Safety and tolerability of 5-grass pollen tablet sublingual immunotherapy: pooled analysis and clinical review

Figures & data

Box 1. Drug summary.

Drug name	5-grass pollen tablet
Phase	I – IV
Indication	Treatment of confirmed grass pollen-induced allergic rhinitis with or without conjunctivitis in many countries worldwide, including the US, Canada, most European countries, Russia and Australia Approved indications and prescribing information vary slightly between countries, and local prescribing information should be consulted for details
Pharmacology description/mechanism of action	The pharmacodynamics effect of the 5-grass pollen tablet is targeted at the immune system, leading to a systemic competitive antibody response toward grass, and an increase in specific IgG [16] The majority of allergens in the 5-grass pollen tablet are a mixture of proteins and glycoproteins. There is limited, if any, release of intact allergens into the bloodstream, and they are thus not directly bioavailable in the blood No studies have been performed to investigate the pharmacokinetic profile and metabolism of the 5-grass pollen tablet
Route of administration	Sublingual administration: the tablet is placed under the tongue and held there until completely dissolved (at least 1 min), and then the contents are swallowed
Chemical structure	Not applicable; the treatment consists of a purified, calibrated freeze-dried extract of pollen from sweet vernal grass (Anthoxanthum odoratum), cocksfoot/orchard grass (Dactylis glomerata), perennial rye grass (Lolium perenne), meadow grass (Poa pratensis) and timothy grass (Phleum pratense) 300 index of reactivity (IR) dose is equivalent to ∼ 20 – 25 μg/mL of the group five major allergens [20]
Pivotal trials	VO34.04 EU Phase IIb/III study investigating the efficacy, safety and optimal dose of the 5-grass pollen tablet in adults having grass-pollen-induced ARC for at least 2 years [20] VO52.06 EU Phase III study investigating the efficacy and safety of 300 IR 5-grass pollen tablet therapy in children and adolescents having grass-pollen-induced ARC for at least 2 years, confirmed by means of a positive skin-prick test response [26] VO61.08 US Phase III study of the 5-grass pollen tablet demonstrating its clinically meaningful efficacy, especially in subjects with measurable grass-pollen-specific serum IgE [19]

Table 1. Summary of the 5-grass pollen tablet clinical trials included in the pooled safety analysis.

Study	Location	Population	Treatment	Exposed patients (n)	Treatment duration
VO33.04DK [24] Phase I 2006	Denmark	Patients allergic to grass pollen Age 18 – 50 years	100 – 500 IR Placebo Total	23 7 30	2 weeks (omitting weekends for 10 treatment days in total)
VO34.04 [20], VO40.05 Phase IIb/III 2005 – 2006	10 EU countries: Austria, Bulgaria, Czech Republic, Denmark, France, Germany, Hungary, Italy, Slovakia, Spain	Patients with grass pollen-related ARC with or without mild asthma Age 18 – 45 years	500 IR (4M) 300 IR (4M) 100 IR (4M) Placebo Total	160 155 157 156 628	∼ 4 months preseasonally and ≥ 1 month coseasonally
VO52.06 [26] Phase III 2007	5 EU countries: Denmark, France, Germany, Poland, Spain	Patients with grass pollen-related ARC with or without mild asthma Age 5 – 17 years	300 IR (4M) Placebo Total	139 139 278	∼ 4 months preseasonally and ≥ 1 month coseasonally
VO53.06 21, 22 Phase III 2007 – 2011	10 countries: Austria, Canada, Czech Republic, Denmark, France, Germany, Italy, Poland, Russia, Slovakia	Patients with grass pollen-related ARC with or without mild asthma Age 18 – 50 years	300 IR (4M) 300 IR (2M) Placebo Total	207 207 219 633	5 years: ∼ 4 months preseasonally and ≥ 1 month coseasonally over 3 years, followed by 2 years without study treatment
VO56.07A [23] Phase I 2007 – 2008	Austria (allergen exposure chamber)	Patients with grass pollen-related ARC without asthma Age 18 – 50 years	300 IR Placebo Total	45 44 89	∼ 4 months
VO60.08 [25] Phase III 2009	5 EU countries: Czech Republic, France, Italy, Netherlands, Spain	Patients with grass pollen-related ARC Age 12 – 65 years	300 IR (2M) Placebo Total	188 193 381	∼ 2 months preseasonally and ≥ 1 month coseasonally
VO61.08 [19] Phase III 2009	US (51 sites)	Patients with grass pollen-related ARC with or without mild asthma Age 18 – 65 years	300 IR (4M) Placebo Total	233 240 473	∼ 4 months preseasonally and ≥ 1 month coseasonally

Subjects in the 300 IR (Study VO34.04 and VO52.06) and the 500 IR (Study VO34.04) treatment groups underwent a dose-escalation phase wherein a 100 IR dose was taken on the first day, that was increased by 100 IR/day until the final randomized dose was reached.

2M or 4M: Patients received active treatment starting 2 or 4 months, respectively, before the pollen season.

ARC: Allergic rhinoconjunctivitis; IR: Index of reactivity.

Table 2. Demographics and baseline characteristics of the safety population (n = 2512).

Parameter	5-grass pollen tablet (n = 1514)	Placebo (n = 998)
Gender, n (%)
Male	870 (57.5)	551 (55.2)
Female	644 (42.5)	447 (44.8)
Age, years
Mean (SD)	29.0 (10.48)	28.8 (11.89)
Range	4 – 65	5 – 65
Allergic rhinoconjunctivitis duration, years*
Mean (SD)	13.6 (9.92)	14.2 (11.03)
Range	2 – 61	2 – 59
Asthma status, n (%)^‡
Presence of mild asthma	242 (16.0)	183 (18.3)
Absence of any asthma	1270 (84.0)	815 (81.7)
Sensitization status, n (%)
Monosensitized	587 (38.8)	364 (36.5)
Polysensitized	927 (61.2)	633 (63.5)

*Data are not available for patients in study VO33.04DK (5-grass pollen tablet, n = 23; placebo, n = 7).

^‡Data are not available for two patients using 5-grass pollen tablet.

SD: Standard deviation.

Table 3. Extent of exposure to study treatment in the safety population (n = 2512), overall and in children and adolescents.

	Overall (all patients, all doses) (n = 2512)		Children and adolescents (n = 312)
Exposure duration (days), n (%)	5-grass pollen tablet (n = 1514)	Placebo (n = 998)	5-grass pollen tablet (n = 154)	Placebo (n = 158)
0* – 90	135 (8.9)	59 (5.9)	7 (4.5)	6 (3.8)
91 – 181	633 (41.8)	524 (52.5)	136 (88.3)	140 (88.6)
182 – 364	566 (37.4)	248 (24.8)	11 (7.1)	12 (7.6)
≥ 365	180 (11.9)	167 (16.7)	–	–

*In study VO53.06, five patients randomized to 5-grass pollen tablet, in a regimen starting 2 months prior to the beginning of the pollen season, withdrew during the period when they were receiving placebo (i.e., before any intake of active treatment).

Figure 1. Treatment-emergent adverse events occurring in ≥ 5% of patients in either treatment group (safety population: n = 2512) are shown.

Figure 2. Time to onset of most frequently reported treatment-emergent adverse events leading to premature study discontinuation in patients treated with the 5-grass pollen tablet.

Table 4. TEAEs occurring in the safety population (n = 2512), overall and by age and treatment groups.

	Overall (all patients, all doses) (n = 2512)		Adults* (n = 1878)		Children* and adolescents (n = 312)
n (%)	5-grass pollen tablet (n = 1514)	Placebo (n = 998)	5-grass pollen tablet (n = 1038)	Placebo (n = 840)	5-grass pollen tablet (n = 154)	Placebo (n = 158)
At least one TEAE	1164 (76.9)	697 (69.8)	805 (77.6)	558 (66.4)	130 (84.4)	125 (79.1)
At least one drug-related TEAE	880 (58.1)	200 (20.0)	606 (58.4)	158 (18.8)	82 (53.2)	31 (19.6)
AE leading to death	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
At least one serious TEAE	22 (1.5)	11 (1.1)	13 (1.3)	5 (0.6)	1 (0.6)	2 (1.3)
At least one serious drug-related TEAE	3 (0.2)	0 (0)	3 (0.3)	0 (0)	0 (0)	0 (0)
TEAE leading to premature study discontinuation	77 (5.1)	12 (1.2)	49 (4.7)	9 (1.1)	7 (4.5)	2 (1.3)

Multiple episodes of a particular AE were only counted once per individual patient. In study VO53.06, patients randomized to 5-grass pollen tablet, in a regimen starting 2 months prior to the beginning of the pollen season (n = 207), received placebo for 2 months before switching to active treatment.

*300 IR only.

AE: Adverse event; TEAE: Treatment-emergent adverse event.

Table 5. TEAEs occurring in the safety population (n = 2512), stratified by sensitization and asthma status.

	Monosensitized (n = 951)		Polysensitized (n = 1560)		With mild asthma (n = 425)		Without any asthma (n = 2085)
n (%)	5-grass pollen tablet (n = 587)	Placebo (n = 364)	5-grass pollen tablet (n = 927)	Placebo (n = 633)	5-grass pollen tablet (n = 242)	Placebo (n = 183)	5-grass pollen tablet (n = 1270)	Placebo (n = 815)
At least one TEAE	453 (77.2)	247 (67.9)	711 (76.7)	449 (70.9)	197 (81.4)	147 (80.3)	965 (76.0)	550 (67.5)
At least one drug-related TEAE	348 (59.3)	76 (20.9)	532 (57.4)	124 (19.6)	144 (59.5)	39 (21.3)	734 (57.8)	161 (19.8)
AE leading to death	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
At least one serious TEAE	9 (1.5)	7 (1.9)	13 (1.4)	4 (0.6)	2 (0.8)	4 (2.2)	20 (1.6)	7 (0.9)
At least one serious drug-related TEAE	2 (0.3)	0 (0)	1 (0.1)	0 (0)	0 (0)	0 (0)	3 (0.2)	0 (0)
TEAE leading to premature study discontinuation	31 (5.3)	8 (2.2)	46 (5.0)	4 (0.6)	14 (5.8)	2 (1.1)	63 (5.0)	10 (1.2)

Multiple episodes of a particular AE were only counted once per individual patient. In study VO53.06, patients randomized to 5-grass pollen tablet, in a regimen starting 2 months prior to the beginning of the pollen season (n = 207), received placebo for 2 months before switching to active treatment.

AE: Adverse event; TEAE: Treatment-emergent adverse event.

Table 6. PASS conducted in Germany: main characteristics.

	PASS conducted in 2008: adults, children and adolescents	PASS conducted in 2009: children and adolescents
Number of patients	808 adults, 91 children and adolescents	829 children and adolescents
Polysensitized patients (%)	71	81
Patients with asthma (%)	23	36
Overall duration of treatment (days)	191.2	190.2
Adherence (%)	95	98
Number of patients with ADRs, n (%)	320 (35.6)	218 (27.4)

ADR: Adverse drug reaction; PASS: Post-marketing authorization safety study.

Figure 3. Nature of adverse drug reactions and serious adverse drug reactions occurring during 6 years of post-marketing experience with the 5-grass pollen tablet.

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