Recent Developments in Allergy Diagnosis and Treatment Miman MC, MD, Professor.

Disclosure Speaker has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the speak.

Introduction Allergic diseases most prevalent, major socio-economic burden. Up to 25% of the population in industrialized countries and their incidence is continuously rising, particularly in children and young adults.

Recent Advances Diagnosis Pharmacological treatment Immunotherapy Future???

Advances in Diagnosis Molecular allergy diagnosis -> more accurate diagnosis -> accurate prescription of therapeutic intervention. in vitro allergy diagnosis -> discriminate between sensitization and true allergy. Recombinant technology -> tremendous advances in allergen characterization vaccine development the knowledge of immune mechanisms involved in allergic diseases.

Standardized allergen Classic allergen extracts’ problem: standardization difficulties Due to their biologic nature, extracts represent a heterogeneous mixture of proteins, glycoprotein, and polysaccharides from a given allergenic source the allergen content of extracts varies between different manufacturers as well as between batches.

Standardized allergen To use of purified recombinant allergens To develop and validate methods for the quantification of allergen content of extracts limitations of allergens extracts molecular allergy diagnosis as an alternative to investigate specific IgE binding to purified molecules (natural as well as recombinant). advantages of molecular allergy diagnosis over extract-based methods the ability to distinguish between genuine sensitization versus cross-reactivity

Advances in Pharmacological Treatment For years, the mainstay of treatment, recommended first line by all AR treatment guidelines Intranasal steroids and antihistamines

Promising recent advances MP-AzeFlu  (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in a single spray), histamine H3 and H4 receptor antagonists toll-like receptor (TLR) targeted treatment. recently discovered compounds (e.g. ciclesonide and phosphodiesterase-4 inhibitors) immunological therapies like omalizumab new biomolecular preparations, cellulose powders and microemulsions are under investigation.

MP-AzeFlu consists of two drugs from two different medication classes with complementary effects, benefiting from antihistamine, mast cell stabilizing, antileukotriene, anti-inflammatory properties targeting both the early- and late-phase allergic responses the volume per spray is greater than that of marketed INS sprays. MP-AzeFlu has surpassed the efficacy of INS for the first time for the treatment of AR the most promising new treatment option.

New antihistamines An H3 receptor antagonist (PF-03654746) targeting multiple histamine receptors (GSK1004723, GSK835726 and WO2010094643) tested in combination with oral H1 antihistamine (fexofenadine) showed reduction in nasal symptoms of patients suffering from out-of-season AR.

TLR (Toll-Like Receptor) agonists TLRs are the first line of defense against invading aeroallergens. TLR agonists show strong immunogenicity and can enhance the efficacy of immunotherapy when used as adjuvants for allergy vaccines. Specific immunomodulation via co-administration of the allergen and TLR2/6 agonist, BPPcysMPEG, reduced allergic airway inflammation from sub-sequent allergen contact in mice. Intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics improved nasal and ocular symptoms in AR, revealing their potential in treatment of AR.

Cellulose powder and microemulsions Barrier protection measures by application of topical nasal cellulose powders or microemulsion to avoid contact with allergens. good promise for the treatment of PAR where aeroallergens are hard to avoid.

Novel Biologicals Biologicals are therapeutic agents with large molecular weights synthesized by living organisms targeting a specific determinant, e.g., monoclonal antibodies (mAbs) that bind to cytokines or receptors involved in the inflammatory pathways.

Novel Biologicals Omalizumab an IgE inhibiting recombinant humanized monoclonal antibody used to treat patients sensitive to perennial aeroallergens who have not responded to more traditional treatment strategies. rapidly reduces free serum IgE levels by over 95% the reduction of receptor density on the mast cells or basophils

bispecific antibodies targeting more than one cell or receptor is an innovative approach for the future

Advances in Immunotherapy Immunotherapies delivered in novel biomolecular preparations reduced allergenicity while maintaining immunogenicity to enable safe and slow release of lower doses over a short period of time. wider applicability of IT Current advances and research focus on novel routes of administration, modification of allergens utilization of new adjuvants adjunct therapies

Advances in Immunotherapy Focusing aspects: The identification of the most important disease- relevant components to diminish the number of allergens necessary for effective therapy The modification of these components to reduce IgE binding and consequently the possibility of side effects Optimization of the formulation and route of application of the allergens in order to maximize therapeutic efficacy The improving immunogenicity led to investigation of T-cell epitope-based peptides and recombinant allergen derivatives.

T-cell epitope peptides the use of sets of short allergen-derived peptides carefully selected and designed to comprise the dominant T-cell-reactive sites of the major allergen sequences but lacking IgE binding and inflammatory cell- activating potential

Recombinant allergens an alternative approach to generate hypoallergenic molecules with retained or potentially enhanced immunomodulatory activity

Sublingual immunotherapy for mites oro-dispersable sublingual tablets its stability on room temperature is higher compared to liquid formulations. The efficacy in patients with allergic rhinitis and asthma.

Adjuvants to immunotherapy different adjuvants increasing the duration of antigen presentation direct effects on the immune response cascade TLR engagement on APC plays an important role in regulating adaptive immunity TLR ligands can be selected to promote Treg responses and immune deviation from Th2 to Th1 profile.

Future biologics that cover a broader spectrum of cytokines involved in the immune response Recombinant HDM allergen tablets are expected to strengthen the efficacy and immunogenity, and reduce allergenity and duration of treatment of allergen vaccines

Thanks for your interest. References Klimek L, Mullol J, Hellings P, et al. Recent pharmacological developments in the treatment of perennial and persistent allergic rhinitis, Exp Op Pharm, (2016) 17:5, 657-669. Tan HTT, Sugita K, Akdis CA. Novel Biologicals for the Treatment of Allergic Diseases and Asthma. Curr Allergy Asthma Rep (2016) 16:70, 2- 14. Sandrini A, Rolland JM, O’Hehir RE. Current developments for improving efficacy of allergy vaccines. Exp Rev Vac, (2015) 14:8, 1073-1087. Bahceciler NN, Hocaoglu AB, Galip N. A milestone in house dust-mite- allergen immunotherapy: the new sublingual tablet S-524101 (actair), Expert Review of Vaccines, (2014) 13:12, 1427-1438. Thanks for your interest.