InSite Vision DOUBle Phase 3 Clinical Program

Transcription

1 InSite Vision DOUBle Phase 3 Clinical Program AzaSite Plus (ISV 502) & DexaSite (ISV 305) For the Treatment of Blepharitis May 2011

2 Today s s Discussion Overview & Opportunity Phase 3 Trial Design/SPA Agreement Primary Endpoints Pre treatment Period & Patient Eligibility Investigator Scoring Instrument (BleSSSED) Patient Quality of Life Instrument (BleQOLITY) Treatment Period Clinical Evaluations Follow up Period Design & Statistical Analysis Plan Why We Think We Can Win Summary & Next Steps 2

3 Blepharitis: : Acute and/or Chronic Inflammation of the Eyelids Signs & Symptoms Possible Causes Prevalence Redness Flaking skin Crusting Cysts Irritation Gritty sensation Itching Vision impairment Discomfort Bacteria Viruses Allergy Environmental conditions Systemic disease Estimated 34 million people in the U.S. alone Widely considered both underdiagnosed and misdiagnosed Blepharitis (also known as Lid Margin Disease) Image Source: WebMD.com 3

4 AzaSite Plus (ISV 502) for Blepharitis Combines low doses of azithromycin and dexamethasone with DuraSite to address both infection and inflammation Intended to rapidly reduce signs and symptoms of acute and chronic blepharitis Dexamethasone = potent short term anti inflammatory effect Azithromycin = potent antibiotic; proven long term antiinflammatory effect Administered twice daily for 14 days Safety and efficacy established in prior clinical studies Evaluated in 174 patients Phase 3: blepharoconjunctivitis; n= 140 Phase 2: blepharoconjunctivitis; n= 11 Phase 1: healthy volunteers; n= 23 4

5 DexaSite (ISV 305) for Blepharitis Low dose dexamethasone in DuraSite Intended to rapidly reduce acute inflammation in non bacterial blepharitis Dexamethasone = potent short term anti inflammatory effect Administered twice daily for 14 days Safety and efficacy established in prior clinical trials versus AzaSite Plus in blepharoconjunctivitis Evaluated in 146 patients Phase 3: blepharoconjunctivitis; n= 136 Phase 2: blepharoconjunctivitis; n= 10 5

6 Blepharitis: : Global Landscape Overview No approved agents Clear market need Ophthalmologists see worst patients; many silent sufferers Off label prescribing by ophthalmologists Scant reimbursement; patients pay out of pocket High FDA hurdle: traditional endpoint Complete (100%) resolution of all clinical signs & symptoms Appropriate in acute infection settings (pink eye) Onerous in chronic settings of inflammation/infection (blepharitis) Industry Holy Grail : front of eye focus 6

7 Classic First to Market to Market Winners/Examples Diseases where waves of silent sufferers emerge post approval of an effective first tomarket pharmaceutical therapy: Overactive Bladder Ditropan XL/Detrol LA Restless Leg Syndrome Horizant Dry Eye Disease Restasis 7

8 The InSite Vision Opportunity Classic first to market advantage Approval = broad reimbursement = promotion = use FDA wants a drug approved for blepharitis Well aware of acute vs. chronic disease endpoint issue Clearly understand reality of ophthalmology clinical practice AzaSite Plus clearly superior to AzaSite Efficacy results (InSite s work): 2007 blepharoconjunctivitis Phase 2 pilot 2008 blepharoconjunctivitis Phase 3 Convenience (Inspire s work): Prior 14 & 28 Day regimens: no difference vs. DuraSite (vehicle) Current Phase 2: BID x 14, then QD x 14 (28 Day regimen) 8

9 Special Protocol Assessment (SPA): DOUBle Phase 3 for AzaSite Plus & DexaSite DOUBle (Dual Ophthalmic agents Used in Blepharitis) Simultaneous evaluations of AzaSite Plus, AzaSite, DexaSite and DuraSite (vehicle) Valuable data on our two agents and AzaSite in one Phase 3 study Four arm Study N= 900 AzaSite Plus (ISV-502) N= 300 AzaSite (Marketed) N= 150 DexaSite (ISV-305) N= 300 DuraSite (Vehicle) N= 150 9

10 Special Protocol Assessment (SPA): DOUBle Phase 3 for AzaSite Plus & DexaSite DOUBle (Dual Ophthalmic agents Used in Blepharitis) Simultaneous evaluations of AzaSite Plus, AzaSite, DexaSite and DuraSite (vehicle) Valuable data on our two agents and AzaSite in one Phase 3 study SPA Primary Endpoint Traditional Complete (100%) resolution of all clinical signs & symptoms (cure) vs. AzaSite Plus (ISV-502) AzaSite (Marketed) DuraSite (Vehicle) vs. vs. DexaSite (ISV-305) DuraSite (Vehicle) AzaSite (Marketed) DuraSite (Vehicle) 10

11 Special Protocol Assessment (SPA): DOUBle Phase 3 for AzaSite Plus & DexaSite DOUBle (Dual Ophthalmic agents Used in Blepharitis) Simultaneous evaluations of AzaSite Plus, AzaSite, DexaSite and DuraSite (vehicle) SPA Primary Endpoint New Time to recurrence: Patients with complete (100%) resolution of clinical signs & symptoms (cure) vs. AzaSite Plus (ISV-502) DexaSite (ISV-305) 11

12 Special Protocol Assessment (SPA): DOUBle Phase 3 for AzaSite Plus & DexaSite DOUBle (Dual Ophthalmic agents Used in Blepharitis) Simultaneous evaluations of AzaSite Plus, AzaSite, DexaSite and DuraSite (vehicle) Valuable data on our two agents and AzaSite in one Phase 3 study SPA Primary Endpoint Novel Improvement in clinical signs & symptoms Exacerbation of clinical signs & symptoms vs. vs. vs. AzaSite Plus (ISV-502) AzaSite (Marketed) DuraSite (Vehicle) DexaSite (ISV-305) DuraSite (Vehicle) AzaSite (Marketed) DuraSite (Vehicle) 12

13 DOUBle Phase 3 Trial: Pre Trial & Eligibility Day -7 0 BID Lid Scrubs Day 7 0: The Pre trial Phase (Pre eligibility) Patients instructed to perform lid scrubs twicedaily for one week (current standard of care) 13

14 DOUBle Phase 3 Trial: Eligibility & Baseline Day -7 BID Lid Scrubs 0 Eligibility/Baseline Ineligible for Study < Total Score = Mild Blepharitis > Score, but without Minimum Sign/Symptom Parameters = Mild Blepharitis Eligible for Study > Total Score & Minimum Sign/Symptom Parameters = Moderate-to-severe Blepharitis Severe Dry Eye Dx: Schirmer s Test Day 0: Investigator's Patient Eligibility Evaluation Quantitative BleSSSED assessment 14

15 InSite s BleSSSED Investigator Instrument: Setting a new Standard for Blepharitis Diagnosis Blepharitis Signs & Symptoms Scoring for Evaluating Disease Study Population Sought: Moderate to severe blepharitis Eligible: > Minimum total score, AND minimum individual scores on specific signs/symptoms of disease Ineligible: Minimum total score, OR > minimum total score but without minimum individual score on specific signs/symptoms of disease, OR severe dry eye diagnosis (Schirmer s test) Investigators use laminated cheat sheet with photographic examples in support of scoring each category and its severity Proprietary and quantitative blepharitis scoring system developed & owned by InSite Vision 15

16 DOUBle Phase 3 Trial: Eligibility & Baseline Day -7 BID Lid Scrubs 0 Eligibility/Baseline Eligible for Study Moderate-to- severe Blepharitis Digital photo Randomized into 1 of of 4 study arms Day 0: Patient Population is now Quantified for Randomization Moderate to severe blepharitis diagnosis quantified via: Investigator BleSSSED scoring Standardized digital photography Cameras, lighting, photo distance Patients least likely to benefit from pharmaceutical therapy are screened out; will not confound study results 16

17 DOUBle Phase 3 Trial: Eligibility & Baseline Day -7 0 Eligible for Study Moderate to to Severe Blepharitis BID Lid Scrubs Digital photo Eligibility/Baseline Randomization AzaSite Plus (ISV-502) AzaSite (Marketed) DexaSite (ISV-305) DuraSite (Vehicle) Patient s BleQOLITY Evaluation Day 0: Patient BleQOLITY Assessment At randomization, baseline Quality of Life is quantified via proprietary scoring system developed & owned by InSite Vision 17

18 BleQOLITY Patient Questionnaire: Quantifying the Patient s Blepharitis Experience Blepharitis Quality Of Life In TherapY Sample Questions (2 of 19) Please circle the number that best describes your symptoms today How important is each of these in addressing your eye problems? 18

19 DOUBle Phase 3 Trial: Treatment Phase Day Eligibility/Baseline Treatment Period Days 0 14: Treatment Period Following randomization, patient administers blinded agent twicedaily (BID) for 14 days Patients continue daily BID lid scrubs After washing/cleaning hands, each agent is applied topically to lids, via a clean finger, and then rubbed/massaged onto lids Novel topical clinical approach & application for blepharitis, a disease of the lid margins, and not the conjunctiva/eye 19

20 DOUBle Phase 3 Trial: 1st Clinical Evaluation Day Eligibility/Baseline Treatment Period 1 st Evaluation Day 15: 1st Evaluation: Traditional Endpoint Determine patients with complete (100%) resolution of all clinical signs and symptoms (cure) Investigator Assessment BleSSSED scoring: zero Standardized digital photography Patient Assessment BleQOLITY scoring Quantifies patient experience through 14 day therapy 20

21 DOUBle Phase 3 Trial: 1st Clinical Evaluation Day Eligibility/Baseline Treatment Period 1 st Evaluation Day 15: 1st Evaluation: Novel Endpoints BleSSSED score/digital photograph also quantifies patients who indeed clinically improved, but did not score complete resolution of all (100%) clinical signs & symptoms (cure) via the traditional endpoint Same is true for patients whose disease exacerbated (worsened) during the 14 day treatment period BleQOLITY scoring also quantifies patient s experience as they improved or exacerbated during the 14 day therapy 21

22 DOUBle Phase 3 Trial: Follow up Evaluations Day st Follow-up Evaluation 6-Month Follow-up Period Day 45: Starts 1 st Evaluation: New Recurrence Endpoint BleSSSED score/digital photograph quantifies recurrence of disease in those patients who had complete (100%) resolution of all clinical signs and symptoms at Day 15 BleQOLITY scoring also quantifies patient s experience as their disease recurred, following complete (100%) resolution of their disease on Day 15 22

23 DOUBle Phase 3 Trial: Follow up Evaluations Day st Follow-up Evaluation 6-Month Follow-up Period Day 45: Continued Evaluations: Novel Endpoints BleSSSED score/digital photograph continues to quantify on study patients over time for Improvements in clinical signs & symptoms Exacerbation of clinical signs & symptoms BleQOLITY scoring also continues to quantify on study patient s experience as their disease status improves or exacerbates 23

24 DOUBle Phase 3 Trial: Follow up Evaluations Day Scheduled follow up evaluations every 30 days (up to 6 months) Investigator Assessment BleSSSED Score Standardized digital photography Patient Assessment BleQOLITY scoring Follow-up Period Patients go off study via pre determined Clinical Events Disease recurrence: Patients with complete resolution of all clinical signs/symptoms at Day 15 Exacerbation of disease: all other patients Patient may schedule MD visit prior to 30 day periods if they believe recurrence and/or exacerbation occurred; if MD confirms, off study 24

25 Special Protocol Assessment (SPA): DOUBle Phase 3 for AzaSite Plus & DexaSite DOUBle (Dual Ophthalmic agents Used in Blepharitis) Simultaneous evaluations of AzaSite Plus, AzaSite, DexaSite and DuraSite (vehicle) Valuable data on our two agents and AzaSite in one Phase 3 study Four arm Study of 900 Patients AzaSite Plus (ISV-502) N= 300 AzaSite (Marketed) N= 150 DexaSite (ISV-305) N= 300 DuraSite (Vehicle) N= 150 Design and Statistical Analysis Plan N= 900 Randomized Quadruple blinded Powered at 80% 2 sided Fisher s Exact Test 25

26 Why We Believe We Can Win Patient eligibility criteria Only enroll patients with moderate to severe blepharitis Mild cases that could confound diagnosis and/or results do not qualify Eliminate patients with severe dry eye disease Frequently misdiagnosed as blepharitis Classic targeted therapy clinical trial strategy Novel Dosing & Administration Rubbed/massaged onto the lids (lid margin disease) vs. into eyes Well defined & SPA agreed clinical endpoints Traditional: Resolution of all (100%) clinical signs & symptoms New: Time to recurrence, following traditional endpoint Novel: Improvement and/or exacerbation of signs & symptoms Covers majority of patients who traditionally would not be followed 26

27 Why We Believe We Can Win (continued) Quantitative & proprietary investigator assessment tools BLeSSSED: quantify eligibility and longitudinal clinical status Standardized digital photography Quantitative & proprietary patient assessment tools BleQOLITY: quantify patient s longitudinal clinical experience Clinically meaningful measurements of how patients suffering from blepharitis feel (better or worse) during and following therapy, as their disease improves or exacerbates, and whether or not they experience complete (100%) resolution of disease (cure) AzaSite Plus has consistently outperformed AzaSite in clinical settings, including head to head studies 27

28 AzaSite Plus Consistently better than AzaSite: Phase 2/3 Results in Blepharitis & Blepharoconjunctivitis Study Design Treatment Period Primary Endpoint Results InSite s Phase 3 AzaSite Plus for Blepharoconjunctivitis (2008) AzaSite Plus vs. AzaSite vs. DexaSite vs. Vehicle 14-day Rx BIDx14 2-week follow-up Resolution of all clinical signs & symptoms AzaSite Plus 27.1% vs. AzaSite 15.6% P= Inspire s Phase 2 ( ) AzaSite for Blepharitis ( ) AzaSite vs. Vehicle 14-day Rx BIDx2; QDx12 2-week follow-up Clearing of lid debris No difference over vehicle Inspire s Phase 2 ( ) AzaSite for Blepharitis ( ) AzaSite vs. Vehicle 28-day Rx BIDx2; QDx26 4-week follow-up Mean lid margin hyperemia No difference over vehicle Inspire s Phase 2 ( ) AzaSite for Blepharitis (Initiated late 2010) AzaSite vs. Vehicle 28-day Rx BIDx14; QDx14 4-week follow-up Unknown TBD; Mid-year 2011 results expected 28

29 Why We Believe We Can Win (continued) Our open and collaborative FDA relationship AzaSite/conjunctivitis interactions through approval AzaSite Plus/DexaSite blepharoconjunctivitis interactions, especially post 2008 Phase 3 study results AzaSite Plus 27.1% vs. AzaSite 15.6%, p= Evidence that other patients got better, but couldn t be counted Traditional, new and novel endpoint discussions Our clinical trial approach, being the first to: Quantify and evaluate blepharitis as a chronic disease over time (versus an acute Day 15; the traditional approach) Blepharitis is a chronic disease characterized by inflammation Tissue depot effect of azithromycin in DuraSite 29

30 Anti inflammatory inflammatory & Tissue Penetrating Properties of Azithromycin are Well Established in Peer reviewed reviewed Literature 30

31 Azithromycin Concentration in Tissue is Dose and Duration Dependent Azithromycin penetrates and concentrates in eye tissues in a dose & duration dependent manner high levels of azithromycin, which can be achieved in ocular surface tissues, particularly eyelids,. and the degree to which these levels persist after discontinuing the drug, distinguish azithromycin. (AzaSite labeled use: BID x 2, QD x 7) Following BID x 14 day dosing onto the lids, we believe azithromycin levels should be detectable in eyelid tissue for ~90 days ( depot effect ) 31

32 Why We Believe We Can Win Summary We believe DOUBle is the most comprehensive and well thought out blepharitis clinical study ever designed We believe DOUBle is the most quantitative blepharitis clinical study design ever designed We are proud to have designed this protocol in collaboration with the FDA, and finalized via this SPA agreement 32

33 What Does This Mean in Simple Terms? Historically, only patients who were cured (complete resolution) of all clinical signs & symptoms counted in the primary endpoint 2008 Study: AzaSite Plus 27.1% vs. AzaSite 15.6%, p= For the first time, patients who did indeed achieve complete (100%) resolution of all clinical signs & symptoms (cure) will continue to be quantitatively evaluated over time for disease recurrence For the first time, patients who did not achieve complete (100%) resolution of all clinical signs & symptoms will continue to be quantitatively evaluated over time for improvement in and/or exacerbation of disease 33

34 What Does This Mean in Simple Terms? BleSSSED, in combination with standardized digital photography, quantifies each patient s clinical improvements, recurrence and/or exacerbation over time BleQOLITY, in combination with BleSSSED and standardized digital photography, quantifies each patient s clinical experience during improvements, recurrence and/or exacerbation over time This gives us, in collaboration with the FDA, the first opportunity to quantitatively examine data on all patients with moderate to severe blepharitis, and determine just how better is better in the clinical setting, and thus put more patients into primary endpoints analyses 34

35 What Does This Mean in Simple Terms? The DOUBLe Phase 3 study strives to improve the way blepharitis is both diagnosed and treated, and also reviewed (and hopefully approved), with the quantitative BleSSSED and BleQOLITY tools leading the way We would gladly pursue BleSSSED and BleQOLITY data and claims into labeling, and in commercialization efforts 35

36 Endpoint Risk: AzaSite Plus vs. AzaSite AzaSite Plus vs. AzaSite AzaSite Plus already beat AzaSite in 14 day BID regimen AzaSite Plus vs. DexaSite Good scientific rationale, following traditional endpoint: Anti inflammatory effect of azithromycin Eyelid tissue depot effect of azithromycin AzaSite vs. DuraSite (Vehicle) 1st 14 day BID evaluation: Phase 3 1st approach using topical/finger application DexaSite vs. DuraSite (Vehicle) Good scientific rationale following 2008 Phase 3 efficacy/safety AzaSite Plus vs. DuraSite (Vehicle) 36

37 AzaSite Plus and DexaSite Market Opportunities Blepharitis estimated to effect up to 34 million adults in U.S. Widely considered under diagnosed and misdiagnosed Moderate to severe disease: clear need for a proven therapeutic No FDA approved drugs Numerous attempts & failures Assuming moderate market penetration and current pricing of drugs prescribed for blepharitis, possible sales ranges are: AzaSite Plus $500M to $1B [Based on 10% at $120/prescription] DexaSite $200M to $400M AzaSite [Based on 5% at $90/prescription] We haven t examined possible $ effects of a positive outcome for AzaSite via this study AzaSite Plus pricing potential could be doubled by the pursuit of an AzaSite indication in blepharitis on 28 day regimen 37

38 Next Steps Validate BleQOLITY assessment Collaboration with UCLA/blepharitis experts Formally re initiate partnering discussions Focus on AzaSite Plus; maintain DexaSite rights SPA validates clinical & regulatory strategy Explore novel financing Maintain options to conduct Phase 3 independently while examining partnership economics Finalize CRO & Phase 3 trial costs Nearly complete Phase 3 supplies available: July Manufactured in May 38

39 Summary: Why We Believe We Can Win Patient eligibility criteria Well defined Phase 3 with SPA agreed clinical endpoints History of AzaSite Plus beating AzaSite: Traditional endpoint Scientific rationale for AzaSite Plus over DexaSite: New endpoint Potential to change the regulatory landscape: Novel endpoints Quantifiable/proprietary investigator measurement tools Digital photography BleSSSED Quantifiable/proprietary patient measurement tools BleQOLITY Open and collaborative FDA relationship Two (three?) potential positive product outcomes Classic first mover advantage 39

40 Thank you