Five-grass-pollen sublingual immunotherapy tablet for the treatment of grass-pollen-induced allergic rhinoconjunctivitis: 5 years of experience

Figures & data

Table 1. Summary of 5-grass-pollen sublingual immunotherapy tablet Phase I–III clinical trials and design.

Study Phase	Design and objectives	Location	Population	Treatment	Exposed patients (n)	Treatment duration	Ref.
VO33.04DK I 2006	Single-center, randomized, double-blind, placebo-controlled Safety	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)	[54]
VO34.04 IIb/III 2005	Pivotal, multicenter, multinational, randomized, double-blind, placebo-controlled Efficacy, dose-finding	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 pre-seasonally and ≥1 month co-seasonally	[45]
VO56.07A I 2007–08	Single-center, randomized, double-blind, parallel-group, placebo-controlled Efficacy, safety	Austria (allergen exposure chamber)	Patients with grass-pollen-related ARC without mild asthma Age 18–50 years	300 IR Placebo Total	45 44 89	∼4 months	[49]
VO52.06 III 2007	Multicenter, multinational, double-blind, placebo-controlled Efficacy, safety	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 pre-seasonally and ≥1 month co-seasonally	[50]
VO53.06 III 2007–11	Multicenter, randomized, double-blind, placebo-controlled Efficacy, safety	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 pre-seasonally and ≥1 month co-seasonally over 3 years, followed by 2 years without study treatment	[28,51]
VO61.08 III 2009	Pivotal, multicenter, randomized, double-blind, parallel-group, placebo-controlled Efficacy, safety	USA (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 pre-seasonally and ≥1 month co-seasonally	[52]
VO60.08 III 2009	Multicenter, multinational, randomized, double-blind, placebo-controlled Efficacy, safety	5 EU countries: Czech Republic, France, Italy, The Netherlands, Spain	Patients with grass-pollen-related ARC Age 12–65 years	300 IR (2M) Placebo Total	188 193 381	∼2 months pre-seasonally and ≥1 month co-seasonally	[53]

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, then increased by 100 IR daily 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; SLIT: Sublingual immunotherapy.

Table 2. Summary of 5-grass-pollen sublingual immunotherapy tablet efficacy from five Phase I–III clinical trials.

Study Phase	Primary end point	Treatment	Primary analysis set (n)	LS mean	LS mean difference vs placebo		p-value vs placebo^†	Ref.
					Absolute point estimate (95% CI)	Relative point estimate (%)
VO34.04 EU study in adults IIb/III	ARTSS	500 IR (4M) 300 IR (4M) 100 IR (4M) Placebo	143 136 142 148	3.74 3.58 4.72 4.93	−1.22 (−1.91, −0.53) −1.39 (−2.09, −0.69) −0.26 (−0.95, 0.43)	−24.7 −28.2 −5.3	0.0006 0.0001 0.4606	[45]
VO56.07A Allergen-exposure chamber study in adults I	ARTSS	300 IR Placebo	45 44	4.85 6.87	−1.97 (−2.99, −0.94)	−29.3	0.0003	[49]
VO52.06 EU pediatric study III	ARTSS	300 IR (4M) Placebo	131 135	3.25 4.51	−1.13 (−1.80, −0.46)	−25.5	0.0010	[50]
VO53.06^‡ Long-term efficacy study in adults III	AAdSS	300 IR (4M) 300 IR (2M) Placebo	149 147 165	3.39 3.25 5.21	−1.82 (−2.61, −1.02) −1.96 (−2.76, −1.16)	−34.9 −37.6	<0.0001 <0.0001	[28,51]
VO61.08 US study in adults III	Daily CS^§	300 IR (4M) Placebo	208 228	0.32 0.45	−0.13 (−0.19, −0.06)	−28.2	0.0003	[52]

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

^†Based on absolute point estimate of LS mean difference.

^‡Year 3 results are presented.

^§Daily CS is derived from the RTSS and RMS and gives equal weight to symptoms and medication use. This score is conventionally expressed on a scale from 0 to 3 and calculated per day for each patient as: daily CS = (daily RTSS/6 + daily RMS)/2.

AAdSS: Average Adjusted Symptom Score; ARC: Allergic rhinoconjunctivitis; ARTSS: Average rhinoconjunctivitis Total Symptom Score; CS: Combined Score; IR: Index of reactivity; LS: Least squares; RMS: Rescue Medication Score; RTSS: Rhinoconjunctivitis Total Symptom Score; SLIT: Sublingual immunotherapy.

Figure 1. Pooled efficacy analysis of the 5-grass-pollen sublingual immunotherapy tablet: Daily Combined Score overall and in subpopulations of interest [30].

Table 3. Summary of 5-grass-pollen sublingual immunotherapy tablet adverse drug reactions in adults from clinical trials [37].

MedDRA SOC	Frequency (%)
	Very common (≥1/10)	Common (≥1/100 and <1/10)	Uncommon (≥1/1000 and <1/100)	Rare (≥1/10,000 and <1/1000)
Infections and infestations		Nasopharyngitis, rhinitis	Oral herpes, otitis
Blood and lymphatic system disorders			Lymphadenopathy
Immune system disorders			Hypersensitivity, oral allergy syndrome
Psychiatric disorders			Depression
Nervous system disorders	Headache		Dysgeusia, somnolence, dizziness	Anxiety
Eye disorders		Eye pruritus, conjunctivitis, lacrimation increased	Eye redness, eye edema, dry eye
Ear and labyrinth disorders		Ear pruritus	Ear discomfort
Vascular disorders				Flushing
Respiratory, thoracic and mediastinal disorders	Throat irritation	Asthma, AR (nasal congestion, sneezing, rhinorrhea, nasal discomfort), cough, oropharyngeal pain, pharyngeal edema, sinus congestion, dyspnea, dysphonia, dry throat, oropharyngeal blistering, oropharyngeal discomfort	Pharyngeal hypoesthesia, throat tightness, wheezing, laryngeal edema
Gastrointestinal disorders	Oral pruritus	Abdominal pain, diarrhea, vomiting, mouth edema, tongue pruritus, lip edema, paresthesia oral, dyspepsia, tongue edema, hypoesthesia oral, stomatitis, lip pruritus, oral discomfort, nausea, glossodynia, dry mouth, dysphagia	Oral pain, gingivitis, cheilitis, gastritis, glossitis, salivary gland enlargement, gastroesophageal reflux, tongue disorder, salivary hypersecretion, mouth ulceration, esophageal pain, palatal edema, oral disorder, odynophagia, eructation
Skin and subcutaneous tissue disorders		Urticaria, pruritus, atopic dermatitis	Angioedema, rash, acne	Face edema
General disorders and administration site conditions		Chest discomfort	Lump feeling in throat, asthenia, influenza-like illness
Investigations				Eosinophil count increased
Injury, poisoning and procedural complications			Excoriation

Within each frequency category, serious reactions are presented first. Overall, the safety profile in the pediatric population is similar to that of adults. The following reactions listed above were reported at a higher frequency in the pediatric population than in adults: cough, nasopharyngitis, mouth edema (very common), oral allergy syndrome, cheilitis, glossitis, lump feeling in throat, ear discomfort (common). Additionally, the following reactions were reported in children and adolescents who received OA: tonsillitis, bronchitis (common), chest pain (uncommon).

AR: Allergic rhinitis; MedDRA: Medical Dictionary of Regulatory Activities; OA: Oralair^®; SLIT: Sublingual immunotherapy; SOC: System Organ Class.

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