SummaryBackgroundCat‐PAD, the first in a new class of synthetic peptide immuno‐regulatory epitopes (SPIREs), was shown to significantly improve rhinoconjunctivitis symptoms in subjects with cat allergy up to 1 year after the start of a short course of treatment.ObjectiveTo evaluate the long‐term effects of Cat‐PAD on rhinoconjunctivitis symptoms following standardized allergen challenge 2 years after treatment.MethodsIn a randomized, double‐blind, placebo‐controlled, parallel group study, subjects were exposed to cat allergen in an environmental exposure chamber (EEC) before and after treatment with two regimens of Cat‐PAD (either eight doses of 3 nmol or four doses of 6 nmol) given intradermally over a 3‐month period. In this follow‐up study, changes from baseline in rhinoconjunctivitis symptoms were reassessed 2 years after the start of treatment.ResultsThe primary endpoint showed a mean reduction in total rhinoconjunctivitis symptom scores of 3.85 units in the 4 × 6 nmol Cat‐PAD group compared to placebo 2 years after the start of treatment (P = 0.13), and this difference was statistically significant in the secondary endpoint at the end of day 4 when the cumulative allergen challenge was greatest (P = 0.02). Consistent reductions in nasal symptoms of between 2 and 3 units were observed for 4 × 6 nmol Cat‐PAD compared to placebo between the 2 and 3 h time points on days 1–4 of EEC challenge at 2 years (P < 0.05). The 8 × 3 nmol dose did not show a meaningful effect in this study.Conclusion and Clinical RelevanceA persistent, clinically meaningful reduction in rhinoconjunctivitis symptoms was observed on EEC challenge 2 years after the start of a short course of treatment with 4 × 6 nmol Cat‐PAD. This study is the first to provide evidence of a long‐term therapeutic effect with this new class of SPIREs.

Background TRPV1 is a ligand gated ion channel activated by a range of physiological factors such at Temperature, pH, and osmotic stress. In the nose, the TRPV1-expressing sensory c-fibres are thought to play a key role in the development of nasal hyper-responsiveness resulting in symptoms in NAR patients. We hypothesise that topical antagonism with a selective TRPV1 antagonist would offer substantial symptom control. SB705498 is a potent selective TRPV1 antagonist in animal and human models. Methods 40 M&F NAR patients were enrolled into a randomised, double-blind, placebo controlled, 2 period crossover study of either 12mg SB705498 i.n. or placebo for 14 days with a 4 week washout. The study was conducted in a validated Environmental Challenge Chamber (Cetero) where patients were exposed to Cold Dry Air (CDA) at 14c, 15% RH, air speed 5 feet/sec. Exposure was over the winter months in Canada. Diary card symptoms were analysed during home dosing on days when the temp was less than 14c. Two chamber sessions of 1hr duration, as well as medical history and neg skin prick testing, at screening were performed to establish a consistent diagnosis with a single challenge on Day 1+1hr, Day14+1hr and Day 14+24hr to establish the drug response. Post dose TSS (rhinorrhoea, congestion, PND), sneezing and ocular symptoms were recorded, as was acoustic rhinomanometry, RQLQ, PK and Safety monitoring. Results The primary outcome of weighted mean TSS over the challenge period or the maximum TSS was not impacted by administration of SB705498 relative to placebo (see figure). There was no impact on sneezing, ocular symptoms, acoustic rhinimanometry, or RQLQ Compared with placebo, repeated doses of SB705498 did not alleviate TSS triggered by cold in a multistimuli wild type setting. PK analysis supported an o.d. regimen with 2 fold accumulation over the dosing period. Conclusions In a robust clinical model of non-allergic rhinitis, intranasal SB705498 12mg o.d. for 14 days did not alleviate the symptoms of NAR triggered by the most common provocation agent: Cold Dry Air. We conclude that despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

RationaleA series of T-cell epitopes from cat allergen, Fel d1, formulated into a short-course peptide vaccine (ToleroMune Cat) was previously shown to significantly reduce allergic rhinoconjunctivitis symptoms shortly after vaccine therapy ended and persistently, one year after dosing start (tolerance). In this study, we evaluated the efficacy of a vaccine from a newly identified series of T-cell epitopes from ragweed allergen Amb a1 (ToleroMune Ragweed) on allergic rhinoconjunctivitis symptoms.MethodsScreened ragweed allergic subjects attended four consecutive 3-hour Baseline Challenges in an Environmental Exposure Chamber (EEC) where airborne ragweed pollen levels were controlled at 3500±500 grains/m3 . Total Rhinoconjunctivitis Symptom Score (TRSS) was scored every 30 minutes on a scale of 0-24. 275 subjects were randomised to placebo, or one of four ToleroMune Ragweed treatment arms. Subjects returned to a series of 4 consecutive, 3-hour Post-Treatment EEC Challenges 18-22weeks after the start of treatment.ResultsTreatment with ToleroMune Ragweed resulted in the largest changes in TRSS in the most symptomatic subjects who had the highest scores at Baseline. In this group, treatment with the highest dose of ToleroMune Ragweed showed a mean change in the TRSS score at the post treatment EEC visit of -5.77±5.31 versus a change of -2.93±5.31 on placebo (p <0.05). The product was safe and well tolerated.ConclusionsThe efficacy of T cell epitope-based peptide immunotherapy has been demonstrated for cat and ragweed allergies. This new treatment modality offers an exciting alternative short-course immunotherapy with an enhanced safety profile that is potentially applicable across multiple allergens. RationaleA series of T-cell epitopes from cat allergen, Fel d1, formulated into a short-course peptide vaccine (ToleroMune Cat) was previously shown to significantly reduce allergic rhinoconjunctivitis symptoms shortly after vaccine therapy ended and persistently, one year after dosing start (tolerance). In this study, we evaluated the efficacy of a vaccine from a newly identified series of T-cell epitopes from ragweed allergen Amb a1 (ToleroMune Ragweed) on allergic rhinoconjunctivitis symptoms. A series of T-cell epitopes from cat allergen, Fel d1, formulated into a short-course peptide vaccine (ToleroMune Cat) was previously shown to significantly reduce allergic rhinoconjunctivitis symptoms shortly after vaccine therapy ended and persistently, one year after dosing start (tolerance). In this study, we evaluated the efficacy of a vaccine from a newly identified series of T-cell epitopes from ragweed allergen Amb a1 (ToleroMune Ragweed) on allergic rhinoconjunctivitis symptoms. MethodsScreened ragweed allergic subjects attended four consecutive 3-hour Baseline Challenges in an Environmental Exposure Chamber (EEC) where airborne ragweed pollen levels were controlled at 3500±500 grains/m3 . Total Rhinoconjunctivitis Symptom Score (TRSS) was scored every 30 minutes on a scale of 0-24. 275 subjects were randomised to placebo, or one of four ToleroMune Ragweed treatment arms. Subjects returned to a series of 4 consecutive, 3-hour Post-Treatment EEC Challenges 18-22weeks after the start of treatment. Screened ragweed allergic subjects attended four consecutive 3-hour Baseline Challenges in an Environmental Exposure Chamber (EEC) where airborne ragweed pollen levels were controlled at 3500±500 grains/m3 . Total Rhinoconjunctivitis Symptom Score (TRSS) was scored every 30 minutes on a scale of 0-24. 275 subjects were randomised to placebo, or one of four ToleroMune Ragweed treatment arms. Subjects returned to a series of 4 consecutive, 3-hour Post-Treatment EEC Challenges 18-22weeks after the start of treatment. ResultsTreatment with ToleroMune Ragweed resulted in the largest changes in TRSS in the most symptomatic subjects who had the highest scores at Baseline. In this group, treatment with the highest dose of ToleroMune Ragweed showed a mean change in the TRSS score at the post treatment EEC visit of -5.77±5.31 versus a change of -2.93±5.31 on placebo (p <0.05). The product was safe and well tolerated. Treatment with ToleroMune Ragweed resulted in the largest changes in TRSS in the most symptomatic subjects who had the highest scores at Baseline. In this group, treatment with the highest dose of ToleroMune Ragweed showed a mean change in the TRSS score at the post treatment EEC visit of -5.77±5.31 versus a change of -2.93±5.31 on placebo (p <0.05). The product was safe and well tolerated. ConclusionsThe efficacy of T cell epitope-based peptide immunotherapy has been demonstrated for cat and ragweed allergies. This new treatment modality offers an exciting alternative short-course immunotherapy with an enhanced safety profile that is potentially applicable across multiple allergens. The efficacy of T cell epitope-based peptide immunotherapy has been demonstrated for cat and ragweed allergies. This new treatment modality offers an exciting alternative short-course immunotherapy with an enhanced safety profile that is potentially applicable across multiple allergens.

RATIONALE: Dust mite allergen (DMA) is one of the most common aeroallergens causing allergic sensitization and asthma worldwide. Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f) are the two major DMA in North America. Induction of ocular symptoms by Der p was assessed in an Environmental Exposure Chamber (EEC). METHODS: Patients with positive SPT to Der p and/or Der f were exposed for 3 hours to aerosolized Der p allergen (10-120ng/m3) on 4 consecutive days (V2-V5). Symptoms were collected and assessed [nasal congestion, rhinorrhea, sneezing, itchy nose, itchy eyes, watery eyes, red eyes and itchy ear/palate; 0-3 scale] at pre-EEC, 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes (Mean±SEM). RESULTS: Significant total ocular symptom scores (itchy, watery, red eyes: TOSS) were reported by patients who qualified based on nasal and total symptoms scores (≥6/12 total nasal symptom score,≥10/24 total symptom score). During the first EEC visit (V2), pre-EEC TOSS was 0.2±0.08. By 150 and 180 minutes, mean TOSS was approximately 4.6 (max=9). There was some “priming” effect as patients returned for V3 with pre-EEC TOSS of 0.7±0.20 units. However, TOSS increased to levels similar to V2 with a maximum mean TOSS of 4.7±0.40 units. Similarly, pre-EEC TOSS was reported at 0.6±0.22 (V4) and 1.1±0.32 units (V5) with maximum TOSS of approximately 4.9 (V4) and 4.6 (V5) units. CONCLUSIONS: Dust Mite Allergen clinical model in an EEC is a safe, well-controlled environment whereby patients can be exposed to consistent levels of aerosolized DMA to evoke significant levels of allergic conjunctivitis symptoms.

RATIONALE: Dust Mite Allergen, including Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f), is a major factor in allergic asthma disease worldwide. The Environmental Exposure Chamber (EEC), which allows for a consistent, well-controlled level of aerosolized Der p allergen exposure, was used to study the effects of Der p in both asthmatic and non-asthmatic dust mite allergic patients. METHODS: Patients with positive skin prick test to Der p and/or Der f were exposed to 10-120 ng/m3 aerosolized Der p allergen for 3 hours on 4 consecutive days. Asthma symptoms were scored (cough, wheezing, and shortness of breath; scale of 0-3; max=9) pre-EEC and at 10, 20, 30, 45, 60 and every 30 minutes for the duration of the challenge. There were two mild asthmatic patients (FEV1 >80%) and one patient with childhood asthma whose scores were compared to all 24 dust mite allergic patients (Mean±SEM). RESULTS: There were distinct symptoms reported by the subsets of patients. When all 24 dust mite allergic patients were assessed, maximum total mean asthma score was approximately 2.4 with cough > shortness of breath & wheezing. However, three asthmatic patients reported cough & shortness of breath > wheezing with maximum total mean asthma score of approximately 4.0. While one asthmatic patient did not show significant FEV1 decrease, one patient showed a mean FEV1 decrease of 17% at mid-challenge and 12% at post-challenge during V2-V5. CONCLUSIONS: Dust Mite Allergen EEC clinical model is a safe model for both allergy and asthma, where anti-allergic and asthma-targeted therapeutics can be studied.

RATIONALE: This study examined the nasal response to ocular allergen and the efficacy of an antihistamine nasal spray (Livostin®) in a Conjunctival Allergen Challenge (CAC) model. METHODS: A randomized, double-blind, parallel, pilot study was conducted, in which 16 patients were randomized to Livostin® or placebo nasal spray. Primary efficacy endpoints were ocular itching and redness, each scored 0-4. At Visit 1 a dose escalating CAC was administered to determine allergen and concentration which elicit a positive response, which was confirmed at Visit 2. At Visit 3, two sprays per nostril of study drug were administered 30 minutes prior to CAC. Acoustic rhinometry was performed pre- and post-CAC at Visit 2, and pre-treatment and post-CAC at Visit 3. RESULTS: Ocular allergen administration decreased nasal patency as measured objectively using acoustic rhinometry. Mean minimal cross-sectional area (MCA) was marginally smaller post-CAC (0.28) compared to pre-CAC (0.35) at Visit 2, indicating increased nasal congestion. This is consistent with total nasal symptoms scores (TNSS) which increased upon CAC, with a mean change from baseline of 2.6 units in TNSS and 0.43 units in nasal congestion specifically. Mean change from baseline of post-to-pre CAC of mean MCA were not significantly different for Livostin® and placebo (both 0.043), demonstrating no change in nasal patency following Livostin® treatment. CONCLUSIONS: These findings demonstrate that CAC induces marginal nasal response and its use as a model to test nasal congestion is limited. The lack of effect of Livostin® to relieve nasal congestion is in agreement with previous reports on antihistamine actions.