HAL Allergy - Scientific Contribution 2015 by superrebelgroup

Scientific Contribution 2015 34th Congress of the European Academy of Allergy and Clinical Immunology EAACI, 6-10 June 2015, Barcelona, Spain

Dear Congress delegate,

At this year’s meeting we also present two abstracts on the characterization and stability of our allergen products. Using antibody-based and physicoche mical methods (i.e., mass spectrometry and circular dichroism) we compare and characterize wasp venom obtained from different sources, and perform extensive analysis on the stability of Phleum pratense extract. Furthermore, we present data on the development of a manufacturing plat form for recombinant Bet v1.0101 using CHO cells. This work was performed using the capability of HALIX, our subsidiary for contract manufacturing of clinical trial materials for third parties. It is shown that a recombinant form of Betula protein can be produced at an industrial scale. We hope you will have a successful congress. If you require further information about our products, or our R&D program, please do not hesitate to visit our booth in the exhibition area. Kind regards,

Dirk-Jan Opstelten, PhD Diderik Boot, PhD Research & Development Director Medical Director

Dirk-Jan Opstelten, PhD Research & Development Director

On behalf of HAL Allergy, we like to welcome you to the EAACI 2015 congress in Barcelona. The theme of this year’s congress is “Allergy: new answers to old questions”. This theme fits HAL Allergy very well. HAL Allergy, is an “old” (more than 55 years) and established company with a long and successful history in the field of allergen immunotherapy. Nevertheless, the company has commit ted itself to continue to generate “new” answers to questions coming from the immunotherapy field: be it on the characterization and clinical efficacy of exis ting products; or about the development of novel products and product claims. In this abstract book you will find our abstracts dealing with various clinical studies and product development activities, including information on specific dates and times of the presentations.

Diderik Boot, PhD Medical Director

HAL Allergy’s clinical development program, aimed at gaining registration for specific immunotherapy products, is progressing successfully. This year, we are presenting the design of the Phase III pivotal study for SUBLIVAC® Birch. This study follows the completion of the Phase II dose range finding study in 2013. We also present clinical data on the possibility of accelerated up-dosing with our PURETHAL® Birch product. This study resulted in the registration of the rush up-dosing scheme for our entire PURETHAL® Pollen portfolio.

Accelerated up-dosing with a registered allergoid birch pollen SCIT preparation is non-inferior to conventional up-dosing 10

Large Scale Manufacturing of Recombinant Bet v1.0101 in Chinese Hamster Ovary cells 18

Development

Safety of a cluster-immunotherapy with a depot allergoid in patients with allergic rhinitis against grasses 16

Characterisation of wasp venom collected via electrostimulation or venom sac extraction 22

Sublingual immunotherapy against alternaria allergens in patients with asthma 12

Poor correlation between symptom scores and absolute levels of allergen-specific serum IgG4 in allergic rhinitis 8

Clinical Design of a phase III short-term efficacy study with allergen specific immunotherapy in patients with birch pollen induced allergic rhinitis/rhinoconjunctivitis 6

Stress stability study on a Phleum pratense extract 20

Scientific Contribution 2015 Contents

Accelerated and conventional up-dosing with a registered allergoid birch pollen SCIT preparation: a comparison of tolerability between adults and adolescents 14

The current study is a randomized, double-blind, placebo-controlled, parallel-group study in 400 adult patients (200 per arm), with moderate to severe birch pollen induced AR with or without mild to moderate persistent asthma (ClinicalTrials.gov NCT02231307). Treatment is started at least 12 weeks before the pollen season whereby the birch pollen season is defined as 3 out of 5 consecutive days birch pollen counts with ≥80 grains/m3 per 24 hours and the birch peak pollen season is defined as all days with birch pollen counts ≥500 grains/m3 per 24 hours. Recently, an EAACI task force has recommended the use of the CSMS as the primary endpoint whereby 6 organ related symptoms (4 nasal, 2 ocular) and the need for anti-allergic medication (stepwise) are balanced in an equally weighted manner. We have selected this score and, in accordance with guidelines, the minimal clinically important difference in the primary endpoint between test and control population has been predefined and justified upfront (23% decrease compared to placebo). The study is performed in 42 clinical study centers in 5 European countries. Results The first patient was recruited in September 2014 and the screening target was met on 21st of October, resulting in 406 randomized patients. The results will be available in the second half of 2015.

Conclusion According to the EMA guidelines we designed a Phase III short-term efficacy study to identify the effect of the optimal dose of SUBLIVAC FIX Birch SLIT in birch pollen allergic rhinitis/rhinoconjunctivitis patients. We implemented the recently recommended EAACI CSMS score as the primary endpoint and the minimal clinically important difference has been defined and justified upfront.

Method

Session title: Sensitization, allergen extracts and efficacy of AIT 6 EAACI, 6-10 June 2015, Barcelona, Spain

Background In order to comply with the 2008 EMA guidelines on the development of SIT products, a clinical development program was started to obtain full marketing authorization for a sublingual IT product for the treatment of birch pollen allergy. Previously the optimal dose has been determined in a phase II dose finding study. The next step is, in patients with birch pollen induced allergic rhinitis/rhinoconjunctivitis (AR), to determine the short-term efficacy. The recommended end-point is a combined symptom and medication score (CSMS) during the pollen season. However, there is a wide variety in both the applied CSMS scores and in the definition of the pollen season. This abstract highlights the design of the phase III study.

O. Pfaar1, P. Kuna2, P. Panzner3, M. Džupinová4, M.J. van Nimwegen5, D. Boot5, C. Bachert6 1 Center for Rhinology and Allergology Wiesbaden, Germany; 2 Poradnia Alergologii i Chorób Płuc Lodz, Poland; 3 Ustav imunologie a alergologie, Plzen, Czech Republic; 4 ALIAN s.r.o. Ambulancia alergológie a klinickej imunológie, Bardejov, Slovakia; 5 HAL Allergy BV, Medical Department, Leiden, The Netherlands; 6 University of Ghent, Clinical Trial Center, Upper Airways Research Laboratory, Ghent, Belgium.

Design of a phase III short-term efficacy study with allergen specific immunotherapy in patients with birch pollen induced allergic rhinitis/rhinoconjunctivitis.

Abstract number: 1101 Session number, date and time: TPS 30, Monday 8 June 2015; 12:00 - 13:30

EAACI, 6-10 June 2015, Barcelona, Spain 7

Design of a phase III short-term efficacy study with allergen specific immunotherapy in patients with birch pollen induced allergic rhinitis/rhinoconjunctivitis.

TPS 30 - Sensitization, allergen extracts and efficacy of AIT

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2015CongressEAACI Allergy.HALofemployeeanispresenterTheinterest.ofconﬂictperceivedorrealfollowing,thedeclareIpresentation,thistorelationIn

Session title: Sensitization, allergen extracts and efficacy of AIT 8 EAACI, 6-10 June 2015, Barcelona, Spain

Methods In a 5-month phase II study, 269 adult subjects (134 females;135 males) with birch pollen induced AR were treated with a sublingual birch pollen preparation (3,333; 10,000; 20,000 or 40,000 AUN/ml) or with placebo. The absolute difference in mean symptom score following a titrated nasal provocation test (TNPT) and the change in birch pollen specific serum IgG4 levels between 5 months of treatment and baseline were determined. Assessment of the correlation between the change from baseline in symptom scores and log serum IgG4 levels was done using a bivariate normal model with and without adjustment for the treatment factor. The dependence was modelled using an unstructured covariance matrix.

O. Pfaar1,2, E. van Twuijver3, D. Boot3, R. El Galta3, L. Klimek1, R. van Ree4, P. Kuna5, P. Panzner6

Abstract number: 1113 Session number, date and time: TPS 30, Monday 8 June 2015; 12:00 - 13:30

1 Center for Rhinology and Allergology Wiesbaden, Germany, 2Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, 3HAL Allergy BV, Leiden, The Netherlands, 4Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands, 5Barlicki University Hospital, Medical University of Lodz, Poland, 6Dept. of Allergology and Immunology, Medical Faculty in Plzen, Charles University Prague, Czech Republic.

Background

Poor correlation between symptom scores and absolute levels of allergen-specific serum IgG4 in allergic rhinitis.

The efficacy of specific immunotherapy has been confirmed in numerous trials in patients with allergic rhinitis (AR) induced by aeroallergens. Enhancement of clinical benefit might be feasible if biomarkers are available to identify (non-)responders, to determine the optimal treatment period and to predict relapse. Therefore, surrogate endpoints might be crucial for the development of new vaccines and to improve current treatment regimes.

Results Following 5 months of treatment a decrease in symptom scores was observed in all treatment groups, with active treatment showing a larger decrease than placebo. Serum IgG4 levels significantly increased in all active treatment groups, but not in the placebo group. Assessing the correlation between symptom scores following TNPT and IgG4 levels with and without adjustment for the treatment effect indicated a lack of association between the two parameters.

Conclusion No significant association could be demonstrated between the change in symptom score and birch pollen specific IgG4 levels. This confirms earlier reports that an increase in IgG4 levels per se is not predictive for clinical outcome. Testing for IgG4 associated inhibitory activity rather than absolute IgG4 levels might have a better correlation with clinical outcome.

EAACI, 6-10 June 2015, Barcelona, Spain 9

TPS 30 - Sensitization, allergen extracts and efficacy of AIT Poor correlation between symptom scores and absolute levels of allergen-specific serum IgG4 in allergic rhinitis.

1113 levelsabsoluteandscoressymptombetweencorrelationPoor– IgGserumallergen-speciﬁcof 4 rhinitisallergicin (AUN/ml)groupTreatment 3,333 LSmeanchangefrombaselineinsymptomscorecomparedto placebo LS mean change from baseline in birch pollen and bet v 1 specific IgG4 compared to placebo (log transformed) 40,00020,00010,000 0 0,5 1,5 2,51 2 -3-2,5-2-1,5-1-0,50 05 fromchangetheagainstScoreSymptombaselinefromchangetheofplotScatter IgG4specificpollenbirchloginbaseline inSymptomScore

4 -5 -10 20-24 IgG4specificpollenbirchloginBaselinefromChange ChangefromBaseline -0.14=coefficientCorrelation40,00020,00010,0003,333groupPlacebo 05 -5 -10 620-24fromchangetheagainstScoreSymptombaselinefromchangetheofplotScatter IgG4specific1VBetloginbaseline IgG4specific1VBetloginBaselinefromChange ChangefromBaselineinSymptomScore -0.17=coefficientCorrelation40,00020,00010,0003,333groupPlacebo 2015CongressEAACIInrelationtothispresentation,Ideclarethefollowing,realorperceivedconﬂictofinterest.ThepresenterisaconsultantofHALAllergy.

A total of 123 birch pollen allergic patients (81 adults, 42 adolescents) were randomized to either the C-reg. (62 patients) or A-reg. (61 patients). A high proportion of patients successfully reached the maintenance dose without safety concerns in both groups (98.4% and 96.7% for A-reg. and C-reg., respectively). The two-sided 95% confidence interval (CI) for the difference in proportions between the two treatment groups was (−3.8% - 7.1%), confirming non-inferiority of the A-reg. treatment. No differences were observed between adult and adolescents, the latter age group having a 100% success rate in both A-reg. and C-reg. At the end of study, significant increases in specific IgG and IgG4 were observed in both groups, independent from age.

Methods In birch pollen allergic patients presenting with rhinitis or rhinoconjunctivitis with or without mild asthma (FEV1 > 70%) an A-reg. (0.1-0.3-0.5 ml at weekly intervals) was compared to the C-reg. (0.05-0.1-0.2-0.3-0.4-0.5 ml at weekly intervals) using a glutaraldehyde-modified birch pollen preparation adsorbed to aluminium hydroxide. After up-dosing the maintenance dose (0.5 ml) was given 3 times at biweekly intervals. The multi-centre study was performed according to an open randomized, parallel group design. Success rate was based on the (predefined) need of additional up-dosing steps because of the occurrence of local and systemic reactions. Cases with more than 2 extra visits or a systemic reaction > grade I were considered as failures.

Accelerated up-dosing with a registered allergoid birch pollen SCIT preparation is non-inferior to conventional up-dosing.

Krzysztof Buczyłko1, Jan F van der Werf2, Diderik Boot2, Ronald van Ree3, Bernadetta Majorek-Olechowska4 1NZOZ Centrum Alergologii, Łódź, Poland, 2HAL Allergy B.V., Leiden, The Netherlands, 3Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands, 4Alergo-Med Specjalistyczna Przychodnia Lekarska Sp. z o.o. in Tarnow, Poland

Results

Session title: Sensitization, allergen extracts and efficacy of AIT 10 EAACI, 6-10 June 2015, Barcelona, Spain

The accelerated SCIT regimen is as safe as the conventional and might be used to up-dose adult as well adolescent patients within 2 weeks. Moreover, both up-dosing regimens resulted in similar immunological effects, as assessed after 3 injections in the maintenance phase.

Abstract number: 1098 Session number, date and time: TPS 30, Monday 8 June 2015; 12:00 - 13:30

Background The conventional registered up-dosing regimen (C-reg.) of the allergoid birch pollen preparation under evaluation requires six injections over five weeks. It is recommended to reach the maintenance dose before the pollen season. Due to climatic changes causing early pollen flight and new allergens prolonging the pollen season it is difficult, however, to up-dose outside the pollen season. An accelerated up-dosing regimen (A-reg.) would also be helpful for patients with multiple pollen allergies, patients coming near the beginning of pollen season, and patients who wish to up-dose faster. We performed a clinical study to investigate if A-reg. is as safe as C-reg.

Conclusion

Accelerated up-dosing with a registered allergoid birch pollen SCIT preparation is non-inferior to conventional up-dosing.

EAACI, 6-10 June 2015, Barcelona, Spain 11

TPS 30 - Sensitization, allergen extracts and efficacy of AIT

1098 –SCITpollenbirchallergoidregisteredawithup-dosingAccelerated up-dosingconventionaltonon-inferiorispreparation percentage AdolescentsAdultsAll Conventional Accelerated 100 90 80 70 60 50

4000 3500 3000 2500 2000 1500 1000 500 0 Conventional Adult EndStartEndStartStartEndStartAdultAdolescentAdolescentEndAdultAdultAdolescentAdolescent Accelerated g/l)(1vBetIgG4g/l)(birchIgG4µµ 2015CongressEAACI study.thisofperformancetheforrenumerationreceivedandinvestigatorcoordinatingwaspresenterTheinterest.ofconﬂictperceivedorrealfollowing,thedeclareIpresentation,thistorelationIn

Antonio Carbonell Martínez1, Ana Escudero Pastor1, Juan Carlos Miralles López1, María-Jesús Cruz Carmona2 1 Hospital Reina Sofía, Murcia, 2 HAL Allergy, Spain

Results In all patients it was possible to achieve the maintenance dose, except in one case where the dose was reduced to three drops after presenting oral itching and abdominal pain. No more side effects were observed during treatment. Regarding the need for medication, after a year of monitoring, 17 patients (39%) did not require any additional treatment, 14 patients (32%) needed rescue treatment only (Salbutamol or Ebastine 10 µg) in 8 patients (18%) it was not possible to reduce the daily dose of inhaled corticosteroids (budesonide 200 µg / every 12 hours) and finally in 5 patients (11%) the SLIT failed to modify the initial treatment (budesonide 160 µg and formoterol 4.5 µg, 1 dose every 12 hours and montelukast 10 mg). In the latter group, 3 patients (7%) attended the emergency department during the study period and required treatment with oral corticosteroids, no hospital admissions were observed.

Abstract number: 1107 Session number, date and time: TPS 30, Monday 8 June 2015; 12:00 - 13:30

Conclusions SLIT is a safe treatment for allergic asthma to Alternaria. After a year of SLIT, it is possible to decrease the pharmacological treatment in approximately 70% of patients.

Material and methods 44 patients (30 men), mean age 16 years, diagnosed with allergic asthma against Alternaria were included. Patients were treated with SLIT against Alternaria alternata using a dosage schedule where the maintenance dose is reached after 5 days of treatment (5 drops per day). All patients had primary treatment with inhaled corticosteroids, long acting beta agonist and montelukast. During the study, control visits were performed during clinic visits at six months and after one year of treatment. The doctor provided an assessment of asthma control and listed all medications prescribed.

Sublingual immunotherapy against alternaria allergens in patients with asthma.

Introduction Sublingual immunotherapy (SLIT) is safe and effective, but data concerning this treatment against Alternaria allergy are insufficient. The aim of this study was to evaluate the safety of SLIT against Alternaria and the possible changes in the need for medication after one year of treatment in patients with asthma.

Session title: Sensitization, allergen extracts and efficacy of AIT 12 EAACI, 6-10 June 2015, Barcelona, Spain

TPS 30 - Sensitization, allergen extracts and efficacy of AIT Sublingual immunotherapy against alternaria allergens in patients with asthma.

EAACI, 6-10 June 2015, Barcelona, Spain 13

1107 –inallergensalternariaagainstimmunotherapySublingual asthmawithpatients 44=n (SD)yrs,Agemean16(11) Sex30male (DS)meankU/L*SLIT;beforeEIglTota146(45) S)SLIT;afterEIglTotakU/L*,mean(D142(43) SLSpecificIgEbeforeIT;class,n(%) Class1 Class2 Class3 Class4 Class5 0 (60%)26 (27%)12 1%)(15 %)(21 44=nreactions.adverserelatedfrequentmost&historyAllergy2:Table

Diagnosis,% Asthma Rh+Asthmainitis 20 80 SLafterAdversereactionsIT,n*1 SLdurisaddepEmergencyt.missionngIT,n3 0 39 20 32 40 18 40 11 051015202530354045 ofAftlinBaseeer1yrtreatment %patients CoidednhalediReNotreatmentscuemcation*Icorticosteros**rticosteroids+LABA+Montelukast*** 2015CongressEAACI Allergy.HALofemployeeanisCruzMJinterest.ofconﬂictperceivedorrealfollowing,thedeclareIpresentation,thistorelationIn

Session title: Immunotherapy vaccines 14 EAACI, 6-10 June 2015, Barcelona, Spain

Conclusion In general a good tolerability was observed for both A-reg. and C-reg. and only small differences in the frequencies of local and systemic reactions and general AEs between the two age groups were observed. In both treatment groups there is a tendency towards better tolerance by the adolescent patients as compared to the adults.

Background Recently we compared accelerated (A-reg.) and conventional (C-reg.) up-dosing regimens with an allergoid birch pollen SCIT preparation. The A-reg. was found to be non-inferior thus providing a safe option to up-dose patients within 2 weeks. In the study both adults and adolescents were included, below an overview of all safety parameters will be given, comparing both populations. Methods In birch pollen allergic rhinitis/rhinoconjunctivitis patients with or without mild asthma (FEV1 > 70%) an A-reg. (0.1-0.3-0.5 ml at weekly intervals) was compared to the C-reg. (0.05-0.1-0.2-0.3-0.4-0.5 ml at weekly intervals) using a glutaraldehydemodified birch pollen preparation adsorbed to aluminium hydroxide. After up-dosing 3 maintenance doses (0.5 ml) were given. The multi-centre study was performed according to an open randomized, parallel group design. Early and late (within 30 min and within 24 hrs after injection) local (ELRs, LLRs) and systemic reactions (ESRs, LSRs) as well as general adverse events (AEs) were recorded. Vital signs were also monitored. Results

Accelerated and conventional up-dosing with a registered allergoid birch pollen SCIT preparation: a comparison of tolerability between adults and adolescents.

A total of 123 birch pollen allergic patients were randomized to either the C-reg. (62 patients, 41 adults) or A-reg. (61 patients, 40 Theadults).majority of the subjects did not show ELRs, only wheals ≤ 5 cm diameter were found with similar frequencies for both age groups. Regarding LLRs, 24.4% (n=30) of the subjects reported reactions with wheals ≤ 5 cm and 16.3% (n=20) with wheals > 5 cm ≤ 12 cm. One reaction with wheal > 12 cm was observed in the adult group (C-reg.). For the LLRs no consistent differences between age groups were found. Concerning ESRs the vast majority of subjects experienced no symptoms or non-specific symptoms (grade 0). None of the adolescents and only one adult patient had an ESR grade I. LSRs of grade I occurred in 3.3 (C-reg.) to 6.5% (A-reg.) of the subjects. No consistent differences between the adult and adolescent groups were found. 146 treatment-emergent (TE) AEs related to the medication were reported. The percentage of patients with a related TEAE appears somewhat lower in the adolescent compared to the adult population.

Abstract number: 529 Session number, date and time: PDS 25, Tuesday 9 June 2015; 10:30 - 12:00

Accelerated and conventional up-dosing with a registered allergoid birch pollen SCIT preparation: a comparison of tolerability between adults and adolescents.

EAACI, 6-10 June 2015, Barcelona, Spain 15

PDS 25 - Immunotherapy vaccines

529 pollenbirchallergoidregisteredawithup-dosingconventionalandAccelerated– adolescentsandadultsbetweentolerabilityofcomparisonapreparation:SCIT Conventional ReactionNo ≤but5> cm12cm12> ≤ cm5AdolescentAdultAll(%) 020406080100 LLRs (%)(%) AdolescentAdultAll(%)(%)(%)(%) TotalAccelerated LSRs

Conventional 0GradeIGradeReactionNoAdolescentAdultAll(%) 0%20%40%60%80%100% (%)(%) AdolescentAdultAll(%)(%)(%)(%) TotalAccelerated 2015CongressEAACIInrelationtothispresentation,Ideclarethefollowing,realorperceivedconﬂictofinterest.ThepresenterisaemployeeofHALAllergy.

Conclusions

Material and methods Thirty patients (14 males), mean age 21 years, diagnosed with allergic rhinitis against grasses with or without mild persistent asthma were included. Patients were treated with SIT. The treatment will be administered with an initial dose of 0.5 ml of the maintenance vial (first injection 0.2 ml + 0.3 ml, at intervals of 30 min between them, and a waiting period of one hour after the second dose), reaching a maximum dose of 0.5 ml two weeks later and repeating it each month. The safety of the treatment will be evaluated with a patient questionnaire on the basis of side effects. The symptoms and need for additional symptomatic medication during the season were also assessed before and after treatment.

The proposed dose could be administered in all patients. No local reactions occurred during the clustered injections. In 3 patients (10%) late mild local reaction was observed at the 0.5 mL dose at two weeks (mean wheal size: 4.5 cm). No systemic adverse reactions were observed. Regarding the need for medication, at baseline all patients were taking antihistaminics and nasal steroids. Eleven patients also needed β2-agonists on demand. After a year of follow-up, six patients (20%) did not require any additional treatment, 22 patients (73%) only needed antihistaminics and 7 of them (23%) plus β2-agonists on demand. Finally, in two patients (7%) was not possible to modify the initial treatment.

Frequency and severity of adverse side effects in cluster-SIT correspond to those described on literature in conventional dosage schedule. This SCIT treatment generated a significant improvement regarding the need of medication. The modified extract used in the study appears to be a safe and well-tolerated treatment for allergy in patients with allergic rhinitis against grasses. Abstract number: 1429 Session number, date and time: TPS 49, Tuesday 9 June 2015; 12:00 - 13:30 Session title: Safety of immunotherapy and immunotherapy for food allergy 16 EAACI, 6-10 June 2015, Barcelona, Spain

Safety of a cluster-immunotherapy with a depot allergoid in patients with allergic rhinitis against grasses.

Susana Monzón Ballarín1, Nuria Pérez Cinto2, Raquel Montijano Sanchez3, María-Jesús Cruz Carmona4 1 Consulta de Alergia. Consorcio Aragones de Salud. Ejea-Tarazona. Zaragoza, Spain; 2 Consulta de Alergia. Consorcio Aragonés de Salud. Centro Cinco Villas. Ejea de los Caballeros. Zaragoza, Spain; 3 Consulta de Alergia. Consorcio Aragonés de Salud. Centro Moncayo de Tarazona. Zaragoza; 4 HAL Allergy, Spain. Introduction Despite the benefits of subcutaneous immunotherapy (SCIT), some patients refuse treatment, partly because of the associated inconvenience. The cluster schemes can provide a more convenient treatment option, but there is a perception that they produce a higher rate of adverse reactions. The aim of this study is to investigate the safety and efficacy of a cluster scheme with a depot allergoid in patients with allergic rhinitis against grasses.

Results

EAACI, 6-10 June 2015, Barcelona, Spain 17

TPS 49 - Safety of immunotherapy and immunotherapy for food allergy

Safety of a cluster-immunotherapy with a depot allergoid in patients with allergic rhinitis against grasses.

30n= (SD)Age,mean (11)21 Sex le14ma )(%nsticDiagnos, isRhinit isRhinit+asthma (60%)18 (40%)12 (SmeankU/LIgEinselBaetotal,D)* (504)354 (SmekU/L,IgEtalFollowuptoanD)* (384)314 (SD)an/LkUIgE,ificinselBaespecme** 1429 –inallergoiddepotawithcluster-immunotherapyaofSafety grassesagainstrhinitisallergicwithpatients 3 1 0,21 0,3 0,5 0,5 0,5 2 3 4 5 1 7 11 Week InitialtreatmentMaintenancetreatment mi30nutes Inection

β β (SD)an/LkUIgE,ificinselBaespec,me lPh p1Phl p5Phl (30)58 (34)50 (37)45 (SmekU/L,IgE,ifFollowupspecicanD)** lPh p1Phl p5Phl (33)62 (38)43 (39)42 )(%nreactions,verseAd reactiotelaLocalns Systemicreactions )(130% 0 000 63 37 20 50 23 0 7 010203040506070 ihhitiAnNotreatmentstaminicsAntistamimics+ isB2agont hitiAnstamimics+ dseroialnasst hitiAnstamimics+ dsoialnasster+ oniB2agst %tsentiPa llFoliBaseneow-up 2015CongressEAACI Allergy.HALofemployeeanisCruzMJinterest.ofconﬂictperceivedorrealfollowing,thedeclareIpresentation,thistorelationIn

J. Rook1, H. Warmenhoven2, O. Brugman1, D. Verbart1, A. Huybens1 and H. van Schijndel2

Compared to bacterial expression systems, CHO cells possess human-like posttranslational modification machineries enabling the production of properly folded recombinant proteins while no endotoxins are produced. Previously, a stable CHO cell line (CHO-rBet v1.0101) was developed for expression of Bet v1.0101, the immunodominant isoform of the major birch pollen allergen Bet v1. In this study, a large scale bioreactor manufacturing process was developed to optimize the yield.

1 HALIX BV, Leiden, The Netherlands; 2 HAL Allergy BV, Leiden, The Netherlands

Methods To assess the feasibility of a large scale manufacturing process, a single use 2 L shaker bag and traditional 10 L bioreactor setup were inoculated with stably growing pre-cultures of CHO-rBet v1.0101 cells and cultured using a fed batch feeding strategy. Cell density, viability and metabolites were monitored at regular time intervals. Expression of rBet v1.0101 was measured using a in house developed Bet v1 ELISA kit. In addition, several commercially available CHO feeds were tested in a fed batch shaker flask setup to optimize the cell growth and rBet v1.0101 expression.

Large Scale Manufacturing of Recombinant Bet v1.0101 in Chinese Hamster Ovary cells.

Abstract number: 1055 Session number, date and time: TPS 26, Monday 8 June 2015; 12:00 - 13:30 Session title: Basic immunology 18 EAACI, 6-10 June 2015, Barcelona, Spain

Conclusion In this study, the feasibility of the CHO production platform for large scale manufacturing of recombinant Bet v1.0101 has been demonstrated. Furthermore, optimizing the feeding strategy may increase the rBet v1.0101 production further. It is expected that similar expression levels may be obtained by using an optimized feeding strategy in combination with a large scale manufacturing process, thus generating sufficient yield per batch for economic viability.

Results Compared to a previously, glucose-fed only batch culture, the Bet v1.0101 titre obtained with the single use 2 L shaker bag and the 10 L bioreactor were respectively 2.4 and 4 fold higher. Testing several commercially available CHO feeds showed higher Bet v1.0101 concentrations, viable cell densities and prolonged viability. The best feed yielded 14 times more Bet v1.0101 compared to the glucose-fed only batch culture.

Background Chinese Hamster Ovary (CHO) cells are the most widely used expression system for the production of therapeutic proteins.

EAACI, 6-10 June 2015, Barcelona, Spain 19

TPS 26 - Basic immunology Large Scale Manufacturing of Recombinant Bet v1.0101 in Chinese Hamster Ovary cells.

• • • 1055 RecombinantforPlatformManufacturingaofDevelopment– cellsOvaryHamsterChineseusingv1.0101Bet 120 100 80 60 40 20 0 rBetv1.0101(mg/L) Control2LbagShakerReactor10L 162024 ControlCBADEF cells/mL)

• • •• • • 0 Control 400300200100 (mg/L)v1.0101rBet A B C F E D 04126(108VCDcells/mL) 18161412108640 (days)Time 2 2015CongressEAACI group.AllergyHALtheHALIX/ofemployeeanispresenterTheinterest.ofconﬂictperceivedorrealfollowing,thedeclareIpresentation,thistorelationIn

HAL Allergy, Leiden, The Netherlands

Stressed conditions: Incubation at 45°C (12 days), 60°C (3 days) or 90°C (1 hour), freeze-thawing (5 times) or shaking (15 min at 2600 rpm). SDS-PAGE: Reduced samples on 4-12% Bis-tris gels and stained with silver. Immunoblot: After SDS-PAGE, proteins were transferred to PVDF membrane and stained using pooled sera from grass allergic patients, HRP-conjugated antibody and CN/DAB substrate. Protein: Bradford assay using BSA as a standard. Major allergen content: An ELISA was used to quantify Phl p 5 content. Potency: the allergenic activity was measured using an IgE-inhibition assay. CD: Spectra were recorded from 260-190 nm. Fluorescence: Emission spectra were recorded from 290-400 nm, excitation at 280 nm. HP-SEC: A Bio-Sec 3 size exclusion chromatography column was used with UV-detection.

Conclusion Temperature stressing of a Phleum pratense allergen extract affected the protein profile and IgE potency. In parallel, protein unfolding and protein aggregation occurred.

Sandipta Acharya, Gert Jan Stam, Niels Sinnige, Rob van den Hout, Dion Luykx

Abstract number: 1134 Session number, date and time: TPS 32, Monday 8 June 2015; 12:00 - 13:30

Session title: Allergen standardization 20 EAACI, 6-10 June 2015, Barcelona, Spain

Background Stressed and non-stressed Phleum pratense extracts were investigated with several analytical assays to monitor identity (SDSPAGE, immunoblot), content (protein, major allergen Phl p 5), potency (IgE potency) and structure (CD, Fluorescence, HP-SEC).

Results SDS-PAGE showed disappearance of bands and appearance of higher molecular weight bands for the Phleum pratense extract upon thermal stressing. Immunoblot showed reduced intensity of major allergen bands for the thermal stressed samples. The protein content was not affected by stressing the Phleum pratense extract whereas the Phl p 5 content decreased for the 90°C sample. The IgE potency decreased by temperature stressing. Temperature stressing induced unfolding of proteins according to CD and fluorescence spectroscopy. HP-SEC showed aggregation of Phleum pratense proteins after thermal treatment. Freeze-thawing and shaking did not affect any of the investigated properties of the Phleum pratense extract.

Stress stability study on a Phleum pratense extract.

Methods

EAACI, 6-10 June 2015, Barcelona, Spain 21

TPS 32 - Allergen standardization Stress stability study on a Phleum pratense extract.

1134 –aonstudystabilityStress pratensePhleum extract ba 250 150 100 75 50 37 25 20 15 10 250 150 100 75 50 37 25 20 15 10 M M 642135 642135 kDakDa ab 1 00,10,20,30,40,50,60,7 Relativepotency MajorAllergeng/mL)µ( 0.80,91 63245102468101214 63245

° ° ° mAU 500 400 300 200 100 0 1312111098657min1.35kDa 670kDa158kDa 17kDa44kDa mAU 50 40 30 20 10 0 1312111098657min 607080 a b stressedNon C45º C60º C90º hawFreezet Shaking 2015CongressEAACI Allergy.HALofemployeeanispresenterTheinterest.ofconﬂictperceivedorrealfollowing,thedeclareIpresentation,thistorelationIn

Results SDS-PAGE protein profiles revealed that wasp venom collected via sac extraction contains a high variety of proteins in comparison to electrostimulation venom. Via immunoblot and MS allergens Ves v 1 (~35 kDa), Ves v 2 (~45 kDa), Ves v 3 (~ 90 kDa) and Ves v 5 (~27 kDa) were identified in the wasp venom collected via the two different methods. The amount of Ves v 5 in relation to total venom protein was higher in wasp venom collected via electrostimulation (4 %) compared to via sac extraction (2 %). The CD-spectrum of sac extraction venom indicated a relative higher amount of α–helical proteins in comparison to electrostimulation venom.

Characterisation of wasp venom collected via electrostimulation or venom sac extraction.

Protein: Spectrophotometric method according to Lowry using BSA as a standard. Major allergen content: An ELISA was used to quantify Ves v 5. CD: Far-UV CD spectra were recorded from 260-190 nm.

Abstract number: 461 Session number, date and time: PDS 20, Monday 8 June 2015; 15:45 - 17:15

Background A characterisation study was performed on wasp venom obtained via either electrostimulation or venom sac extraction. Different assays with respect to identity, content and protein structure were applied.

Methods SDS-PAGE: Reduced samples were applied to 4-12% Bis-tris gels combined with silver staining. Immunoblot: After SDSPAGE, proteins were transferred to a PVDF membrane and stained using pooled sera of wasp venom allergic patients, HRP conjugated antibodies and CN/DAB substrate. MS: Tryptic digests were prepared from wasp venom samples. Peptides were separated via nano-HPLC before electrospray ionisation. Ionised peptides were fragmented revealing amino acid sequences.

Niels Sinnige, Susanne Quaak, Diederik van Deursen, Jolanda Meijlis, Rob van den Hout and Dion Luykx HAL Allergy, Leiden, The Netherlands

Conclusion The SDS-PAGE profiles and Ves v 5 (%) in total protein indicate that wasp venom collected via venom sac extraction contains more unidentified proteins compared to collection via electrostimulation. Ves v 1, 2, 3 and 5 were identified in both venoms.

Session title: Diagnosis and treatment of anaphylaxis and hymenoptera venom allergy 22 EAACI, 6-10 June 2015, Barcelona, Spain

EAACI, 6-10 June 2015, Barcelona, Spain 23

PDS 20 - Diagnosis and treatment of anaphylaxis and hymenoptera venom allergy

Characterisation of wasp venom collected via electrostimulation or venom sac extraction.

461 electrostimulationviacollectedvenomwaspofCharacterisation– extraction.sacvenomor 321123 kDa 3vVes 2vVes 1vVes 5vVes 3vVes 2vVes 1vVes 5vVes 250 150 100 75 50 37 25 20 15 10 kDa 250 150 100 75 50 37 25 20 15 10

8 6 4 2 0 250230210190 -2 -4 -6 -8 Ellipticity(mDeg) (nm)WavelengthextractionsacVenom Electrostimulation 2015CongressEAACIInrelationtothispresentation,Ideclarethefollowing,realorperceivedconﬂictofinterest.ThepresenterisanemployeeofHALAllergy.

Abbreviated leaflet texts. 24 EAACI, 6-10 June 2015, Barcelona, Spain

Composition: Suspensions for subcutaneous injection, containing allergenic substances chemically modified with glutaraldehyde and absorbed onto aluminium hydroxide from pollen (20,000 AUM/ml) or mites (20,000 AUeq/ml). Excipients: NaCl, phenol, aluminium hydroxide, water for injection. Areas of application: Specific immunotherapy for immediate-type allergic disorders (IgE-mediated), like hay fever (allergic rhinitis), allergic inflammation of the eye (conjunctivitis) and allergic bronchial asthma triggered by sensitisation to allergens. Contraindications, absolute: Acute inflammatory processes/infectious diseases in the afflicted organ; secondary changes to the afflicted organ (e.g. emphysema, bronchiectasis); autoimmune disorders; immunodeficiencies; concurrent use of immunosuppressants; severe, uncontrollable bronchial asthma, especially with a persistent FEV1 under 70% predicted value; diseases with contraindications against the use of adrenaline; concurrent treatment with ß-blockers (including ß-blocker-containing eye drops); malignant tumour with active clinical significance; treatment must not be started during pregnancy; sensitivity to an excipient; relative: Pregnancy and lactation; acute allergic symptoms; not for children under the age of 5 years. See specialist information for details of intervals to be maintained from vaccinations and other information. Side effects: Local and/or general allergic reaction. Flu, otitis externa, sinobronchitis, sinusitis, staphylococci pharyngitis. Hypersensitivity, anaphylactic shock. Eating disorders. Headache, dizziness, sleepiness, paresthesia, dysgeusia, attention deficit disorder. Eye oedema, conjunctivitis, rhinoconjunctivitis, eye irritation, itchy eyes, increased tearing. Dizziness, ear oedema, itchy ears. Arrhythmia, tachycardia. Circulatory collapse, hot flushes, haematoma. Rhinitis, blocked nose, nasal oedema, rhinorrhoea, sneezing, asthma, shortness of breath, coughing, bronchitis, dry throat, throat irritation, painful throat, laryngeal irritation, nasopharyngitis, nasal bleeding. Abdominal pain, gastritis, nausea, diarrhoea. Angioedema, urticaria, erythema, pruritis, eczema, atopic dermatitis, rash, acne, skin irritation. Musculoskeletal symptoms. Oedema, swelling, fatigue, asthenia, chest pain, pallor, fever. At the injection site: mostly transient granuloma, hardening, swelling, urticaria, erythema, hypersensitivity, pruritis, pain. Monitor patients for at least 30 minutes after injection, and an anaphylactic shock kit must be at hand. Adverse events can also manifest later. For further information and for the treatment of adverse events, see the specialist information. In rare cases, slight fatigue can develop after the injection, which should be taken into account when driving or handling machinery. Note: Prescription-only. (Status: February 2015)

Basic information for SUBLIVAC ®

Basic information for PURETHAL ®

Composition: SUBLIVAC ®, sublingual drops, contains allergen extracts that are specifically prescribed for the patient on the basis of a diagnostic examination. Indication: Treatment of IgE-mediated allergy in patients with symptoms of allergic rhinitis, allergic conjunctivitis and/or allergic asthma, caused by allergens. Dosage and administration: The treatment is started with a daily dose of one drop. This dose is then increased every day with one drop until the highest daily dose of five drops is reached. The treatment is continued with five drops. The drops are to be kept under the tongue for at least 1 minute (preferably 2 - 3 minutes) before they are swallowed. The treatment should be continued for 3 to 5 years in order to remain as symptom-free as possible after the completion of the course of treatment. Contraindications: Acute infections of the eye, airways or organs involved in the immune system, secondary changes in the lungs(e.g. lung emphysema or bronchi-ectasie), severe immunopathological diseases or malignancies (e.g. autoimmune diseases of the kidneys, thyroid glands or the nervous system, rheumatism, tuberculosis and HIV), immunodeficiencies (including as a consequence of immunosuppressants), severe uncontrolled asthma with FEV1 Warnings and precautions: If the treatment with pollen extracts is started during the pollen season, there is an increased risk of side effects. Take special care in case of pregnancy, inflammations in the mouth, after tooth extraction and in case of treatment with ß-blockers (including ß-blocker containing eye preparations). In the rare case that an anaphylactic shock occurs with the concomitant use of a ß-blocker, adrenaline as a rescue medication can be less efficacious and a higher dose of adrenaline may be required. Severe systemic allergic reactions should be treated with Adrenalin. under 70%, or hypersensitivity to any of the excipients. Side effects: Local reactions in the mouth and throat, stomach upset and diarrhoea. Worsening of allergic reactions such as rhinitis, conjunctivitis, coughing and atopic eczema. Intensified systemic reactions (such as shortness of breath, generalised urticaria or Quincke’s oedema) can develop in rare cases. Intensified allergic reactions can particularly develop in very hypersensitive patients. These symptoms generally arise within 30 minutes after intake of the drops. In individual cases anaphylactic shock has been reported in patients with concomitant asthma. Typical warning signs are burning, itching and heat sensation up and under the tongue, throat and palm of the hand and sole of the foot. Conditions for storage: Store in a refrigerator (2°C8°C). When the product is in use, it can be stored for a maximum of 6 months below 25 °C. Package: A SUBLIVAC ® Initial and maintenance treatment set consists of one bottle with dropper containing 24 ml fluid. The complete product information is available upon request at HAL Allergy BV, P.O. Box 1204, 2302 BE Leiden, The Netherlands. Date: July 2013

Basic information for VENOMEN HAL ®

Composition: VENOMENHAL® Bee, active ingredient: bee venom. VENOMENHAL® Wasp, active ingredient: wasp venom. Six injection bottles each containing 120 μg pure, freeze-dried bee or wasp venom. Excipients: HSA (human serum albumin) and mannitol. Solvent: 6 injection bottles each containing 1.2 ml of a solution of sodium chloride, phenol, HSA and water for injection. Indications: Dermal testing and specific immunotherapy for patients with IgE-mediated insect venom allergy, who experienced a systemic reaction after being stung by a bee or wasp. Contraindications: Acute inflammatory process/febrile infectious diseases; secondary disorders (e.g. emphysema, bronchiectasis); autoimmune disorders; immunodeficiency (including that induced by immunosuppressants); severe or inadequately controlled asthma (especially with FEV1 < 70% of reference value); cardiovascular disorders with increased risk when using adrenaline; treatment with ß-blockers (including ß-blocker-containing eye drops) and ACEinhibitors; malignant tumours with current clinical significance; sensitivity to one of the excipients. These listed contraindications must be weighed against the danger to the patient from another insect sting. Do not start treatment when pregnant. Details about the interval to leave after vaccinations and further information, see Instructions for use and specialist information. In addition, the known contraindications to conducting dermal testing, e.g. skin disease near the test site (see specialist information). Adverse effects: Along with local reactions, systemic allergic reactions of varying severity can occur during dermal testing and therapy: anaphylactic shock, headache, flushing, coughing, dyspnoea, wheezing, diarrhoea, dyspepsia, nausea, vomiting, itching, rash, urticaria, angioedema, eczema, erythema, arthralgia, swelling or pruritus or urticaria at the injection site, feeling unwell, fatigue, malaise, pain, fever, swelling, irregular pulse, irregular blood pressure. In rare cases a slight fatigue may be evident after the injection, which should be considered when driving or operating machinery. Patients must be monitored at least 30 minutes after the injection, and a shock kit must be on hand. Adverse effects can also develop several hours after the injection. For more information and for the treatment of adverse effects, see specialist information. NB: prescription-only. The complete product information is available on request: HAL Allergy BV, P.O. Box 1204, 2302 BE Leiden, The Netherlands. Date: April 2014

EAACI, 6-10 June 2015, Barcelona, Spain 25

Basisinformationen

Hinweis: Verschreibungspflichtig. (Stand: 02/2015)

Nebenwirkungen: Neben Lokalreaktionen können bei der Hauttestung und der Therapie systemische allergische Reaktionen unterschiedlicher Schweregrade auftreten: Anaphylaktischer Schock, Kopfschmerz, Gesichtsrötung (Flush), Husten, Dyspnoe, Giemen, Diarrhö, Dyspepsie, Übelkeit, Erbrechen, Juckreiz, Ausschlag, Urtikaria, Angioödem, Ekzem, Erythem, Arthralgie, Schwellung oder Pruritus oder Urtikaria an der Injektionsstelle, Unwohlsein, Müdigkeit, Krankheitsgefühl, Schmerzen, Fieber, Schwellung, Pulsanomalien, Blutdruckanomalien, In seltenen Fällen kann nach der Injektion leichte Müdigkeit auftreten, was beim Führen von Kraftfahrzeugen oder beim Bedienen von Maschinen zu berücksichtigen ist. Patienten nach der Injektion mindestens 30 Minuten überwachen, eine Schockapotheke muss bereitgestellt sein. Nebenwirkungen können auch mehrere Stunden nach der Injektion auftreten. Für weiterführende Informationen und zur Behandlung von Nebenwirkungen siehe Fachinformation. Hinweis: (Stand: 04/2014)

Basisinformationen VENOMEN HAL ® Biene / VENOMEN HAL ® Wespe Zusammensetzung: VENOMENHAL® Biene, Wirkstoff: Bienengift. VENOMENHAL® Wespe, Wirkstoff: Wespengift. 6 Durchstechflaschen enthalten jeweils 120 µg reines, gefriergetrocknetes Bienen- bzw. Wespengift. Sonstige Bestandteile: HSA (humanes Serum Albumin) und Mannitol. Lösungsmittel: 6 Durchstechflaschen enthalten jeweils 1,2 ml einer Lösung von Natriumchlorid, Phenol, HSA und Wasser zur Injektion. Anwendungsgebiete: Hauttestung und spezifische Immuntherapie von Patienten mit IgE - vermittelter Insektengiftallergie, bei denen systemische Reaktionen nach Bienen- oder Wespenstich aufgetreten sind. Gegenanzeigen: Akute Entzündungsprozesse/fieberhafte Infektionskrankheiten; Sekundärveränderungen (z.B. Emphysem, Bronchiektasen); Autoimmunerkrankungen; Immundefekte (auch durch Immunsuppressiva induziert); schweres oder unzureichend behandeltes Asthma (insbesondere bei FEV1 < 70% vom Sollwert); Herz- und Kreislauferkrankungen mit erhöhtem Risiko bei der Anwendung von Adrenalin; Behandlung mit ß-Blockern (auch ß-Blocker enthaltenden Augentropfen) und mit ACE-Hemmern; maligne Tumorerkrankungen mit aktuellem Krankheitswert; Sensibilisierung gegenüber einem der sonstigen Bestandteile. Die genannten Kontraindikationen sollten gegen die Gefährdung des Patienten durch einen erneuten Insektenstich abgewogen werden. Einleitung der Behandlung nicht während der Schwangerschaft. Zum zeitlichen Intervall zu Schutzimpfungen und für weiterführende Informationen siehe Gebrauchs- und Fachinformation. Ferner gelten die bekannten Gegenanzeigen für die Durchführung von Hauttestungen, wie z.B. Hautkrankheiten im Testbereich (siehe Fachinformation).

PURETHAL ® Zusammensetzung: Suspensionen zur subkutanen Injektion, enthalten an Aluminiumhydroxid adsorbierte, mit Glutaraldehyd chemisch modifizierte allergene Substanzen aus Pollen (20.000 AUM/ml) oder Milben (20.000 AUeq/ml). Sonstige Bestandteile: NaCl, Phenol, Aluminiumhydroxid, Wasser zur Injektion. Anwendungsgebiete: Spezifische Immuntherapie allergischer Erkrankungen vom Soforttyp (IgE-vermittelt), wie Heuschnupfen (allergische Rhinitis), allergische Bindehautentzündung (Konjunktivitis) und allergisches Asthma bronchiale, ausgelöst durch eine Sensibilisierung gegenüber den enthaltenen allergenen Substanzen. Gegenanzeigen, absolute: Akute Entzündungsprozesse/Infektionskrankheiten am Reaktionsorgan; Sekundärveränderungen am Reaktionsorgan (z.B. Emphysem, Bronchiektasen); Autoimmunerkrankungen; Immundefekte; gleichzeitige Anwendung von Immunsuppressiva; schweres, unkontrollierbares Asthma bronchiale, insbesondere bei einem persistierenden FEV1 unter 70% Sollwert; Erkrankungen mit Kontraindikationen gegen die Anwendung von Adrenalin; gleichzeitige Behandlung mit ß-Blockern (auch ß-Blocker enthaltende Augentropfen); maligne Tumorerkrankungen mit aktuellem Krankheitswert; Einleitung der Behandlung nicht während der Schwangerschaft; Sensibilisierung gegenüber einem der sonstigen Bestandteile; relative: Schwangerschaft und Stillzeit; akute allergische Beschwerden; nicht für Kinder unter 5 Jahren. Zum zeitlichen Intervall zu Schutzimpfungen und für weiterführende Informationen siehe Fachinformation. Nebenwirkungen: Allergische Lokal- und/oder Allgemeinreaktionen. Grippe, Otitis externa, Sinobronchitis, Sinusitis, Staphylokokkenpharyngitis. Überempfindlichkeit, anaphylaktischer Schock. Essstörung. Kopfschmerz, Schwindelgefühl, Schläfrigkeit, Parästhesie, Geschmacksstörung, Aufmerksamkeitsstörungen. Schwellung des Auges, Konjunktivitis, Rhinokonjunktivitis, Augenreizung, Augenjucken, Tränensekretion verstärkt. Schwindel, Ohrschwellung, Ohrenjucken. Arrhythmie, Tachykardie. Kreislaufkollaps, Hitzegefühl, Hämatom. Rhinitis, Nasenverstopfung, Nasenödem, Rhinorrhoe, Niesen, Asthma, Atemnot, Husten, Bronchitis, Halstrockenheit, Rachenreizung, Rachenschmerzen, Kehlkopfirritation, Nasopharyngitis, Nasenbluten. Abdominalschmerzen, Gastritis, Übelkeit, Diarrhoe. Angioödem, Urtikaria, Erythem, Juckreiz, Ekzem, atopische Dermatitis, Ausschlag, Akne, Hautreizung. Muskuloskelettale Beschwerden. Ödem, Schwellung, Ermüdung, Schwäche, Brustschmerz, Blässe, Fieber. An der Injektionsstelle: meist vorübergehende Granulome, Verhärtung, Schwellung, Urtikaria, Erythem, Überempfindlichkeit, Juckreiz, Schmerz. Patienten nach der Injektion mindestens 30 Minuten überwachen, eine Schockapotheke muss bereitgestellt sein. Nebenreaktionen können auch noch zu einem späteren Zeitpunkt auftreten. Für weiterführende Informationen und zur Behandlung von Nebenwirkungen siehe Fachinformation. In seltenen Fällen kann nach der Injektion leichte Müdigkeit auftreten, was beim Führen von Kraftfahrzeugen oder beim Bedienen von Maschinen zu berücksichtigen ist.

Verschreibungspflichtig.

Dinatrium-hydrogenphosphat,

Basisinformationen SUBLIVAC ® FIX / SUBLIVAC ® Zusammensetzung: Allergenlösungen zur sublingualen Immuntherapie. Genaue Bezeichnung und Stärke der Allergene s. Etikett. SUBLIVAC ® enthält Allergenextrakte nach individueller ärztlicher Rezeptur. Sonstige Bestandteile: Glycerol, Wasser, 6-Aminohexansäure (ε-Amino-Capronsäure/ EACA), Natrium dihydrogenphosphat, Pfefferminzöl. Anwendungsgebiete: Spezifische Immuntherapie allergischer Erkrankungen vom Soforttyp (IgE-vermittelt). Gegenanzeigen: Sekundärveränderungen am Reaktionsorgan (z.B. Emphysem, Bronchiektasen); Schwere Autoimmunerkrankungen; Immundefekte (auch durch Immunsuppressiva induziert); Krebserkrankungen mit aktuellem Krankheitswert; schweres oder unzureichend behandeltes Asthma (FEV1 < 70% vom Sollwert); Überempfindlichkeit gegenüber einem der sonstigen Bestandteile; akute Entzündungsprozesse/Infektionskrankheiten am Reaktionsorgan; Infektionen des Mund-/Rachenraumes; nach zahnärztlicher Behandlung (z.B. Zahnentfernung). Eine Hyposensibilisierungsbehandlung soll nicht während der Schwangerschaft begonnen werden. Zum zeitlichen Intervall zu Schutzimpfungen und für weiterführende Informationen siehe Fachinformation. Nebenwirkungen: Lokalreaktionen leichter Art im Zungen-/ Mundbereich wie Juckreiz, Brennen, Prickeln, Kribbeln oder Schwellung; milde allergische Allgemeinreaktion (Augenjucken, Fließschnupfen, Niesreiz, Husten, Verschlechterung eines atopischen Ekzems). In Einzelfällen gesteigerte Allgemeinreaktion wie Atemnot, generalisierte Urtikaria, oder Quincke-Ödem. Bauchschmerzen und Durchfall können mit zeitlicher Verzögerung vorkommen. In Einzelfällen ist ein anaphylaktischer Schock bei Patienten mit Asthma aufgetreten. Für weiterführende Informationen und zur Behandlung von Nebenwirkungen siehe Fachinformation. Hinweis: Verschreibungspflichtig. (Stand: 04/2014)

Notes.

IRISSloveniaMednarodna Trgovina D.O.O. Cesta v Gorice 8 1000 Ljubljana Tel.: +386-1-200-6684 www.iris.si

A.M.D.PortugalPassos, Lda. Edif. República 2º Piso Escritório X Avenida da República 2645-143 ALCABIDECHE Tel.: +351-21-4578087

HALSpainAllergy S.L.U Parque Empresarial Mas Blau II Avda. Les Garrigues 46 08820-El Prat de Llobregat Barcelona Tel.: +34-902-110-686 www.halallergy.es HALItaly Allergy s.r.l. Piazzale Asia, 21 Scala B, Piano 4, Interno 21, 00144 Roma Tel: +39-06-97243570 www.halallergy.it Belgium / Benelux HAL Allergy Benelux B.V. J.H. Oortweg 15-17 2333 CH Leiden The Netherlands Tel.: +32-(0)2-5278380 www.hal-allergy.nl Distributors BaltiEstoniaIntermed OÜ Tartu mnt 84d 10112 Tallinn Tel.: +372-601-4140

HungaropharmaHungary Zrt. 1061 Budapest Király u.12 Tel.: +36-1-327-6700

HALAustriaAllergy Handels-GmbH Johnstraße 4-6 1150 Wien Tel.: +43-(0)1-4893100 www.hal-allergy.at

International Offices. Offices HALGermanyAllergie GmbH Poststraße 5-6 40213 Düsseldorf Tel.: +49-(0)211-977650 www.hal-allergie.de

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Headquarters The Netherlands HAL Allergy Group J.H.Oortweg 15-17 2333 CH Leiden P.O. Box 1204 2302 BE Leiden Tel.: +31-(0)88-1959 000 www.hal-allergy.com