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Dogmas, fallacies and misconceptions regarding SIT Speaker: Pascal Demoly

29 September 2012


Dogmas, fallacies and misconceptions regarding allergen SIT

Prof Pascal DEMOLY University Hospital of Montpellier H么pital Arnaud de Villeneuve - INSERM U657 Montpellier, FRANCE


Disclosures: Lecture fees: ALK, Stallergènes Consultancy: ALK, Stallergènes, Circassia

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100 years of allergen immunotherapy Allergen immunotherapy has been around for 100+1 years It has been built on personal beliefs and empiricism, which prompted the appearance of false beliefs concerning its efficacy, onset of action and administration regimens In the last 20 years, clinical studies have validated SIT efficacy and safety

Regulatory changes and better clinical development have turned allergen products into pharmaceutical specialties, with the creation of a new therapeutic class

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Dogmas, fallacies and misconceptions Dogma 1: There is no need for SIT Dogma 2: SIT has never been properly tested Dogma 3: SIT is less effective than pharmacotherapy Dogma 4: SIT must be taken several years to be efficacious Dogma 5: SIT does not work in polysensitized patients Dogma 6: SCIT secures better compliance than SLIT

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Dogma 1: “There is  no  need  for  allergen  immunotherapy” • Many patients with allergic rhinitis (AR) can gain enough relief from symptomatic medications 14% of the French population (8.8 million people) suffer from AR to grass pollens

• No pollen  no symptoms

• Mild discomfort (OTC H1-antihistamines…) • Severe discomfort:  Many different symptoms (nose/eyes)  Impact on quality of life (sleep, school/work, etc.)

 Allergic patients have different therapeutic needs 6


Dogma 1: “There is  no  need  for  allergen  immunotherapy” 14% of the French population suffer from AR to grass pollen

50%

Self-medication: OTC H1-antihistamines No medical consultation

70% 50%

Consultation with a GP Prescription of H1-antiHs and nasal corticosteroids

2/3 of patients are controlled

30%

Non-controlled patients

 A third of treated patients are not controlled by symptomatic medications  These patients have unmet medical needs

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Dogma 1: “There is  no  need  for  allergen  immunotherapy”  Allergists often see patients with unmet medical needs after extensive "doctor-hopping” Mean time since diagnosis: 4.6 years

9% 11% 15%

Mild intermittent Mild persistent

Moderate-severe intermittent

66%

Moderate-severe persistent

81% The REALIS survey: clinical and sensitization profiles of patients consulting allergists for respiratory allergies (2714 patients) Migueres et al. - CFA 2009

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SIT addresses this residual unmet therapeutic need left by symptomatic allergic rhinitics ~1,500,000 patients were treated with SIT in Europe in 2012

NL ~40,000 UK ~5,000

Belgium ~20,000

Germany ~560,000

Switzerland ~25,000 France ~350,000

CZ ~55,000

SK ~55,000

Austria 45,000

Italy ~145,000

Portugal ~20,000 Spain ~220,000

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Dogma 2: “SIT has  never  been  properly  tested”  Even though SIT is widely prescribed and used, the perception of an empiricism-based therapy persists  However, across Europe, health agencies are reevaluating SIT registration status and: • In 2009, the European Medicines Agency issued guidelines on the clinical development of SIT for allergic rhinitis • These guidelines require SIT products to show the same level of evidence as other pharmaceutical products

http://www.emea.europa.eu/pdfs/human/ewp/1850406enfin.pdf

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Dogma 2: “SIT has  never  been  properly  tested” A benchmark with the most recent in market NCS Avamys®

Items

Grazax®

Indication

Allergic rhinitis

Grass pollen allergic rhinitis with or without rhinoconjunctivitis

Clinical trials

2 DBPC Phase II, 3 Phase III - 1528 adults & adolescents (>12 y) - 554 children (5-12 y)

2 DBPC Phase II/III 7 pivotal Phase III (2 on-going) - 3861 adults - 1410 children (5-17 yrs)

Primary endpoint

TNSS (4 rhinitis symptoms)

RTSS (6 symptoms: 4 rhinitis + 2 eye) Rhinoconjunctivitis medication score

Assessment period

2 weeks

Entire pollen season

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Dogma 2: “SIT has never been properly tested” Pivotal phase III clinical studies in sublingual SIT •  Oralair® - Stallergenes: - 5 studies: 2101 patients adults & children •  Grazax® - ALK: - 7 studies: 4302 patients adults & children

•  10 completed Phase III •  2 on-going Phase III •  4793 patients (completed) •  Short term •  Long term •  Carry-over effect •  Prevention (on-going)

! Similar clinical development to that of other pharmaceutical specialties, although much more demanding than for any other specialties

1"


Dogma 3: “SIT is  less  effective  than  pharmacotherapy”  Comes from contradictory results of studies published before 2000 (often small cohorts and with sometimes debatable methodologies) • Even though it is impossible to perform a direct comparison with SIT, symptomatic medications appear to be less effective in relieving the symptoms of allergic rhinitis: • different study methodologies • variation in pollen counts • use of rescue medications

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Dogma 3: “SIT is  less  effective  than  pharmacotherapy” SIT effectiveness evaluation in DBPC trials takes into account the whole spectrum of symptoms Eye

Nose NCS

T4SS [ 0 – 12]

Anti H1

T5SS [ 0 – 15] T6SS [0 – 18]

AIT 3

Nasal pruritus Rhinorrhoea

6

9

Nasal congestion Ocular pruritus

12

15

18

Sneezing Watery eyes

 Symptomatic treatments do not take into account symptoms for which they might be ineffective (although these symptoms do exist and bother the patients)

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GT-08 – Variation of pollen counts 0 10 20 30 40 50 60 70

2005

2006

0 10 20 30 40 50 60 70

2007

2008

2009

150 140

Pollen counts (grains/m3)

130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70

0 10 20 30 40 50 60 70

Days after define start of the grass pollen season Durham SR et al. J Allergy Clin Immunol 2012; 129(3):717-725

0 10 20 30 40 50 60 70


Evaluation period: twice as long in allergen immunotherapy Symptom score

12

10

Anti-H1 / NCS 15 days 8

6

SIT 4

SIT = 30 days

2

Pollen count

Pollen season 0

-25 -20 -15 -10

-5

0

5

10

15

20

25

30

35

40

45

ďƒ¨ Variations in pollen count due to the longer evaluation period added to the variation of pollen count seen between centres

50

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When the evaluation period is longer, the mean symptom score under placebo is lower Symptom score

12

Anti-H1 / ICS 15 days

10

Placebo mean score with anti H1 / NCS

Placebo mean score with SIT

8

SIT

6

4

2

SIT = 30 days

Pollen count

Pollen season

0

-25 -20 -15 -10

-5

0

5

10

15

20

25

30

35

40

45

50

ďƒ¨ The mean symptom score in the placebo group in SIT studies is lower than in symptomatic treatment studies (there is an overlap zone but the difference is important) especially in the decreasing phase of the season

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Comparison of symptomatic medications and SIT in seasonal allergic rhinitis

Meta-analysis Benninger

Meta-analysis Wilson

Clinical trials with Oralair® Clinical trials with Grazax®

Number of studies

Number of patients

Type of treatment

Number of symptoms scored

Evaluation period

38

12 926

Anti H1

5

2 weeks

NCS

4

2 weeks

Anti H1

5

2 weeks

NCS

4

2 weeks

LTRAs

4

2 weeks

SIT

6 (all the symptoms)

 30 days (pollen season)

11

3

3

3 924

1 539 (VO34, VO53, VO52)

1 742 (GT-02, GT-08, GT-12)

Benninger et al. Ann Allergy Asthma Immunol 2010 & Wilson et al. Am J Med. 2004

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Comparison of symptomatic medications and SIT in seasonal allergic rhinitis

Meta-analysis Benninger

Meta-analysis Wilson

Clinical trials with Oralair® Clinical trials with Grazax®

Numbe r of studie s

Number of patients

Type of treatment

Number of symptoms scored

Evaluation period

% improvement vs. placebo

38

12 926

Anti H1

5

2 weeks

 9%

NCSs

4

2 weeks

 26%

Anti H1

5

2 weeks

 7%

NCSs

4

2 weeks

 17%

LTRAs

4

2 weeks

 5%

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3

3 924

1 539 (VO34, VO53, VO52)

SIT

3

1 742 (GT-02, GT-08, GT-12)

Benninger et al. - Ann Allergy Asthma Immunol 2010 & Wilson et al. - Am J Med. 2004

6 (all the symptoms)

 30 days (pollen season)

 30%  40% for the highest tertile

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Dogma 3: “SIT is  less  effective  than  pharmacotherapy”

Oralair® – Analysis per Tertiles*/centers 9 8 7

40%

34% 7.87 7.87

7.47 7.47

44% 6.92 6.92

AAdSS

6 5 4

4.96

Placebo

4.68

3.9

3

Oralair 4M

2 1 0 high placebo AAdSS VO34

High placebo AAdSS VO52

High placebo AAdSS VO53

* Analysis per tertiles, defined by grouping centres that have a low, medium or high level of symptoms observed in the placebo group

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Dogma 3: “SIT is  less  effective  than  pharmacotherapy”

 The effect size of SIT appears to be greater than that of symptomatic medications, notably in severely affected patients Durham SR et al. J Allergy Clin Immunol 2012; 129(3):717-725


Dogma 4: “SIT must  be  taken  several  years  to  be  efficacious”  The fact that several consecutive seasons/years of SIT are recommended for full treatment efficacy has given rise to the false belief that the benefits only appear after this long period of treatment

Significant clinical benefits have been demonstrated:  in the first treatment season  and even from the first month of treatment onwards

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Dogma 4: “SIT must  be  taken  several  years  to  be  efficacious”  Efficacy as early as the first year Total daily rhinoconjunctivitis symptom score (median values) Placebo Grazax

44%

Durham SR et al. J Allergy Clin Immunol 2012; 129(3):717-725

37%

End of treatment

32% 31%

31%


Dogma 5: “SIT does  not  work  in  polysensitized  patients”

 In 2001, the ARIA stated that SIT might be less effective in polysensitized patients than in monosensitized patients

• Since then, rigorous clinical trials have shown that polysensitized patients do indeed benefit from single-allergen SIT (Multiallergen SIT in polysensitized patients however, needs more supporting data from large clinical trials)

Bousquet J et al. J Allergy Clin Immunol 2001 & Calderon MA et al. J Allergy Clin Immunol 2012

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Dogma 5: “SIT does not work in polysensitized patients” • demonstrated in the VO34 Oralair® adult study Placebo Sensitization status

n

300 IR

Monosensitized

Polysensitized

Monosensitized

Polysensitized

63

85

66

70

4.59

5.18

3.93

3.25

RTSS (ITT population)

mean

• and in the GT-08 Grazax® first year adult study: median symptom scores reduced by 31%, 44%, and 30% for monosensitized, polysensitized grass plus tree, and polysensitized grass plus other allergens

 The treatment effect is similar in monosensitized and polysensitized patients Malling AJ et al. Clin Exp Allergy 2009 & Emminger W et al. J Allergy Clin Immunol 2009

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Dogma 6: “SCIT secures  better  compliance  than  SLIT”  “Subcutaneous  treatment is better to control and helps to optimize  treatment  compliance” • But how many patients fail to keep one or more appointments over the course of the year? • There is no solid evidence to suggest that patients on subcutaneous SIT are any more compliant than those on sublingual formulations  A Medicaid survey reported that only 16% of children finished a three-year course of SCIT

Tucker MH et al. Ann Allergy Asthma Immunol 2008 & Hankin et al. J Allergy Clin Immunol 2008

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Dogma 6: “SCIT secures  better  compliance  than  SLIT”

Persistence in grass pollen SIT prescriptions, 2005-2007 in Germany for: SLIT natural (n=112) SCIT natural (n=695) SCIT allergoid (n=602) SLIT

SCIT

SCIT

(natural)

(allergoid)

 Persistence with SLIT was significantly higher than persistence with SCIT during both years  The perception of a better compliance with SCIT, due to controlled drug administration by a physician, is WRONG Sieber S et al. CMRO 2011

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Conclusion (1) • AR patients do not all have the same medical needs: o 30% have severe symptoms that are not controlled by

symptomatic treatment o SIT addresses these patients' medical needs

• Thanks to a clinical development programme that meets the EMA's strict standards, the efficacy of SIT has been unambiguously demonstrated • The large studies have provided a better understanding of SIT and have facilitated the application of EBM to therapeutic decisions: o short onset of action o efficacy in polysensitized patients o efficacy of continuous and discontinuous regimens 28


Conclusion (2) • Despite recent progress in understanding allergy and the standardization of products and regimens, SIT is still haunted by a number of fallacies and misconceptions • These false beliefs are no longer justified: we have entered the “second  age"  of  SIT,  with  robust  clinical  trials  and   rigorous evaluation of products for registration as pharmaceutical specialties • SIT is moving from experience and dogma to evidencebased medicine and facts • Allergy specialists can accelerate this process by applying the principles of evidenced-based medicine in their daily practice and thus contribute to the next 100 years of SIT 29

4.Demoly_Finalv2  
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