Safety and efficacy of immunotherapy with the recombinant B-cell epitope–based grass pollen vaccine BM32 - 31/01/18

Doi : 10.1016/j.jaci.2017.09.052

Verena Niederberger, MD ^a, Angela Neubauer, PhD ^b, Philippe Gevaert, MD ^c, Mihaela Zidarn, MD ^d, Margitta Worm, MD ^e, Werner Aberer, MD ^f, Hans Jørgen Malling, MD ^g, Oliver Pfaar, MD ^h,ⁱ, Ludger Klimek, MD ^h, Wolfgang Pfützner, MD ^j, Johannes Ring, MD ^k, Ulf Darsow, MD ^k, Natalija Novak, MD ^l, Roy Gerth van Wijk, MD ^m, Julia Eckl-Dorna, MD, PhD ^a, Margarete Focke-Tejkl, PhD ⁿ, Milena Weber, MSc ⁿ, Hans-Helge Müller, PhD ^o, Joachim Klinger, PhD ^p, Frank Stolz, PhD ^b, Nora Breit, MSc ^b, Rainer Henning, PhD ^b, Rudolf Valenta, MD ^n,^q,^⁎
^a Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria
^b Biomay AG, Vienna, Austria
^c Department Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium
^d University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia
^e Allergy Center, Charité, Berlin, Germany
^f Department of Dermatology and Venerology, Medical University Graz, Graz, Austria
^g Allergy Clinic Copenhagen University Hospital, Gentofte, Denmark
^h Center for Rhinology/Allergology, Wiesbaden, Germany
ⁱ Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^j Department of Dermatology and Allergology, Medical Center Giessen and Marburg GmbH, Marburg, Germany
^k Department of Dermatology and Allergy Biederstein, Technical University Munich (TUM) and ZAUM-Center of Allergy and Environment, Munich, Germany
^l Clinic for Dermatology and Allergology, University of Bonn, Bonn, Germany
^m Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
ⁿ Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University Vienna, Vienna, Austria
^o Institute for Medical Information Technology, Biometrics and Epidemiology, Ludwig-Maximilians-Universität, Munich, and the Institute for Medical Biometry and Epidemiology, Philipps-University, Marburg, Germany
^p SynteractHCR Deutschland GmbH, Munich, Germany
^q NRC Institute of Immunology FMBA of Russia, Moscow

^∗Corresponding author: Rudolf Valenta, MD, Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Waehringer Guertel 18-20, 3Q, 1090 Vienna, Austria.Division of ImmunopathologyDepartment of Pathophysiology and Allergy ResearchCenter for Pathophysiology, Infectiology and ImmunologyMedical University of ViennaWaehringer Guertel 18-20, 3QVienna1090Austria

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Abstract

Background

BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein.

Objective

We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen–induced rhinitis and controlled asthma.

Methods

A double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 μg, n = 60) or high dose (160 μg, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC.

Results

Although statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year.

Conclusions

Injections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

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Key words : Allergy, grass pollen allergy, allergen, allergen immunotherapy, recombinant allergen, B-cell epitope–based immunotherapy, efficacy, hypoallergenic, clinical trial, safety

Abbreviations used : AE, AIT, API, AR/C, EAACI, FAS, GPS, HBV, IDMC, LS, MS, RQLQ, SA, SMS, SPT, SS, VAS

Plan

Assessment of clinical efficacy parameters

Statistical analysis

Assessment of safety

Assessment of immunologic parameters

Results

Preseasonal treatment with 3 injections of BM32 improves the SMS during the GPS

Improvement of the SMS is best in subjects with high levels of grass pollen–specific IgE

Preseasonal treatment with BM32 improves well-being and rhinoconjunctivitis-related quality of life during the GPS

Treatment with BM32 improves grass pollen–related asthma symptoms

Vaccination with BM32 induces significant increases in allergen-specific IgG, IgG₁, and IgG₄ responses

Vaccination with BM32 does not induce increases in grass pollen allergen–specific IgE levels and prevents seasonally induced boosts of grass pollen–specific IgE production

Treatment with BM32 is safe and well tolerated

Discussion

Supported by Biomay AG, Vienna, Austria, and research grants F4605 and F4613 of the Austrian Science Fund (FWF). R.V. is recipient of a Megagrant of the Government of the Russian Federation, grant number 14.W03.31.0024.

Disclosure of potential conflict of interest: A. Neubauer is employed by Biomay and is a minor stockholder. W. Aberer has received travel support from Biomay AG. O. Pfaar's institution received grant funds from Biomay, and he has received consultant fees from HAL-Allergy Holding B.V./HAL-Allergie GmbH, Allergy Therapeutics/Bencard Allergie GmbH, Novartis Pharma, Laboratorios LETI/LETI Pharma, MEDA Pharma, ALK-Abelló, Anergis S.A., Biotech Tools S.A., Sanofi US Services, Mobile Chamber Experts (a GA²LEN partner), Pohl-Boskamp, Stallergenes-Greer, Lofarma, and Allergopharma; he has received grants from Stallergenes-Greer, HAL-Allergy Holding B.V./HAL-Allergie, Allergy Therapeutics/Bencard Allergie GmbH, Laboratorios LETI/LETI Pharma, and Anergis S.A.; his institution has received funds from these along with ALK-Abelló, Allergopharma, Lofarma, Nuvo, Circassia, and Biotech Tools S.A.; he has received lecture fees from HAL-Allergy Holding B.V./HAL-Allergie GmbH, Allergy Therapeutics/Bencard Allergie GmbH, Novartis Pharma, Laboratorios LETI/LETI Pharma, ALK-Abelló, Allergopharma, Lofarma, and Stallergenes-Greer; and he has received payment for educational presentations from Stallergenes-Greer. L. Klimek's institution has received consultant fees from ALK-Abelló, Allergopharma, Bionorica, Boehringer Ingelheim, Lofarma, Novartis, MEDA Pharma, and GlaxoSmithKline; has grants with ALK-Abelló, Allergopharma, Bencard, Biomay, HAL, GlaxoSmithKline, LETI, Lofarma, Novartis, and Roxall; has received fees for lectures from ALK-Abelló, Allergopharma, Bionorica, Boehringer, GlaxoSmithKline, Lofarma, Novartis, and MEDA Pharma; receives fees for manuscript preparation from MEDA Pharma and Bionorica; and receives fees for Board membership from MEDA Pharma and Novartis. W. Pfützner and his institution have received clinical study fees from Biomay. He has received consultant fees from ALK-Abelló and lecture fees from ALK-Abelló and Novartis and has grants from ALK-Abelló and Biomay. U. Darsow's institution has received funds as clinical study compensation. N. Novak's institution contributed study patients and has received funding from ALK-Abelló; she received consultant fees from LETI Pharma, ALK-Abelló, and Stallergenes and for lectures from ALK-Abelló, LETI Pharma, Stallergenes, HAL Allergy, and Novartis. R. Gerth van Wijk's institution has received funding for study participation and grant funds from Dutch Lung Foundation and STW, and he has received consultant and lecture fees from ALK-Abelló and Allergopharma and travel funding from the European Academy of Allergy and Clinical Immunology and UEMS. H.-H. Müller received fees from SynteractHCR and Deutschland GmbH for statistical analysis and his institution receives funding from St Jude Medical for statistical analysis not relevant to this work. J. Klinger's institution has received fees for review activities from SynteractHCR. F. Stolz is employed by Biomay. N. Breit has received consulting fees and travel support from Biomay. R. Henning is employed by Biomay AG, holds stock, and has patents with the company. R. Valenta's institution has grant funding from Biomay AG, Thermo Fisher, and Fresenius Medical Care, and he has received consultant fees from Biomay AG, Thermo Fisher, and Fresenius Medical Care. The rest of the authors declare that they have no relevant conflicts of interest.