challenges in the development of allergen immunotherapies · 4 allergic rhinitis is a global...

fde

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


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.“


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.”


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



compounds


12

Key challenges and opportunities in the field


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



compounds


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


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



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


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


Baseline Challenge

TRSS

16

TRSS

16

TRSS

8


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



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

35

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:


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)

38

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


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


1.6 vs. placebo (p = 0.035)

Subjects with mean baseline TRSS ≥12



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%

42

Contact us: Investors Financial and Corporate

Communications

Circassia Ltd

Northbrook House

Robert Robinson Avenue

The Oxford Science Park

Oxford, OX4 4GA

w: www.circassia.com

e: [email protected]

Steven Harris, CEO

Julien Cotta, CFO

t: +44 (0) 1865 405560

FTI Consulting

200 Aldersgate

Aldersgate Street

London EC1A 4HD

t: +44 (0) 20 7831 3113

e: [email protected]

challenges in the development of allergen immunotherapies · 4 allergic rhinitis is a global...

Documents