U.S. Food and Drug Administration

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1 U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2 C-1 Rejena (Sodium Hyaluronate Ophthalmic Solution, 0.18%) United States Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee June 26, 2009

3 C-2 Rejena (Sodium Hyaluronate Ophthalmic Solution, 0.18%) Safety and Efficacy Review River Plate Biotechnology, Inc. Presenters: Russell Ellison, MD Roger Vogel, MD

4 C-3 Sponsor Attendees Russell Ellison, MD, MS - Chairman Luis Molina, PhD - President/CSO Terry W. Laliberte, BS - Director of Development Roger Vogel, MD - Medical Monitor, Consultant Christine Miller, PharmD - Regulatory, Consultant Gary Koch, PhD - Statistics, Consultant Steve Crockett, PhD - Statistics, Consultant

5 C-4 River Plate Biotechnology Presentation Introduction Rejena Efficacy and Safety Russell Ellison, MD Roger Vogel, MD

6 Dry Eye Disease Affects 5 Million Patients C-5 In the United States, an estimated 3.2 million women and 1.7 million men, a total of 4.9 million people are affected by dry eye disease. (Tsubota, 1992; Craig, 1997) Dry eye symptoms (dry-, gritty-, or scratchyfeeling eyes, itching, redness, blurred vision, and sensation of foreign body in the eye) are the leading cause of ophthalmology visits.

7 Efficacy Criteria for the Treatment of Dry Eye Disease C-6 Significant improvement in an objective sign of dry eye disease (ie, does drug have an effect on the disease) For example: Corneal erosion (fluorescein or lissamine green staining) Tear break up time (TBUT) Tear production (Schirmer s test) and Significant improvement in a symptom of dry eye (PRO) (ie, does drug have a clinical benefit perceived by patient) Reasonable, pragmatic, and rational criteria but very hard to meet

8 C-7 Dry Eye Study Challenges Variability of assessments Effectiveness of placebo or vehicle Signs and symptoms are poorly correlated Time course of signs and symptoms resolution can be different

9 C-8 Current Therapies Many products have been tested in clinical trials, but No prescription product is currently approved for the treatment of the signs and symptoms of dry eye disease Artificial tears (OTC) Provide only transient relief and are formulated with preservatives, which are irritants Certain products can aggravate the condition; tears with decongestants/antihistamines can decrease production of the tear film Cyclosporine ophthalmic emulsion (Restasis ) Topical immunosuppressant approved to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with KCS Slow onset of action (months)

10 Rejena - Sodium Hyaluronate Ophthalmic Solution, 0.18% C-9 Preservative free Marketed in Europe and parts of Asia since January 1998 in 27 countries Vismed Vislube Hylovis ~ 9.5 million boxes (20 units/box) sold through Dec 31, 2008

11 Rejena Clinical Development Overview C subjects in 10 clinical trials with Rejena a 8 supportive clinical studies 5 studies against artificial tear products, all showing improvement over comparator 3 open label studies 2 adequate and well-controlled studies Baudouin 2005 study RP-001 study a There are several earlier studies using different formulations.

12 Baudouin 2005 Clinical Study Report Errata C-11 Sponsor recalculated all endpoints presented in briefing document resolving inconsistencies identified by FDA analysis Transcription errors from analysis files into summary tables appear in CSR and were carried forward into briefing document Primary endpoint: VAS summed score Descriptive statistics transcribed from PP population instead of ITT/LOCF P-value generated from ITT/LOCF as specified Secondary endpoints: Lissamine green staining and symptom frequency score P-values actually transcribed from analysis of absolute change from baseline whereas protocol specified percent change from baseline

13 Rejena Clinical Development Hypothesis Generation and Confirmation, and Replication C-12 Hypothesis generation Early studies positive for signs and/or symptoms vs artificial tears Rolando 1994 Rapisarda 1994 Baudouin 2001 Adequate and well-controlled study: Baudouin 2005 Did not meet primary endpoints 2 secondary endpoints showed an effect - selected for the design and powering of confirmatory study (RP-001) Lissamine green staining (sign) Symptom frequency score (symptom)

14 C-13 Rejena Clinical Development Hypothesis: Rejena is superior to vehicle (gold standard for comparator) for improvement in a sign (lissamine green staining) and a symptom (global symptom frequency score) in the same study Hypothesis confirmation: RP-001 Rejena was statistically significantly superior to vehicle for these 2 co-primary endpoints Replication: analysis of Baudouin 2005 using RP-001 analytical methodology

15 C-14 Efficacy and Safety of Rejena (Sodium Hyaluronate Ophthalmic Solution 0.18%) Roger Vogel, MD

16 C-15 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

17 C-16 Sodium Hyaluronate Ubiquitous molecule Occurs naturally in all vertebrates in the vitreous body of the eye, the extracellular matrix of the skin, and synovial fluid Viscoelastic properties similar to natural tears Rejena sodium hyaluronate is obtained by bacterial fermentation High degree of purity No appreciable toxicity or immunosensitizing activity

18 C-17 Sodium Hyaluronate Extremely wide safety margin Sodium hyaluronate (SH) used Intraocularly as a viscoelastic during cataract extraction to protect corneal endothelium Intra-articularly as injections for synovial fluid replacement As a dermal filler

19 Sodium Hyaluronate Ophthalmic Solution 0.18% C-18 Under shear stress (during blinks) At rest between blinks Solution is elastic, nonviscous, and spreads easily over the ocular surface Solution is less elastic, more viscous

20 Actions of Sodium Hyaluronate Ophthalmic Solution 0.18% C-19 Stabilizes the precorneal tear film Restores tear film and ocular surface homeostatic states Allows recovery of goblet cells Entraps water and hydrates and lubricates the ocular surface As a result improves ocular comfort and quality of life

21 C-20 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

22 6/19 3:30 pm C-21 Dry Eye Efficacy Endpoints - Signs Inflammatory suppression of tear secretion Decreased tear production Tear film instability Hyperosmolarity Decreased mucin production Loss of goblet cells Conjunctival & corneal epithelial damage Tear film break-up time (TBUT) Time required for the eye to lose its wet surface after a blink Normal eye: 10 to 12 seconds Dry eye: Less than 10 seconds

23 C-22 Dry Eye Efficacy Endpoints - Signs Inflammatory suppression of tear secretion Decreased tear production Tear film instability Hyperosmolarity Decreased mucin production Loss of goblet cells Conjunctival & corneal epithelial damage Corneal and conjunctival staining Fluorescein (corneal) stains the area between surface cells (extent to which epithelial cells are drying and shrinking) Lissamine green (corneal and conjunctival) stains keratinized and devitalized epithelial cells, goblet cells, mucous, and epithelial filaments (more sensitive dye than fluorescein)

24 Rejena Clinical Studies Efficacy Endpoints - Signs C-23 3 dose-finding studies used TBUT Baudouin 2005 Primary endpoint: fluorescein staining Secondary endpoints: lissamine green staining (also TBUT, Schirmer s test, tear prism height) RP-001 Primary endpoint: lissamine green staining

25 Rejena Clinical Studies Efficacy Endpoints - Symptoms C-24 Symptoms assessed Dryness Soreness Scratchiness Grittiness Burning Scoring Symptom intensity Symptom frequency Composite symptom Global symptom frequency

26 C-25 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

27 C-26 Dose Selection Rationale: Concentration 3 clinical dose-finding studies Effects of sodium hyaluronate in solutions ranging from 0% (vehicle/placebo) to 0.3% on the prolongation of TBUT Higher concentrations more effective than lower concentrations 0.18% concentration was highest concentration that could be feasibly formulated

28 C-27 Clinical Program Objective Demonstrate that sodium hyaluronate ophthalmic solution 0.18% is safe and effective for the treatment of the signs and symptoms of dry eye disease

29 C-28 Rejena Clinical Development Hypothesis generating Early studies a Rapisarda 1994, Rolando 1994, and Baudouin 2001 all showed differences in signs and symptoms vs artificial tears Baudouin 2005 a 2 additional phase 4 studies with similar results, Prabhasawat 2007 and Johnson 2008.

30 C-29 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

31 Hypothesis Generating: Baudouin 2005 C-30 Rejena (n = 74) vs 0.9% saline (n = 77) Subjects with 3 months history of bilateral moderate dry eye disease or moderate dry eye disease due to Sjögren s syndrome Primary endpoints Objective endpoint: Percent change from baseline of the fluorescein staining summed score (average of the sum of the total scores over both eyes) at Day 28 Subjective endpoint: Percent change from baseline of the VAS summed intensity score (average of the sum of five VAS symptom scales for soreness, scratchiness, dryness, grittiness, and burning) at Day 28

32 Baudouin 2005 Study Conduct C-31 Sponsored by TRB Chemedica, SA (manufacturer in Europe) Study management and monitoring by Clirophtha, an experienced CRO in Europe 100% source document validation Study conducted under GCP according to ICH Experienced, well-published, principal investigator (who served as a principal investigator for Restasis development)

33 Baudouin 2005 Data Management & Statistical Analysis C-32 Data entry and management and statistical analysis performed by MD Research (CRO in Germany) Data listings and statistical tables and figures were forwarded to the EU sponsor, TRB Chemedica, SA, who prepared the clinical study report Abstract and poster authored by Dr. Baudouin, based on the CSR, presented in ARVO 2004

34 Baudouin Primary Endpoints (% Change From Baseline) C-33 Measure Visit Study drug Mean (SD) 1-sided P-value Fluorescein staining of cornea VAS summed score Day 7 Active (38.36) Saline (38.26) Day 28 Active (47.21) Saline (44.75) Day 7 Active (32.75) a Saline (33.55) Day 28 Active (31.68) a Saline (43.17) ITT = Intent to treat; SD = Standard deviation; VAS = Visual analogue scale a Calculated in ITT population, LOCF (correct analysis).

35 Hypothesis Generating: Baudouin 2005 Secondary Endpoints (% Change from Baseline, 1-sided P-values) C-34 Measure Visit Study drug Mean (SD) b CSR a P-value Lissamine green staining Symptom frequency score P-value per SAP (recalculated by Sponsor) b Day 7 Rejena (34.48) Saline (41.81) Day 28 Rejena (31.24) Saline (39.60) Day 7 Rejena (33.03) Saline (30.60) Day 28 Rejena (26.38) Saline (34.68) a Calculated from absolute change from baseline (transcription error). b Calculated from percent change from baseline.

36 Baudouin 2005 Summary C-35 Baudouin 2005 showed positive results in secondary endpoint for sign (lissamine green staining) and symptom (symptom frequency score) at Days 7 and 28 On agreement with FDA, Study RP-001 adopted a similar study design and these 2 endpoints as co-primary

37 C-36 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

38 Hypothesis Confirmation: RP-001 C-37 Hypothesis: Rejena is significantly superior to vehicle for improvement in a sign and a symptom in the same study Agreed with FDA under a Special Protocol Assessment (SPA) Sign: absolute change from baseline in lissamine green staining (co-primary endpoint) Symptom: absolute change from baseline in global symptom frequency score (co-primary endpoint) Wilcoxon rank sum test primary analysis method: t-test secondary α = sided (α = sided)

39 Hypothesis Confirmation: RP-001 Sample Size Calculation C-38 Rejena (n = 221) vs vehicle (n = 223) RP-001 sample size based on 2-sided α = 0.05 Used difference in means and SD based upon subjects in Baudouin 2005 matching the entry criteria for RP-001 to determine the sample size for a power of 80% Prespecified masked interim analysis showed increased variance requiring sample size increase from 300 to 440

40 Inclusion Criteria RP-001 C-39 Subjects with 3 months history of diagnosed KCS or dry eye due to Sjögren s syndrome Experienced in the same eye: At least 2 symptoms of dry eye Rated as 2 (often) Scored as 50 mm on VAS intensity Objective parameters of dry eye: Corneal fluorescein staining total score of 3 Lissamine green staining total score of 3

41 RP-001 Change From Baseline at Day 7 Primary Endpoints (ITT, LOCF) C-40 Primary endpoint Visit Study drug Mean (SD) Lissamine green staining Global symptom frequency Day 0 Rejena 5.71 (2.42) Vehicle 5.52 (2.36) Wilcoxon rank sum test a 2-sided P-values van Elteren Student s t-test Day 7 Rejena 1.1 (2.01) Vehicle 0.7 (1.79) Day 0 Rejena 8.33 (2.23) Vehicle 8.22 (2.47) Day 7 Rejena 1.7 (2.78) Vehicle 1.1 (2.62) a Primary analytical method.

42 RP-001 Global Impact of Dry Eye on Daily Life C-41 Study drug % reporting improvement by 1 or more grades at Day 7 Rejena 40.3% Vehicle 30.4% Scale is 0 to 3, absent to severe

43 C-42 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

44 C-43 Replication: Steps 1. Baudouin 2005 is supportive of efficacy Results suitable for integrated analysis (side-by-side comparison) 2. RP-001 confirmed results from Baudouin 2005 Efficacy demonstrated for same selected sign and symptom as those achieved in Baudouin Replication Side-by-side comparative analysis was conducted to evaluate how Baudouin 2005 and RP-001 replicate each other using RP-001 analytical methodology agreed upon with FDA

45 RP-001 Endpoints Used for Comparative Analysis C-44 Absolute change from baseline in lissamine green staining score Absolute change from baseline in global symptom frequency score Primary endpoint: Day 7 RP-001 time points: Days 7 and 14 Baudouin 2005 time points: Days 7 and 28

46 C-45 RP-001 Statistical Methodology for Comparative Analysis Reanalysis of Baudouin 2005 using analytical methodology for RP-001 that was agreed upon with FDA Selected study eye for lissamine green staining score Eye with lower baseline Schirmer s I test score ITT population (LOCF) defined as all randomized subjects: baseline observation carried forward Wilcoxon rank sum test (primary) Student s t-test (supportive)

47 Efficacy: Lissamine Green Staining Score Change from Baseline (ITT, LOCF) C-46 Baudouin 2005 Study RP sided P-values 2-sided P-values Wilcoxon Wilcoxon Visit Study drug Mean (SD) rank sum t-test Mean (SD) rank sum t-test Day 0 Rejena 4.03 (2.12) 5.71 (2.42) Control 3.83 (2.28) 5.52 (2.36) Day 7 Rejena 1.1 (1.51) (2.01) Control 0.6 (1.38) 0.7 (1.79)

48 Efficacy: Global Symptom Frequency Scores Change from Baseline (ITT, LOCF) C-47 Visit Study drug Mean (SD) Baudouin sided P-values Wilcoxon rank sum t-test Mean (SD) Day 0 Rejena 8.35 (2.27) 8.33 (2.23) Control 8.04 (1.76) 8.22 (2.47) Study RP sided P-values Wilcoxon rank sum t-test Day 7 Rejena 2.0 (2.44) Control 1.2 (2.58) (2.78) (2.62)

49 Phase 3 Efficacy Analysis Conclusion C-48 Hypothesis generated: early studies and Baudouin 2005 provided basis for generating hypothesis that Rejena was superior to vehicle in reducing lissamine green staining and global symptom frequency score Hypothesis confirmed: RP-001 statistically significant for these 2 co-primary endpoints Replication achieved: analysis of Baudouin 2005 with RP-001 analytical methodology

50 C-49 Summary of Efficacy 10 clinical studies assessed efficacy (957 subjects) for up to 2 months and were consistently positive 5 studies showed improvement over artificial tears 3 exploratory studies show improvement in ocular surface disease 2 Phase 3 studies: reduction in lissamine green staining and improvement in global symptom frequency score versus both saline and vehicle Rejena is effective for the treatment of the signs and symptoms of dry eye

51 C-50 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

52 C-51 Safety Results 3 studies form basis of safety profile (n = 305) Phase 3 studies (Baudouin 2005, RP-001) Phase 2 study (Baudouin 2001) Safety evaluations included Slit lamp examination Best-corrected visual acuity (BCVA) Ophthalmic examination Collection of AEs Intraocular pressure (RP-001)

53 C-52 Safety Studies SH ophthalmic solution 0.18% compared with Dose regimen Average exposure Baudouin 2001 Baudouin 2005 RP-001 Carboxymethyl- Saline 0.9% Vehicle cellulose 1% 1 drop 3 times/ day or as needed, for up to 56 days 3.8 daily instillations 1 drop at least 3 and up to 8 times/day or as needed, for up to 28 days 3.7 daily instillations 1 to 2 drops at least 3 and up to 6 times/day or as needed, for up to 14 days 3.7 units used daily

54 C-53 Adverse Events Overview Patients, n (%) Baudouin 2005 RP-001 Rejena N = 74 Saline N = 77 Rejena N = 221 Vehicle N = 222 Any AE 10 (13.5) 9 (11.7) 57 (25.8) 48 (21.6) Any SAE (0.5) 1 (0.5) AE leading to 1 (1.4) 2 (2.6) 2 (0.9) 1 (0.5) withdrawal Death No AEs were reported in Baudouin 2001 (N = 10) No ocular SAEs reported in the 3 safety studies

55 Ocular Treatment-Emergent AEs in 1% of Subjects C-54 Adverse event Baudouin 2005 Rejena N = 74 Patients, n (%) Saline N = 77 Rejena N = 221 RP-001 Vehicle N = 222 Dry eye a (8.1) 14 (6.3) Eye pain a (5.9) 7 (3.2) Eye irritation a 2 (2.7) 0 4 (1.8) 5 (2.3) Foreign body sensation in eyes (2.3) 7 (3.2) Visual acuity reduced (1.8) 6 (2.7) Eye pruritis (1.8) 4 (1.8) Vision blurred a (1.8) 0 Ocular hyperaemia (1.4) 3 (1.4) Eyelid margin crusting a (1.4) 1 (0.5) a TEAEs that occurred at a greater frequency in Rejena-treated subjects.

56 C-55 Worldwide Marketing Experience Approximately 9.5 million boxes (20 units each) sold (Jan 1998 to Dec 31, 2008) Estimated 2.8 million patients have used Rejena 39 reports of post-marketing medical complaints reported (through 30 April 2009)

57 Spontaneous Complaint Reports Marketed Product Surveillance C-56 Adverse event Total complaints, n Burning sensation 16 Hypersensitivity/intolerance 13 Eye reddening 5 Foreign body sensation 1 Eye injury a 1 Local swelling 1 Blurred vision 1 Other 1 Total 39 a This complaint was due to incorrect handling of the delivery device.

58 C-57 Summary of Clinical Safety Rejena has an acceptable safety profile for the treatment of the signs and symptoms of dry eye No ocular SAEs Low incidence of AEs 14.4% of subjects experienced 1 AE Most were mild in intensity Ocular TEAEs No ocular AE occurred at a frequency greater than 8.1% Only 3 Rejena-treated subjects withdrew due to an ocular adverse event

59 C-58 Efficacy and Safety of Rejena Sodium hyaluronate Efficacy endpoints Dose selection rationale Baudouin 2005 RP-001 Integrated analysis Safety results Summary and conclusions

60 C-59 Summary and Conclusions RP-001 (Rejena /vehicle) confirms and replicates positive endpoints in Baudouin 2005 (Rejena/saline) Rejena is currently widely marketed outside the US; the safety profile is well established Clinical trial data demonstrate that Rejena is safe and well tolerated Clinical data demonstrate that Rejena is safe and effective for the treatment of dry eye disease