Summary Basis of Decision for Saflutan

Clinical Pharmacology

Tafluprost, the medicinal ingredient of Saflutan, is a fluorinated analogue of prostaglandin F2α. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor.

The clinical pharmacology program included reports on the human pharmacodynamic and pharmacokinetic studies. The Phase II studies demonstrated that Saflutan was superior to placebo in reducing intraocular pressure (IOP) in patients. Among the three concentrations of Saflutan, the 0.0015% solution exhibited the numerically largest mean IOP-reducing effect. These results support the use of 0.0015% Saflutan in the pivotal Phase-III studies. The Phase I and II studies showed that tafluprost acid is rapidly absorbed and eliminated from human plasma, appearing at low plasma concentrations. Pharmacokinetic parameters were similar between the preservative-containing and preservative-free formulations. The relative order of effectiveness in reducing IOP (with estimated mean change in IOP) was latanoprost > Saflutan > timolol.

Overall, the clinical pharmacological data support the use of Saflutan for the specified indication. Appropriate warnings and precautions are in place in the approved Saflutan Product Monograph to address the identified safety concerns.

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

Clinical Efficacy

The efficacy of Saflutan was evaluated in three Phase II studies (15-001, 15-002 and 74457), two Phase III pivotal studies (15-003 and P-001), two Phase III supportive studies (74458 and 77550) and one open-label Phase IIIb study (Study 77552). Several study protocol amendments were made during the course of the clinical development. All amendments were considered acceptable.

The Phase II study 15-001 was a randomized, double-masked, placebo- and active-controlled, parallel-group, multicentre dose-response study comparing the safety and efficacy of three concentrations of Saflutan ophthalmic solution (0.001%, 0.0025%, and 0.005%) with placebo and 0.005% latanoprost in patients diagnosed with open-angle glaucoma (OAG) (primary OAG, pseudoexfoliation syndrome, or pigmentary dispersion syndrome) or OHT. A total of 152 patients were enrolled and 142 completed the study as planned. The primary efficacy endpoint was change from baseline in mean diurnal IOP in the study eye on Day 28. The results from this study demonstrated that Saflutan and latanoprost were more effective than placebo in lowering IOP in patients with OAG or OHT. Following once daily administration for four weeks, all three concentrations of Saflutan tested (0.001%, 0.0025%, and 0.005%) were significantly superior to placebo in lowering mean diurnal IOP in patients with OAG or OHT. Among the Saflutan concentrations, the average change in mean diurnal IOP after four weeks of dosing was: 0.0025% Saflutan (-5.29 mm Hg, -22.7%) >0.001% Saflutan (-5.03 mm Hg, -19.9%) >0.005% Saflutan (-4.44 mm Hg, -19.5%). These IOP data suggested that Saflutan may exhibit a multiphasic dose-effect relationship, in which the response increases with increasing concentration until reaching a maximal effect, followed by decreasing response with further increases in concentration.

The Phase II Study 15-002 was a randomized, double-masked, active-controlled, parallel-group, multicentre study comparing the safety and efficacy of three concentrations of Saflutan ophthalmic solution (0.0003%, 0.0015%, and 0.0025%) with 0.5% timolol maleate and 0.005% latanoprost in subjects diagnosed with OAG or OHT. A total of 144 patients were enrolled and 139 completed the study as planned. The primary efficacy endpoint was a comparison of the mean change from baseline in IOP at each time point on Day 28 between the timolol group and each of the three Saflutan groups. The results from this study demonstrated that all three concentrations of Saflutan reduced IOP in subjects with OAG or OHT, and that 0.0015% Saflutan produced the greatest overall IOP-lowering efficacy among the concentrations tested with the relative order of effectiveness being: 0.0015% >0.0025% >0.0003%. After four weeks of treatment, the reduction in IOP was slightly greater with 0.0015% Saflutan (-4.76 to -7.28 mm Hg, -20.91 to -27.55%) compared to either 0.0025% Saflutan (-4.46 to -7.14 mm Hg, -16.84 to -25.86%) or 0.0003% Saflutan (-3.72 to -6.22 mm Hg, -15.82 to -23.77%). Among all study treatments, latanoprost produced the greatest IOP-lowering effect during the study with the relative order of effectiveness being: latanoprost > Saflutan > timolol.

Study 74457 was a pilot Phase II study on the duration and stability of the IOP lowering effect and tolerability of Saflutan 0.0015% ophthalmic solution as compared to latanoprost 0.005% eye drops. It was a randomized, double-masked, active-controlled, parallel-group, multinational and multicentre study in 38 patients with primary OAG, capsular glaucoma or OHT. The primary efficacy variables were the extent and duration of action at the end of the 6-week treatment period using the IOP measurements at Days 42 and 43 (measurements up to 48 hours after the last dose) and stability of IOP based on the individual fluctuations at Days 42 and 43. The results of the study show that the full IOP lowering effect of both Saflutan and latanoprost was reached at the 8 hours measurement of Day 7 one week after the first dose). At this point, the mean change (% change) from baseline was -9.6 mm Hg (-35.6%) for Saflutan and -8.8 mm Hg (-32.9%) for latanoprost. The full IOP lowering effect of both Saflutan and latanoprost was maintained up to 24 hours after the last dose and therefore supported once daily dosing. In fact, a clear IOP lowering effect could be seen even beyond 24 hours, though the IOP started to slowly increase in both treatment groups 36-48 hours after the last dose. This indicated that the duration of action of Saflutan is maintained for up to 24 hours post dosing. On Day 42 at 12 hours and 16 hours, the estimated overall treatment difference (Saflutan-latanoprost) reported was 1.055 and 0.444 with the upper 95% confidence interval (CI) >1.5 mm Hg indicating that Saflutan was clinically inferior to latanoprost. However, Saflutan was non-inferior to latanoprost at other time-points. The preliminary data provided in this study involving a limited number of patients indicate that Saflutan 0.0015% eye drops, dosed once daily at 20:00 hours, suggestively lowers IOP in patients with open-angle glaucoma or ocular hypertension and IOP reduction was maintained until 36 hours post dose and therefore supported once daily dosing.

The Phase III pivotal study 15-003 was a multicentre, randomized, double-blind, parallel-group, 12-month, non-inferiority study comparing the efficacy and safety of Saflutan 0.0015% ophthalmic solution with timolol maleate 0.5% ophthalmic solution in patients with OAG, pseudoexfoliative glaucoma, pigmentary glaucoma, or OHT. A total of 458 patients were enrolled in the study. A total of 267 patients were randomized to receive Saflutan 0.0015% and 191 patients received timolol 0.5% twice a day (b.i.d). The primary efficacy variable was the change from baseline in the overall diurnal IOP at Month 6. The study also characterized the long-term efficacy of Saflutan and timolol at 12 months and their sustained IOP lowering effect from 6 to 12 months. The results demonstrated that both Saflutan and timolol reduced IOP substantially and the reduction in IOP was maintained throughout the duration of the study (12 months). The IOP lowering effect of Saflutan was consistently larger than that of timolol throughout the study. Saflutan reached the pre-determined criteria for non-inferiority (upper limit of 95% CI for the difference in IOP-reducing effect between the drugs <1.5 mm Hg) at all visits and time-points (both at 6 and 12 months of treatment) thus demonstrating non-inferiority to timolol (0.5% b.i.d.).

The Phase III pivotal Study P-001 was a prospective, multicentre, multinational, double masked, parallel group, randomized, active-controlled, non-inferiority study designed to evaluate the efficacy and safety of preservative free Saflutan 0.0015% ophthalmic solution compared to preservative-free timolol maleate 0.5% ophthalmic solution in patients with OAG or OHT. A total of 643 patients were randomized, among which 320 patients received treatment with Saflutan out of which 306 completed the study. Of the 323 patients randomized to timolol, 312 completed the study. The primary efficacy variable was the mean IOP change from baseline at all 9 time-points during the study from the study eye. The study results demonstrated that the average IOP was reduced at all the post-baseline time-points in both treatment groups. The IOP lowering effect (mean IOP decrease) was seen at the 2-week visit (17.5 to 18.9 mm Hg for Saflutan and 18.3 to 19.2 mm Hg for the timolol group) and was maintained through Week 12 in both treatment groups. The criterion for declaring Saflutan non-inferior to timolol in the test of the primary hypothesis was met: all the upper limits of the two-sided 95% CI for the between-group differences in mean change from baseline in IOP for the study eye were less than the pre-specified non-inferiority margin of 1.5 mm Hg. Saflutan reached the predetermined criteria for non-inferiority at each visit and time-point.

Supportive Studies

Study 74458 was a randomized, double-masked, active-controlled, parallel-group, multinational and multicentre Phase III study comparing the efficacy and safety of Saflutan 0.0015% with latanoprost 0.005% in patients with primary OAG, capsular glaucoma, pigmentary glaucoma, or OHT. A total of 533 patients (269 in the Saflutan group and 264 in the latanoprost group) were enrolled to the study. The primary efficacy variable was the change from baseline in the overall diurnal IOP (at Month 6). Overall, both Saflutan and latanoprost had a substantial IOP lowering effect throughout the study. There was a reduction in IOP by Week 2 that was sustained to Month 24. At Month 6, the mean change in IOP at 8 hours was -8.05 mm Hg (-31.0%) in the Saflutan group and -9.16 mm Hg (-35.9%) in the latanoprost group. Therefore, it can be concluded that the IOP lowering effect of latanoprost at the 8 hour time-point was larger (from 0.44 mm Hg to 1.11 mm Hg) than that of Saflutan. During 12-month extension phase, the effect of latanoprost was larger (from 0.25 mm Hg at 16 hours on Month 3 to 1.39 mm Hg at 12 hours on Month 6) than that of Saflutan. Similarly, during the 24-month extension study, the mean change from baseline for latanoprost was larger (from 0.27 mm Hg at 20:00 hours on Month 24 to 1.19 mm Hg at 8 hours on Month 15). Overall, the IOP lowering effect of latanoprost was larger than that of Saflutan (approximately 1-1.50 mm Hg). Study 74458 failed to demonstrate non-inferiority of efficacy of Saflutan compared with latanoprost using the predefined 1.50 mm Hg non-inferiority margin.

Study 77550 was a randomized, investigator-masked, multicentre, cross-over Phase III study with two formulations (preserved and unpreserved) of Saflutan 0.0015% in patients with OAG or OHT. A total of 43 patients were randomized to the study (21 in the preserved and 22 in the unpreserved sequence). The primary efficacy variable was the changes from baseline at 4 weeks in the overall diurnal IOP and these changes were evaluated using a repeated measurements analysis of covariance (repeated measures ANCOVA) model. Overall, it can be concluded that the two formulations exhibited an equivalent IOP reduction and the removal of preservative benzalkonium chloride (BAK) from the Saflutan ophthalmic formulation had no effect on IOP control.

Study 77552 was an open-label, multinational and multicentre Phase IIIb study on the changes in ocular signs, symptoms and conjunctival inflammatory markers in patients with OHT, primary OAG, or capsular glaucoma who switched from preservative-containing latanoprost 0.005% eye drops to preservative-free Saflutan 0.0015% eye drops. A total of 158 patients were enrolled in the study. The results indicated improvements with Saflutan across a number of areas (ocular symptom scores, ocular signs, Quality of Life measures, and drop discomfort) at Week 12. There were improvements in one conjunctival inflammatory marker; however, the other marker (HLA-DR positive epithelial cells) was only significantly improved at 6 weeks and not at 12 weeks. Furthermore, the results indicated maintenance of IOP control over 12 weeks of treatment following the switch from latanoprost to Saflutan. However, due to the open uncontrolled study design, these findings have limited significance and the results should be interpreted with caution.

Irrespective of the results comparing Saflutan to latanoprost, the adequate, well-controlled studies demonstrating statistically and clinically significant decreases in IOP in patients treated with Saflutan 0.0015% (tafluprost ophthalmic solution) support the effectiveness of this treatment. Furthermore, sustained efficacy over a 24-month monitoring period was also observed.

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

Clinical Safety

The clinical safety of Saflutan was assessed in the Phase II and Phase  III studies by recording adverse events (AEs), laboratory evaluations (blood chemistry, haematology, and urinalysis) and vital signs assessment. In addition, specific ocular safety assessments were conducted.

The results showed that Saflutan elicited more AEs than latanoprost. As well, there was no improvement in ocular AEs with Saflutan compared to latanoprost (conjunctival/ocular hyperemia, eye pain, eye pruritus). Compared to non-prostaglandin treatment (timolol), Saflutan 0.0015% once a day (q.d.) was associated with increased rates of eyelid pigmentation, eyelash changes, and iris pigmentation, which are AEs commonly associated with prostaglandin analogues.

The ocular AEs of special interest (also the most common ocular AEs), reported without regard to causality, for the Saflutan group in the five pooled masked Phase II/III studies included conjunctival hyperemia (10.7%), ocular stinging/irritation (7.2%), ocular pruritus (4.9%) and ocular pain (3.4%). The drug-related AEs of special interest for Saflutan were hyperemia (9.7%), ocular stinging and irritation (6.2%), ocular pruritus (3.8%), and ocular pain (2.8%). Study results also indicated that the AEs observed are likely prostaglandin-related and may not be entirely attributable to the BAK preservative.

The most common systemic AEs (≥2% pooled masked Phase II/III), reported without regard to causality, during treatment with Saflutan 0.0015% q.d. were headache (5.6%), common cold (4.0%), cough (3.0%) and urinary tract infection (2.0%). Clinical evidence of lack of effect on vital signs and, in particular, the lack of cardiovascular effect with the use of Saflutan was demonstrated in the human Phase I-III clinical studies. Overall, for biomicroscopy and ophthalmoscopic findings, the effects of Saflutan were mostly mild and no clinically meaningful differences between Saflutan 0.0015% q.d., latanoprost 0.005% q.d, or timolol 0.5% b.i.d were observed.

Local ocular AEs including ocular/conjunctival hyperemia, eye irritation, eye pain, eye pruritus, eyelid oedema, erythema of eyelid, hypertrichosis of eyelid, blepharitis and foreign body sensation have been reported as part of the post-marketing safety experience. Iris darkening and blepharal pigmentation is a common AE of all prostaglandins. Due to the lack of detailed medical information presented in the post-marketing adverse drug reports (ADR), no definitive conclusions or inferences can be drawn concerning possible association between Saflutan treatment and cardiovascular adverse events. Based on reported cases of dizziness and asthma/cough in post-market safety studies, the proposed Saflutan Product Monograph was updated to include these reported ADRs.

A Notice of Deficiency (NOD) for the New Drug Submission (NDS) (control number 135836) was issued on February 11, 2011, regarding concerns of cardiovascular toxicity caused by Saflutan. Health Canada was of the opinion that a thorough QT/QTc prolongation study in humans was lacking. Health Canada refused the sponsor's request for the waiver to perform a thorough QT/QTc prolongation study. In response, the submission was re-filed on June 10, 2013. The sponsor addressed all of the NOD issues, provided additional clinical and post-marketing data and a clear rationale for waiver of a QT/QTc prolongation study based on the clinical pharmacology and safety profile of the product. An overall evaluation of the safety pharmacology studies submitted in the refiled NDS was performed. Health Canada agreed with the sponsor that the completed pre-clinical studies were adequate to assess the risk of QTc prolongation. As there were no pre-clinical QTc signals with large exposure margins in multiple models, the sponsor was granted the waiver for a clinical QTc prolongation study in humans. The submitted data (including the pharmacologic profile, pre-clinical testing and clinical data) were considered comprehensive and sufficient to characterize the cardiovascular safety of Saflutan ophthalmic solution for the treatment of elevated IOP in patients with OAG and OHT.

Overall, the data contained in the current submission established the safety and efficacy of Saflutan 0.0015% q.d. for the treatment of elevated IOP in patients with OAG and OHT. Appropriate warnings and precautions are in place in the approved Saflutan Product Monograph to address the identified safety concerns.

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