Regulatory Decision Summary for Ryaltris

Ryaltris is a combination corticosteroid (mometasone furoate) plus antihistamine (olopatadine hydrochloride) nasal spray intended for the treatment of allergic rhinitis symptoms. The Sponsor has provided adequate data from clinical studies conducted in adult and adolescent patients with seasonal allergic rhinitis (SAR), as well as a study conducted in children 6-11 years of age with SAR, to support an indication for the symptomatic treatment of moderate to severe SAR in patients 6 years of age and older.

Two pivotal replicate double-blind, randomized, parallel-group Phase 3 studies were conducted in adult and adolescent patients. Patient symptoms and quality of life scores at randomization were generally consistent with moderate to severe SAR. In these studies, and other studies provided for this submission, change from baseline in the reflective Total Nasal Symptom Score (rTNSS) over a 2-week treatment period was used as the primary efficacy endpoint. The rTNSS endpoint assesses an aggregate of four subject-reported nasal symptoms. Secondary endpoints included determinations of onset of action and scores from a quality of life questionnaire (conducted in adult patients). A similarly conducted Phase 3 study in children 6-11years of age used similar endpoints, with a pediatric-adapted quality of life questionnaire. The key endpoints that were used are standard, validated endpoints that are commonly used in the study of allergic rhinitis treatments. While adequate data was provided to support an indication for the treatment of SAR, one 52-week Phase 3 study that enrolled patients with perennial allergic rhinitis (PAR) did not address efficacy as a primary endpoint, and contained insufficient data to make a conclusion regarding the overall benefit for the treatment of PAR.

In the replicate Phase 3 SAR studies, as well as similarly conducted Phase 2 study, Ryaltris provided a statistically and clinically meaningful benefit relative to both placebo and monotherapy treatments. The difference in change from baseline in average rTNSS over the 2-week treatment period, compared to placebo, ranged from -0.98 to -1.17, on a 12-point scale. In the study of children 6-11 years of age, this difference was smaller (-0.6), but still statistically significant and clinically meaningful. Changes from baseline in quality of life scores were consistent with the findings of the primary endpoint and other key secondary endpoints.

Though intranasal corticosteroids are regarded as the gold standard for allergic rhinitis treatment, intranasal antihistamines have a faster onset of action (minutes vs. hours). It is already recognized in published treatment guidelines that the combination of intranasal antihistamine plus corticosteroid can provide faster and greater symptom relief relative to the use of intranasal corticosteroids alone. Onset of action data provided for Ryaltris were consistent with this, showing a significant relief of nasal symptoms relative to placebo by 15 minutes after treatment initiation in the replicate Phase 3 studies.

Both monocomponents act locally to exert efficacy, and have minimal systemic exposure. The dosages for the monocomponents used in Ryaltris correspond to those used in currently marketed monotherapy nasal sprays. No pharmacokinetic (PK) interaction between the components was found. PK modelling indicated comparable systemic exposures between children and adults, when used as recommended.

Safety was demonstrated with adverse event reporting in the above-mentioned clinical studies, as well as in a 52-week safety study conducted in patients with PAR. Non-clinical findings were consistent with clinical data, and did not indicate any novel risks associated with the combination. The most common side effects in clinical studies were altered sense of taste, headache, and nosebleed. All treatment-related adverse events were consistent with the known side effects of the monocomponents. No treatment-related serious adverse events were reported in any of the clinical studies provided for this submission. The Sponsor’s Risk Management Plan specifies no activities beyond the use of routine pharmacovigilance post-marketing, which is acceptable given the low risks associate with this drug combination.

A Notice of Deficiency (NOD) was previously issued on May 26, 2021 based on data integrity issues at the Glenmark Pharmaceuticals Limited (Unit III), Baddi-Nalagarh Road, India (173205) drug product manufacturing site. The company resolved the issues in the response to the Health Canada issued NOD. No other significant quality issues were noted during the review.

Following a review of the brand name, Patient Medication Information (used for the package insert), carton labels, and bottle labels, all labeling material was found to be considered acceptable with changes made in response to requested revisions.

Overall, the Ryaltris combination nasal spray demonstrated benefits consistent with those of its monocomponents, with no unexpected safety issues arising from synergistic effects. Thus, the benefits of Ryaltris for the symptomatic treatment of SAR in patients 6 years of age and older outweigh the risks. 

For further details about Ryaltris, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.