16). Logistical and technical problems of repeated intravenous
`(IV) injections and the pharmacokinetic (PK) profile make it chal-
`lenging to maintain the Cl—IN H level above a threshold value.
`Subcutaneous (SC) administration of Cl-INH offers sev-
`eral potential advantages including easier access for self-
`administration and more consistent I’Ks. The feasibility of
`SC administration of an IV Cl-INH concentrate (1000 [U in
`20 ml) was previously demonstrated in a pilot study in
`patients with HAE (l7). Herein, the PK, pharmacodynamic
`(PD), and preliminary safety of an investigational, volume-
`reduced Cl-INH concentrate (CSL830; CSL Behring, Mar-
`burg, Germany) developed for SC injection is reported.
`
`Sn bjert. US «item: right Laws
`
`Marbnrg, Germany). The manufacturing process of CSL830
`is almost identical to that of pnf Cl-INH, the major differ—
`ence being the concentration after reconstitution. The final
`concentration of CSL830 is 500 lU/ml, whereas the final con—
`centration of Berincrt is 50 IU/ml.
`
`Study design
`
`This was a prospective, multicentcr, open-label, crossover
`phase II study to characterize the PK5, PBS, and safety of
`CSL830 administered subcutaneously to 18 subjects with
`HAE (COMPACT phase 11 study). The study period spanned
`April 2012 to December 2012. Data were collected at three
`sites in Germany and five in the USA. For organizational
`details of the study setup, please refer to the Appendix 81.
`Following a screening period of up to 30 days, subjects
`were sequentially allocated to one of six CSLSSO treatment
`sequences by predetermined computer-generated assignment
`(Fig. 1A). A single dose of Berincrt 20 U/kg was adminis-
`tered 1V 2—7 days prior to the first CSLXBO dosing period.
`Each subject received two of three possible CSL830 doses
`(1500, 3000, or 6000 IU administered as a short SC injection
`twice-weekly) for two 4-week treatment periods with a wash-
`out period of up to 4 weeks between periods. Administration
`of rescue medication (IV Cl-lNH) was permitted for break-
`through attacks.
`The study protocol and all amendments were approved by
`the independent ethics committees of the participating sites.
`The study was carried out in accordance with the principles
`of the current International Conference on Harmonization
`Good Clinical Practice.
`
`Study population
`
`Male or female subjects aged 218 with HAE with type I or
`type II HAE, based on clinical history and confirmed by cen-
`tral laboratory testing at screening (Cl-lNH functional activ-
`ity <50% or a Cl-INH antigen level below the laboratory
`reference range), were eligible for the study. Subjects were
`required to have a body weight 250 and 5110 kg at screening
`and have experienced $5 HAE attacks within the 3 months
`prior to the screening visit, of which 51 occurred within
`30 days prior to the screening visit. The relatively low attack
`rate for the inclusion criteria was chosen to minimize the
`need for
`rescue therapy with Cl-lNH concentrate which
`would interfere with the PK measurements.
`
`Key exclusion criteria included current Cl—INH prophylac-
`tic therapy, androgen therapy within 30 days of screening,
`and any HAE-specific treatment within 7 days of screening
`(for full inclusion and exclusion criteria, see Appendix SI).
`
`Endpoints
`
`The primary endpoint was the mean trough Cl-INH func-
`tional activity at
`the fourth week, based on modeling and
`simulation. Model-derived rather than observed trough levels
`were chosen to account for the confounding nature of possi-
`ble rescue IV Cl-lNH use during the study.
`
`Methods
`
`Study medication
`
`CSL830 is a volume-reduced formulation of the pasteurized,
`nanofiltered Cl—INH concentrate (pnf Cl-INH; Berinert‘”,
`
`1320
`
`Allergy 70 (2015) 13194328 © 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.
`
`Th is material was copied
`at the NLM and may be
`
`Page 6 of 14
`
`

`

`Zuraw ct al.
`
`Subcutaneous C1-INH replacement for HAE
`
`CSL830 Treatment period
`Dosing period 2
`Dosing period 1
`Se uence A
`
`1500 IU 2x perweek
`
`3000 IU 2x perweek
`
`30001U 2x per week
`
`1500 IU 2x perweek
`
`W3000 IU 2x per week
`
`8000 IU 2x per week
`
`u uenceD
`
`1500 IU 2x perweek
`
`6000 lUprerweek
`
`15001U2xperweek I
`I: 6000 IU2xperweek
`' 6000lU2xperweek
`3000lU2xperweek I
`L___,r___J L1_J L___gr___J L__T__J
`
`4 weeks
`(13 visits)
`
`Up to 4
`weeks
`
`4 weeks
`(13 visits)
`
`1 week
`(1 visit)
`
`Screening
`
`18
`subjects
`
`Single lV
`dose of
`pdC1-INH
`20 lUIkg
`
`L-w—JH—’
`
`Within 30 days of
`Dosing Period 1
`(1 visit)
`
`2 to 7 days before
`Dosing Period 1
`(3 visits)
`
`Subject USCopyright Laws
`
`The secondary endpoints were the mean and mean change
`from baseline in trough Cl-lNH functional activity, Cl-lNI—I
`antigen level, and C4 antigen levels at
`the fourth week of
`each dosing regimen, based on observed data.
`The dosing scheme and sample collection is illustrated in
`Fig. 18. The initial single IV dose of Cl-INH was adminis-
`tcred to aid the PK model in accounting for any administra-
`tion of IV Cl-INH rescue doses and to enable a within-study
`estimate of bioavailability of SC CSL830. Cl—INH functional
`activity, Cl-INH plasma concentrations, and C4 antigen lev-
`els were assessed at several time points throughout each dos-
`ing
`period.
`Plasma Cl-INH functional
`activity was
`additionally assessed immediately before CSL830 administra-
`tion.
`
`I
`.lVC1-INH
`
`.
`
`CSL830 administration
`
`I
`
`;
`
`-
`‘ r
`
`v
`
`I
`
`I
`
`I
`
`it
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`I
`IIIIII I
`
`I
`
`:‘I,
`
`I
`I
`ii
`. arm;
`
`all].l]|
`
`I
`I
`I
`I
`I
`I
`I
`I II I IIIIIII
`
`I
`
`Wait
`
`3
`
`Plasma Ct-INH functional activity and C1-lNHIC4 antigen level assessment
`
`Figure 1 Study schema (A) Dosing scheme and sample collection
`during the study,
`(B) I = single dose of IV CI-INH;
`1 = single dose
`of subcutaneous (SC) CSL830; I= assessment of Cl-INH func-
`
`tional activity and plasma Cl-lNH and C4 antigen concentrations:
`I = additional assessments of plasma C1-INH functional activity,
`
`reference range: 70-1300/0 of norm). Plasma Cl-INH antigen
`(Cl
`reagent N-Antisera; Siemens Healthcare Diagnostics
`(Eschbom, Germany); reference range: 0.187032 mg/l) and
`C4 antigen levels were assessed by nephclometry (C4 reagent,
`Beckman Coultcr (Krefeld, Germany); reference range: 0.1—
`0.4 g/l). All measurements were performed at a central labo-
`ratory using a validated assay (CSL Behring GmbH).
`C4 antigen levels were defined as a PD parameter as C4
`activity occurs downstream from Cl—INH; Cl-INH replace-
`ment would therefore affect C4 levels. Levels of C4 antigen
`have been shown to rise slowly over time following IV pdCl-
`lNll administration.
`
`PK and PD analysis
`
`The complete analysis set (18 patients who received 21 dose
`of CSL830 and provided _>_1 Cl-INH functional measure-
`ment) was used for the primary endpoint analysis and to
`determine modeling-derived Cl-INH functional
`activity.
`
`PK and PD measurements
`
`Plasma Cl-INH functional activity was assessed by a vali-
`dated chromogenic assay (Berichrom Cl-Inhibitor, Siemens;
`
`Allergy 70 (2015) 1319—1328 © 2m 5 The Authors. Allergy Published by John Wiley & Sons Ltd.
`
`1321
`
`Th is material was-{sowed
`at the NLM and maybe
`
`Page 7 of 14
`
`

`

`Subcutaneous C1-INH replacement for HAE
`
`Zuraw et al.
`
`PK results after SC CSL830
`
`The mean as—observed steady—state trough Cl-INH functional
`activity at
`the fourth week increased with CSL830 dose
`(Fig. 2);
`increase from baseline was 16.4%, 33.2%, and
`63.3% for the 1500, 3000, and 6000 IU doses, respectively.
`CI-INH antigen levels also increased with CSL830 dose;
`increase from baseline in Cl—INI—I antigen at the fourth week
`was 0.02, 0.05, and 0.14 mg/ml for the three dosing regimens,
`respectively.
`
`Population PK model
`
`Cl-INII functional activity was deseribcd by a linear one-
`Compartrucntal PK model with first-order absorption. The
`relationships between model parameters and the following
`ba5cline covariates were examined: age, gender, body weight,
`body mass index, ideal body weight, lean body mass, creati-
`nine CL, and CI-INH functional activity. The only statisti-
`cally significant covariate effect on a model parameter
`identified was the effect of body weight on CL and V, which
`was described by the following relationships:
`
`_
`WTAkg)
`CL, — 0.398 - (789(ng
`
`0.379
`
`n”
`
`exp
`
`,
`
`wry-(ks)
`78.9(kg)
`
`0'66”. exp“,
`
`’
`
`V,- :30.8-(
`the indi-
`where CL,- is the individual value of clearance; Vi,
`vidual volume of distribution; and W1),
`the body weight of
`subject 1‘.
`Goodness-of-fit plots of the model (Fig. 3) reveal that the
`model prediction was consistent with the observed data, as
`the points are uniformly distributed around the line of iden-
`tity. Therefore, no systematic bias was evident.
`
`Twelve subjects per dosing regimen were sufficient to provide
`an estimate of Cl-INII activity, based on PK modeling of
`previous study results. Tile data for each treatment were
`summarized using descriptive statistics and a mixed mode].
`Subcutaneous and IV Cl—INH functional activity data
`were collectively subjected to a population-based approach
`using nonlinear mixed-effects modeling (NONMEM version
`7.2). Exploratory PK characteristics of CSL830 were assessed
`by estimating typical and individual values for parameters
`such as clearance (CL) and volume of distribution (V) along
`with associated interindividual variability. The influence of
`subject baseline characteristics was also investigated. Pharma-
`eokinetic parameters such as CL, V, bioavailability (F),
`absorption rate constant (K3), half-life (11/2), and incremental
`recovery were estimated with the final population PK model.
`I’harmacokinetie simulations were conducted to examine
`whether steady-state trough levels of Cl-INH functional
`activity were dependent on body weight. The body weight
`effect was evaluated by examining the distributions of model-
`predictcd steady-state trough serum Cl-INH functional activ-
`ity at doses of 40 and 60 IU/kg and fixed doses of 3000 and
`45001U, for baseline body weight ranges of <60, 607100,
`and >100 kg. For the as-observed endpoint analysis,
`the
`fourth-week trough levels and increase in trough levels from
`baseline were summarized for Cl-INH functional activity,
`Cl-INH antigen levels, and C4 antigen levels
`for each
`CSL830 dosing regimen using descriptive statistics,
`
`Subject UStCzapyright Laws
`
`Safety assessment
`
`Safety and tolerability were evaluated by continuous observa-
`tion of adverse events (ABS) and by safety assessments that
`were conducted at
`specified times
`throughout
`the study.
`These assessments included infusion site tolerability, labora-
`tory parameters, vital signs, body weight, physical examina-
`tion, and concomitant medication usage. Local side-effects
`(pain, swelling, bruising, and itching at
`the injection site)
`were assessed by the investigator and intensity graded from
`mild (grade 1: present, but no interference with activity) to
`severe (grade 3: prevents daily activity and/or requires Lise of
`pain relie