Background and Rationale ZEDS Training Meeting Background and Rationale

Background and Rationale Acute high dose systemic antiviral treatment is approved and recommended for herpes zoster ophthalmicus, and reduces eye disease at 6 months from 50% to 30%, but there is no standard approach to antiviral treatment for ocular complications of HZO. Rationale Relatively recent knowledge of infectious pathogenesis of complications of HZO Significant benefit of suppressive antiviral treatment in reducing recurrent herpes simplex virus (HSV) eye disease HZO and HSV keratitis, caused by different herpes viruses, have similarities Retrospective pilot data showing evidence of comparable, marked benefit of suppressive antiviral treatment of chronic HZO and HSV

Rationale for Zoster Eye Disease Study (ZEDS) Evidence that Herpes Zoster is associated with chronic active infection with the varicella zoster virus (VZV) Active infection contributes to chronic eye disease Dendriform epithelial keratitis PCR+ for VZV and responds to topical ganciclovir (antiviral) Pavan Langston D. Arch Ophthalmol 1995; 111:1381-5 Hu AY, Am J Ophthalmol 2010; 149:214-220 Aggarwal S. Cornea. 2014; 33(2):109-13. Uveitis: anterior chamber PCR+ for VZV Takase Jpn J Opthalmol 2014; 58:473-82 Presentation Title Goes Here

Evidence of Chronic Active Varicella Zoster Virus (VZV) Infection Contributing to Complications of Zoster Postherpetic neuralgia: VZV DNA in peripheral blood mononuclear cells Strokes Anti-VZV antibody in CSF, VZV DNA in walls of cerebral blood vessels Temporal arteritis VZV DNA in temporal artery biopsies Gilden D. Future Neurol. 2009; 4:103-117 Nagel MA. Neurology. 2013; 80:2017-2021 Mahalingam R. J Neurovirol. 1995; 1:130-3. Nagel M A. Neurology. 2007; 68:1069-73. Nagel, M A. Curr Opin Neurol. 2014; 27:356. Nagel, M A. J Neurol Sci. 2013; 335:228-30. Nagel, M A. Neurology. 2013; 80:2017-21. Presentation Title Goes Here

Rationale of Zoster Eye Disease Study Herpetic Eye Disease Study (HEDS) Acyclovir Prevention Trial (APT) HEDS Study Group N Eng J Med 1998; 339:300-306 HEDS Study Group. Arch Ophthalmol 2000;118: 1030-36. Long-term suppressive treatment with oral acyclovir resulted in 45% reduction in recurrent Herpes Simplex Virus (HSV) disease over 1 yr Antiviral treatment was most beneficial in reducing stromal keratitis Although role of active viral infection unclear in stromal keratitis, evidence is strong that antiviral suppression reduces it. ZEDS trial analogous to the HEDS APT study for ocular disease caused by varicella zoster virus (VZV) Valacyclovir, prodrug of acyclovir, higher plasma concentrations, more effective against VZV than acyclovir Randomized, double-masked, placebo-controlled multi-center clinical trial of 1 yr of suppressive valacyclovir v placebo with follow-up every 3 months for 18 months Presentation Title Goes Here

HEDS Results

Pilot Data Miserocchi E. et al Cornea. 2014; 33(6):565-70. Retrospective study using valacyclovir 500 mg daily or acyclovir 400 mg bid reduced the overall number of HZO recurrences to 2.1 per year, compared to 3.4 episodes without antiviral treatment, a 35% reduction (P<.05). Same suppressive antiviral treatment of HSV keratitis patients reduced recurrences to 2.3 from 3.8, a 39% reduction (P<0.05). The percent reduction of recurrent HSV (39%) was comparable to the percent reduction of HSV (45%) in HEDS, and comparable to the reduction of recurrent inflammation in HZO (35%) in this study. This supports the projected risk reduction (30%) postulated for ZEDS and used to calculate sample size. (ZEDS using higher dose) Presentation Title Goes Here

Preliminary Studies Retrospective study HZO onset < 60yrs vs 60+ at Wills Eye Ghaznawi Ophthalmology 2011;118:2242 ~100 patients, half < age 60 Younger onset More likely to have dendriform epithelial keratitis More likely to have recurrent episodes of inflammation Less likely to have PHN, neurotrophic keratopathy, microbial superinfection Contributed to our decision to stratify at randomization by onset < age 60 vs. 60+

Surveys #1 of 100 cornea specialists via keranet re current practice patterns 85% treated cases of chronic HZO within past year Oral antivirals used most frequently for 10-14 days 30% used oral antivirals for at least a year or as long as on topical steroids (SY Cornea 2012; 31:786) #2 cornea leaders and keranet (N=171) re selection of antiviral /interest 64% valacyclovir 500 mg bid or 1000 daily 33% acyclovir 800 mg bid 4% famciclovir 250 mg bid > 60% interested in participating in study (Sackel Eye Contact Lens 2014; 40:200) Contributed to selection valacyclovir as drug to study #3 potential study centers from #2 plus ex- cornea fellows 4 programs 84 potential centers confirmed interest in participating 60 centers completed participating center applications, including 18 that treated >100 HZO patients in previous years

Incidence and Disease Burden of HZ/HZO Increasing incidence of zoster since 2000 in USA and worldwide, both before and after introduction vaccination against varicella Recent reports average age HZOdecreased~5 yrs from >60 to <60 since ~2005 Chan Cornea 2015; 34:535 Davies Br J Ophthalmol 2016; 100:312 Disease burden HZ more common, severe in women (standard to analyze results by gender) HZO increased risk of PHN and stroke compared to HZ

Remaining Gaps in Knowledge Morbidity due to HZO substantial and greater than zoster in other locations due to eye disease, increased risk PHN and stroke Important for public health to determine if long-term antiviral reduces complications of HZO Effectiveness of early vs delayed suppressive antiviral treatment unknown At Study Design Studio hosted by NYU with participation by cornea leaders and NEI decided Important to determine if early treatment reduces chronic disease, and if delayed treatment is effective or not Define recent onset as < 6 months, chronic onset as 6+ months Stratify at randomization by recent onset v. chronic disease, in addition to age of onset <60 vs 60+ years

Study Medication: Valacyclovir FDA approved for: Acute treatment for Zoster: 1000 mg 3 times daily for 7 days within 72 hours of onset of rash Suppressive treatment for HSV genital infections: 1000 mg daily for one year (500 mg twice daily for immunocompromised) FDA IND necessary and obtained for this study as approved dose is being used for a different patient population IND training required

Valacyclovir Valacyclovir (val) is prodrug of acyclovir (acv) with better oral absorption and bioavailability Peak plasma concentration of acv: after 500 mg val = 3.28 mcg/ml after 1000 mg val = 5.65 mcg/ml Median inhibitory conc acv to dec VZV counts 50% (IC50)~ 3 mcg/ml By comparison to HEDS use of acyclovir as study medication: Peak plasma concentration of acv after 400 mg acv = 1.21 mcg/ml IC50 of acyclovir for HSV1 = 0.45-1.47 mcg/ml Varicella zoster virus (VZV) IC50 data supports use of valacyclovir over acyclovir in this study, cost differences not large since both generic, decision by Studio to study single drug most likely to be effective

Study Medication Regimen Double masked randomized controlled clinical trial Study treatment: valacyclovir 1000 mg once daily Chosen because same as suppressive dosage approved for genital herpes simplex virus (HSV) infection Use of medication daily enhances compliance, although 500 mg twice daily approved for immunocompromised patients with genital HSV and may be more effective To be given as two 500 mg tablets taken once daily in morning 1000 mg val tablets too large to encapsulate as needed to appear same as placebo with filler of active medication (no lactose in both) If side effects, use of 500 mg tablets makes it possible to take one pill twice daily, or once daily is side effects recur on divided dose If study medication discontinued, study participant will continued to be followed until completion of 18 month study

Risks of Valacyclovir Most common side effects at this dose: Abdominal pain, nausea in 11% vs placebo 6,8% Headache 35% vs placebo 34% Thrombotic thrombocytopenia purpura (TTP) has been reported only in severely immunocompromised patients at high dose of 8000 mg daily for CMV. Unexpected in this study. Pregnancy: Category B, used if benefits outweigh risks In ZEDS pregnancy, nursing are exclusion criteria, and women required to agree to use birth control CNS side effects can occur, especially in the elderly. HZO can have CNS complications too. If CNS complications, study medication discontinued temporarily, refer to neurologist, if participant safety requires unmasking, helpline available 24/7

Valacyclovir and Renal Insufficiency If eGFR (estimated glomerular filtration rate) < 30 then val dose reduced from 1000 mg to 500 mg per FDA package insert In ZEDS: Baseline eGFR obtained in all patients after screening/consent visit and prior to randomization/enrollment visit If normal, 60 or above, not repeated If less than 45 ineligible for study enrollment If 45-59, eligible per recommendations of MDs, test repeated prior to 3, 6, 9, 12 month visits. If less than 45 during follow-up, test is repeated, study medication discontinued, participant is referred to medical doctor, and participant continues to be followed off study medication until study completed

Valacyclovir and Acute Kidney Disease Acute kidney disease can occur, especially in the elderly Dehydration contributes to it, participants instructed to drink 4-6 glasses of fluids If urinary symptoms, refer to medical doctor, obtain urinalysis for crystals Expected, uncommon complication, will be monitored

Suppressive Valacyclovir for HZO Valacyclovir has long, excellent safety record since approval in 1995 ZEDS study for its use in immunocompetent HZO patients age 18 years and older is designed to maximize safety Valacyclovir available as generic medication since 2009 Cost < $1 per pill, so if effective in decreasing complications of HZO, will likely be highly cost-effective If suppressive valacyclovir is effective in secondary aim of reducing postherpetic neuralgia after HZO, it may benefit patients with HZ in other anatomic locations.