Summary Basis of Decision for Miebo

Clinical Pharmacology

The exact mechanism of action of Miebo for the treatment of dry eye disease is unknown. Perfluorohexyloctane, the medicinal ingredient in Miebo, is a semi-fluorinated alkane which belongs to the group of per- and polyfluoroalkyl substances. It contains 6 perfluorinated carbon atoms and 8 hydrogenated carbon atoms. The compound demonstrates amphiphilic behavior and self-assembly effects involving lipophilic and lipophobic effects on the ocular surface. Perfluorohexyloctane forms a monolayer at the air‑liquid interface of the tear film, which stabilizes the natural tear film and reduces evaporation.

Clinical pharmacology and pharmacokinetics was evaluated in a Phase II multicentre, double‑masked, saline‑controlled study, SEECASE. The aim of the SEECASE study was to evaluate the effective of perfluorohexyloctane at two different dosing regimens for “signs” and “symptoms” of dry eye disease. In this study, subjects with dry eye disease associated with meibomian gland dysfunction were treated with either a single or repeated (i.e., twice daily [BID] or four times daily [QID]) ocular instillations of Miebo or a saline solution for 8 weeks. The systemic exposure to perfluorohexyloctane was assessed using a validated gas chromatography-tandem mass spectrometry (GC‑MS/MS) method. The pharmacokinetic cohorts consisted of a total of 79 subjects, including 30 subjects in the BID cohort, 23 subjects in the QID cohort, and 26 subjects in the combined BID and QID saline solution cohort. Systemic exposure of Miebo after a single topical ocular administration was low, with 75% of post‑dose samples containing perfluorohexyloctane concentrations below the lower limit of quantification of 1 ng/mL. In contrast, the systemic exposure of perfluorohexyloctane following repeated BID or QID ocular administration could not be characterized due to the high number of false positive results in the saline group. Further investigations were conducted; however, the root‑cause for the high false positive rate could not be identified. In summary, results from the pharmacokinetic cohorts demonstrated an overall low blood levels of perfluorohexyloctane after topical ocular administration, which is consistent with the non‑clinical pharmacokinetic data demonstrating limited systemic distribution of 14C‑perfluorohexyloctane in rabbits instilled daily for 5 days. While there is no clinical data to reflect accumulative potential following repeated exposure, low level systemic accumulation was shown in rabbits administered perfluorohexyloctane via ocular instillation twice daily for five days compared to a single instillation. However, due to the bioanalytical issues identified during the sample analysis, a confirmative conclusion on the system exposure in humans following repeated exposure was not reached. Therefore, the pharmacokinetic data from this study cannot be used for the quantitative pharmacokinetic characterization of perfluorohexyloctane or for labelling purposes.

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

Clinical Efficacy

The clinical efficacy of Miebo was evaluated in two replicate multicentre, randomized, double‑masked, saline‑controlled Phase III pivotal studies, GOBI and MOJAVE. A total of 1, 217 adult subjects with dry eye disease associated with meibomian gland dysfunction were randomized in a 1:1 ratio to receive either Miebo (number of subjects [n] = 614) or a saline solution (n = 603) administered one drop per eye four times daily (QID) for a duration of 8 weeks (Day 57 ± 2).

For enrollment in either study, subjects had to be at least 18 years of age; have a subject‑reported history of dry eye disease in both eyes for at least 6 months; and have each of the following at Visit 0 and Visit 1: tear film break-up time ≤5 seconds; ocular surface disease index score ≥25; an unanesthetized Schirmer’s test I score ≥5 mm; total meibomian gland dysfunction score ≥3 (range, 0 to 15); total corneal fluorescein staining (tCFS) score between 4 and 11 based on the National Eye Institute (NEI) scale. Furthermore, subjects had to have at least one eye (the same eye) that satisfied all criteria listed above for Visit 0 (Screening) and Visit 1 (Randomization and treatment). All subjects had to provide written informed consent and be able and willing to follow instructions, including participation in all study assessments and visits. Mechanical therapies for meibomian gland dysfunction (lid scrubs, lid wipes, and warm compresses) were allowed throughout the studies. The mean age of subjects was 57 years (age range: 19 to 88 years) with the majority of subjects being female (76%).

In both pivotal studies, two primary efficacy endpoints were assessed: the change from baseline at week 8 (Day 57) in total corneal fluorescein staining (tCFS) using the National Eye Institute (NEI) scale, and dry eye symptoms based on a visual analog scale. For the tCFS, five areas on the cornea (inferior, superior, central, nasal, and temporal) were graded 0 to 3 (0 = no staining, 3 = heavy staining) by the principal investigator at each study visit. A total score was calculated with a maximum score of 15 for each eye. The tCFS score served to measure the “signs” of dry eye disease. For the VAS score, study subjects were instructed to rate at each study visit the severity of eye dryness using a visual analog scale (VAS). The severity of dryness was scored 0 to 100 (0 = no discomfort, 100 = maximal discomfort). The VAS score served to measure the “symptoms” of dry eye disease.

Four key secondary efficacy endpoints were also assessed in the evaluation. The change from baseline in tCFS (based on the NEI scale) and eye dryness VAS score at Day 15, as well as the change from baseline in central corneal fluorescein staining (cCFS; based on NEI scale) and burning/stinging VAS score at Day 57.

Given that the two pivotal studies had identical study designs and study populations, the efficacy results were analyzed individually as well as in a pooled dataset. Upon completion of the review, it was determined that the individual study findings were consistent with those from the pooled dataset. Study 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 in favour of Miebo treatment.

For each of the four key secondary efficacy endpoints, mean decreases from baseline (indicating improvement) were observed in both treatment groups, and the differences between the Miebo and saline solution groups were shown to be statistically significant (p<0.0001), in favour of Miebo. Therefore, both primary efficacy endpoints and all four key secondary efficacy endpoints were met in the pooled dataset and individually within each study.

Sub‑group analyses were also performed in the pooled dataset to explore the implications for efficacy among the sub‑populations of age, race, sex, and baseline dryness VAS score. For both primary efficacy endpoints, the 95% confidence interval for all subject sub‑groups (Age range: ≥18 to <65 years and ≥65 years; Race: white and non‑white; Gender: female and male; Baseline eye dryness VAS score: <70 vs. ≥70) entirely favoured Miebo (i.e., none overlapped) except for eye dryness score in the male sub‑group (p = 0.0715).

Long‑term efficacy of Miebo was evaluated in 208 subjects in a 52‑week multicentre, single‑arm, open‑label extension study, KALAHARI. Upon completion of the GOBI study, 208 subjects then enrolled in the KALAHARI study. Of the 208 subjects enrolled, 97 continued to receive Miebo QID. The remaining 111 subjects who had previously received a saline solution in the GOBI study, now received Miebo QID in the KALAHARI study. The majority (76.9%) of the subjects completed the long‑term safety extension study.

The efficacy results from in the KALAHARI study supported long‑term use of Miebo up to 52‑weeks. Mean decreases from baseline in tCFS and cCFS score, as well as dryness and burning/stinging VAS score (indicating improvement) were observed in all subjects throughout the study at all timepoints up to Week 52. Therefore, the efficacy shown in the two pivotal studies (GOBI and MOJAVE) did not wane over the 52 weeks of follow‑up and was maintained with long‑term use of Miebo in subjects with dry eye disease with meibomian gland dysfunction.

Indication

The New Drug Submission for Miebo was filed by the sponsor with the following proposed indication:

Miebo (perfluorohexyloctane ophthalmic solution, 100% w/w) is indicated for the treatment of the signs and symptoms of dry eye disease associated with meibomian gland dysfunction.

Health Canada approved the following indication:

Miebo (perfluorohexyloctane ophthalmic solution, 100% w/w) is indicated for the treatment of the signs and symptoms of dry eye disease.

The proposed indication was modified to expand the indicated population to the treatment of the signs and symptoms of dry eye disease based on the rationale that (i) the mechanism of action for perfluorohexyloctane is independent of meibomian gland function, (ii) the inclusion of subjects in the pivotal studies (GOBI and MOJAVE) did not adequately distinguish clearly between patients with meibomian gland dysfunction and overall dry eye disease, as well as (iii) the challenge in distinguishing dry eye disease due to meibomian gland dysfunction from dry eye disease in clinical practice.

Prescription status was recommended based on the need for supervision by a practitioner, and that the level of uncertainty justifies supervision by a practitioner. Namely, there is uncertainty associated with the health of corneal endothelial cells after prolonged exposure to Miebo, a clear determination of the risk of Miebo to an infant during lactation and on fertility could not be made, and there is uncertainty associated with the development of toxicity and bioaccumulation potential of perfluorohexyloctane due to its classification as a per- and polyfluoroalkyl substance.

For more information, refer to the Miebo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The short‑term clinical safety of Miebo was evaluated in two pivotal Phase III studies (GOBI and MOJAVE) and one Phase II dose‑ranging study, SEECASE. Across the three 8‑week studies, 1,553 subjects received at least one dose of Miebo (n = 839) or a saline solution (n = 714). The occurrence of ocular and non-ocular treatment-emergent adverse events (TEAEs), best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, and dilated fundoscopy were assessed as the safety endpoints for these studies.

Based on the pooled safety data, the proportion of subjects who experienced treatment-emergent adverse events (TEAEs) was 17.6% in Miebo‑treated subjects versus 15.8% in subjects receiving a saline solution. As for drug-related adverse events, 6.0% of Miebo‑treated subjects versus 5.0% of those receiving a saline solution were similar. Most of these TEAEs were mild or moderate in severity. The most common TEAEs reported in ≥1% of subjects treated with Miebo QID were blurred vision (2.2%) and ocular hyperemia (1.1%). These events were mild, transient in nature, and usually resolved within 5 to 10 minutes post‑instillation. No ocular treatment-emergent serious adverse events were reported. Five (0.3%) of subjects did experience an ocular TEAE that led to treatment discontinuation and study withdrawal.

Mean changes from baseline in best-corrected visual acuity and intraocular pressure at Day 57 were minimal in each treatment group. The proportion of subjects who had a worsening shift in slit-lamp examination or dilated fundoscopy results observed from baseline to any given post-baseline visit was very low (≤1.0 or ≤0.3%, respectively). In summary, safety results from the pooled studies SEECASE, GOBI, and MOJAVE demonstrate that Miebo administered QID for 8 weeks is safe and well‑tolerated in adults with dry eye disease associated with meibomian gland dysfunction.

Sub‑group analyses were also conducted in the pooled dataset to explore the implications for safety among the sub‑populations of age, race, sex, and baseline dryness VAS score. The overall ocular TEAE profile was similar among the patient sub‑groups of age (≥18 to <65 years and ≥65 years), gender (females and males), and baseline eye dryness VAS score (<70 vs. ≥70). For race, the incidence of ocular TEAEs and drug-related ocular TEAEs was shown to be higher in whites than in non-whites. As no pre-study sample size calculations were conducted for the sub‑group analysis of the pooled studies, the results should be considered exploratory or supportive in nature.

Long‑term safety of Miebo up to one year was assessed in a 52‑week open label extension study, KALAHARI. A total of 208 subjects who completed the pivotal Phase III GOBI study were then enrolled in the KALAHARI study and received Miebo QID. Sixty‑nine (33.2%) subjects had at least one TEAE (ocular or non-ocular) and 14 (6.7%) subjects had at least one drug-related TEAE. Most of the TEAEs were mild or moderate in severity, including 39 (18.8%) subjects with a mild TEAE, 25 (12.0%) subjects had a moderate TEAE, and 5 (2.4%) subjects had a severe TEAE. Ten (4.8%) subjects experienced a treatment-emergent serious adverse event, all of which were non-ocular in nature. One death due to gastric cancer was reported and the event was not considered to be treatment-related. Nine (4.3%) subjects had a TEAE that led to treatment discontinuation. The combined ocular and non-ocular TEAE profiles were generally similar between subjects assigned to the Miebo group and those assigned to the saline solution group in the parent study GOBI.

In the KALAHARI study, 29 (13.9%) subjects had at least one ocular TEAE and 13 (6.3%) subjects had at least one drug-related ocular TEAE. Most of the ocular TEAEs were mild in severity, including 21 (10.1%) subjects with a mild ocular TEAE, 7 (3.4%) subjects with a moderate ocular TEAE, and 1 (0.5%) subject with a severe ocular TEAE. No ocular treatment-emergent serious adverse events were reported. In addition, 5 (2.4%) subjects had an ocular TEAE that led to treatment discontinuation. Ocular TEAE profiles were generally similar between the study, as well as between subjects assigned to the Miebo group and those assigned to the saline solution group in the parent study GOBI. The most common ocular TEAEs observed in ≥1% of subjects were vitreous detachment (1.9%) and allergic conjunctivitis, increased lacrimation, and blurred vision (1.4% each). The incidence of individual ocular TEAEs was low and similar between subjects assigned to the Miebo group and those assigned to the saline solution group in the parent study GOBI.

No appreciable differences in mean changes from baseline in best-corrected visual acuity or intraocular pressure at Week 52 were observed between subjects assigned to the Miebo group and those assigned to the saline group in the parent study GOBI. The proportion of subjects who had a worsening shift in slit-lamp examination or dilated fundoscopy results observed from baseline to any given post-baseline visit remained very low (≤1.0 or ≤0.3%, respectively). In summary, safety results from the long-term extension study KALAHARI demonstrate that Miebo administered QID for 52 weeks is safe and well‑tolerated in subjects with dry eye disease associated with meibomian gland dysfunction.

For more information, refer to the Miebo Product Monograph, approved by Health Canada and available through the Drug Product Database.

The Sponsor submitted an adequate non-clinical package to support the market authorization of Miebo, including pharmacodynamic, pharmacokinetic, and toxicology studies.

Pharmacodynamics

Ocular instillation of perfluorohexyloctane four times daily to rabbits for 7 days resulted in a statistically significant increase in tear film break‑up time, suggesting that perfluorohexyloctane can stabilize the tear film and prolong the time it takes for the eye to become dry. Perfluorohexyloctane was also shown to promote corneal damage healing in ex vivo systems. No cardiovascular or respiratory safety pharmacology studies were conducted. Given that the drug product is applied ocularly, these studies were waived for the non‑clinical review and for marketing authorization.

Pharmacokinetics

Low levels of radioactivity were detected in blood after a single dose of 14C‑perfluorohexyloctane instilled bilaterally to the eyes of rabbits, suggesting that ocular instillation of perfluorohexyloctane is systemically absorbed. However, systemic accumulation of perfluorohexyloctane is possible given that the concentration of substance‑related radioactivity in the blood of rabbits was more than 2‑fold higher after twice daily instillation of 14C‑perfluorohexyloctane for 5 days compared to after a single administration. Autoradiography analysis of the whole body suggested limited systemic distribution of 14C‑perfluorohexyloctane in rabbits instilled daily for 5 days, with the highest concentrations of substance‑related radioactivity observed between 0.25 and 4 hours post‑dose, with the highest concentration in the order of tears, meibomian glands, palpebral conjunctiva, cornea, bulbar conjunctiva, and accessory lacrimal gland. Perfluorohexyloctane is not metabolized by hepatic microsomes from humans, rabbits or rats, and is mainly excreted in the feces. It is unknown whether perfluorohexyloctane can be excreted in the milk.

Toxicology

In a 26‑week repeat‑dose ocular toxicity study in rabbits, bilateral instillation with perfluorohexyloctane four times daily (427.8 mg/day) was well‑tolerated and did not induce any ocular or systemic signs of toxicity or mortality. The ocular no observed adverse event level (NOAEL) was 427.8 mg/day and the systemic NOAEL was 147.5 mg/kg (human equivalent dose of 47.8 mg/kg), which provides a margin of safety of 3.6‑fold and 24.4‑fold, respectively, based on the maximal recommended human dose of 117.7 mg/day (ocular) or 1.96 mg/kg (systemic).

In a 28‑day repeat‑dose oral toxicity study in rats, once daily oral administration of perfluorohexyloctane at doses up to 2,000 mg/kg was well‑tolerated but resulted in an increase in the incidence and severity of microscopic acute peribronchiolar/perivascular inflammatory infiltrate in the lungs at the high dose. The NOAEL was established at 200 mg/kg (human equivalent dose of 32.4 mg/kg), which provides a systemic margin of safety of 16.5‑fold based on the maximal recommended human dose of 1.96 mg/kg.

In an embryofetal development study in pregnant rats between gestational day 6 (GD6) and GD7 (during organogenesis), oral administration of perfluorohexyloctane did not cause any mortality or test‑article related toxicity. The NOAEL was established at 2,000 mg/kg (human equivalent dose of 324 mg/kg), which provides a systemic margin of safety of 165‑fold based on the maximal recommended human dose of 1.96 mg/kg.

In another embryofetal study in pregnant rabbits during organogenesis, oral administration of perfluorohexyloctane (0, 250, 500, and 1,000 mg/kg/day) resulted in abortions in all perfluorohexyloctane-treated groups compared to none in the vehicle‑treated group. A dose‑dependent decrease in mean maternal body weight gain and mean food consumption was observed in all perfluorohexyloctane‑treated groups. Consistent with the severe maternal toxicity, mean fetal weight was lower in all perfluorohexyloctane‑treated groups. A dose dependent increase in external, visceral and/or skeletal malformation was observed in the fetuses (litters) of all perfluorohexyloctane‑treated groups compared to only one observed in the vehicle‑treated group. Although the incidences of fetal malformations are within the test facility historical controls groups, given the substantially higher number of fetal malformations observed in the mid‑ and high‑dose groups compared to the vehicle and low‑dose groups, the NOAEL was set at 250 mg/kg (human equivalent dose of 81 mg/kg), which provides a systemic margin of safety of 41‑fold based on the maximal recommended human dose of 1.96 mg/kg.

Perfluorohexyloctane is a member of the per‑ and poly‑fluoroalkyl substances chemical group. Per‑ and poly‑fluoroalkyl substances are considered to be highly persistent substances with some demonstrating the capacity to bioaccumulate in humans. Per‑ and poly‑fluoroalkyl substances persist in the environment indefinitely, and some can bioaccumulate in the human body based on multi‑year half‑lives reported for many representative per‑ and poly‑fluoroalkyl substances. Current scientific research suggests that exposure to some per‑ and poly‑fluoroalkyl substances may lead to adverse health outcomes and that some per‑ and poly‑fluoroalkyl substances can accumulate in the body over time. Research is ongoing to determine how different levels of exposure and types of per‑ and poly‑fluoroalkyl substances can lead to a variety of health effects, including immune and cardiometabolic dysfunction, poor perinatal health, and cancer. Therefore, uncertainties remain regarding the toxicity of individual per‑ and poly‑fluoroalkyl substances associated with chronic exposure. Given that the only ingredient in Miebo is a per‑ and poly‑fluoroalkyl substance, uncertainty remains regarding adverse outcomes that may develop as a result of chronic exposure to perfluorohexyloctane.

For more information, refer to the Miebo Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (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. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life is acceptable when the drug product is stored at room temperature (20 ºC to 25 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies, as needed).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Miebo is of human or animal origin.