Regulatory Decision Summary for Miebo

This New Drug Submission (NDS) for a New Active Substance (NAS) was filed to obtain market authorization for Miebo (perfluorohexyloctane ophthalmic solution, 100% w/w) for the treatment of the signs and symptoms of dry eye disease (DED) associated with meibomian gland dysfunction (MGD). Upon review, Health Canada authorized Miebo for the treatment of the signs and symptoms of dry eye disease.

The proposed indication was supported by the results of two replicate multi-center, randomized, double-masked, saline-controlled Phase 3 pivotal studies GOBI (NVU-003) and MOJAVE (BL-904), in which a total of 1,217 adult subjects with DED associated with MGD across 68 US sites were randomized to receive either Miebo (N = 614) or saline (N = 603) administered one drop per eye four times daily (QID) for 8 weeks.

The primary efficacy endpoints in both studies were change from baseline in the total corneal fluorescein staining (tCFS) score using the National Eye Institute (NEI) scale (assessed the signs of DED) and the eye dryness score using the visual analog scale (VAS) (assessed the symptoms of DED) at day 57. For the tCFS (NEI) score, five areas on the cornea (inferior, superior, central, nasal, and temporal) were graded 0-3 (0 = no staining, 3 = heavy staining) by the investigator at each visit with a total maximum score of 15 for each eye. For the dryness VAS score, the severity of dryness was rated 0-100 (0 = no discomfort, 100 = maximal discomfort) by subjects at each visit. The results showed a statistically significant reduction in tCFS (GOBI: -0.95, p<0.0001; MOJAVE: -1.28, p<0.0001) and eye dryness VAS score (GOBI: -7.59, p=0.0004; MOJAVE: -10.22, p<0.0001) at Day 57 favoring Miebo in both trials. Key secondary efficacy endpoints supported the primary efficacy outcomes, including change from baseline in tCFS (NEI scale) and eye dryness VAS score at Day 15, and change from baseline in central corneal fluorescein staining (cCFS) (NEI scale) and burning/stinging VAS score at Day 57. In addition, responder analyses further supported the efficacy of Miebo.

The clinical safety of Miebo was assessed in the two pivotal Phase 3 studies and a Phase 2 dose-ranging study, SEECASE (NVU-002). A total of 1,553 subjects across the three 8-week studies received at least 1 dose of Miebo (N = 839) or saline (N = 714). The most common ocular treatment emergent adverse events (TEAEs) that occurred in ≥1% of subjects treated with Miebo QID and higher than in the saline control were blurred vision (2.2%) and ocular hyperemia (1.1%); all of which were mild in severity, transient in nature, and typically resolved within 5-10 minutes post-instillation. The long-term safety of Miebo QID for 52 weeks was investigated in 208 subjects in a multi-center, single-arm, open label extension (OLE) study, KALAHARI (NVU-004). Patients enrolled in KALAHARI were previously enrolled in GOBI. 97 of the 208 subjects continued Miebo QID treatment through GOBI into KALAHARI for a total of 60 weeks. The remaining 111 subjects were switched from saline in GOBI to Miebo in KALAHARI. In this study, the most common (≥1%) ocular TEAEs were vitreous detachment (1.9%), allergic conjunctivitis (1.4%), increased lacrimation (1.4%), and blurred vision (1.4%), and the most common non-ocular TEAEs were COVID-19 (2.9%), hypertension (1.9%), and hypercholesterolaemia (1.4%). Most of the ocular TEAEs were mild in severity, with the exception of one subject with a report of severe ocular TEAE of eyelid irritation. No treatment-related deaths were reported. No differences in efficacy or safety were observed among the sub-populations of age (≥18 to <65 years and ≥65 years), race (white and non-white), sex (female and male), and baseline VAS dryness score (<70 and ≥70), based on results from the subgroup analyses in the pooled studies.

Although Miebo treatment has shown reduced corneal damage (i.e., tCSF score) due to DED, the corneal endothelial cell health after prolonged Miebo exposure was not fully investigated. This uncertainty is mitigated by an ongoing 12-month, randomized, concurrently controlled clinical study to compare corneal endothelial cell counts in subjects with and without Miebo treatment. Furthermore, perfluorohexyloctane is a member of the class of semi-fluorinated alkanes, which are classified as per- and polyfluorinated alkyl substances (PFAS). Notwithstanding the low systemic exposure with ophthalmic use, there is no information regarding the accumulative potential for perfluorohexyloctane following chronic, long-term use. Additionally, no studies were conducted to investigate the presence of perfluorohexyloctane in breast milk following ocular administration; therefore, the use of perfluorohexyloctane during pregnancy and breastfeeding is unknown. These and other uncertainties are managed by proper labelling in the Product Monograph and prescription status.

In addition to the Product Monograph, risk mitigation measures are outlined in the Risk Management Plan (RMP) for Miebo, which includes the safety of long-term use including corneal endothelial health, and routine pharmacovigilance activities to monitor and report new safety concerns.

The proposed indication for the treatment of the signs and symptoms of DED associated with MGD was expanded to the treatment of the signs and symptoms of DED. This was done in consideration of the fact that the proposed mechanism of action for Miebo is independent of meibomian gland function (i.e., to interact with the lipophilic part of the tear film and form a monolayer at the air-liquid interface that prevents excessive evaporation of the aqueous tear film), the target population of DED associated with MGD was not clearly distinguished from the general DED population based on the inclusion criteria in the two pivotal studies, and it is clinically challenging to distinguish DED due to MGD from DED without MGD involvement.

The chemistry and manufacturing information submitted for Miebo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Miebo administered QID for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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