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XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015 Presidente: Alfonso Mario Cepeda Sarabia
Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai:
2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza Buenos Aires, marzo 14-16, 2015 - http://www.slaai2015.com
Programa Congreso Para Todos XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015
Monomeric allergoid: the new advances of AIT, in only one product
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Monomeric)allergoid:)the)new)advances)of)AIT,)in)only)one)product!
Enrico)Compala>)M.D.,)Ph.D.))Specialist)in)Allergy)and)Clinical)Immunology)))
!University!of!Genoa!
Italy!
E!Compala5!Buenos!Aires!2015! 2!
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A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.!
In relation to my presentation, I declare the following, real or perceived conflicts of interest: • Financial interests : Honoraria, travel and accommodation sponsored by LOFARMA spa, Milan. Italy • Research interests
• Organizational interests
!
Disclosure
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Unmet!needs!
Tolerability:!!risk!of!side!effects,!also!lifeGthreatening!
Low!adherence:!!!number!of!injec5ons!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!lenght!of!treatment!course!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!occurrence!of!side!effects!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!not!perceived!benefit!
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SCIT!safety!from!US!surveys!
Risk of fatal reactions: < 1 / 2.500.000 injections Severe or uncontrolled asthma is the most important and independent risk factor for both nonfatal and fatal adverse reactions to SCIT A remote risk of severe side-effects exists, mainly when improperly prescribed or administered!!
Lockey'RF'et#al.#Fatali)es#from#immunotherapy#(IT)#and#skin#tes)ng#(ST).#J#Allergy#Clin#Immunol#1987;#79:660–677.#Reid'MJ'et#al.#Survey#of#fatali)es#from#skin#tes)ng#and#immunotherapy#1985–1989.#J#Allergy#Clin#Immunol#1993;#92:6–15#Cox'L,#Aaronson#D,#Casale#TB,#Honsinger#R,#Weber#R.#J!Allergy!Clin!Immunol!Pract.!2013!September!G!October;1(5):455G457.!#.#
Allergy)Immunotherapy)Safety:))Loca>on)MaDers!))!SCIT!has!an!EXCELLENT!SAFETY!PROFILE!largely!due!to!the!safety!measures!that!are!implemented!when!SCIT!is!administered!in!a!medically!supervised!se\ng!with!appropriate!staff!and!equipment!to!immediately!recognize!and!treat!anaphylaxis!
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AIT!–!pa5ents’!acceptance!KEY!MESSAGE!!Early!studies!with!demanding!schedules!!and!!very!frequent!injec5ons,!reported!a!low!compliance!!
Incorvaia'et#al.#Pa)ent’s#compliance#with#allergen#immunotherapy.#Pa)ent#Preference#and#Adherence#2008:2#247–251#E!Compala5!Buenos!Aires!2015! 7!
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RealGlife)compliance)and)persistence)among)users)of)subcutaneous)and)sublingual)allergen)immunotherapy.)!
Kiel)MA,!Röder!E,!Gerth!van!Wijk!R,!Al!MJ,!Hop!WC,!RuhenGvan!Mölken!MP.!J!Allergy!Clin!Immunol.!2013!Aug;132(2):353G60!
Retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapyfor 1 or more of the allergens of interest between 1994 and 2009. 2796= SCIT 3690= SLIT!
Summary!of!5me!to!treatment!discon5nua5on!by!route!of!administra5on!
SCIT!
SLIT!
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��!�)�&���"**,�*�)�$�+���+'�*,�$"& ,�$�"%%,&'+!�)�(/��*�(�)��"-����/��$$�) "*+*�
Scura5!S.!Pa5ent!Prefer!Adherence.!2010!
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SLIT!–!risk!of!anaphylac5c!reac5ons!
Calderón'MA.#Sublingual#allergen#immunotherapy:#mode#of#ac)on#and#its#rela)onship#with#the#safety#profile#.#Allergy.#2012#Mar;67(3):302Z11.##
14)cases)of)anaphylaxis)to)SLIT))
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Pediatr!Allergy!Immunol.!2014!Nov;25(7):714G5!
J!Allergy!Clin!Immunol!Pract.!2014!JulGAug;2(4):485G6!
300!IR/mL!HDM!allergen!(maintenance!of!8!presses!3!5mes!per!week)!
SLIT!prepara5on!!!!(70%!L.!perenne!and!30%!C.!dactylon)!
100!IR!tablet!(5Ggrass!pollen)!
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Unmet!needs!
Tolerability!!!!!!!!Low!adherence!!
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Improving!the!‘risk/benefit’!profile!
#
#
Improve#the#immunogenicity#of#AIT#without#increasing#its#allergenicity#
! !bypassing!IgE!and!targe5ng!T!cells!
! !enhancing!immunological!s5mula5on!
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Altering!the!allergen!extract!structure!
• Chemically!modified!allergens!(allergoids)!
• Gene5cally!engineered!allergens!!!!!!!!!!!!!!!!!!!(recombinant!technology,!pep5des,!etc.)!
14!
Bypassing!IgE!and!targe5ng!T!cells!
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a) TLRG4,!TLRG9,!TLRG7!agonists,!!VirusGlike!par5cles,!!CarbohydrateGbased!par5cles!skew!the!cytokine!balance!from!TH2!to!TH1!
!!
15!
Enhancing!immunological!s5mula5on!!
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b)!Novel!route!of!administra5on:!Intralympha5c,!intradermic!
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ILIT!
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Biologically!ac5ve!dose!
Enhancing!immunogenity!
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! !bypassing!IgE!and!targe5ng!T!cells!
! !enhancing!immunological!s5mula5on!!
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Monomeric)allergoids,))the)new)advances)of)AIT,)in)only)one)product!
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monomeric ~40 kda polymeric >1000 kda
Der)p)1)))))N))M)
only)E!Compala5!Buenos!Aires!2015! 19!
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! !bypassing!IgE!and!targe5ng!T!cells!
! !enhancing!immunological!s5mula5on!!
20!
Monomeric)allergoids,))the)new)advances)of)AIT,)in)only)one)product!
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Allergoid)
allergenicity) Low)allergenicity)
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demonstrated in-vitro (comparison between native and modified grass extract by EAST-inhibition)
REDUCED REACTIVITY with IgE )
demonstrated in-vivo (comparison between native and modified
grass extract by SPT) !
Mistrello!et!al.!Allergy.!1996!Jan;51(1):8G15!E!Compala5!Buenos!Aires!2015! 22!
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nanoLCGMSMSGbased!sequence!analysis!
Most!lysine!residues!(>80%)!of!the!modified!extracts!were!determined!to!be!carbamylated.!
Betula!verrucosa!!and!Alnus!glu5nosa!
Bet!v!1,!Aln!g!1,!!Bet!v!2,!!Bet!v!6!
Phleum!partense,!!Holcus!lanatus!and!Poa!pratense!
group!1!G!5!
mix!mite!
Der!f!1,!3,!7,!10,!11,!14!!Der!p!1,!2,!7,!10,!11!
Detected!allergens!aqer!modifica5on!E!Compala5!Buenos!Aires!2015! 23!
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SLIT)posi>on)paper)2009)
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G!prospec5ve,!openGlabel,!randomized!study#G #1000#AU#five#)mes#a#week#without'any'upGdosing!!Vs!pharmacotherapy'G ##pre/coGseasonally!for!12!weeks/year!for!2!consecu5ve!years.!G #40#allergic#children#(16#with#rhini)s#and#24#with#rhini)s#and#asthma)#G !range!4G16!years!
no)systemic),)no)local)adverse)events) X!Maintenance!!
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! !bypassing!IgE!and!targe5ng!T!cells!
! !enhancing!immunological!s5mula5on!!
26!
Monomeric)allergoids,))the)new)advances)of)AIT,)in)only)one)product!
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PROTEASES!
PROTEIN!
Enzymatic degradation
High)bioavailability)
Reduced Enzymatic
degradation
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Biologically!ac5ve!dose!like!a!“novel!route”!of!administra5on…!
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Int!J!Immunopathol!Pharmacol.!2010;!23!(4):!1021G1031.!
Peyer’s)patches)
Allergen!immune!response!and!GALT!
Exposure!of!the!allergoid!exclusively!to!the!GALT!induces!a!tolerogenic!response!
OVA)–)PP)–TCD4+25+IL10+)
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Treatment))Purposes)
)1))MODIFICATION)of))immunological)response)))2))REDUCTION)of)immunoGinflamma>on))3))REMISSION))of)symptoms)and)drug)use))5))MODIFICATION)of)natural)history)of)disease)
v
31!
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1))increased)ILG10)cytokine)))
Before!!
Aqer!6!months!
Group)1:!Lais!
Group)2:!untreated!controls!
Cosmi!G!Maggi!G!Romagnani!.!Clin!Exp!Allergy2006!
2))reduced)lymphocytes)prolifera>ve)capacity))a_er)specific)s>mula>on)
Untreated!Lais!
3))No)early)IgE)peak))
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*:p=0.06; #:p=0.062; §:p=0.05 In)vitro)G)ex)vivo)cytokine)release))by)PBMCs)))preG)and)postGinduc>on Derp1 stimulated PBMCs)
IfnGγ! ILG4! TnfGα!
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Treatment))Purposes)
)1))MODIFICATION)of))immunological)response)))2))REDUCTION)of)immunoGinflamma>on))3))REMISSION))of)symptoms)and)drug)use))5))MODIFICATION)of)natural)history)of)disease)
v v
34!
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CPT)
Passalacqua.!Lancet!1998!E!Compala5!Buenos!Aires!2015! 35!
EOS)
ICAMG1)
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Treatment))Purposes)
)1))MODIFICATION)of))immunological)response)))2))REDUCTION)of)immunoGinflamma>on))3))REMISSION))of)symptoms)and)drug)use))5))MODIFICATION)of)natural)history)of)disease)
v v v
36!
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Clinical!Development!of!Monomeric!allergoid!1994G2012! 1994 1995 1996 1996 1997 1998 2000 2001 2005 2006 2007 2008 2009 2010 2011 2012
Pharmaco- kinetic Studies
Allergy Allergy JACI CEA IAAI Mistrello
Par j1 Fallagiani
Par j1 Bagnasco
Par j1 Bagnasco
Par j1 Bagnasco
Der p2
Lais Mites RPM Not. All. Lancet IJIP Allergy CEA PAI IAAI EAACI Allergy IJIP
2 DBPC 76 Patients
9 open 364 Patients
Pacor open
A
14 P
LaRosa open vs. SCIT
C
30 P
Passalacqua DBPC
A
20 P
Marogna open vs. control
A 41 P
Passalacqua DBPC
A
56 P
Cosmi open vs. control
A 25 P
Ippoliti open
C
40 P
Marogna retrosp.
A
65 P
Marogna retrosp.
A
101 P
Agostinis open
C
40 P
Di Gioacch. Open
A
48 P
Lais Parietaria
IACI All.Imm.
1 DBPC 30 Patients
1 open 65 Patients
Ariano DBPC
A
30 P
D’Anneo open
A
65 P
Lais Ragweed
Not. All. Not. All. 1 DBPC
60 Patients 1 open
60 Patients
Mezei DBPC C+A 60 P
Cerhati open C+A 60 P
Lais Grass
GIAI RPM Not. All. Allergy JIACI Allergol. Immunopath. AAAI EAAIC EAACI 4 DBPPC
190 Patients 5 open
168 Patients
Bordignon DBPC
C+A 60 P
Pacor open
A
34 P
Cavagni DBPC
C
44 P
Caffarelli DBPC
C
48 P
Lombardi open vs. control
A 51 P
Palma-Carlos DBPC
A
38 P
Burastero open
A
11 P
Agostinis Open
C
40 P
Quercia Open
A
32 P
Lais Trees
IJIP All. Imm. 2 open
87 Patients Burastero
open A
11 P
Marogna open
A
76 P
EAACI Eur. Ann. Allergy Clin Immunol GIAI Giornale It. Allergol. Immunol. EAAIC Eur. Ann. All. Immun. Clin. IJIP Int. Journ. Imm. Pharm. EACI Euro. Ann. Clin. Immunol. RPM Rec. Prog. Med. JIACI Journ. Invest. Allergol. clin. Immunol. PAI Pediatr. Allergy Immunol. CEA Clin. Exp. All. AAAI Ann All Ast Imm. IAAI Int Arch. All. Immunol. IACI Invest. All. Clin. Immunol. All Imm Allergology and Immunophatology (Madr.)
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rela5ve!clinical!impact!100!×!(scorePlacebo!!G!scoreAc5ve)!!!!!!!!!!!/scorePlacebo.!
An5GH1!
An5G!LTR!
Nasal!steroids!
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[9] Devillier P, Dreyfus JF, Demoly P, Calderón MA. A meta-analysis of sublingual allergen immunotherapy and pharmacotherapy in pollen-induced seasonal allergic rhinoconjunctivitis. BMC Med. 2014 May 1;12:71.!
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4.3.1)Early)studies))4.3.2)DoseGfinding)studies)(phase)II))))4.3.4)Confirmatory)efficacy)studies)(phase)III))))
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Clinical!Development!G!Registra5ve!trials!G!
Grass!pollen!tablet!
adults! children!
Phase!II!Phase!III!
Phase!II!Phase!III!
Phase!II!Phase!III!
Phase!II!Phase!III!
concluded!
concluded!Ongoing!!
!Ongoing!
concluded!star5ng!
concluded!star5ng!
Phase!III!
Phase!III!
Phase!III!
Phase!III!
PIP!G!planned!
PIP!G!planned!
PIPG!planned!
PIP!G!planned!
2024!2011!
Tree!pollen!tablet!
Ambrosia#pollen!tablet!
HDM!tablet!
Parietaria#pollen!tablet! Phase!II!
planned!
Phase!III!planned!
Phase!III!PIP!G!planned!
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Clinical!Development!G!Registra5ve!trials!G!Mul5center,!prospec5ve,!doubleGblind,!randomized!!
DOSEGRANGING!!studies!
12!WEEKS!
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Clinical!Development:!phase!II!doseGfinding!trials!
Grass! Birch!
Ragweed!Mites!
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! All TRAEs were mild in nature
! 5,9% of all patients under active treatment experienced local TRAEs
! 4,9% of all patients under active treatment experienced systemic TRAEs
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Treatment))Purposes)
)1))MODIFICATION)of))immunological)response)))2))REDUCTION)of)immunoGinflamma>on))3))REMISSION))of)symptoms)and)drug)use))5))MODIFICATION)of)natural)history)of)disease)
v v v v
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65!pa5ents!(18G41!y)!with!rhini5s!and!BHR!caused!by!!HDM!allergy:!!15!pts!!for!1!year!10!pts!!for!2!years!14!pts!for!!3!years!14!pts!for!!4!years!
4)years))))))))))))))))7G8)years)
Int#Arch#Allergy#Immunol.#2007;142(1):70Z8.#
" !!
47!
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Preven>on)asthma))&))new))sensi>za>ons)
Sublingual)immunotherapy)in)the)context)of)a)clinical)prac>ce)improvement)program)in)the)allergological)sehng:)results)of)a)longGterm)observa>onal)study.)Marogna!M,!Massolo!A.!Eur#Ann#Allergy#Clin#Immunol.#2003#Apr;35(4):133Z40.###
Aqer!3!years!treatment!SLIT!pa5ents!(mean!age!19,6)!
48!
From) To) SLIT) Control)
rhini5s! rhini5s!BHR!asthma!
48!(100%)!0!0!
33!(51%)!14!(22%)!26.6!(15%)!
P<0.001!P=0.001!P<0.001!
Baseline) New)sensi>za>on)
SLIT!!!!!!!!!106!Control!!!170!
3!(2.8%)!64!(37.6%)!
P<0.001!
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Real!life!convenience!?'
" Reduced!allergenicity……………….tolerability!!" Tolerability……………………………….high!manageability!" High!manageability………………….adherence!!" Enhanced!tolerogenic!ac5vity…..efficient!doses!" Good!clinical!outcome………………pa5ents’!acceptance!" Pa5ents’!acceptance…………………adherence!
49!Thank!You!!!
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XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015!Presidente: Alfonso Mario Cepeda Sarabia
Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai:
2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza Buenos Aires, marzo 14-16, 2015
http://www.slaai2015.com/comites-del-congreso/ Información Slaai: www.slaai.org
Programa Congreso Para Todos Conferencias XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología
Sociedad Latinoamericana de Alergia, Asma e Inmunología, SLaai
