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Challenges in the Development of Allergen Immunotherapies
Rod Hafner 8th July 2015
2
Disclaimer
This presentation has been prepared, issued and disclosed to a limited number of recipients for the sole purpose of introducing Circassia Limited and its Affiliates ( the ‘Circassia Group’) and their products (‘Products’) to those recipients. This presentation is made available on the express understanding that it will not be used by the recipients in connection with the purchase of or investment in securities of the Circassia Group or purchase or use of any Products which are manufactured or sold by or on behalf of the Circassia Group. This presentation is accordingly not intended to form the basis of any investment decision and does not constitute or contain anyrecommendation by the presenter or the Circassia Group or any director employee agent or adviser. This document does not constitute a prospectus or an offer or invitation for the sale or purchase of any shares or other securities in, or any underlying assets of the Circassia Group.
No representation or warranty, express or implied, is made by the presenter or the Circassia Group or any director employee agent or adviser as to the adequacy, fairness, accuracy, or completeness of the information or opinions contained in the presentation or in any statements made orally in connection with this presentation and no liability is accepted by any such person in relation to any such information or opinion for any loss or damage of whatever description suffered by any persons arising from any reliance on the information or any of the statements, opinions or conclusions set out in this presentation or the comments, written or oral, of any person made in connection with this presentation.
This document contains certain estimated historical and prospective financial and operating data. Any financial information contained in this document regarding any part of the Circassia Group has been obtained from information prepared by the Circassia group for internal purposes only and not with a view toward disclosure to third parties and may not comply with any GAAP. No attempt has been made by the Circassia Group to audit or verify such financial information and such information should not be taken as a reliable indication of financial performance of the Circassia Group or any member thereof or of any Product.
The contents of this presentation are subject to copyright which will be asserted by Circassia Limited and no part of this presentation may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means without prior permission in writing from Circassia Limited.
3
Agenda
An introduction into the current situation in allergen
immunotherapies
Identification of key challenges and opportunities in the field
Synthetic Peptide Immuno-Regulatory Epitopes: a new class of
compounds
Modern, 21st century product made to pharma standards
4
Allergic rhinitis is a global healthcare problemAffects 10-20% of global population
Allergic diseases affect over 1 billion people worldwide3
Allergic rhinitis is the world’s most prevalent chronic non-communicable disease3
Allergy is medical condition with greatest impact on work productivity in US4
Allergy is a precursor of asthma; treatment with immunotherapy halts “allergic march”
3. EAACI Global Atlas of Allergy 2014
4. Gemson & Eng, August 2004
1. US Census Bureau, 2012
2. World Bank, 2012
Immunotherapy is the only way to treat the underlying disease
Europe
Rank AllergenSkin prick test positive
(% Popln) (million)2
1 House dust mite 22 82
2 Grass pollen 17 63
3 Cat 8-10 30-37
4 Birch pollen 6 22
5 Mould 4 15
6 Olive pollen 3 11
Source: Bousquet et al. Allergy. 2007: 62: 301-9
USA
Rank AllergenSkin prick test positive
(% Popln) (million)1
1 House dust mite 28 86
2 Perennial rye 27 84
3 Short ragweed 26 82
4 Cockroach 26 82
5 Bermuda grass 18 57
6 Cat 17 53
Source: Arbes et al. J Allergy Clin Immunol. 2005 Aug;116(2):377-83.
Future potential targetsTargeted by Circassia
5
An introduction into the current situation in
allergen immunotherapies
Allergen Immunotherapy more than 100 years old
Major differences in clinical practice in Europe and US
– Europe branded products, typically adsorbed onto alum
– US bulk allergens mixed by Allergists, typically not alum adsorbed
Whole allergen typically has local and systemic side effects associated
with it, in the worst case including anaphylaxis
Evidence of efficacy especially with bulk allergens mixed by US Allergists
is poor
– Few if any industry standard double blind placebo controlled studies
Modern, 21st century product made to pharma standards
6
Evidence of efficacy is weak
“Immunotherapy with cat extract has been studied by several investigators. It
is generally believed that hyposensitization with this product is helpful in
reducing allergic symptoms associated with exposure to cat allergens in
homes or the environment.”
Greer US cat allergen pack insert
7
Systemic reactions must be expected
“Adverse systemic reactions may occur within minutes with any allergenic extract, includingcat. These reactions consist primarily of allergic symptoms such as generalized skin erythema,urticaria, pruritus, angioedema, rhinitis, wheezing, laryngeal edema and hypotension. Lesscommonly, nausea, emesis, abdominal cramps, diarrhea and uterine contractions may occur.Severe reactions may cause shock and loss of consciousness. Fatalities with allergenic extractshave occurred rarely. (21) Anaphylaxis and deaths following the subcutaneous injection ofextracts have also been reported by the British Committee on Safety of Medicine.(22) Systemicreactions occur with varying frequency in different clinics and are usually less than 1%. Tosome extent, the reaction rate is related to the type and dose of administered extract and tothe degree of sensitivity of the patient. In general, immunotherapy with allergenic extracts isconsidered to be safe. (23)Despite all precautions, occasional reactions are unavoidable.“
Greer US cat allergen pack insert
8
Even “standardised” products are not
standardised (and they may be unstable)
“Standardized Cat Hair Extract labeled in Bioequivalent Allergy Units is not interchangeable withStandardized Cat Pelt Extract or with cat extracts labeled in Allergy Units. Patient doses stated orcalculated in Allergy Units should not be confused with Bioequivalent Allergy Units because the BAU is tentimes as potent as the Allergy Unit used for cat extracts before September 1992.
The dosage must be reduced when starting a patient on fresh Standardized Cat Hair Extract or whentransferring a patient from any other cat extract product to Standardized Cat Hair Extract (even thoughthe labeled strength of the old and new vials may be the same). This reduction in dosage may benecessary due to a loss of extract potency during storage in the physician's office. The cat allergencontent of old and new extracts must be compared and adjusted by dosage reduction and/or dilutionbefore the new extract is administered. The amount of new extract given should not exceed 25% of thelast dose given from the old vial, assuming both extracts contain comparable amounts of cat allergens.Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages ofimmunotherapy, as well as during maintenance therapy.”
Greer US cat allergen pack insert
9
Sub-lingual immunotherapy tablets
Allergen given under tongue as drops or fast dissolving tablet
Double blind placebo controlled studies have been conducted for Grass, Ragweed, and House Dust Mite
– Grass products licensed in EU/US; Ragweed in US
Local reactions at site of administration
– Requires prescription and training in use of Epinephrine autoinjector in US
Requires long duration of treatment
– Daily 4 months before season and through season
– Daily for three years to have sustained duration of treatment effect
– Low adherence (7% complete 3yrs1) in real world studies
1J Allergy Clin Immunol. 2013 Aug;132(2):353-60.e2. doi: 10.1016/j.jaci.2013.03.013
10
10
Grazax markedly more adverse events than placebo
Sublingual has high incidence of adverse events
11
Agenda
An introduction into the current situation in allergen immunotherapies
Identification of key challenges and opportunities in the field
Synthetic Peptide Immuno-Regulatory Epitopes: a new class of
compounds
Modern, 21st century product made to pharma standards
12
Key challenges and opportunities in the field
Modern, 21st century product made to pharma standards
Challenge Opportunity
Systemic reactions mediated by 3D structure Eliminate 3D structure
Consistency of manufacture Synthetic/ recombinant manufacturing
Increasing scrutiny by MS/MS reveals multiple isoforms in whole allergen
Control isoforms or eliminate via synthetic/ recombinant manufacturing
Ensuring consistency of product through shelf life and avoiding need for cold chain
Develop room temperature stable product with 3 year shelf life
Long treatment regimens = poor compliance Short course of treatment
European standard PIP calls for paediatric studies with 3 years of treatment followed by two years off treatment
Significant barrier to competitor product entry for those that make investment
FDA requirement to rule out “pre-specified delta”
Significant barrier to competitor product entry for those that make investment
13
FDA presentation at Oralair advisory panel
Explaining the required “95% confidence
interval”
14
Agenda
An introduction into the current situation in allergen immunotherapies
Identification of key challenges and opportunities in the field
Synthetic Peptide Immuno-Regulatory Epitopes: a new class of
compounds
Modern, 21st century product made to pharma standards
15
Proprietary ToleroMune® technology
ToleroMune® technology identifies T cell epitopes
– Short linear stretches of amino acids within allergen sequence
– Bind to antigen presenting cells to induce regulatory T cells
– Identified from blood of allergic individuals
– Basophil histamine release assay to confirm absence of IgE cross-
linking
SPIREs – Synthetic Peptide Immuno-Regulatory Epitopes
Provides efficacy with short treatment & without the safety issues
– Regulatory T cells down-regulate allergic response
– Lack of B cell epitopes in peptides avoids cross-linking of mast
cells eliminating early response / no need to dose escalate
– Synthetic manufacture – no extraction from whole allergens
T cell
epitopes
selected
Whole
allergen
Final product is a
room temperature
stable, lyophilisate
containing a mix
of 7 peptides for
reconstitution for
injection
Modern, synthetic, rationally-designed pharmaceutical products
treating underlying disease with minimal side-effects
16
Cat-SPIRE epitope identification
Cat allergic individuals donate blood
Peripheral Blood Mononuclear Cells prepared – 1 in 20,000 to 1 in 50,000 cells epitope specific
Putative T cell epitopes screened for ability to induce proliferation
responses in fresh culture
IL-10, IL-13 and IFN-ɣ responses in supernatants also measured
Design goal to identify a set of peptides which give comparable response
on a population basis to whole cat dander
Modern, 21st century product made to pharma standards
17
Distribution of T cell responses to Cat-SPIRE peptides
84 cat-allergic volunteers
PBMC responses (IL-13, IFNg, IL-10)
assessment of response based on
background signal and assay sensitivity
MLA01
MLA03
MLA04
MLA05
MLA07
MLA12
MLA14
cat-PAD
whole allergen
no single peptide is dominant
all contribute to activity
population is heterogeneous
response of population to peptide
mixture is similar to whole allergen
- response observed in 1/3 cytokines
- response observed in 2/3 cytokines
- response observed in 3/3 cytokines
18
Each of the seven peptides is manufactured individually as
a modern day pharmaceutical API to cGMP
Seven synthetic peptides, each built up one amino acid at a time using
Fmoc chemistry
UPLC and MS/MS characterization to confirm sequence of each peptide
and to quantify degradants and impurities– Reference standard characterised by Edman degradation
Consistent batches of starting material
No risk of cross contamination
No issues with variable amounts of isoforms
Pathogen free
19
MS/MS Analysis of MLA04
MS spectra of MLA04 [M+H]+
[Mm+0+H]+ MS/MS Spectra
Analysis of b and y ion MS/MS peptide fragments confirm amino acid sequence
Position 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
AA Lys Ala Leu Pro Val Val Leu Glu Asn Ala Arg Ile Leu Lys Asn Cys Val
b-ion (m/z) 128.9 199.9 313 410 509.1 608.1 721.2 850.2 964.3 1035.4 1191.5 1304.6 1417.7 1545.8 1660 1763.1 1861.7
y-ion (m/z) 1880.1 1752.1 1681 1567.8 1470.8 1371.6 1272.5 1159.4 1030.3 916.3 845.2 689.1 576 463 334.9 220.9 n.d.
20
Cat-SPIRE drug product is manufactured as a modern day
pharmaceutical product to cGMP
Final product is a mixture of seven peptides
Prepared as a room temperature stable lyophilisate for reconstitution with
WFI– Scaled up to 100,000 vial batch size
– Can be stored at 25oC, 60% RH for three years
UPLC assays confirm content of each individual peptide and impurities/
degradants; – Two orthogonal assays using either acetonitrile or methanol gradients to
assure all possible degradants and impurities identified
– Mass spec. tracking assures correct assignations
Product standardised from vial to vial and batch to batch
21
UPLC-MS Analysis of Cat-SPIRE
UPLC UV Chromatogram
Extracted ESI-MS Spectra
of MLA04
Ref Std S1 (161210); 23 May 2012 21:48:03 BST
2.0
37
2.1
15
2.2
07
2.7
75
2.8
32
2.9
63
3.1
45
3.4
77
3.5
68
4.0
06
10.2
90
10.2
97 10.9
26
11.1
04
11.3
24
11.8
82
12.1
64
12.4
46
12.8
52
14.7
92 17.0
37
17.6
73
17.8
67
18.9
91
19.2
25
19.4
03
19.6
71
19.9
59
20.3
58
20.7
57
21.1
89
21.7
71
21.9
55
22.4
89
22.7
77
22.9
88
23.1
53
23.6
89
23.9
88
24.3
02
24.4
63
25.6
81
26.2
10
27.7
04
28.5
58
28.6
92
AU
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
1.30
1.40
1.50
Minutes
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00
24.644 Extracted
622.0
627.8
784.9
941.1
941.9
943.0952.1 1881.7
Inte
nsity
0.0
5.0x106
1.0x107
1.5x107
2.0x107
2.5x107
3.0x107
m/z
500.00 1000.00 1500.00 2000.00
[M+2H]2+
[M+3H]3+
[M+H]+
22Note: Excludes mechanistic studies
Clinical trials in over 3,500 subjects22 studies complete; 6 ongoing
TR002B:
1-year follow-up
2008 2009 20112010 2012 2013
Cat-
SP
IRE
HD
M-S
PIR
ER
ag
weed
-SP
IRE
Gra
ss-S
PIR
E
CP001: PhIIa /
n=88 / dose finding
CP003: PhII / n=48
/ asthmatics
CP002: PhIIb /
n=121 / EEC
CP005: PhIIb / n=202 /
commercial formulation
TH001: PhIIa / n=50
/ dose finding
TH002: PhIIb / n=172 / EEC
TH003: n=109 /
observational study
TR001: PhIIa / n=50 /
dose finding
TR003: n=88 / observational
study
TR002: PhIIb / n=275 / EEC
TG001: PhIIa / n=50
/ dose findingTG002A: 2nd
season follow-upTG002: PhIIb / n=282
/ EEC
PE
RE
NN
IAL
SE
AS
ON
AL
CP009: PhII / n ≥12 / Paediatric
TR007: Ph II /
n=53 / asthma
TG004: phase II /
n=54 / asthma
2014
CP005B: 2-year
follow-up
CP007A: 2-5 year
follow-up
TR006: Phase Iib / n=280
/ EEC
TG003: n=108 /
observational studyOngoing
CompletedTG002B: 3rd
season follow-up
CATALYST / CP007: PhIII / n=1,409 / field study
TH002A: 2 year
follow-up
TH004: PhII /
n=30 / asthma
TH005: Phase IIb /
n=660 / field study
CP005A: 1-year
follow-up
CP008: n=105 /
observational study
23
Screening
Baseline
Challenge
EEC
4 days
3hrs/day
50 ng/m3
Fel d 1
Post
treatment
challenge
EEC
18-22 wk
50ng/m3
Fel d 1
Dosing (3 months)
8 x 3 nmol 2 wks
apart
4 x 6 nmol 4 wks
apart*
8 x placebo 2 wks
apart
Intradermal
Design
Post
treatment
challenge
EEC
50-54 wk
50ng/m3
Fel d 1
Post
treatment
challenge
EEC
100-104 wk
50ng/m3
Fel d 1
N=202 N=89 N=51
CP005 CP005A CP005B
* infill placebo to maintain blind
Cat-SPIRE: Environmental Exposure ChamberStudy design
24
Cat-SPIRE Environmental Exposure Chamber studyDose ranging study using commercial formulation
Randomised, placebo-controlled parallel group exposure
chamber study– Using final room-temperature stable formulation
202 subjects randomised
– 2 Cat-PAD dosing regimes and placebo
Primary objective: to evaluate efficacy of Cat-SPIRE
treatment regimens in cat allergic subjects following cat
allergen challenge
Subjects in exposure chamber 3 hours per day for 4 days
at baseline and post treatment challenge– Exposed to standardised concentrations of cat dander
– Recorded symptoms every 30 minutes
Room-temperature-stable
formulation
Exposure
chamber
Toronto
25
TRSS – Symptom scoring for allergy trials
Total Rhinoconjunctivitis Symptoms Score (“TRSS”)
‒ Scoring scheme fulfilling regulatory requirements
‒ Used for approval of intranasal steroids, antihistamines etc.
Patient self-rated symptom scores used as primary measure of efficacy
Measurement of symptom scores on a 4-point rating scale
‒ 0: absent
‒ 1: mild, barely noticeable,
‒ 2: moderate, annoying / bothersome,
‒ 3: severe, very annoying / very bothersome
SPIRE studies monitor 8 different symptoms, resulting in a 24-point rating scale. Cat-SPIRE used
nasal symptoms: Runny nose, sneezing, blocked nose, itchy nose, and ocular symptoms: Itchy eyes,
watery eyes, red eyes, sore eyes
TRSS score of 8 could be 8 “mild / barely noticeable scores”
TRSS score of 12 could be 4 “mild / barely noticeable” and 4 “moderate / annoying” scores
26
Cat-SPIRE Environmental Exposure Chamber studyOne year follow-up to test duration of effect
Following sight of initial study results subjects recruited back into a one year
follow-up study
– Designed to look at duration of effect
No further dosing
New principal investigator to maintain blinding
– Subjects not unblinded; study staff not unblinded; new subject numbers issued
89 of 167 eligible subjects agreed to participate; 2 screen fails
Further 4 days of 3 hour challenge in exposure chamber performed 50-54
weeks after start of dosing in original study
Primary endpoint was the same as the original study: change in TRSS from
baseline
27
TRSS scores at 18-22 weeksSubjects participating in one year follow-up
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0
4
8
12
16
20
Placebo
8 x 3 nmol 2w apart
4 x 6 nmol 4w apart
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0
4
8
12
16
Placebo
8 x 3 nmol 2w apart
4 x 6 nmol 4w apart
TRSS
16
TRSS
16
TRSS
8
Day 1 Day 2 Day 3 Day 4
Baseline Challenge
Post Treatment Challenge 18-22 weeks
Day 1 Day 2 Day 3 Day 4
Patel et al JACI (2013) 131: 103-109
28
Day 1
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0
4
8
12
16
20
Placebo
8 x 3 nmol 2w apart
4 x 6 nmol 4w apart
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
0
4
8
12
16
20
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0
4
8
12
16
20
Placebo
8 x 3 nmol 2w apart
4 x 6 nmol 4w apart
Post Treatment Challenge 50-54 weeks
Day 1 Day 2 Day 3 Day 4
Baseline Challenge
TRSS
16
TRSS
16
TRSS
8
Day 1 Day 2 Day 3 Day 4
Patel et al JACI (2013) 131: 103-109
TRSS scores at 50-54 weeksSubjects participating in one year follow-up
29
Delta TRSS on all 4 days in exposure chamberPTC at 18-22 weeks and 50-54 weeks for subjects
participating in one year follow-up
DeltaTRSS -8
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Placebo
8 x 3 nmol 2w apart
4 x 6 nmol 4w apart
CP005A-2A CP005A-2B CP005A-2C CP005A-2D
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Time(Hours)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
TR
SS
Ch
an
ge
fro
m B
ase
line
-10
-8
-6
-4
-2
0
2
4
Placebo
8 x 3 nmol 2w apart
4 x 6 nmol 4w apart
Challenge at 50-54 weeks
Challenge at 18-22 weeks
DeltaTRSS -8
Day 1 Day 2 Day 3 Day 4
Day 1 Day 2 Day 3 Day 4
Patel et al JACI (2013) 131: 103-109
30
All subjects at 50-54 weeksData for same subjects at EEC visit at 18-22 weeks also shown
Placebo 4 x 6nmol 8 x 3nmol
ITT (N) 36 24 28
Mean change + SD
at 18-22 weeks-3.10 ± 4.98 -4.99 ± 5.68 -4.61± 5.14
Median change
at 18-22 weeks-3.60 -5.20 -4.10
ITT (N) 36 24 28
Mean change + SD
at 50-54 weeks-2.49 ± 5.39 -6.35 ± 5.75 -3.64 ± 5.14
Median change
at 50-54 weeks-3.20 -6.03 -3.30
p value vs placebo (ANCOVA) 0.0057
Patel et al JACI (2013) 131: 103-109
31
Secondary endpoint - ocular & nasal symptomsNon asthmatics, Days 2,3,4 time points after 1 hour
Placebo 4 x 6nmol 8 x 3nmol
mITT population (N)29 21 23
Mean change Total Nasal
Symptom Scores (±SD) -1.63 ± 2.95 -3.44 ± 3.05 -2.18 ± 2.76
p value vs placebo (ANCOVA)0.0200
Mean change Total Ocular
Symptom Score (±SD) -1.28 ± 2.92 -3.34± 3.05 -1.72 ± 3.17
p value vs placebo (ANCOVA)0.0121
Patel et al JACI (2013) 131: 103-109
32
Cat-SPIRE represents therapeutic step changeMore effective and more convenient
Product/Study3 Treatment Difference Active vs. Placebo
TRSS
Cat-SPIRE chamber study1 4 doses 4 weeks apart 3.9
ALK-Abelló Grazax® pivotal field study2
(licensed in Europe) SLIT tablets
Daily 16 weeks before and during
season1.0
Stallergenes Oralair® grass field study2
(licensed in Europe) SLIT tablets
Daily 16 weeks before and during
season1.4
Allergy Therapeutics Pollinex® Quattro
grass field study2 (filed Germany in
2009, not yet approved) adjuvanted
whole allergen IT
4 administrations 1 week apart 1.1
GSK fluticasone furoate perennial
rhinitis field study2 intranasal steroidOnce daily for 4 weeks 0.86
Sanofi fexofenadine cat chamber study2
antihistamine
180 mg 2 hours before chamber (ie
pre-symptoms)1.3
1 Based on the 4 x 6 nmol dose of Cat-SPIRE in CP005A
2 Source: Summary of product characteristics for each product, except i) Fexofenadine: Ann Allergy Asthma Immunol. 2006 Feb;96(2):327-33 and ii) Pollinex Quattro: EAACI XXVIII Congress 2009 Poster presentation
3 TRSS scoring ranges from 16 – 24 points for these studies
33
Tolerance persists at least 2 years without further dosing
1 year follow-up study:
Efficacy enhanced over time
Overall TRSS improvement
of 3.9 vs. placebo (p = 0.01) Overall TRSS improvement
of 3.9 vs. placebo (p=0.13)
Secondary endpoint: TRSS
improvement at end of day 4:
5.1 vs. placebo (p=0.02)
Cat-SPIRE phase IIbSustained benefit at 1 and 2 years with no additional dosing
2 years follow-up study:
Efficacy persists at 2 years
Published: J Allergy Clin Immunol. 2013 Jan;131(1):103-9.e1-7 / Clin Exp Allergy. 2015 May;45(5):974-81. doi: 10.1111/cea.12488
34
Cat-SPIRE has an excellent safety profile in studies
completed to date
Most common adverse events
– Headache (15.6% vs 18.2% after placebo)
– Upper Respiratory Tract Infections (15.6% vs 12.6%)
– Bronchospasm (8.1% vs 8.4%)– mostly related to environmental chamber exposure
– Cough (4.7% vs 4.9%)
Two severe adverse events
– both headache: one serious but not related to Cat-SPIRE
Local reactions
– indistinguishable from placebo in almost all subjects, following intradermal injection
Conclusion
– studies to date demonstrate Cat-SPIRE is well tolerated in subjects with allergic
rhinoconjunctivitis
– safety profile similar to placebo after administration by the intradermal route
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Cat-SPIRE phase III study fully recruitedMulti-year follow up initiated
Screening Study Medication Administration (every 4 weeks ± 2days)
Visit 1A 1B/C 2A 2B 3A………………………………………….3H 3I
4A 4B 4C 4D 4E 4F 5
Period 3 (Post Administration Collection)
PAC1
x3 wks
PAC2
x3 wks
PAC3
x3 wks
Follow-Up
(3-10 days after PAC3)
Week -8 -3 0 20-22 28 30 37-39 52-54 Year 2 Year 3 Year 4 Year 5
Annual
Allergy
Evaluation*
Annual
Allergy
Evaluation*
Annual
Allergy
Evaluation*
Annual
Allergy
Evaluation*
* Timed to occur annually after Baseline Allergy Evaluation Period in CP007
Reporting of Health Economics (Subjects)
Quarterly Visits to confirm and evaluate Safety Information (Sites)
Period 1 Period 2
Baseline Allergy
Evaluation
x3 wks
End of Dosing
Assessment
(2 wks ± days since
last dose)
Randomisation
Cat-SPIRE phase III: recruitment complete
Two – five year follow-up
1,409 cat-allergic subjects in North
America, EU and Russia
Baseline TRSS ≥10
Primary endpoint 1 year after start dosing
Results expected H1 2016
Single phase III & supporting studies
sufficient for registration
36
Tolerance persists at least 2 years without further dosing
1 year follow-up study:
Efficacy enhanced over time
Overall TRSS improvement
of 3.9 vs. placebo (p = 0.01) Overall TRSS improvement
of 3.9 vs. placebo (p=0.13)
Secondary endpoint: TRSS
improvement at end of day 4:
5.1 vs. placebo (p=0.02)
Cat-SPIRE phase IIbSustained benefit at 2 years with no additional dosing
2 years follow-up study:
Efficacy persists at 2 years
Published: J Allergy Clin Immunol. 2013 Jan;131(1):103-9.e1-7 / Clin Exp Allergy. 2015 Jan 20. doi: 10.1111/cea.12488 [Epub ahead of print]
37
HDM-SPIRE phase IIb (n=172)
Efficacy demonstrated at 1 year
Excellent data –
similar to Cat-SPIRE at 1 year
Overall TRSS improvement of 2.8
vs. placebo (p = 0.02) at one year
1 Arbes et al. J Allergy Clin Immunol. 2005 Aug;116(2):377-83
2 Bousquet et al. Allergy. 2007: 62: 301-9
Selected for oral presentation at AAAAI 2014
Increasing symptom severity
Treatment effect maintained in more
symptomatic subjects
Skin prick +ve HDM:
US: 28%1 (86m)
EU:22%2 (82m)
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HDM-SPIRE phase IIb 2 year follow-up studyImprovement maintained; enhanced effect in more symptomatic
Overall TRSS improvement of 1.4 vs
placebo at two years
Overall TRSS improvement of
1.4 vs placebo at one year
Overall TRSS improvement of
3.0 vs. placebo
Matched subjects at year 1 and 2 Subjects with baseline TRSS >12
Symptom improvement sustained at same level in same patients
39
Grass-SPIRE phase IIb (n=282)Efficacy demonstrated after first grass season
Increasing treatment effect over time
Overall TRSS improvement of
1.6 vs. placebo (p = 0.035)
Subjects with mean baseline TRSS ≥12
Overall TRSS improvement of
2.0 vs. placebo (p=0.040)
Subjects with mean baseline TRSS ≥8
Enhanced efficacy in the more symptomatic
Skin prick +ve
Grass:
US: 27%1 (84m)
EU: 17%2 (63m)
1 Arbes et al. J Allergy Clin Immunol. 2005 Aug;116(2):377-83 (Perennial rye)
2 Bousquet et al. Allergy. 2007: 62: 301-9 (Grass pollen)
40
Initial treatment effect maintained after three grass pollen seasons despite no further doses
Matched subjects (8 x 6 nmol group)
TRSS -2.9 vs.
placebo (p = 0.075)
Grass-SPIRE phase IIb long-term follow-up studiesSymptom improvement confirmed in same subjects
Matched subjects (4 x 12 nmol group)
TRSS -5.0 vs.
placebo (p = 0.004)
TRSS -3.4 vs.
placebo (p = 0.033)
TRSS -4.0 vs.
placebo (p = 0.016)
TRSS -4.5 vs.
placebo (p = 0.008)
TRSS -4.1 vs.
placebo (p = 0.010)
41
Mean Combined Score and mean ragweed
pollen count
Ragweed-SPIRE phase IIb (2014)Field score endpoint
Mean change in Combined Score from pre-
season to peak season
Placebo 8 x 12 nmol
ITT population 68 69
Mean change in CS 0.79 0.53
p value vs placebo - 0.090
Field endpoint: combined TRSS (0-24 scale) and
rescue medication use (RMS) score (0-3 scale)
- Combined Score = (TRSS / 8) + (RMS); 0-6 scale
Treatment effect 33% vs placebo
- FDA requires at least 15% treatment effect1
- World Allergy Organization: at least 20% treatment
effect clinically meaningful
1 With upper bound of 95% confidence interval minimum10%
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