A New Paradigm in NSAID Treatment

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1 V 5/6 pg Contents Common Uses of Ophthalmic NSAIDs A New Paradigm in NSAID History of (bromfenac ophthalmic solution).9% Efficacy of Phase III trials Pain data Post-Approval trials Pharmacokinetics, Penetration, and Potency Safety of Oral NSAIDs vs. Ophthalmic NSAIDs Japanese experience and post-approval surveillance data US Pivotal trials V 5/6 pg Current Uses of Ophthalmic NSAIDs Intraoperative miosis Relief of: Pain Inflammation,,4 photophobia Ocular allergy 5 Xibrom dosed BID is indicated only for the treatment of postoperative inflammation and the reduction of ocular pain in patients who have undergone cataract surgery Reduction of post-cataract cystoid macular edema (CME) Current NSAIDs Common Issues Dosing Schedule: Compliance & Convenience BID Patient Tolerability : Burning & Stinging: Acular 4%; Acular LS % Voltaren 5-5%.4% TID Nevanac QID Acular ; Acular LS; Voltaren Sticky Sensation: Nevanac 5-% Conditions for which bromfenac ophthalmic solution has been studied or for which data are available. Note: All topical nonsteroidal anti-inflammatory drugs may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Acular onset of effect Statistical Significance vs placebo st demonstrated: Day 4-6 for reduction in anterior chamber cells Day 6-8 for reduction in anterior chamber flare Day 6-8 for ocular pain. Ohara K, et al. Jpn J Clin Ophthalmol. 4;58:5-8.. Data on File, ISTA Pharmaceuticals; Xibrom US Phase III Trials. Kawaguchi T, et al. Folia Ophthalmol Jpn. ;54:6. 4. Ohara K, et al. Jpn J Cataract & Refractive Surgery 4;8: Miyake-Kashima M, et al. Jpn J Ophthalmol. 4;48:58. V 5/6 pg. Physicians Desk Reference. 4 & 6.. Heier, J. Ketorolac Tromethamine.5% Ophthalmic Solution in the treatment of Moderate to Severe Ocular Inflammation after cataract Surgery: A Randomized, Vehicle-Controlled Clinical Trial: AJO, Mar 999; : 5-59 V 5/6 pg4 History of Published Comparative Papers From Trials in Japan Japan Approval, May : blepharitis, conjunctivitis, scleritis and post-operative inflammation 6 Years & approximately. million patient uses established track record of efficacy & safety US Approval, March 5: same formulation as used in Japan Inflammation Post-Surgery Significantly less flare in first 4 days for bromfenac (BID) vs. diclofenac (QID) Significantly less AC cells & protein in first days for bromfenac (BID) than diclofenac (TID) Relief of Seasonal Allergy Bromfenac equal in efficacy to pemirolast Prevention of Miosis in Cataract Surgery Bromfenac equal in efficacy to diclofenac 4. Data on File. ISTA Pharmaceuticals V 5/6 pg5. Kawaguchi T, et al. Folia Ophthalmol Jpn. ;54:6.. Ohara K, et al. Jpn J Cataract Refract Surgery 4;8:-.. Miyake-Kashima M, et al. Jpn J Ophthalmology 4; 48; Ohara K et al. Jpn J Clin Ophthalmol 4; 58; 5-8 V 5/6 pg6

2 V 5/6 pg (bromfenac ophthalmic solution).9% Indicated as: the first and only BID dosed NSAID for the treatment of postoperative inflammation and the reduction of ocular pain in patients who have undergone cataract extraction In The US: Contraindicated: in patients with known hypersensitivity to any ingredient in the formulation Most commonly reported adverse experiences: Abnormal sensation in eye, conjunctival hyperemia, eye irritation, eye pain, eye pruritus, eye redness, headache and iritis. These events were reported in %-% of patients Effect of BID on Compliance Evaluation and Multivariate Statistical Analysis of Factors Influencing Patient Adherence to Ophthalmic Solutions Proper Use M isuse ophthalmic patients Ophthalmology Department at Hiroshima University Drugs Applied - x daily, 6% Drugs Applied - 5 x daily 44% Drugs Applied - 5 x daily, 56% Drugs Applied - x daily, 94% % % % % 4% 5% 6% % 8% 9% % % of Patients. Published: Yakugaku Zasshi ;():99-86 V 5/6 pg8 Phase III Trials: Key Points US Phase III Protocol Review No pre-surgical dosing of an NSAID No anti-inflammatory agent until ONE DAY after surgery Summed Ocular Inflammation score prior to treatment =. High level of inflammation for routine cataract procedure : Dosed BID Data presented in following slides represent patients treated with Xibrom as their only anti-inflammatory (no steroid used) V 5/6 pg9 Number of cataract surgery patients Number of US sites Baseline summed cells and flare: (prior to treatment) Pre-Surgery Dosing w/nsaid or Steroid Xibrom (or placebo) Dose Efficacy Endpoint Measures SOIS = Summed Ocular Inflammation Score: Anterior chamber cell grade added to anterior chamber flare grade 5 (56 Xibrom, placebo) 9. NO BID for 4 days Reduction in Summed Cell & Flare Score Reduction in AC Cell Score Reduction in AC Flare Score Resolution of Pain Randomized, double masked, placebo-controlled studies Similar protocol to ketorolac.5% Phase III ONLY NSAID pivotal trial requiring an end-point of zero V 5/6 pg Visit & Schedule US Phase III Trials: Inflammation Reduction: Summed Ocular Inflammation Score Evaluation Days Post-Surgery Day = Day of Surgery Days Post- Initiation Approximate Doses of Xibrom High Inflammation.5 Days After Cataract Surgery 8 5 P =. P <. vs. placebo st nd rd 4th 5th Day : Return to office for Entry Criteria Evaluation (still no anti-inflammatory used) Day Day 8 Day 5 Day Day No Inflammation.5 SOIS Score.5.5 Days of Xibrom achieved statistical significance on st treatment evaluation ( treatment days) achieved statistically significant reduction from baseline at all study visits Xibrom TM Note: Day represents Return to office for entry Criteria Evaluation (no antiinflammatory used) Day represents the nd day of therapy V 5/6 pg Data represent results from patients on Xibrom or placebo, only. No rescue medications V 5/6 pg

3 V 5/6 pg US Phase III Trials: Individual Mean Cell and Flare Scores by Visit : Summary Of Phase III Efficacy Results Statistical Significance Achieved in Every Time-Point Measure High.5 Inflammation Cells Score.5.5 No Inflammation Days of treatment P<. P<. Flare Score Days After Cataract Surgery Days After Cataract Surgery Note: Day represents Return to office for entry Criteria Evaluation (no antiinflammatory used) Day represents the nd day of therapy.5 Days of treatment Xibrom statistical significance achieved on st treatment visit for both cell and flare reduction Statistical significance achieved through each treatment visit: Days 8 to 5 Reduction in Summed Ocular Inflammation Score Reduction in Cells Reduction in Flare Patients Achieving Summed Cells & Flare Score of Zero Use of NSAIDs pre-operatively was disallowed Achievement of Statistical Significance vs placebo Day Day Day 4 p <. p =. p <. p<. Data represent results from patients on Xibrom or placebo, only. No rescue medications V 5/6 pg4 Acular.5% Pivotal Trial : Statistical Significance Achieved within 6 4 Day Measures In this specific study, use of NSAIDs pre-operatively was disallowed Reduction in Cells Reduction in Flare Patients Achieving Summed Cells & Flare Score of Zero Reduction in Ocular Pain Achievement of Statistical Significance vs placebo Day - 4 Day 6-8 Day 4-6 p <.5 p <. ISTA Pharmaceuticals, Inc US Phase III Trials: ndary End. Point Time to Resolution of Ocular Pain Percent Unresolved Time to Resolution of Ocular Pain (days) log rank p<.. Heier, J, et al. Am J Ophthalmol 999; : 5-59 V 5/6 pg5 Estimated median for Time to Resolution of Ocular Pain: Xibrom =. days : = 5. days (p =.) V 5/6 pg6 Overall Pain Relief: Percentage of All Subjects Pain Free Percentage of Patients Pain Free % 9% 8% % 6% 5% 4% % % % % 5.% 6.8% 8.6% 9.% 9.5% 59.% 6.% 8 4 Study day Xibrom (n = 56) 69.6% (n=) No patients in Xibrom group reported pain at day 4. Subjects with missing data points on day were treated as treatment failures. Missing data were treated as LOCF. p=.6 p<. At Day 8 = 9.% of all Xibrom subjects were pain free vs. 6.% placebo Post-Approval US Trials Comfort vs. Acular LS H.D. Perry, MD, T.Y. Chou, MD Physician Satisfaction 589 Ophthalmologists/, Patient Experiences CME Post-Cataract Surgery vs. Acular and Voltaren D.S. Rho, MD, S.M. Soll, MD, B.J. Markovitz, MD Macular Edema Post-Glaucoma Surgery vs. Acular A.M. Solish, MS, MD V 5/6 pg V 5/6 pg8

4 V 5/6 pg9 Post-Approval Trials: Comfort A Comparison of and Acular LS in a Test of Comfort and Corneal Anesthesia Henry D. Perry, MD Timothy Y. Chou, MD Purpose: Compare comfort of Xibrom and Acular LS normal healthy volunteers Methods: subjects administered single drop of each test agent to their eyes in a random and masked fashion. Burning and stinging on a 4 scale. Results: Subjective Assessment of Comfort Upon Instillation Level of Burning or Stinging Xibrom Acular LS Number of Patients Reporting None to Severe Burning & Stinging None Mild Moderate 5 Severe Xibrom: of (85%) reported no burning or stinging Acular LS: of (5%) reported no burning or stinging Xibrom: of (%) reported moderate or severe burning or stinging Acular LS: 6 or (%) reported moderate or severe burning or stinging V 5/6 pg Post Marketing Trials: Physician Satisfaction Xibrom First Experience (XFE) Trial MDs placed a minimum of patients on Xibrom May through June, 5 Jan through Mar, 6 MDs rated Xibrom performance: Very Satisfied: Exceeded My Expectations Satisfied: Met All My Expectations Dissatisfied: Met Some of My Expectations Very Dissatisfied: Did Not Meet My Expectations Robust MDs experiences captured: 589 MDs reported to date, patients experiences reported V 5/6 pg ISTA Pharmaceuticals, Inc :. Early Experience Program Exceeded All Expectations Met All Expectations 589 ophthalmologists:, patient experiences MD Expectations: Exceeded or Met in 99% to % of Reports Met Some Expectations Did Not Meet Expectations % 5% % 58% 6% 6% 4% 9% 8% Over all Patients Satisfaction Safety Comfort Upon Instillation % 9% Patient Compliance 8% 9% Ease of Use by Patients % % % % % % % % % % % % 46% 5% Control of Inflammation V 5/6 pg Phase 4 Trials: Cystoid Macular Edema (CME) Phase 4 Trials: Cystoid Macular Edema (CME) A Comparison of Bromfenac, Ketorolac, and Diclofenac for of Acute Pseudophakic Cystoid Macular Edema (Preliminary Data) David S. Rho, MD, Stephen M. Soll, MD, Bruce J. Markovitz, MD Purpose: Comparison of Xibrom, Acular, and Voltaren for treatment of acute CME post-cataract surgery Methods: 64 post-cataract patients with acute CME randomized to one of three regimens: Xibrom BID, Acular QID, or Voltaren QID, in the affected eye Visual acuities measured; Snellen VA charts and ETDRS charts Initial VA Initial VA (ETDRS letters) Final VA Final VA (ETDRS letters) ETDRS Letters gained Bromfenac /5 ± ±. /58.4 ± ±.6 5. ±. P-values for ETDRS letters gained within treatment groups: Bromfenac p <.5 Diclofenac p <.5 Ketorolac p <.5 Diclofenac /5 ± ± 5. / ± 4..6 ± ±.5 Ketorolac /6 ± ±. / ± 4.6. ±.9.6 ± 8.6 P-values for ETDRS letters gained between treatment groups: Bromfenac vs Diclofenac p =.8 Bromfenac vs Ketorolac p =.5 Ketorolac vs Diclofenac p =.96. Rho DS. ARVO 6; A5 V 5/6 pg. Rho DS. ARVO 6; A5 V 5/6 pg4

5 V 5/6 pg5 Phase 4 Trials: Macular Edema Post-Glaucoma Surgery A Prospective, Randomized Comparison of Bromfenac with Ketorolac for the of Patients with Reduced Visual Acuity Following Glaucoma Surgery Alfred M. Solish, MS, MD Purpose: Comparison of Xibrom and Acular for treatment of macular edema post-glaucoma surgery Methods: post-glaucoma surgery patients with decreased corrected visual acuity (VA), whose vision had not improved with topical steroids, were randomized to either Xibrom BID or Acular QID Corrected visual acuities were compared following 4-6 weeks of treatment Phase 4 Trials: Macular Edema Post-Glaucoma Surgery Initial IOP (mmhg) Follow-up IOP (mmhg) Follow-up (days) Change in VA (lines corrected) Patients gaining VA (> lines) Patients losing VA (> line) Bromfenac /6 (.5%) /6 (.5%) Ketorolac /9 (%) 5/9 (6.%) P (t-test) More patients had VA improvement with Xibrom than with Acular, though the difference was not statistically significant. Solish AM. AGS 6; A95. Solish AM. AGS 6; A95 V 5/6 pg6 Chemical Structures and Related Activities Bromfenac Amfenac O O Penetration & Potency Data Br C C H N CH CO Na. ½H O H N CH CO Na. H O Helps answer the question: How and why is Xibrom BID? Chemical structure of bromfenac is similar to amfenac, shown above Substitution of the benzoyl ring has pronounced effects on in-vivo and in-vitro potency and absorption (B >x more potent than A in this study) In general, compounds that contain a halogen, are more potent (I-~ Br- > Cl > F > H).. Walsh D. J Medicinal Chem. 984;:9-88 V 5/6 pg V 5/6 pg8 Octanol/Water (O/W) Partition Coefficients Amfenac Penetration: Data From Amfenac Patent 6,646, B The octanol/water partition coefficient for bromfenac compared to other NSAIDs and Steroids at physiological ph.4 Drug Bromfenac Amfenac O/W Partition Coefficients.. Ketorolac.88 The higher the coefficient, the higher the penetration across membranes.. unit difference = fold difference. Ruiz J et.al Journal of Computer-Aided Molecular Des QSAR tables V 5/6 pg9 No level detected: Aqueous humor Choroid at hrs Retina at 6 hrs V 5/6 pg

6 V 5/6 pg Concentrations of Radioactivity in Ocular Tissues Following a Single Topical Ocular Dose of 4 C-Bromfenac Comparison of Ocular Concentrations of 4C- Bromfenac and 4C-Nepafenac 4C-Bromfenac 4C-Nepafenac 8 4 Retina and choroid detectable through 4 hour time-point Choroid not detectable at hours Detectable levels thru 4 hours and beyond for the above ocular tissues. Baklayan GA. ASCRS 6;P. Retina not detectable at 6 hours V 5/6 pg Concentrations of Radioactivity in Ocular Tissues Following a Single.9%Topical Ocular Dose of 4 C-Bromfenac Concentration (ug equiv./g) Iris-Cliary Body Aqueous Humor Choroid Retina hr hr 4 hr 8 hr hr 4 hr Time Detectable levels thru 4 hours and beyond for the above ocular tissues. McNamara TR. ARVO 6;A586. V 5/6 pg PK Profile of a Single.9%Topical Ocular Dose of Bromfenac in Subjects Undergoing Cataract Surgery BF conc. in Time of instillation aqueous humor No. of cases before surgery (min) (ng/ml) (mean + SD) t < 9.8 < t < < t < < t < < t < < t < < t < < t < < t < < t < < t <. +.5 t > 5 Bromfenac concentrations in aqueous humor at grouped -min intervals. Ogawa T. ARVO 6;A68. V 5/6 pg4 PK Profile of a Single.9%Topical Ocular Dose of Bromfenac in Subjects Undergoing Cataract Surgery PK Profile of a Single.9%Topical Ocular Dose of Bromfenac in Subjects Undergoing Cataract Surgery Human recombinant prostaglandin G/H synthase Rabbit alveolar macrophages IC5 4. nm,.5 ng/ml nm, 8.8 ng/ml Human Rabbit Tmax (hr).. Cmax (ng/ml) T / (hr).4. IC5 value of bromfenac in human and rabbit COX- inhibitory activity PK parameters of bromfenac in aqueous humor of human and rabbit. Ogawa T. ARVO 6;A68. V 5/6 pg5. Ogawa T. ARVO 6;A68. V 5/6 pg6

7 V 5/6 pg PK Profile of a Single.9%Topical Ocular Dose of Bromfenac in Subjects Undergoing Cataract Surgery COX- Hypothesis, BF Conc. in AH (ng/ml)... Human data Human COX- IC5 Rabbit data Rabbit COX- IC Time after instillation (hrs) Estimation of duration for retaining the effective concentration of bromfenac after instillation over the IC5 value of COX-. Ogawa T. ARVO 6;A68. COX- constitutive PGs GI cytoprotection Platelet aggregation Renal function (blood flow) Arachidonic acid. Oka T. Curr Eye Res 4;9():-4. Guex-Crosier Y. Klin Monatsbl Augenheilkd ;8(5):5-8 COX- inducible PGs Inflammation Fever Pain Headache Carcinogenesis V 5/6 pg8 Potency Measurement: IC 5 Relative Potency of NSAIDs In Vitro: IC 5 vs COX- and COX- enzymes Drug concentration required to inhibit enzyme activity by 5% The smaller the number, the more potent the molecule Lower IC 5 = Greater Potency IC5, COX - IC5, COX - Bromfenac.5 um. um Diclofenac.95 um.85 um Amfenac.5 um.5 um.x V 5/6 pg9 6.5X COX II Enzyme most responsible for pain and inflammation IC5 of bromfenac for COX- is 8 fold greater than ketorolac The clinical significance of these data is unknown. The Cox- and Cox- in vitro assay is highly variable between laboratories and types of assays used.. Data on file BR54. ISTA Pharmaceuticals:. Gamache et al Inflammation LS:. Waterbury et al. Curr Med Res Opin 6;(6):-4 V 5/6 pg4 Safety US Phase III Trials: Common - Emergent Ocular Adverse Events (> % incidence rate) Extensive testing from Phase I Phase III 6 years of ophthalmic use Over. million ophthalmic uses,45 patients officially tracked by institutions A very safe drug: No reported drug related serious systemic side effects Clinical studies demonstrated a minimal incidence of adverse events n (% of Subjects) Adverse Event (n = 56) (n = ) Iritis 5 (.%) (8.%) Ocular pain 5 (4.%) (.%) Abnormal sensation in eye (6.5%) 4 (8.%) Eye pruritus 4 (.9%) 5 (.9%) Eye irritation 9 (.5%) 8 (4.%) Eye redness 8 (.%) (.6%) Photophobia (.%) 9 (.%) Other Reported Adverse Events: ONLY.4% incidence of burning and stinging in Xibrom patients CME reported: Xibrom.4% : 4.% (p <.5) V 5/6 pg4 Note: Xibrom is not indicated for the treatment of CME nor Photophobia V 5/6 pg4

8 V 5/6 pg4 Experience with Bromfenac Sodium Ophthalmic Solution in Japan (-6) Well established 6 Year safety profile (Bronuck) Post Marketing Safety Report (Japan) Filed with Minister of Health, Labour and Welfare /5 Marketed since /: There have been no drug related serious systemic adverse events reported with use of bromfenac sodium ophthalmic solution. million uses & in over.8 million patients in Japan Zero drug related serious systemic events reported Serious ocular adverse events Reported in.% of patients (6) 4 corneal events reported in the Japanese post-marketing surveillance program involving,45 patients observed from May to January 4 (.4%). Dosing schedules, length of therapy, and indications may vary between Xibrom and bromfenac ophthalmic solution used in Japan Products in Japan and U.S. are identical Patients or Usage of Xibrom (Bronuck) Total Patients Surveyed (/ /6) Patient Age: Month to 5 Years Patient Age: 65 Years or Older Patients with known pre-existing liver disorders Patients with known pre-existing kidney disorders More than times per day More than 4 times per day Between 5-99 drops of drug Between -49 drops of drug Between 5-99 drops of drug Number of patients,45 49, , Over drops of drug 45. Data on file. ISTA Pharmaceuticals. Kitao N, Shimoji H, Fukuda M. Atarashii Ganka 5;:99-8. Xibrom, in the US, is indicated for BID dosing for 4 days of treatment V 5/6 pg44 Summary of HIDDEN/BACK-UP SLIDES A Very Potent NSAID IC 5 data for bromfenac & diclofenac & amfenac in similar models Rapidly Treats Significant Inflammation Excellent penetration BID dose Compliance & Convenience Comfortable.4% burning/stinging Safe 6 years experience &. million uses V 5/6 pg45 V 5/6 pg46 US Phase III Trials: Grading Scale for Cells & Flare : US Phase III Trials Grade 4 Cells (Count) -5 (trace) > 5 Grade 4 Flare Complete Absence Very Slight Moderate Marked Intense Inclusion Criteria: Patients were required to have a Summed Ocular Inflammation Score (cell score + flare score) at 6 to hours, after surgery PRIOR to Patients with EXISTING significant inflammation were treated with Xibrom, or placebo, BID started AFTER inflammation had developed Cells & flare graded each visit st treatment visit: days of Xibrom treatment SOIS = Summed Ocular Inflammation Score: Anterior chamber cell grade added to anterior chamber flare grade V 5/6 pg4 V 5/6 pg48

9 V 5/6 pg49 Safety Issues have occurred with all ORAL NSAIDs Diclofenac (Voltaren ) Gastrointestinal perforations, ulcerations, and bleeding Ketorolac (Toradol ) Gastrointestinal perforations, ulcerations, and bleeding Black box warning in U.S., withdrawn from market in France and Germany 4 deaths from Bromfenac (Duract ) Hepatotoxicity, acute hepatic failures, when used outside of labeled dosage Manufacturer voluntarily withdrew from US market 4 deaths in US Phase III Trials: Liver Function Tests Show No Effect on Liver Liver Function Test Aspartate aminotransferase (AST) Alanine transaminase (ALT) γ-glutamyl transpeptidase (GGT) Total bilirubin Direct bilirubin Alkaline phosphatase No significant differences between treatment groups No subjects with results > CTC grade n (% of Patients) With Toxicity Grade = at Study Termination (n = 4) (.9%) 4 (.%) 8 (.%) (.6%) (n = 5) (.%) (.%) (.9%). Macario A, et.al Pain Medicine Vol.,. Physicians Desk Reference. 4. CTC = common toxicity criteria V 5/6 pg5 ISTA JapanPost-MarketingSurveilanceProgram programto document saf et y a n d ef f i c ac y V5/6pg5