Research Article

FV-100 versus Valacyclovir for the Prevention of Post-Herpetic Neuralgia and the
Treatment of Acute Herpes Zoster-Associated Pain: A Randomized-Controlled
Trial†

Running Title: FV-100 for Herpes Zoster-Associated Pain

Stephen K. Tyring, MD, PhD1, Patricia Lee, MD2, Gordon T. Hill, Jr., MD3, Joel C.
Silverfield, MD4, Angela Yen Moore, MD5, Theresa Matkovits, PhD6, and John
Sullivan-Bolyai, MD, MPH6*

1. University of Texas Health Sciences Center, Houston, TX

2. Center for Clinical Studies, Webster, TX
3. Oakwell Clinical Research, LLC, San Antonio, TX
4. Bay Care Medical Group, Inc., Health Point Medical Group, Inc., Burnette &
Silverfield MDS, Tampa, FL
5. Arlington Center for Dermatology, Arlington Research Center, Arlington, TX
6. ContraVir Pharmaceuticals, Inc., Edison, New Jersey

*Corresponding author:
John Sullivan-Bólyai, MD, MPH
Chief Medical Officer
ContraVir Pharmaceuticals Inc.
399 Thornall Street First Floor
Edison, New Jersey 08837
+1 732 902 4019 (office)
jsullivan-bolyai@contravir.com

†
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
[10.1002/jmv.24750]

Additional Supporting Information may be found in the online version of this article.

Received 26 September 2016; Revised 28 November 2016; Accepted 2 December 2016

Journal of Medical Virology
This article is protected by copyright. All rights reserved
DOI 10.1002/jmv.24750

This article is protected by copyright. All rights reserved

Abstract

This prospective, parallel-group, randomized, double-blind, multicenter study compared the efficacy

and safety of FV-100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ).

Patients, ≥ 50 years of age, diagnosed with HZ within 72 hours of lesion appearance who had HZ-

associated pain, were randomized 1:1:1 to a 7-day course of either: FV-100 200 mg QD (n = 117), FV-

100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis

of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically

significant pain (CSP); pain scores; incidence and severity of post-herpetic neuralgia (PHN); and times

to full lesion crusting and to lesion healing. Safety was evaluated on the basis of Adverse Event

(AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The

burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV-100 200 mg, FV-

100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV-100

200 mg, FV-100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively.

Adverse event and SAE profiles of the 2 FV-100 and the valacyclovir groups were similar and no

untoward signals or trends were evident. These results demonstrate a potential for FV-100 as an

antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and

reduce the incidence of PHN compared with available treatments. This article is protected by copyright.

All rights reserved

Keywords: Antiviral agents, Herpes simplex virus, Herpes virus, reinfection

This article is protected by copyright. All rights reserved 2

Background

Varicella zoster virus (VZV) is a human alpha herpes virus, which causes varicella (chicken pox) and

herpes zoster (HZ). Approximately one out of three people in the United States aged 60 years or older

will develop shingles [Center for Disease Control and Prevention].

Herpes zoster results from the reactivation of latent VZV and its spread from the ganglion to the

corresponding cutaneous dermatome [Gnann and Whitley, 2002; Schmader and Dworkin, 2008]. The

characteristic vesicular rash (shingles) of HZ pustulates and crusts within 7 to 10 days but may take up

to a month to heal; however, pain is an important feature of the disease that is often the most

debilitating for patients.

Zoster-associated pain is experienced by approximately 90% of patients. The chronic neuropathic pain

phase of the disease, known as postherpetic neuralgia (PHN), is defined as pain that persists 90 days or

more after rash onset [Arani et al., 2001; Johnson et al., 2010].

Postherpetic neuralgia causes the largest HZ-related burden of illness [Bowsher, 1999; Jung et al.,

2004; Massengill and Kittredge, 2014; Tontodonati et al., 2012]. Risk factors for PHN include greater

acute pain severity, presence of a prodrome, greater rash severity, and older patient age at onset [Forbes

et al., 2016]. Current interventions for PHN, such as lidocaine patches, opioids, tricyclic

antidepressants, and anti-epileptics, are palliative and fail to treat the underlying disease. A substantial

proportion of patients fail to obtain satisfactory pain relief using the available medications [Tontodonati

et al., 2012]. This pain burden is associated with negative effects on their quality of life such as

impaired physical functioning, higher levels of emotional stress, and decreases in social functioning

[Katz et al., 2004].

Although the widespread use of the herpes zoster vaccine has reduced the incidence of HZ and PHN

[Oxman et al., 2005], a large percentage (~90% in the US) of the at-risk population does not receive the

This article is protected by copyright. All rights reserved 3

vaccine [National Health Interview Survey, 2009]. About half of people 60 years of age or older who

have had the shingles vaccine fail to respond (eg, primary failure meaning they failed to seroconvert

after vaccination) and may go on to develop HZ [Oxman et al., 2005; Pannuti et al., 2004]. In addition,

the efficacy of the vaccine has been shown to decline over time (eg, secondary vaccine failure)

[Morrison et al., 2015; Schmader et al., 2012].

Several drugs, including acyclovir, valacyclovir, and famciclovir, have demonstrated minimal efficacy

in terms of pain control for patients with HZ [Beutner et al., 1995]. Additionally, a significant

proportion of these patients (~20% to 40% and sometimes more) go on to develop PHN [Drolet et al.,

2010; Schmader and Dworkin, 2008]. These drugs require multiple doses of medication each day

[ZOVIRAX® [package insert], 2005; FAMVIR® [package insert], 2013; VALTREX® [package

insert], 2008]. Furthermore, doses of these antiviral agents must be modified for patients with renal

impairment. It is evident that a drug with greater antiviral activity, better pain relief, and a more

simplified dosing regimen represents a significant unmet medical need. Brivudine is also available in

some countries for treating shingles [Lilie and Wassilew, 2003].

FV-100 is a prodrug for the bicyclic nucleoside analogue CF-1743 [McGuigan et al., 2007]. CF-1743

demonstrates high potency against clinical VZV isolates (EC50 ~440 pM). The inhibitory activity of

FV-100 and CF-1743 is highly specific for VZV. Renal clearance for FV-100 and CF-1743 was

demonstrated to be low for all doses tested (100, 200, 400, and 800 mg QD), indicating that renal

elimination is not likely to be an important pathway for either compound. In light of these results, a

Phase 2 clinical trial was undertaken in patients with HZ in order to evaluate the efficacy of once-daily

(QD) FV-100 at both the 200 mg and 400 mg doses, compared with valacyclovir 3000 mg administered

three times daily (1000 mg TID) in reducing the acute herpes zoster burden of illness (BOI) and

reducing the incidence of PHN.

This article is protected by copyright. All rights reserved 4

Study Design

This was a multicenter, randomized, parallel-group, comparative study of FV-100 versus valacyclovir

in patients with HZ conducted at 90 centers in the United States between May 2009 and December

2010. Patients who presented within 72 hours of zoster rash and met all eligibility criteria were

randomized 1:1:1 to one of 3 treatment groups: 1) FV-100 200 mg QD, 2) FV-100 400 mg QD, or 3)

valacyclovir 3000 mg (1000 mg TID). Patients were centrally randomized by an interactive web

response system and stratified by 1), age category (<65 vs. ≥ 65) and 2) Visit 1/Day 1 ZBPI Worst Pain

in the Last 24 hours score (<6 vs. > 6). Sites were blinded to all ZBPI subset pain scores throughout the

study.

The primary endpoint was the reduction in the mean BOI-30AUC, a standardized score measuring the

overall severity of pain experienced by study subjects during the 30 days after the first dose of study

drug (see Endpoints below). A sample size of at least 333 patients (111 per arm) was calculated to

achieve 80% power to detect a 25% reduction in the mean BOI-30AUC in the FV-100 treated group

compared to the valacyclovir-treated group. Estimates of BOI-30AUC and SD (constant SD across

treatment arms) were extrapolated from the Zostavax Shingles Prevention Study and the ZBPI

validation study [VALTREX® [package insert, 2008; Rohan] [Coplan et al., 2004].

All eligible patients were treated for 7 days and followed through Day 30. Patients who continued to

have HZ-associated pain or whose rashes had not healed by Day 30 were followed through Day 90 or

until their rash healed and they had two documented Zoster Brief Pain Inventory (ZBPI) worst pain

scores of 0, whichever occurred first.

The study was approved by a central institutional review board (IRB) or local IRBs and conducted in

accordance with the International Committee on Harmonization Guidelines for Good Clinical Practice

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and the 1964 Declaration of Helsinki [World Medical Association; Clinical Safety Data Management].

This study was registered on clinicaltrials.gov (NCT00900783).

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Patients

Patients were ≥50 years of age, had a clinical diagnosis of HZ as evidenced by a unilateral dermatomal

rash present for ≤72 hours, and had zoster-related pain as defined by a ZBPI worst pain score >0.

Patients were excluded for multidermatomal, disseminated, or ophthalmic HZ; impaired renal function,

immunosuppression; gastrointestinal dysfunction that could interfere with absorption; chronic pain

requiring narcotic analgesics; the use of tricyclic antidepressants, systemic or cutaneous antivirals

within 30 days of enrollment, or CYP3A4-inhibiting protease inhibitors, and strong CYP3A4 inhibitors

and inducers.

Assessments

At screening (Day 1), a complete medical history, physical exam, lesion assessment, vital signs,

electrocardiogram (ECG), clinical laboratory specimens (blood for hematology and chemistry, and

urine for urinalysis), and a lesion swab for qualitative VZV determination, were obtained. Pain and

zoster pain-related interference in functional categories were evaluated using the ZBPI. When

eligibility was confirmed, patients received their first dose of study drug.

Patients completed visits on Days 3, 5, and 7 during the dosing period, and at Days 10, 14, 21, 30, 42,

56, and 90 days post-dose. Lesion assessments continued until complete healing was demonstrated.

Patients continued to complete ZBPIs on Days 42, 56, and 90 unless they achieved 2 consecutive visits

(starting on Day 30 or later) without HZ-associated pain.

At each visit, the investigators assessed lesions and patients completed the ZBPI. Blood and urine

samples for laboratory testing were collected on Days 3, 7, 14, and 30. Vital signs were taken on Days

5 and 7, and ECGs were performed on Days 3, 7, and 30. Adverse events and concomitant medications

This article is protected by copyright. All rights reserved 7

(including pain medications) were recorded throughout the study. The numbers of capsules and caplets

remaining in the study drug wallet on Day 7 were recorded to assess study medication compliance.

Endpoints

The primary efficacy measure was the reduction of the HZ BOI over 30 days (measured by BOI-

30AUC). This endpoint was derived from a patient’s reported score on a scale from 0 (no pain) to 10

(pain as bad as you can imagine) on question #3 of the ZBPI, which rated a patient’s “worst pain in the

last 24 hours” over the period from Study Day 1 to Study Day 30. Secondary endpoints included the

following: HZ BOI scores through 14 days (BOI-14AUC) and 90 days (BOI-90AUC), incidence and

severity of PHN at 90 days after lesion appearance, time to full lesion crusting and lesion healing, use

of concomitant pain medication, and zoster pain-related interference in functional categories as

assessed by the ZBPI. CSP was defined as a worst pain score > 3 as reported on the ZBPI. Safety was

assessed using adverse events (AEs), clinical laboratory testing, vital signs, electrocardiograms, and

physical exams. DNA samples were extracted from lesion swabs on days 1 and 7 and analyzed for

phenotypic resistance.

The main efficacy analyses were conducted on a modified intent-to-treat population (MITT2), defined

as all randomized patients who received at least one dose of study drug.

The burden of illness (BOI-AUC) was calculated as follows:

n
1
 2 (p n  pn 1 )(t n 1  t n )
BOI-AUC = 1 where:

p = worst pain score,

t = time point [actual day or nominal day],

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n = maximum time point for AUC [actual day ± visit window, n = 14 ± 2, 30 ± 3,

90 ± 7; nominal day, n = 14, 30, 90]

Statistical analyses

The acute HZ burden of illness values over 14, 30, and 90 days (measured by BOI-14AUC, BOI-30AUC,

and BOI-90AUC) were evaluated using analysis of covariance (ANCOVA) model, controlling for

stratified age (50-69 and ≥ 70 years of age), sex, and baseline pain.

The main efficacy analyses were conducted on a modified intent-to-treat population (MITT2), defined

as all randomized patients who received at least one dose of study drug, except for those whose lesion

swabs were positive by polymerase chain reaction (PCR) for herpes simplex virus (HSV) and negative

by PCR for VZV. The acute HZ burden of illness over 30 days (measured by BOI-30AUC) was

evaluated using an F test from an analysis of covariance model, controlling for age, gender, and

baseline level of pain. BOI-14AUC and BOI-90AUC were evaluated in the same manner. A sample size of

at least 333 patients (111 per arm) was calculated to achieve 80% power to detect a 25% reduction in

the mean BOI-30AUC in the FV-100 treated group compared to the valacyclovir treated group, with a 2-

sided  of 0.05 and a valacyclovir mean BOI-30AUC of 91 (SD 60) in the study.

The incidence of PHN at 90 days after lesion appearance was summarized by treatment group and

evaluated using the chi-square test from a logistic regression. The severity of PHN was evaluated using

a Poisson model controlling for treatment group, age, sex, and concomitant pain medication. Clinically

significant pain (CSP) was defined as a worst pain score > 3 as reported on the ZBPI.

For each study day, treatment group means and corresponding standard deviations (SDs) were

calculated, and the estimates of mean differences (between each active arm individually and the active

This article is protected by copyright. All rights reserved 9

control arm) are presented with resulting P values from an analysis of covariance (ANCOVA) model,

controlling for stratified age (50-69 and ≥ 70 years of age), sex and baseline pain.

Comparison of mean time to full lesion crusting and mean time to lesion healing for patients treated

with FV-100 to those treated with valacyclovir were completed through calculation of the Kalplan-

Meier estimators.

The Safety Population consisted of all randomized patients who received at least one dose of study

drug. All safety analyses were descriptive.

This article is protected by copyright. All rights reserved 10

Results

Of the 466 patients screened, 350 were randomized and received at least one dose of study drug (Figure

1). Some patients (34) were excluded due to their low creatinine clearance (<50 mL/min/1.73 m2),

leaving 329 for the modified ITT efficacy analysis. The mean age of patients was 64.6 years. Most

patients (65%) were women. All other baseline demographic characteristics were similar between

groups (Table 1). Approximately 15% of patients overall had a history of HZ. The mean number of

prior occurrences was 1.5 for the study (range 1-5). Fewer than 5% of the patients had received the HZ

vaccine.

Most patients (78.4%) reported baseline prodromal pain. At onset of treatment the mean (SD) worst

pain score was 6.3 (2.5). However, 30% of baseline average pain scores were rated at 3 or below by

patients, limiting the ability of this study to analyze the impact of the treatment on pain.

Burden of Illness

The LS mean BOI-30AUC values (SD) for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg

were 114.5 (6.2), 110.3 6.1), and 118.0 (6.3), respectively (Table 2). This Phase 2 study was not

powered to show differences in the BOI-30AUC between groups of less than 25%, however, the results

suggested a dose response for FV-100. Notably, the differences between the mean BOIs for FV-400 mg

and valacyclovir 3000 mg became more pronounced with time.

Post-Herpetic Neuralgia

A numerically lower incidence of PHN was observed for the patients receiving the 200 and 400 mg

doses of FV-100 compared with those receiving 3000 mg of valacyclovir (17.8% and 12.4% vs. 20.2%,

respectively) (Table 3). Even though this study was not powered to demonstrate a difference, there was

also a numerical trend for patients treated with FV-100 at either 200 mg or 400 mg to have a lower

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severity of pain than those treated with valacyclovir. Both the incidence and severity of PHN results

suggest the presence of a dose response in the efficacy of FV-100.

Pain Endpoints

Trends in faster resolution of pain in both the FV-100 groups compared to valacyclovir were noted for

other a priori endpoints, with potential dose effects observed between the two groups (Table 4). The

mean duration of CSP was 31.3 and 27.3 days in the FV-100 200 mg and 400 mg groups respectively,

and 32.3 days in the valacyclovir group. These results suggest a dose response effect with a quicker

elimination of pain at the higher dose of FV-100. Likewise, the median duration until the first

resolution of CSP was 26.7 and 25.1 days in the FV-100 200 mg and 400 mg groups, respectively, vs.

28.8 days in the valacyclovir group. A higher proportion of patients achieved a permanent resolution of

CSP in the FV-100 groups (77.6 % for the 200 mg dose and 80.5% for 400 mg dose) compared with

the patients on valacyclovir (75.2%). A difference in mean worst pain scores between valacyclovir and

the 2 FV-100 doses and a potential dose effect between the 2 FV-100 doses was observed from Study

Day 14 onward, with the same consistent pattern occurring with least pain, average pain, and pain right

now scores favoring the FV-100 treatment arms.

Post-Hoc Analyses

Post hoc analyses were conducted to gain more insight into the effect of FV-100 on subacute and

chronic pain. BOI-14-90AUC and BOI-30-90AUC both showed that patients on FV-100 generally had

lower burdens of illness than those on valacyclovir. A dose response was suggested for BOI-14-90AUC

and a trend toward better pain management from week 2 onward was observed for FV-100 400 mg.

This article is protected by copyright. All rights reserved 12

These results corroborated the prospective observations. These post hoc analyses results are shown in

the supplemental material.

Virology

The virology results are described in the supplemental material.

Safety

Approximately 48% of the total population experienced an AE (FV-100 200 mg = 47%, FV-100 400

mg = 54%, and valacyclovir = 42%) (Table 5). Overall, most AEs were mild in severity, and there were

no Grade 4 AEs in either of the FV-100 arms. The only grade 4 event (fatal congestive heart failure)

occurred in one patient in the valacyclovir group. Overall, headache was the most frequently observed

AE for both the FV-100 and valacyclovir arms (7.4% of patients overall, 5% for FV-100 200 mg and

valacyclovir and 13% for FV-100 400 mg). Nausea was the second-most frequently observed AE

(7.1% overall, approximately 6.0% for FV-100 200 mg and valacyclovir and 9.5% for FV-100 400

mg).

Only 2 patients in each treatment arm had an AE that led to study drug discontinuation. No SAEs were

observed in the FV-100 200 mg arm. The SAEs were approximately equal in the FV-100 400 mg and

valacyclovir arms of the study (approximately 4%).

Laboratory results were unremarkable, no evidence for renal or hepatic toxicity was noted, and vital

signs and electrocardiograms demonstrated no untoward safety signal.

This article is protected by copyright. All rights reserved 13

Discussion

Postherpetic neuralgia is known to cause the largest burden of illness for patients with HZ [Massengill

and Kittredge, 2014; Tontodonati et al., 2012]. A significant proportion of patients with HZ develop

PHN despite treatment with the current antiviral agents [Bowsher, 1999; Jung et al., 2004]. These

antivirals require dosing regimens (3-5 times daily) that must be modified for patients with renal

impairment [ZOVIRAX®, 2005; FAMVIR®, 2013; VALTREX®, 2008]. In addition, the current

medications used to treat the pain associated with PHN fall short in terms of relief for many patients

[Tontodonati et al., 2012]. In addition pain medications are only palliative and do not provide a cure for

HZ. Hence, a drug with greater antiviral activity, the ability to prevent PHN, better pain relief, and a

more simplified dosing regimen is needed.

Although there was no statistically significant difference among the treatment groups for the primary

endpoint of BOI-30AUC, a difference between the FV-100 400 mg and valacyclovir groups emerged in

the 90-day data (a 14% reduction), suggesting a potential effect of FV-100 on subacute and chronic

pain. Numerical differences in the incidence and severity of PHN at 90 days favored both doses of FV-

100 over valacyclovir. These results represent a clinically meaningful reduction in pain with FV-100.

Faster resolution of pain in both the FV-100 groups compared to valacyclovir was consistently noted,

with potential dose effects observed between the two FV-100 groups. The mean duration of CSP was

shorter in the FV-100 groups compared with the valacyclovir group. Likewise, the resolution of CSP

was quicker and a higher proportion of patients achieved a permanent resolution of CSP in the FV-100

groups compared with the patients on valacyclovir. These differences are clinically meaningful since

pain following lesion healing is likely a better measure of chronic pain than is pain after study

enrollment.

This article is protected by copyright. All rights reserved 14

In the post-hoc analysis, the 400 mg dose of FV-100 provided a 20% reduction in the burden of illness

for pain in both the 14 to 90 day periods and 30 to 90 day periods when compared to valacyclovir.

Patients receiving the 400 mg dose of FV-100 experienced on average a 37% reduction in the incidence

of PHN over valacyclovir. The proportions of patients on valacyclovir 3000 mg experiencing PHN

were comparable to those from previous published reports, which lends validity to the overall design of

the study [Beutner, 1995; Beutner et al., 1995]. Average pain scores demonstrated consistent

improvement over the 3 months of the study for the FV-100 400 mg group. The consistent advantages

of FV-100 over valacyclovir indicate that FV-100 supports a therapeutic role for this new agent in the

reduction of subacute and chronic HZ-associated pain.

We acknowledge that the assessment of pain is a relatively subjective measure. However, the ZBPI

[Drolet et al., 2010], developed from the standard Brief Pain Inventory [Cleeland and Ryan, 1994] for

use in the clinical trials for an anti-HZ vaccine, is a validated instrument for the measurement of HZ-

associated pain and the effect of that pain on functional activities of daily living [Coplan et al., 2004].

This index measures the impact of HZ and PHN across all 4 domains of health: physical,

psychological, social, and functional [Johnson et al., 2010] and is a sensitive and reliable measure of

the impact of HZ and PHN on patients’ daily lives [Coplan et al., 2004]. In addition, the use of worst

pain score of ≥ 3 in the definition of PHN has been validated as part of the development of the ZBPI

[Coplan et al., 2004] and reflects consensus that this level of pain constitutes clinically meaningful

chronic pain.

Clinicians should not underestimate the fact that neuralgic pain can be quite severe [Gnann and

Whitley, 2002]. Some studies of postherpetic neuralgia suggest the early attenuation of acute pain may

prevent the onset of central mechanisms of chronic pain, thus potentially reducing the risk of

This article is protected by copyright. All rights reserved 15

postherpetic neuralgia [Dworkin et al., 2000; Gnann and Whitley, 2002]. Thus antiviral therapies such

as FV-100 may act to inhibit these mechanisms of pain transmission.

Several design characteristics likely affected the study’s ability to identify statistically significant

differences between the two antiviral agents, including the use of BOI as a primary efficacy measure, a

pain score of >0 at study entry, and the possibility that 14 days may not have been a sufficient length of

time for differences in pain to be assessed. However, this Phase 2 study demonstrated proof of concept

for FV-100 in terms of efficacy and safety in the treatment of HZ and provided valuable data, which

guided the subsequent design of a larger potentially pivotal Phase 3 trial.

In spite of the availability of antiviral drugs approved for the treatment of HZ, and the availability of

the HZ vaccine, up to 40% of all patients with HZ will go on to develop PHN [Bowsher, 1999; Chen et

al., 2014; Jung et al., 2004; Kawai et al., 2015; Oxman et al., 2005; Oxman et al., 2008]. Pain

associated with PHN is often refractory to treatment, and symptomatic relief is obtained in fewer than

half of PHN sufferers despite the frequent use of multiple drugs for pain control [Christo et al., 2007;

Johnson and McElhaney, 2009; Oster et al., 2005; Serpell et al., 2014]. While the majority of patients

experience complete resolution of their pain by one year, long-term studies indicate that PHN may

persist indefinitely [Helgason et al., 2000; McKendrick et al., 2009; Oster et al., 2005].33, 35, 36 Taken as

a whole, these findings support the conclusion that PHN represents a significant unmet medical need.

Based on the analyses in this Phase 2 study, a multicenter, randomized, double-blind, parallel-group

Phase 3 study has been designed, which is powered to assess the safety and efficacy of 400 mg FV-100

dosed either once or twice daily. The study measures the effect on HZ-associated subacute and chronic

pain, compared with TID valacyclovir 1000 mg (3000 mg daily dose). This Phase 3 study is designed

to confirm that FV-100 will address the need for a more effective medication to prevent and treat HZ.

This article is protected by copyright. All rights reserved 16

In conclusion, the comprehensive results of the burden of illness, PHN, time to clinically significant

pain resolution, and pain score analyses demonstrate a potential role for FV-100 in the reduction of

subacute and chronic pain as well as the prevention of PHN. The safety profile of FV-100 remains

favorable both in isolation and when compared to valacyclovir. Current antiviral medications have

limited effectiveness in the reduction of subacute and chronic pain, do not satisfactorily prevent or

adequately treat PHN, and require dosing modifications in patients with renal insufficiencies. The

efficacy results from this study support further investigation of FV-100 to address these unmet medical

needs.

Funding: Research support was provided by Inhibitex, Inc. Medical Writing was funded by ContraVir

Pharmaceuticals

Competing interests: JSB and TM are employees of ContraVir Pharmaceuticals. JSB is a stockholder in

ContraVir Pharmaceuticals. No other competing interests.

Ethical approval: Integ Review

This article is protected by copyright. All rights reserved 17

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Figure Legends

Figure 1. Study Flow Chart. The chart shows the relationships between all analysis populations. All
patients were included in both the Safety and ITT Populations. The differences in Ns of the treatment
groups between the Safety and ITT populations are because of errors in dispensing for 2 patients that
received a treatment different from their randomized assignment. The ITT Population consisted of all
randomized patients who received at least 1 dose of study drug. The MITT1 Population consisted of all
randomized patients who receive at least 1 dose of study drug except for patients whose lesion swabs
were positive by PCR for HSV and negative by PCR for VZV or who had a calculated creatinine
clearance < 50 mL/min/1.73m2. The MITT2 Population consisted of all randomized patients who
received at least 1 dose of study drug except for patients whose lesions swabs were positive by PCR for
HSV and negative by PCR for VZV. The Per-Protocol Population consisted of all patients from the ITT
Population who had a lesion swab positive for VZV, were followed for at least 30 days, received at
least 6 of 7 days of study drug, and had no major protocol violations. HSV = herpes simplex virus; ITT
= intent-to-treat; MITT = modified intent-to-treat; PCR = polymerase chain reaction; QD = once daily;
TID = three times daily; VZV = Varicella zoster virus

This article is protected by copyright. All rights reserved 21

Table 1. Demographic Characteristics by Treatment Group

FV-100 FV-100 Valacyclovir

200 mg QD 400 mg QD 1000 mg TID Total
Characteristic N = 117 N = 116 N = 117 N = 350

Sex

Male, n (%) 40 (34.2 42 (36.2) 38 (32.5) 120 (34.3)

Female, n (%) 77 (65.8) 74 (63.8) 79 (67.5) 230 (65.7)

Age (years)

Mean 63.95 64.66 64.27 64.29

Minimum – maximum 50.0 – 94.3 50.4 – 87.9 50.4 – 90.6 50.0 – 94.3

Race and Ethnicitya

Caucasian non- 88 (75.2) 97 (83.6) 97 (82.9) 282 (80.6)

Hispanic/Latino, n (%)

Caucasian 14 (12.0) 6 (5.2) 11 (9.4) 31 (8.9)

Hispanic/Latin, n (%)

Black/African 13 (11.1) 9 (7.8) 9 (7.7) 31 (8.9)

Descent, n (%)

Asian, n (%) 2 (1.7) 1 (0.9) 0 3 (0.9)

Native North 0 1 (0.9) 0 1 (0.3)

American/Alaskan, n
(%)
Native 0 1 (0.9) 0 1 (0.3)
Hawaiian/Pacific
Islander, n (%)
Mixed Race 0 1 (0.9) 0 1 (0.3)
Hispanic/Latino, n (%)

Body Mass Index (kg/m2)

Mean 29.39 29.99 28.86 29.41

Minimum - maximum 17.1 – 54.9 17.9 – 52.1 19.8 – 47.8 17.1 – 54.9
a
Race and ethnicity (whether or not Hispanic/Latino) were collected as separate variables. All subjects for whom
Hispanic/Latino ethnicity was recorded were of Caucasian race except one subject who was of mixed race.

This article is protected by copyright. All rights reserved 22

Table 2. Burden of Illness Area under the Curve by Treatment Group

Endpoint FV-100 FV-100 Valacyclovir

Measure 200 mg QD 400 mg QD 1000 mg TID
Statistic n = 107 n = 113 n = 109

Primary Efficacy Endpoint

BOI-30AUC
LS Mean (SE) 114.485 (6.2396) 110.309 (6.0823) 117.956 (6.2529)

LS Mean -3.471 -7.647

Difference from
Valacyclovir
1000 mg TID

95% CI -22.1017, 15.1595 -26.0468, 10.7527

P value 0.883 0.553

Secondary Efficacy Endpoint

BOI-14AUC
LS Mean (SE) 65.354 (2.4385) 63.078 (2.3770) 63.781 (2.4437)

LS Mean 1.573 -0.703

Difference from
Valacyclovir
1000 mg TID
95% CI -5.7076, 8.8543 -7.8935, 6.4881

P value 0.846 0.966

Secondary Efficacy
Endpoint
BOI-90AUCa
LS Mean (SE) 221.526 (19.5052) 196.942 (19.0133) 229.587 (19.5467)

LS Mean -8.061 -32.645

Difference from
Valacyclovir
1000 mg TID

95% CI -66.3008, 50.1789 -90.1631, 24.8732

P value 0.933 0.346

a
Patients reporting no pain after Study Day 30 on 2 consecutive visits were relieved of subsequent visits (Study
Days 56 and/or 90) and presumed to have a "worst pain in the last 24 hours" score of 0 on those days. CI =
confidence interval; LS Mean = least squares mean; SD = standard deviation; SE = standard error.

This article is protected by copyright. All rights reserved 23

Table 3. Postherpetic Neuralgia (PHN) Incidence and Severity at 90 Days
Endpoint FV-100 FV-100 Valacyclovir
Measure 200 mg QD 400 mg QD 1000 mg TID
Statistic N = 107 N = 113 N = 109
PHN Incidence

n (%) 19 (17.8) 14 (12.4) 22 (20.2)

Odds Ratio vs. 0.9 0.6

Valacyclovir
1000 mg TID

95% CI 0.4, 1.8 0.3, 1.2

P value 0.703 0.158

PHN Severity
Number of Patients 19 14 22
with PHN
LSMean (SE) 5.4 (0.47) 5.3 (0.52) 5.7 (0.46)

LSMean Ratio vs. 0.9 0.9

Valacyclovir
1000 mg TID

95% CI 0.8, 1.2 0.7, 1.2

P value 0.547 0.491

Modified intent-to-treat population. Missing values were imputed using the last observation carried forward
approach. CI = confidence interval; LSMean = least squares mean; SD = standard deviation; SE = standard error.

This article is protected by copyright. All rights reserved 24

Table 4. Duration and Resolution of Clinically Significant Pain

FV-100 FV-100 Valacyclovir

Measure 200 mg QD 400 mg QD 1000 mg TID
Statistic N = 107 N = 113 N = 109
Duration of CSP (Days)

n (%) 102 (95.3) 105 (92.9) 104 (95.4)

Mean (SD) 31.3 (32.29) 27.3 (28.24) 32.3 (32.92)

Median 14.0 15.0 20.5

Range (minimum, 1, 114 1, 93 1, 96

maximum)

Duration until First

Resolution of CSP (Days)
n (%) 102 (95.3) 105 (92.9) 104 (95.4)

Mean (SD) 26.7 (30.95) 25.1 (28.69) 28.8 (32.43)

Median 12.0 14.0 13.5

Range (minimum, 1, 114 1, 93 1, 96

maximum)
Permanent Resolution of
CSP

Yes - n (%) 83 (77.6) 91 (80.5) 82 (75.2)

Study Day on Which

Permanent Resolution
of CSP was Achieved
Mean (SD) 26.0 (24.02) 26.5 (23.06) 24.4 (21.08)

Median 15.0 21.0 17.0

Range (minimum, 3, 96 3, 97 2, 92
maximum)

No – n (%) 19 (17.8) 14 (12.4) 22 (20.2)

CSP not Experienced – 5 (4.7) 8 (7.1) 5 (4.6)
n (%)

This article is protected by copyright. All rights reserved 25

Table 5. Burden of Illness Area under the Curve by Treatment Group
– Study Days 14 to 90 and 30 to 90

FV-100 FV-100 Valacyclovir

Measure 200 mg QD 400 mg QD 1000 mg TID
Statistic N = 107 N = 113 N = 109

BOI-14-90AUC
LS Mean (SE) 155.0, (18.0) 132.091 (17.6) 164.739 (18.1)

LS Mean Difference -9.7 -32.6

from Valacyclovir
1000 mg TID

95% CI -63.5, 44.1 -85.8, 20.5

P value 0.890 0.292

BOI-30-90AUC

LS Mean (SE) 106.5 (14.5) 85.838 (14.2) 107.794 (14.5)

LS Mean Difference -1.3 -22.0

from Valacyclovir
1000 mg TID

95% CI -44.7, 42.0 -64.8, 20.9

P value 0.997 0.415

This article is protected by copyright. All rights reserved 26

Table 6. Overall Summary of Adverse Events by Treatment Group

FV-100 FV-100 Valacyclovir

200 mg QD 400 mg QD 1000 mg TID Total

N = 117 N = 116 N = 117 N = 350

n (%) n (%) n (%) n (%)

Number of AEs 117 154 108 379

Number (%) of 55 (47.0) 63 (54.3) 49 (41.9) 167 (47.7)
patients with any
AE

Severity
Grade 1 (Mild) 32 (27.4) 27 (23.3) 22 (18.8) 81 (23.1)

Grade 2 19 (16.2) 28 (24.1) 23 (19.7) 70 (20.0)

(Moderate)

Grade 3 4 (3.4) 8 (6.9) 3 (2.6) 15 (4.3)

(Severe)

Grade 4 0 0 1 (0.9) 1 (0.3)

(Potentially
life-
threatening)
Leading to study 2 (1.7) 2 (1.7) 2 (1.7) 6 (1.7)
drug discontinuation

Number of SAEs 0 6 5 11

Number (%) of 0 5 (4.3) 4 (3.4) 9 (2.6)

patients with any
SAE

Any SAE within 0 3 (2.6) 2 (1.7) 5 (1.4)

first 10 days of the
study

Drug-related 0 0 2 (1.7) 2 (0.6)

Leading to study 0 1 (0.9) 1 (0.9) 2 (0.6)

drug discontinuation

n = Number of subjects reporting at least one adverse event; (%) = Percentage of subjects among treatment
group (N)

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 Figure 1

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