Page 1

Safety and efficacy of ragweed allergy immunotherapy tablets

Speaker: Hendrik Nolte

29 September 2012


Allergen Immunotherapy Tablet Short Ragweed Ambrosia Artemisiifolia Hendrik Nolte, MD, PhD Merck Research

2


Disclosures

Hendrik Nolte, MD, PhD Merck Research Laboratories •

Employer: Merck & Co., Inc., US


NHANES III Survey Skin Test Sensitization in US population aged 6 to 59 years Skin testing was conducted 10508 subjects 65

% Positive

55

54%

45

26% 35 25 15 5 -5

Any

HDM

J Allergy Clin Immunol 2005;116:377-83.

Grass

Ragweed Cockroach

Cat

Oak

Alternaria

4


Ragweed sensitization is increasing in Europe GA2LEN Network Study Finland 2.4% Denmark 19.8% Netherlands 15.2% Germany 14.2% Hungary ~57%

Modified after Burbach et al. Allergy 2009; 64:664-5

5


Previous Ragweed Studies Controlled Trials  SCIT ‒ 2009 Cochrane Review (Calderon et al.)

12 Controlled Trials  SLIT ‒ 2009 Cochrane Review (Wilson et al.)

1 Controlled Trial

6


0.001 μg Amb a 1 11.1 μg Amb a 1

Van Metre et al. JACI 1979; 66:500-513

7


AIT Ragweed Studies Three Phase I Safety Studies • RT-01 28-Day dose escalating study in adults ragweed allergics • P06081 28-Day safety study in ≥50 yo ragweed allergics • 3 arms (6, 12 Amb a 1-U, placebo) • 196 subjects (~65/arm) • P05751 28-Day safety study in ≥18 yo ragweed allergics • 2 arms (12 Amb a, placebo) • 914 subjects (304/610 Placebo/Active)


AIT Ragweed Studies Three Phase I Safety Studies • RT-01 28-Day dose escalating study in adults ragweed allergics • P06081 28-Day safety study in ≥50 yo ragweed allergics • 3 arms (6, 12 Amb a 1-U, placebo) 2517 • 196 subjects (~65/arm)

Total

• P05751 28-Day safety study in ≥18 yo ragweed allergics • 2 arms (12 Amb a, placebo) 1747 • 914 subjects (304/610 Placebo/Active)

Active

Two Phase II/III studies

692 • P05234 52 week study (1 season) • 4 arms (1.5,6,12 Amb a, placebo) • 800 subjects (200/arm) • P05233 Pivotal 52 weeks study (1 season) • 3 arms (6,12 Amb a, placebo) • 600 subjects (200/arm)

1 yr tx


Ragweed AIT Clinical Trial Results

10


Criteria for Evaluation  Subjects recorded ARC symptoms and rescue medication use daily in electronic diaries during RS  Efficacy

‒ Total combined score (TCS); sum of rhinoconjunctivitis DSS and DMS ‒ DSS and DMS separately ‒ Weekly RQLQ  Season Definition ‒ First day of 3 consecutive recorded days with pollen count ≥10 grains/m3

‒ Last day of 3 consecutive days with pollen count ≥10 grains/m3

11


Symptoms & Rescue Medication Assessment Daily Symptom Score (DSS; Maximum=18) 0

No symptoms

1

Mild symptoms

2

Moderate symptoms

3

Severe symptoms

Individual symptoms:  runny nose  blocked nose  sneezing  itchy nose  gritty eyes  watery eyes

Daily Medication Score (DMS; Maximum=36) Rescue Medication

Score/Dose Unit

Maximum Daily Score

Loratadine 10-mg tablet

6 points/tablet

6

Olopatadine HCl 0.1% ophthalmic solution

1.5 points/drop

6

Mometasone furoate nasal spray 50 µg

2 points/spray

8

Prednisone 5-mg tablet

1.6 points/tablet

16 12


Study Assessments Primary Endpoint: Total Combined Score (TCS) Combined (sum of) rhinoconjunctivitis daily symptom score (DSS) and rhinoconjunctivitis daily medication score (DMS) over the peak RS season ‒

TCS = Daily Sum of DSS and DMS

Key Secondary Endpoints: 1. TCS for the entire RS. 2. DSS for the peak RS. 3. DSS over entire RS. 4. DMS over the peak RS.

13


Study 1 Diagram April 2010

April 2011

Ragweed Season 2011

6 Amb a 1-U

12 Amb a 1-U

Placebo

52 Week (Randomization) (Screening)

(PreSeason)

(OnSeason)

(End of Season)

(PostSeason)

(Final)

14


Study 2 Diagram April 2010

1.5 Amb a 1-U

Ragweed Season 2011

6 Amb a 1-U

N=1349

12 Amb a 1-U

Placebo

52 Week (Randomization) (Screening)

(PreSeason)

(OnSeason)

(End of Season)

(PostSeason)

(Final)

15


Ragweed Pollen Season

Weighted Average of Pollen Counts per Day (grains/m3)

 The mean RS lasted approximately 44 days,  The mean daily pollen count during the entire season was 122 grains/m3,  The mean daily pollen count during peak season was 204 grains/m3

Days From Defined Ragweed Pollen Season Start

16 16


Overall Subject Characteristics Demographics

P05233 (n=565)

P05234 (n=784)

49

49

35 18-51

36 18-51

78 22

88 17

Ragweed Skin Sensitivity Mean Wheal Diameter (mm)

11

12

Ragweed IgE level (kU/L)

16

16

Sensitive to other allergens (%) (Multi-allergic)

85

78

Sex (%) Male Age, y Mean Range Race (%) Caucasian Subjects with asthma (%)

17


Most Frequent Additional Sensitizations  Grasses ~50%  Trees ~50%

 Cat 36%  Mites 31%

 Mold 22%

18


P05234 Dose-related Reduction in TCS † p<0.05 vs placebo n=783 adults

Entire

Peak

9 9%

Adj Mean Score

8

19%

7

24%

6

12%

5

18% 27%

4 3 2 1 0 Placebo

1.5 Amb

6 Amb

12 Amb


P05234 Dose-related Reduction in TCS † p<0.05 vs placebo n=783 adults

Entire

Peak

9 9%

Adj Mean Score

8

19%

7 6

24%

12% 18%

5

27%

4 3 2 1 0 Placebo

1.5 Amb

6 Amb

12 Amb


P05233 Dose-related Reduction in TCS † p<0.05 vs placebo P05233, n=560 adults

Entire

Peak

9

Adj Mean Score

8

7

21%

27%

6

12%

18%

5

27%

4 3 2 1 0 Placebo

6 Amb 21

12 Amb


P05233 Dose-related Reduction in TCS † p<0.05 vs placebo P05233, n=560 adults

Entire

Peak

9

Adj Mean Score

8

21%

7

27%

6

12%

16%

5

26%

4 3 2 1 0 Placebo

6 Amb 22

12 Amb


Ragweed pollen tablet demonstrated efficacy during Ragweed Season in two replicate trials Total daily rhinoconjunctivitis combined score During Entire Season (Adjusted mean values)

8 77 66 55 44 33 22 11 0 8

8 77 66 55 44 33 22 11 0 8

12%

Placebo

Placebo

Amb 1.5

18%*

Amb 6

1.5Study Amb P05234 6 Amb

27%*

Amb 12

12 Amb

16%*

26%*

Placebo

Amb 6

Amb 12

Placebo

Study6 Amb P05233

12 Amb

*percent reduction p â&#x2030;¤0.05 vs placebo

16 Amb


Reduction in Total RQLQ Scores during PEAK Maximum score=6 (extremely troubled) Placebo

12 Amb

â&#x20AC; p<0.05 vs placebo P05233, n=560 adults P05234, n=783 adults

Worse 2 Adjusted Mean Score

1.8 â&#x20AC;

1.6

18%

24%

1.4 1.2 1 0.8 0.6 0.4 0.2

Better 0 P05233

P05234 24


Number (%) of Subjects Reporting Use of Rescue Medication During the Peak RS was Reduced 6 Amb 1 1-U N=150

12 Amb 1 1-U N =159

Placebo N=164

Loratadine

46.7%

42.8%

58.5%

Olopatadine

15.3%

13.8%

23.2%

Mometasone

18.7%

14.5%

29.3%

0%

0%

0%

1.5 Amb 1 1-U N=169

6 Amb 1 1-U N=167

12 Amb 1 1-U N=152

Placebo N=169

Loratadine

49.1%

47.3%

40.8%

54.4%

Olopatadine

20.7%

19.2%

13.8%

26.0%

Mometasone

29.0%

22.8%

17.8%

32.5%

Prednisone

2.4%

0.6%

1.3%

1.2%

P05233

Prednisone

P05234

25


IgG4 Levels over Time log10-transformed

12 Amb a 1-U 6 Amb a 1-U 1.5 Amb a 1-U

Placebo

26


Common Treatment Emergent AEs Pooled Results: Phase 3 Trials Event

6 Amb a 1-U (%)

Approx. 9% discont. due to Seven-to-ten subjects (approx. 1%) with Placebo local (%) 12 Amb a 1-UAEs (%)

Throat Irritation

24

25

Swollen tongue

14

19

Ear pruritus

15

15

Oral pruritus

17

14

Tongue pruritus

13

12

2

Paraesthesia Oral

8

8

2

Lip swelling

5

7

1.1

Eye pruritus

4

4

1

Dyspnea

1

3

2

Pharyngeal edema

2

3

1

Throat tightness

1

3

1

Urticaria

2

2

2

application site 6 reactions had events 2 as that were assessed severe. None were2 considered serious. 2

27


Epinephrine Administration  There has been 1 Treatment related epinephrine administration.

‒ Treatment related => Day 20; developed upper airway obstruction, mouth swelling, oral pruritus minutes after IMP (6 Amb a 1 U); treated in an ER; not self-administered discontinued the trial following the event

28


Across All Ragweed Tablet Trials Treatment was well tolerated  No cases of anaphylactic shock  No treatment related SAEs.  No systemic allergic reactions  Most common AEs were local application site reactions: ‒ oral pruritus, throat irritation, ear pruritus, swollen tongue

29


Conclusions  A dose-related response was observed with Ragweed AIT 12 Amb a 1-U showing the greatest reductions in TCS, DSS, and DMS  Ragweed AIT was well tolerated; adverse events were generally mild-moderate and transient  There were no systemic reactions  Overall safety profiles of 6 and 12 Amb a 1-U are similar  Ragweed is a promising novel treatment of Ragweed allergy

30

Hendrik Nolte  
Read more
Read more
Similar to
Popular now
Just for you