Regulatory Decision Summary for Cuvposa

The efficacy of Cuvposa was demonstrated in one randomized, double-blind, placebo-controlled 8-week study conducted in 38 children with severe problem drooling mainly due to cerebral palsy. The rate of responders (improvement in drooling of ≥3 points in the Modified Teachers Drooling Scale) was statistically and clinically significantly larger (75%) than the placebo (11%). The resulting magnitude of the benefit was large and consistent in sensitivity analyses, reflecting the robustness of the results. Secondary endpoints results were generally supportive of the primary endpoints findings.

The safety profile of Cuvposa was consistent with known peripheral effects of anticholinergic therapy (e.g., mainly gastrointestinal effects), and only few central effects were noted. The long-term safety was assessed in a 6-month (instead of 12-month) open-label single arm study in 136 of these pediatric patients. This is acceptable considering glycopyrrolate is a known and long-time approved active substance pertaining to a well-established therapeutic class, and the chronic pediatric indication covers children with severe morbidity with no alternative approved drug therapy. The adverse event profile of Cuvposa was not disproportionally worse as treatment duration increased in the 6-month study. The dosing regimen was tailored to each patient based on the bodyweight and response to treatment (efficacy and safety), which would avoid unnecessarily high daily doses (less adverse effects for optimal efficacy). Finally, and though no definitive conclusions can be drawn from this long-term study given its design, there was no evidence that the beneficial effect significantly decreased over time.

In both the pivotal study and the long-term study, cardiac safety (ECG data) showed an average increase in heart rate of about 10 bpm with Cuvposa as compared to placebo (three cases of tachycardia), which may be consistent with anticholinergic effects. In both studies, the sponsor did not report any significant changes in cardiac conduction, depolarization, or repolarization. Finally, a literature-based report describing a thorough QTc study of glycopyrrolate inhaled formulation was negative, and thus provided acceptable evidence that Cuvposa at the intended clinical dose is not likely to produce significant effects on QTc interval.

There were post-marketing reports of events consistent with anticholinergic effects, and few serious events which were isolated cases and/or of unclear relation to Cuvposa. In order to further mitigate potential risks with the use of Cuvposa, the Product Monograph was updated to include two Contraindications (Obstructive uropathy or vesicoureteral reflux, and obstructive disease of the gastrointestinal tract). In addition, risks of severe renal impairment, cardiac patients, hepatic impairment, poorly controlled psychiatric conditions, and/or seizures were included under Warning and Precautions. A requirement to weigh the patient regularly was included to decrease the risk of unnecessarily high doses, and class adverse effects of anticholinergics were also added. A Risk Management Plan was also submitted to identify routine pharmacovigilance for Cuvposa in the target population.

In non-clinical studies, the adverse effects of glycopyrrolate (mydriasis, significantly reduced food consumption and reduced body weight gains) were mostly observed at dose levels which exceeded the recommended human clinical dose by multiple folds, and were considered to be exaggerated pharmacological (anticholinergic) effects of glycopyrrolate, and thus can be predicted and clinically monitored. There were no direct hazards related to glycopyrrolate identified at the proposed clinical dose. Any potential harm in sensitive or over-dosed individuals can be monitored as all potential hazards identified in this nonclinical program were related to the secondary (anticholinergic) pharmacokinetic effects of glycopyrrolate.

Cuvposa exhibited a treatment benefit of relatively large magnitude, with adverse effects that were in line with known anticholinergic drugs. The overall risk-benefit profile of Cuvposa was deemed favorable, for chronic severe drooling in children (3 to 18 years old) with cerebral palsy or other neurological conditions.