Regulatory Decision Summary for Jorveza

The pharmacological characteristics of budesonide is well-established and the only non-clinical pharmacology data provided in this submission was from an in vitro pharmacology safety study that evaluated the effect of budesonide on hERG channels and showed no significant risk for potential QT prolongation.

While the Sponsor referred mainly to published toxicology data obtained in mice, rats and dogs, new studies were submitted, including a local tolerance study that used the hamster cheek pouch model to investigate the effects of budesonide orodispersible tablets, and two repeat dose dog studies with the rectal foam formulation. In the local tolerance study, severe systemic toxicity was noted including premature deaths, reduction of body weight and changes in hematology at systemic exposures that were 10- to 15-fold higher than that observed at the human recommended dose (HRD). Mild local irritation effects in the oral and esophageal mucosa were also noted at doses that were 30-to-70-fold higher than the equivalent HRD based on body weight. In dogs, systemic corticosteroid toxicity was observed at exposures that were 2.2- to 2.7-fold higher than the expected systemic exposures at the HRD, and some effect were also observed at lower doses. However, these effects are well known for this class of products and are labelled accordingly in the Product Monograph (PM).

The systemic exposure with Jorveza was lower than reported for two other marketed oral formulations of budesonide at their respective recommended doses. Therefore, adverse effects beyond those reported for approved budesonide products are not expected. Overall, the non-clinical data of Jorveza did not raise any new or unexpected safety concerns.

The efficacy of Jorveza was mainly supported by a Phase II safety/efficacy dose finding study (BUU-2/EEA), a pharmacokinetics/pharmacodynamics study (BUU-1/BIO) and a pivotal Phase III randomized double-blind placebo-control parallel-group study (BUL-1/EEA). Although only one pivotal study was submitted instead of two, this was considered to be acceptable given the low prevalence of the eosinophilic esophagitis (EoE) and its seriousness, the lack of approved or marketed drugs for EoE, and the extensive cumulative knowledge (over two decades) of the safety profile of budesonide in other indications.

In the pivotal trial, 59 patients with EoE were treated with Jorveza 1 mg BID and 29 with placebo for six weeks. At the end of the six weeks, non-remitters from the double blind (DB) phase could enter an optional 6-week open-label (OLI) treatment phase. The overall design, choice of dose, duration of treatment, and statistical analyses were acceptable. The patients selection criteria were reasonable to allow the extrapolation of results to the target population. The primary efficacy endpoint was the rate of patients with clinicopathological remission at week 6, defined as patients achieving both histological remission (peak of <16 eosinophils per mm² high power field (eos/mm² hpf) in esophageal biopsies) AND symptoms resolution (severity of ≤2 points on 11 points scale) of dysphagia AND odynophagia on each day in the week prior to week 6. This endpoint was found acceptable as it encompasses both an objective measure and a patient reported endpoint. Key secondary endpoints included the two individual components of the primary outcome, and four other endpoints. Jorveza 1 mg BID was statistically and clinically significantly superior to placebo for the induction of clinicopathological remission in active EoE (57.6% vs 0%). The between-group difference was consistently larger in the interim and final overall analyses, with a difference of 57.6% (N=88), and strong statistical significance (p-values of 0.000002). Key secondary endpoints of histological remission (93.2% vs 0%, p≤0.01), and symptoms resolution (59.3% vs 13.8%, difference of 45.5% p≤0.01) were also in favour of Jorveza. Additional analyses using a very strict threshold of symptoms improvement (i.e., total resolution), showed that the difference (23.7%) in clinicopathological remission rates against placebo was still clinically relevant. The efficacy of Jorveza was thus demonstrated.

The open-label phase, however, was of limited value as only 23 patients were treated for an additional six weeks. The safety and efficacy profile could not be established beyond six weeks, and the Dosing recommendations in the Product monograph were therefore restricted to six weeks only.

The safety data showed that patients treated with Jorveza were more likely to have adverse events (AEs) (39.0% vs 3.4% with placebo), and adverse drug reactions (ADRs) (23.7% vs 0% with placebo). This was mostly due to esophageal candidiasis (16.9%) and oral or pharyngeal candidiasis (3% to 5% each). The sponsor reported that only 5.3% had histological/endoscopic signs and clinical symptoms; the rest did not have clinical symptoms. Other ADRs included three cases of decreased plasma cortisol. Overall, the nature of the adverse reactions was consistent with the known adverse effects of corticosteroids. These risks were mitigated through labelling by restricting treatment duration to six weeks, adding two contraindications (uncontrolled infections and active tuberculosis) and reinforcing the warnings.

The Phase II dose-ranging study did not show any clear dose response effect and hence the most adequate dose was not identified. Therefore, the lowest dose was selected for the pivotal phase 3 study. The pharmacokinetics study showed that systemic exposure to the new formulation was unlikely to be higher than that observed with other marketed oral budesonide formulations. The safety data from these two studies did not provide significant information beyond that of the pivotal trial given their duration and small sample size. The post-market data did not raise any significant unexpected safety signals that would change the risk-benefit profile of Jorveza.

Overall, the risk-benefit profile of Jorveza is acceptable for the induction of clinicopathological remission in adults with eosinophilic esophagitis (EoE).