OPHTHALMIC COMPOSITION FOR TREATMENT OF DRY EYE DISEASE

Abstract

The invention provides pharmaceutical compositions comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane for use in the topical treatment of dry eye disease and provides for dosing and treatment methods thereof. The invention further provides kits comprising such compositions.

Claims

1.-15. (canceled)

16. A method for treating dry eye disease, the method comprising the step of topically administering to a human patient in need thereof an ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutylpentane and up to about 1.0 wt % ethanol, wherein the composition is administered twice per day per eye as a single drop having a volume of about 10 μl, and wherein the composition comprises 2-perfluorobutylpentane.

17. The method according to claim 16, wherein the composition comprises up to 2% (w/w) of 2-perfluorobutylpentane or up to 1% (w/w), or up to 0.5% (w/w) of 2- perfluorobutylpentane.

18. The method according to claim 16, wherein the dry eye disease is moderate to severe dry eye disease.

19. The method according to claim 18, wherein the patient is not responsive to treatment with artificial tears.

20. The method according to claim 18, wherein the patient suffering from moderate to severe dry eye disease is characterized by at least one or a combination of the following: i) a total corneal fluorescein staining score of>6; ii) being symptomatic with a score of>40 on the dryness visual analogue scale (VAS); iii) a score>20 on the Ocular Surface Disease Index (OSDI); and iv) a Schirmer's Test I score of>2 mm and<8 mm.

21. The method according to claim 18, wherein the patient is characterized by having at least one eye with: i) a score of>40 on the dryness visual analogue scale (VAS); ii) a total corneal fluorescein staining score of>6; iii) a total lissamine green conjunctival staining score of>2; or iv) a Schirmer's Test I score>2 mm and<8 mm.

22. The method according to claim 16, wherein the patient experiences symptoms selected from blurring, pain, and irritation, or corneal surface damage.

23. The method according to claim 16, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg.

24. The method according to claim 16, wherein the total daily dosage of cyclosporine administered per eye is about 20 μg.

25. The method according to claim 16, wherein an onset of action is achieved within about 2 to 4 weeks.

26. A method for reducing corneal and/or conjunctival staining, the method comprising the step of topically administering to a human patient in need thereof an ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutylpentane and up to about 1.0 wt % ethanol, wherein the composition is administered twice per day per eye as a single drop having a volume of about 10 μl, and wherein the composition comprises 2-perfluorobutylpentane.

27. The method according to claim 26, wherein the ophthalmic composition further comprises up to 2% (w/w), or up to 1% (w/w), or of up to 0.5% (w/w) of 2-perfluorobutylpentane.

28. The method according to claim 26, wherein the corneal staining is fluorescein staining and the conjunctival staining is lissamine green staining.

29. The method according to claim 26, wherein the method is a method for reducing corneal staining in patient in need thereof.

30. The method according to claim 29, wherein the patient is characterized by having at least one eye with: i) a total corneal fluorescein staining score of at least 6; or ii) a central corneal fluorescein staining score of at least 1.

31. The method according to claim 26, wherein the method is a method for reducing conjunctival staining in a patient in need thereof.

32. The method according to claim 31, wherein patient is characterized by having at least one eye with a total lissamine green conjunctival staining score of at least 2.

33. The method according to claim 26, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg and wherein the total daily dosage of cyclosporine administered per eye is about 20 μg.

34. The method according to claim 26, wherein an onset of action is achieved within about 2 to 4 weeks.

35. The method according to claim 26, wherein the patient suffers from moderate to severe dry eye disease.

36. The method according to claim 26, wherein the patient is not responsive to treatment with artificial tears.

37. The method according to claim 26, wherein the patient suffers from moderate to severe dry eye disease characterized by at least one or a combination of the following: i) a total corneal fluorescein staining score of>6; ii) being symptomatic with a score of>40 on the dryness visual analogue scale (VAS); iii) a score>20 on the Ocular Surface Disease Index (OSDI); or iv) a Schirmer's Test I score of>2 mm and<8 mm.

38. The method according to claim 26, wherein the patient is characterized by at least one eye with: i) a score of>40 on the dryness visual analogue scale (VAS); ii) a total corneal fluorescein staining score of>6; iii) a total lissamine green conjunctival staining score of>2; or iv) a Schirmer's Test I score>2 mm and<8 mm.

39. The method according to claim 26, wherein the patient achieves a reduction in one or more symptom selected from eye irritation, blurred vision, conjunctival hemorrhage, conjunctivitis and instillation site pain.

Description

DESCRIPTION OF THE DRAWINGS

[0428] FIG. 1 depicts the study schedule including the screening and a 2-week run-in phase (subjects were provided with lubricant eye drops), followed by a 4-month treatment phase.

[0429] FIG. 2 demonstrates Corneal Fluorescein Staining (the National Eye Institute (NEI) Scale) of patients suffering from moderate to severe dry eye disease treated with a) a 0.05% (w/v) cyclosporine solution in 1-perfluorobutyl-pentane and 1.0% (w/v) ethanol (CyclASol 0.05%); b) a 0.1% (w/v) cyclosporine solution in 1-perfluorobutyl-pentane and 1.0% (w/v) ethanol (CyclASol 0.1%); c) Restasis® (comprising 0.05% (w/v) cyclosporine) and d) the vehicle (1-perfluorobutyl-pentane and 1.0% (w/w) ethanol) alone. Depicted is the change over time of the Corneal Fluorescein Staining Total Score (NEI Scale) as compared to baseline scores obtained prior to commencement of treatment (V1, day 1) for visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up) and V5 (16-week follow-up). It is observed herein that both CyclASol 0.05% and CyclASol 0.1% provide an earlier onset of effect as well as a higher efficacy when compared to the open label comparator Restasis®. This is surprising since lower volumes (10 μl) were administered to the patients as compared to Restasis® (28.5 μl), which translates to a 30 to 65% reduction of daily exposure of cyclosporine A but at the same time resulting even higher efficacy.

[0430] FIG. 3 features results based on Conjunctival Lissamine Green Staining (Oxford Scale) following treatment of patients suffering from moderate to severe dry eye disease with CyclASol 0.05%, CyclASol 0.1%, Restasis® and the vehicle. Depicted is the change of the Conjunctival Lissamine Green Staining Total Score (Oxford Scale) as compared to baseline (V1, day 1) for visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up) and V5 (16-week follow-up). It is observed that both CyclASol 0.05% and CyclASol 0.1% show an earlier onset of effect as well as higher efficacy when compared to the open label comparator Restasis®. This is surprising since lower volumes (10 μl) are administered to the patients as compared to Restasis® (28.5 ml), which translates to a 30-65% reduction of daily exposure of cyclosporine A to the patients resulting in even higher efficacy.

[0431] FIG. 4 demonstrates the effect on the treatment of reading impairment of patients suffering from moderate to severe dry eye disease by administration of CyclASol 0.05% and CyclASol 0.1% based on data derived from assessment of the reading assessment portion of the OSDI questionnaire (OSDI, Ocular Surface Disease Index) which relates to a scale of 0 to 4 (with 0 indicating no reading problems and 4 translating to most severe reading problems). In FIG. 4, the relative reading impairment (expressed as a percentage %) observed in patients treated with CyclASol 0.05% and CyclASol 0.1% versus Baseline (V1, day 1) is compared to the vehicle over visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up) and V5 (16-week follow-up). Negative relative values indicate an improvement of reading impairment. The comparison demonstrates that reading capability in patients treated with CyclASol 0.05% and CyclASol 0.1% was improved, compared to vehicle at visit V5 (16-week follow-up), resulting in a reduction in reading impairment of 28% and 31% respectively.

[0432] FIG. 5 demonstrates Central Corneal Fluorescein Staining (the National Eye Institute (NEI) Scale) of patients suffering from moderate to severe dry eye disease treated with a) a 0.05% (w/v) cyclosporine solution in 1-perfluorobutyl-pentane and 1.0% (w/v) ethanol (CyclASol 0.05%); b) a 0.1% (w/v) cyclosporine solution in 1-perfluorobutyl-pentane and 1.0% (w/v) ethanol (CyclASol 0.1%); c) Restasis® (comprising 0.05% (w/v) cyclosporine) and d) the vehicle (1-perfluorobutyl-pentane and 1.0% (w/w) ethanol) alone. Depicted is the change over time of the Central Corneal Fluorescein Staining Score (NEI Scale) as compared to baseline scores obtained prior to commencement of treatment (V1, day 1) for visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up) and V5 (16-week follow-up). It is observed herein that both CyclASol 0.05% and CyclASol 0.1% provide an earlier onset of effect as well as a higher efficacy when compared to the open label comparator Restasis®. This is surprising since lower volumes (10 μl) were administered to the patients as compared to Restasis® (28.5 μl), which translates to a 30 to 65% reduction of daily exposure of cyclosporine A but at the same time resulting even higher efficacy.

[0433] The following examples serve to illustrate the invention, however should not to be understood as restricting the scope of the invention.

EXAMPLES

Example 1

[0434] Study Setup A Phase 2, multi-center, randomized, double-masked, placebo (vehicle)-controlled clinical study with an open label comparator arm to assess the efficacy, safety and tolerability of topical CyclASol for treatment of dry eye disease was conducted. This dose finding trial in moderate to severe dry eye patients not responding to artificial tears was set up as a 4-arm randomized parallel double masked vehicle controlled study with 2 doses of CyclASol (0.05% and 0.1%) and an open label comparator arm.

[0435] CyclASol is a clear ophthalmic solution of Cyclosporine A dissolved in 1-perfluorobutyl-pentane. 1-perfluorobutyl-pentane, which is commonly abbreviated F4H5 is used as the vehicle. The only other component in the formulation is ethanol (1.0% (w/w) as co-solvent.

[0436] In addition to the masked vehicle control arm, an open-label treatment arm consisting of Restasis® was included to allow a head to head comparison of effects of CyclASol and Restasis®. Restasis® is an approved medication for dry eye disease, comprising 0.05% Cyclosporine A, formulated as an aqueous emulsion.

[0437] Study Plan

TABLE-US-00001 Study # Arm Medication Subjects Dosage 1 CyclASol 0.05% N = 51 one drop 2 CyclASol 0.1% N = 51 per eye, 3 Vehicle N = 52 twice daily 4 Restasis 0.05% N = 53 (BID), for 4 (open label comparator) months [0438] CyclASol 0.05%=0.05% (w/v) cyclosporine A, dissolved in 1-perfluorobutylpentane (F4H5) and 1% (w/w) ethanol [0439] CyclASol 0.1%=0.1% (w/v) cyclosporine A, dissolved in 1-perfluorobutylpentane (F4H5) and 1% (w/w) ethanol [0440] Vehicle=solution of 1-perfluorobutylpentane (F4H5) and 1% (w/w) ethanol

[0441] Study Population

[0442] In total of 207 (153 female, 54 male) patients with a subject-reported history of dry eye in both eyes and meeting all other study eligibility criteria were included, with a similar distribution of age and sex across the groups. The subjects were randomized to receive treatment with 0.05% CyclASol, 0.1% CyclASol, Vehicle, or Restasis® in a 1:1:1:1 ratio. The study consisted of two periods: a 14-day run-in period and a 112-day treatment period.

[0443] Patients included in the study had to fulfill following criteria: [0444] (a) Be at least 18 years of age; [0445] (b) Provide written informed consent; [0446] (c) Have a subject reported history of dry eye disease in both eyes for at least 6 months prior to Visit 0; [0447] (d) Current use (within 30 days prior to Visit 0) of over-the-counter and/or prescription eye drops for dry eye symptoms at Visit 0; [0448] (e) Have a score of≥40 on the dryness visual analogue scale at Visit 0 and Visit 1; [0449] (f) Have a total corneal fluorescein staining score of≥6 (e.g. sum of inferior, superior, central, nasal, and temporal) according to the NEI grading at Visits 0 and Visit 1; [0450] (g) Have a total lissamine green conjunctival score (sum of temporal and nasal) of≥2, based on the Oxford grading at Visits 0 and Visit 1; [0451] (h) Have a Schirmer's Test I score between≥2 mm and≤8 mm at Visits 0 and Visit 1; [0452] (i) Have at least one eye (the same eye) satisfy all criteria for (f), (g), and (h) above; [0453] (j) Be able and willing to follow instructions, including participation in all study assessments and visits.

[0454] The patients were examined during the 112-day treatment period according to the following schedule:

TABLE-US-00002 Visit Day Purpose V0 Day −14 ± 2 Screening V1 Day 1 Baseline/Randomization V2 Day 15 ± 1 2-week follow-up V3 Day 29 ± 2 4-week follow-up V4 Day 85 ± 3 12-week follow-up V5 Day 113 ± 3 16-week follow-up/Study

[0455] Instructions for Use

[0456] The study subjects were instructed to instill one dose (one single droplet) in each eye two times daily (in the morning and in the evening before bed).

[0457] The application volume per single dose (10 μL) of CyclASol 0.05%, CyclASol 0.1% solution and vehicle and as well as the amount of active ingredient was significantly lower as compared to the administered single dose of Restasis® 0.05% aqueous (o/w) emulsion (28.5 μL, ref. Restasis NDA 21-023, Clinical Pharmacology Biopharmaceutics Review(s)).

TABLE-US-00003 CyclASol, CyclASol, Restasis ® 0.05% 0.1% 0.05% Drop volume (1 droplet) 10 μl 10 μl 28.5 μl Single dose, per eye 5 μg 10 μg 14.25 μg Daily dose (2 x per day), 10 μg 20 μg 28.5 μg per eye Dose relative to 35.1% 70.2% 100.0% Restasis ® Total reduction in daily 64.9% 29.8% 0.0% dose exposure

[0458] Study Analysis

[0459] At each visit during the 112-day treatment period, each subject was assessed in terms of treatment efficacy using tests including corneal fluorescein staining (NEI Grading); conjunctival staining (Lissamine, Oxford grading) as well as subject symptom assessment questionnaires such as Ocular Surface Disease Index (OSDI, ref. Schiffman R. M. et al 2000; 118:615-621.) questionnaire (including question 6 relating to reading impairment) and dryness severity visual analogue scale (VAS).

[0460] For corneal staining (Sook Chun Yet al., Am J Ophthalmol. 2014 May; 157(5):1097-102), 5 μl of 2% preservative-free sodium fluorescein solution was instilled into the inferior conjunctival cul-de-sac of each eye. In order to achieve maximum fluorescence, the fluorescein staining is evaluated only after approximately 3-5 minutes after instillation. A Wratten #12 yellow filter was used to enhance the ability to grade fluorescein staining.

[0461] The staining was graded with the NEI Grading Scale (The National Eye Institute grading system), with only the cornea being graded. Corneal fluorescein staining scores were obtained for each of the inferior, superior central, temporal, and nasal regions of the cornea based on a 0-3 scale, where a score of 0 means no staining is observed. The term “total corneal fluorescein staining total score” (ref. FIG. 2) refers to a sum of scores from the inferior, superior, central, temporal, and nasal regions of the cornea.

[0462] Conjunctival Lissamine Green Staining (Bron A. J. et al, Cornea. 2003; 22:640-650) was conducted by instillation of 10 μl of lissamine green solution into the inferior conjunctival cul-de-sac of a subject. After waiting for approximately 30 seconds the staining was evaluated. The subject was instructed to blink several times to distribute the lissamine green. The staining was graded with the Oxford Grading Scale. Herein, the lissamine staining is represented by punctate dots on a series of panels (A-E). Staining ranges from 0-5 for each panel and 0-10 for the total exposed inter-palpebral conjunctiva. Both nasal and temporal regions were graded separately. A score of 0 meaning no staining. Total conjunctival lissamine green staining scores were obtained, referring to the sum of scores from both temporal and nasal regions of the conjunctiva.