WO2006076169A2

WO2006076169A2 - Treatment or prevention of genital viral infections with immunomodulator compounds

Info

Publication number: WO2006076169A2
Application number: PCT/US2005/047311
Authority: WO
Inventors: Cynthia W. Tuthill; Alfred R. Rudolph
Original assignee: Sciclone Pharmaceuticals, Inc.
Priority date: 2004-12-28
Filing date: 2005-12-27
Publication date: 2006-07-20
Also published as: WO2006076169A3

Abstract

An immunomodulatory compound is administered to a subject having, or at risk of a genital viral infection, e.g., papilloma virus infection or herpes virus infection.

Description

TREATMENT OR PREVENTION OF GENITAL VIRAL INFECTIONS WITH IMMUNOMODULATOR COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATION This application claims benefit from U.S. Provisional Application Serial No. 60/639,404, filed December 24, 2004 and from U.S. Provisional Application Serial No. 60/703,472, filed July 29, 2005.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to the field of treatment or prevention of respiratory viral infections.

Description of the Background Art

Human papilloma virus (HPV) infections of the urogenital tract represent the most often sexually transmitted viral disease in humans. HPV is a double stranded DNA virus and with the recent developed molecular biological techniques, more than 55 different HPV types have been recognized. HPV is associated with a wide spectrum of clinical states including condylomata acuminata, latent and subclinical infection, and Bowen's disease. Subclinical infections may cause intraepithelial neoplasia, based on the frequent detection of HPV DNA in invasive carcinomas, especially in urogenital region. A significant risk for the development of an invasive cancer is ascribed to the infections by HPV types 16, 18 and 33.

Herpes simplex virus (HSV) commonly referred to as "herpes virus" or "herpes," is an infectious disease which has reached crisis proportions nationally with estimated numbers of infected people at 70%-80% of our population as reported by the American Social Health Association (ASHA) and growing annually by 500,000 people or more. There are two common types of herpes: herpes simplex virus 1 (HSV 1) and herpes simplex virus 2 (HSV 2).

Herpes enters the human body through minuscule breaks in the epidermal tissue usually by contact with an infected host and is marked by eruption of one or more vesicles, usually in groups, following an incubation period of approximately four to ten days. Typically the course of the infectious outbreak initiates with the prodromal stage; advancing to vesicular eruption; followed by: ulceration; coalescing; resolution; and the latency period. The outbreak can last for several weeks and on average lasts two-three weeks. In some immune compromised individuals the outbreak can last for months. Herpes simplex virus (HSV) infection is recrudescent, residing in the nerve ganglia, then recurring due to some, as yet unknown, stimulus or stimuli. Recurrent herpetic infections can be precipitated by many things, including: overexposure to sunlight; nutritional deficiencies; stress, menstruation; immunosuppression; certain foods; drugs; febrile illness; etc.

HSV 1 and HSV 2 infections pose very serious health threats often causing: blindness; increased cancer risk of the cervix; aseptic meningitis and encephalitis; neonatal deaths; viremia; etc. HSV is responsible for serious psychological and emotional distress as well as substantial economic loss to the nation and the world.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method of treatment or prevention of a genital viral infection in a subject comprises administering to said subject an effective amount of an immunomodulator compound of formula A:

In Formula A, n is 1 or 2, R is hydrogen, acyl, alkyl or a peptide fragment, and X is an aromatic or heterocyclic amino acid or a derivative thereof. Preferably, X is L-tryptophan or D-tryptophan.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with one embodiment, the present invention relates to treatment or prevention of genital viral infections by administering an immunomodulator compound to a mammalian subject, preferably a human patient.

In accordance with a further embodiment, the invention relates to treatment or prevention of papilloma virus infection, particularly HPV infection, in a patient by administering an immunomodulator compound.

In accordance with another embodiment, the invention relates to treatment of herpes virus infection, including HSV 1 and/or HSV 2 infection, in a patient by administering an immunomodulator compound. Administration for prevention can be to persons at high risk because of contact with suspected disease carriers, or in carriers who are asymptomatic. lmmunomodulator compounds in accordance with the present invention, comprise immunomodulators of Formula A:

(A)

Appropriate derivatives of the aromatic or heterocyclic amino acids for "X" are: amides, mono-or alklyl substituted amides, arylamides, and (C₁-C₆) alkyl or aryl esters. Appropriate acyl or alkyl moieties for "R" are: branched or unbranched alkyl groups of 1 to about 6 carbons, acyl groups from 2 to about 10 carbon atoms, and blocking groups such as carbobenzyloxy and t-butyloxycarbonyl. Preferably the carbon of the CH group shown in Formula A has a stereoconfiguration, when n is 2, that is different from the stereoconfiguration of X.

Preferred embodiments utilize compounds such as γ-D-glutamyl-L-tryptophan, γ-L-glutamyl-L-tryptophan, γ-L-glutamyl-N_ιn-formyl-L-tryptophan, N-methyl-γ- L-glutamyl-L-tryptophan, N-acetyl-γ-L-glutamyl-L-tryptophan, γ-L-glutamyl-D-tryptophan, β-L-aspartyl-L-tryptophan, and β-D-aspartyl-L-tryptophan. Particularly preferred embodiments utilize γ-D-glutamyl-L-tryptophan, sometimes referred to as SCV-07. These compounds, methods for preparing these compounds, pharmaceutically acceptable salts of these compounds and pharmaceutical formulations thereof are disclosed in U.S. Patent No. 5,916,878, incorporated herein by reference.

SCV-07, Y-D-glutamyl-L-tryptophan, is a member of a class of immunomodulatory drugs that possess γ-glutamyl or β-aspartyl moieties, which was discovered by Russian scientists and is being examined for efficacy in several indications in the U.S. by SciClone Pharmaceuticals, Inc. SCV-07 possesses a number of immunomodulatory activities in vivo and in vitro. SCV-07 increases Con-A-induced thymocyte and lymphocyte proliferation, increases Con-A-induced interleukin-2 (IL-2) production and IL-2 receptor expression by spleen lymphocytes, and stimulates expression of Thy-1.2 on bone marrow cells. In vivo, SCV-07 has a strong immunostimulatory effect on 5-FU-immune-suppressed animals and in a model of immunization with sheep red blood cells.

The Formula A compounds may be administered as dosages in the range of about 0.001-10 mg. Dosages may be administered one or more times per week, preferably on a daily basis, with dosages administered one or more times per day. Administration can be by any suitable method, including orally, nasally, transdermal^, sublingually, by injection, periodic infusion, continuous infusion, and the like. The dosages may be administered by intramuscular injection, although other forms of injection and infusion may be utilized, and other forms of administration such as oral or nasal inhalation or oral ingestion may be employed.

In preferred embodiments, the compounds of Formula A are administered at a dosage within a range of about 0.01-10 mg, more preferably 0.1-1 mg, most preferably at a dosage of about 0.1 mg. Dosages may also be measured in micrograms per kilogram, with dosages in the range of about 0.001-1 ,000 micrograms per kilogram, more preferably within the range of about 0.01-50 micrograms per kilogram, and most preferably about 2-20 micrograms per kilogram, still more preferably about 10 micrograms per kilogram.

Included are biologically active analogs having substituted, deleted, elongated, replaced, or otherwise modified portions which possess bioactivity substantially similar to that of SCV-07, e.g., an SCV-07 derived peptide having sufficient homology with SVC- 07 such that it functions in substantially the same way with substantially the same activity as SCV-07.

According to one embodiment, a Formula A compound may be administered to a patient in need of immune stimulation so as to substantially continuously maintain an immune stimulating-effective amount of the Formula A compound in the patient's circulatory system during a treatment or prevention period. Although much longer treatment periods are contemplated in accordance with the present invention, embodiments of the invention include substantially continuously maintaining an immune stimulating-effective amount of the Formula A compound in the patient's circulatory system during treatment periods of at least about 6, 10, 12 hours, or longer. In other embodiments, treatment periods are for at least about a day, and even for a plurality of days, e.g., a week or longer. However, it is contemplated that treatments, as defined above, in which immune stimulating-effective amounts of the Formula A compound are substantially continuously maintained in the patient's circulatory system, may be separated by non-treatment periods of similar or different durations. In accordance with one embodiment, the Formula A compound is continuously infused into a patient, e.g., by intravenous infusion, during the treatment period, so as to substantially continuously maintain an immune stimulating-effective amount of the Formula A compound in the patient's circulatory system. The infusion may be carried out by any suitable means, such as by minipump.

Alternatively, an injection regimen of the Formula A compound can be maintained so as to substantially continuously maintain an immune stimulating-effective amount of the Formula A compound in the patient's circulatory system. Suitable injection regimens may include an injection every 1 , 2, 4, 6, etc. hours, so as to substantially continuously maintain the immune stimulating-effective amount of the lmmunomodulator compound peptide in the patient's circulatory system during the treatment period.

Although it is contemplated that during continuous infusion of the Formula A compound, administration will be for a substantially longer duration, according to one embodiment the continuous infusion of the Formula A compound is for a treatment period of at least about 1 hour. More preferably, continuous infusion is carried out for longer periods, such as for periods of at least about 6, 8, 10, 12 hours, or longer. In other embodiments, continuous infusion is for at least about one day, and even for a plurality of days such as for one week or more.

In some embodiments, the Formula A compound is present in a pharmaceutically acceptable liquid carrier, such as water for injection, saline in physiological concentrations, or similar.

Effective amounts of Formula A compound can be determined by routine dose- titration experiments.

The Formula A compound also can be administered with other immune stimulators or antiviral agents.

Example 1

Study Title: Effect of SCV-07 on Papilloma Virus Induced Skin

Papillomas in Rabbits

Purpose: To assess the Effect of SCV-07 on the Development of Papilloma Virus-induced Skin Papillomas in

Rabbits

Test Article: SCV-07

Test Article Storage: Stored at Room Temperature

Positive Control Article: Cidofovir

Vehicle: 0.9% Saline (NaCI) Experimental Design:

Animals: Adult New Zealand White Rabbits

Source: Covance, Inc.

Sex: Males and Females

Rabbits were quarantined and cleared (14 days). They were inoculated at four sites on the back with CRPV wild type virions at 10^'2 dilution. Papillomas on the left side were treated with control or test article. Contralateral lesions are integral controls:

Virus dose Treated Controls

10-² L1 R1

10-² L2 R2

Seven groups of 4 rabbits (2M, 2F) were treated with control or test article at a dose volume of 0.1 ml as described below:

Group Left side Right side - No Rx

1 Vehicle (control) Untreated

2 Compound SCV-07 (570 μg/kg subcutaneous) Untreated

3 Compound SCV-07 (170 μg/kg subcutaneous) Untreated

4 Compound SCV-07 (50 μg/kg subcutaneous) Untreated

5 Compound SCV-07 (20 μg/kg subcutaneous) Untreated

6 Compound SCV-07 (2 μg/kg subcutaneous) Untreated

7 +ve control (cidofovir 0.5% topical) Untreated

Rabbits were treated once per day, five days/week (MTWThF)₁ at approximately the same time each day. SCV-07 in saline was given as a subcutaneous treatment of 0.1 mL under each of the left papillomas; cidofovir was given as a topical application of 0.1 mL. Treatments began 7 days following CPRV inoculation, and continued for 6 weeks. Doses of SCV-07 were 2, 20, 50, 170 and 570 μg/kg (based on dosing solutions of 0.03, 0.3, 1 , 3, and 10 mg/mL; 0.1 mL was provided in each of two sites, and the animals were approximately 3.5 kg). Papillomas were measured weekly for 6 weeks, after which time, animals were sacrificed using appropriate methods. Papillomas were measured (length, width, height) in mm weekly. A geometric mean diameter (GMD) was calculated for each papilloma and plotted against time (Days) after infection of sites with CRPV. For each dose group, there were 4 rabbis, giving a total of 8 treated papillomas (and 8 untreated contralateral papillomas). Data were entered into a desk-top computer and calculations conducted of the geometric mean diameter of each papilloma, mean + SEM for each group, Student's T- test between each paired groups and plots made of papilloma size vs time.

Papilloma growth rates versus time show that topical treatment of the papillomas with the positive control cidofovir had a strong suppressive effect on papilloma size and growth rate, but as expected had no effect on contralateral lesions.

SCV-07 showed an inhibition of papilloma growth, with significant growth inhibition seen at doses of 2 and 20 μg/kg. Interestingly, the effects of SCV-07 appear to be occurring systemically after subcutaneous injection, as the effect on growth of papillomas on the contralateral (untreated) sites was similar to the effect on the treated papillomas.

Example 2

SCV-07 as an immunodulating anti-herpetic in the HSV-2 genital mouse model.

Project Goal:

To evaluate an immunomodulating dipeptide (gamma-D-glu-trp) designated SCV-07 for activity against HSV-2 infections in the mouse model of genital disease. The study evaluated the utility of this compound as a preventative and as a therapeutic.

Mouse Study: HSV-2 genital infection

Purpose:

To determine whether selected therapy courses (timing and dosages) of SCV-07 in PBS administered via subcutaneous (sc) injection prior to or just after viral inoculation protect mice against disease and lethal outcome following intravaginal HSV -2 challenge.

General Study Design:

From one hundred and twenty female outbred Swiss Webster mice (Harlan Laboratories), eight groups of 15 mice were generated randomly and then treated prior to viral inoculation as indicated below: Group N Treatment 1 15 (O.lmg/kg) SCV-07 -3d, -2d and-2h delivered SC

2 15 (l.Omg/kg) SCV-07 -3d, -2d and -2h delivered SC

3 15 (lO.Omg/kg) SCV-07 -3d, -2d and-2h delivered SC

4 15 (O.lmg/kg) SCV-07 +2h PI delivered SC

5 15 (l.Omg/kg) SCV-07 +2h PI delivered SC

6 15 (lO.Omg/kg) SCV-07 +2h PI delivered SC

7 15 PBS vehicle -3d, -2d and -2h delivered SC

8 15 No Treatment

After treatment, as indicated above, animals were inoculated intravaginally with a lethal dose of HSV-2 (strain 186; 104 pfu/animal). On days 2 and 3 after HSV-2 inoculation, vaginal swab samples were collected for viral titration and then selected swabs samples were tittered on VERO cell monolayers. Animals were assessed daily for symptomatic disease through d14 Pl and followed for survival for 21d Pl. The viral titration data were analyzed using unpaired tests assuming equal variances. Incidence/survival curves were generated and were analyzed by log rank testing (GraphPad Prism v4.0b).

Results:

Dose ranging and administration time of SCV-07 was evaluated to determine if this immunomodulating dipeptide impacted HSV-2 pathogenesis in the mouse vaginal model. The primary outcome measures included reduction in or delay of the incidence of disease signs and survival. Additionally, any animal that survived the lethal challenge was evaluated for vaginal viral replication to determine if SCV-07 produced resolution of the HSV-2 infection or if the animal was not infected. To accomplish this measure, vaginal viral swabs, collected on days 2 and 3 Pl, were titered for viral content on VERO cell monolayers. Replication on either day indicated an active infection while no evidence of virus was attributed to either SCV-07-induced resistance or inherent resistant to the viral challenge. In this study, animals that resisted the lethal challenge (had no vaginal viral replication) were observed in treatment groups and in the untreated group. The number of animals without viral replication was too small to achieve statistical significance (p>O.05, ANOVA) making it impossible to conclude that SCV-07 produced this outcome or a natural resistance was responsible.

A clear, dose-dependent trend was observed with regard to disease signs. There were statistical differences (log rank) in the development of disease (time to first disease sign) relative to PBS vehicle-treated controls. These differences were small relative to other anti-herpetics but became more pronounced as the SCV-07 dosage was increased from 0.1 mg/kg to 10mg/kg or was increased by multiple deliveries of the compound (e.g. 3 doses but not a single dose of 0.1 mg/kg significantly delayed disease signs. Due to a lower infection rate in the untreated mice the data are less compelling but the maximal tested dose of 10mg/kg delivered three times did result in a significant delay relative tot eh untreated controls.

Survival was not impacted by any of the dosing regimen of SCV-07. No statistically significant improvements in survival or delays in mortality were observed for the treated animals relative to the controls. These data may indicate that the delay in disease at the local site of infection did not represent a systemic impact despite the systemic delivery route. As an additional measure of impact we also examined titers in selected mice to determine if SCV-07 reduced vaginal viral replication. A subset of d2 and d3 swabs were titered on VERO cell monolayers and the results again supported the trend observed in the disease signs results. Titers generally were lowest in the 3 x 10mmg/kg animals and highest in the PBS-treated controls. Significant differences (p<0.05, ANOVA) were only found between the high dose group and the PBS-treated control titers, however.

Collectively, the data indicate a positive outcome and a potential for improved efficacy with alternate dosing, vehicles or administration sites. Conclusions: A clear trend for reduced disease development was observed in this study of subcutaneous delivery of SCV-07. This trend is statistically different from the control animals and had a dose dependent nature. SCV-07 is useful against HSV-2. SCV-07 may also be useful against for HSV-1 infections. HSV-1 infection of the mouse eye models the herpetic keratitis that is the most common cause of infectious blindness in the United States. Other HSV-1 infections are also well modeled by the mouse including oro-facial and dermal infections.

Example 3

SCV-07 as an immunomodulating anti-herpetic in the HSV-2 genital guinea pig model

Study Goal:

To evaluate SCV-07, for therapeutic activity against HSV-2 in the guinea pig model of recurrent genital disease. This study evaluated the utility of this compound as a therapeutic and its impact on frequency and magnitude of HSV-2 _^genital tract shedding to provide proof-of-concept data for the reduction of transmission of the virus by the compound. Purpose:

To determine whether selected therapy courses of SCV-07 administered via subcutaneous (sc) injection with PBS or via oral delivery with 2% sucrose 21 days post infection (d Pl) reduced the frequency of recurrent genital disease and/or decreased the frequency or magnitude of HSV-2 genital tract shedding.

Study Design:

96 female Outbred Hartley guinea pigs were divided into 7 experimental groups to study two routes and doses of SCV-07administration.

Group N Treatment

1 12 SCV-07 delivered orally lOug/kg, d21-26 Pl

2 12 SCV-07 delivered orally 100ug/kg, d21-26 Pl

3 12 Zovirax ointment (bid 7d) d21 pi

4 12 Vehicle delivered orally, d21-26 Pl

5 12 No Treatment

6 12 SCV-07 delivered SC 10ug/kg, d21-26 Pl

7 12 SCV-07 delivered SC 100ug/kg, d21-26 Pl

SCV-07 SC 10ug/kg, d21-26 Pl + Zovirax (bid

8 12 7d)

Animals were inoculated intravaginally with a sub-lethal dose of HSV-2 strain MS on dθ. Daily scoring was performed for primary disease from d3-14 and for recurrent disease from d 15-62. Daily scoring for d23-28 was not performed, and the start of treatments and swab collection was delayed until d35. The animals were allowed recovery time (d29-35) to reduce the effect of the sub-optimal conditions during the campus-wide emergency status and to re-establish a baseline recurrence frequency. Treatments were performed from d35-39 and swab collection was from d35-53. Mean cumulative lesion score curves were generated utilizing the daily recurrent scoring and analyzed for significance (GraphPad, Prism). Frequency and magnitude of HSV-2 shedding was determined by quantitative PCR.

Fasting Study:

After d62 scoring, 54 infected guinea pigs were selected randomly from non- Zovirax treated groups (Zovirax effects have longer duration than that observed for SCV- 07) and were placed into 3 groups (n=18) to determine the effects of fasting on the delivery of SCV-07 orally. Group N Treatment

SCV-07 delivered orally lOOug/kg, 63-67d Pl (12h

1 18 fast)

2 18 Vehicle delivered orally, 63-67d Pl (12h fast)

SCV-07 delivered orally 100ug/kg , 63-67d Pl (no

3 18 fast)

Daily scoring was performed for recurrent disease from d63-74 and mean cumulative lesion score curves were generated utilizing the daily recurrent scoring and analyzed for significance.

RESULTS AND DISCUSSION:

Two delivery routes and doses of SCV-07 were evaluated for therapeutic benefit against recurrent genital HSV2 disease and for any impact upon shedding of virus from the genital tract in the absence of lesions. Primary disease was scored for each animal from d3-14 to calculate the mean lesion scores for each group. Animals were distributed based upon scores to establish groups with statistically similar mean lesion scores. The primary data indicate that the two groups with the most severe disease states, that have been shown to correlate with recurrent disease, were SC lower dose (10ug/kg) and the Zovirax/SC combo treatment. The groups with the least amount of primary disease unfortunately were the no treatment group and the oral vehicle. Statistically, the lowest primary disease group was similar (p>0.05) to the highest disease group but this distribution clearly impacted later results when historical averages are considered.

Overall, the results indicated that SCV-07 showed no adverse reactions in the guinea pigs (fever, weight loss, irritability) and was generally well tolerated. It appeared that SCV-07 had an unpleasant taste and that initially resulted in difficulties for oral dosing. This issue was addressed by addition of 2% sucrose to the PBS vehicle. This

'formulation' was received well as was the associated vehicle. The animals that received subcutaneous injections showed substantial stress responses to the injection process. No indications of SCV-07 specific negative effects were indicated but rather the injection itself led to consistent vocalization and aversion behavior. These behaviors have been associated with increased recurrent disease frequency and severity similar to stress induced recurrences in humans.

As infected animals age, the frequency of recurrences and shedding events declines, reducing the total number of comparable values and the power of the study for statistical comparisons. The study did provide clear outcomes when the fasting study, discussed below, was completed. Recurrent disease was quantified by daily scoring of each animal and then calculation of the mean cumulative lesion score for each of the experimental groups. Values were compared to the controls (no treatment and oral vehicle groups) via a one-tailed unpaired t-test and no significant reduction (p<0.05) in the mean cumulative lesion score was observed.

A lack of SCV-07 durability could have prevented the identification of any efficacy and so an additional data window was evaluated via a one-tailed unpaired t-test. The oral vehicle group experienced the fewest recurrences of any of the groups followed. A dose response trend, that failed to achieve significance (p=0.54), was indicated with the 100ug/kg oral dose generally reducing recurrence frequency relative to the 10ug/kg group. The no treatment group confounded the outcomes. Overall the SC routes were not effective but again the higher dose showed a lower overall frequency, albeit not significantly different. Finally the SC SCV-07 and Zovirax combo was not significantly better than Zovirax alone, however, the stress associate with the injection clearly increased the frequency of recurrence and limited the strength of this finding.

Collectively, the data from the first round of treatments suggested that oral dosing may have shown some efficacy but the SC route was not effective.

Unfortunately, the study did not include a combination group with oral and topical Zovirax. This should be included in a future experiment. The results prompted us to further investigate oral delivery and it was suggested that SCV-07 uptake may be enhanced by fasting of the animal. Utilizing the animals that had been 'rested' and not treated with Zovirax, we established 3 groups of 18 animals with a more even recurrence frequency distribution. These animals were then subjected to a modified study plan to address the effect of fasting on SCV-07 efficacy.

For the second round of treatments, daily recurrent scoring was utilized again to determine the mean cumulative lesion scores for each experimental group and one- tailed unpaired t-tests were performed to determine if there was any significant difference. A week of scoring for each of the three groups was completed prior to treatment and proved to be statistically similar removing confounder concerns. Treatment began on day 63 Pl but was reset to dO for analysis purposes. The data include the 7 days following treatment to assess durability of the response. For dθ-d11 a significant difference was observed between the SCV-07 oral fasting group and the vehicle oral fasting group (p=0.0007). This pronounced difference also indicates the stress effect caused by the fasting illustrated in the slope of the curve of the vehicle treated controls from d 0-5. Once unlimited access to food was restored the frequency returned to a more normal level. Despite this fasting-induced stress, the SCV-07 treatment limited the frequency of recurrence in most of the 18 animals. Interestingly, non-fasted animals showed a positive outcome relative to the stressed vehicle controls. There were too few animals available to include a non-fasted vehicle alone group but no significant difference was observed when the two SCV-07 groups were compared. Again, statistically fewer recurrences were observed in the non-fasted SCV-07 group than in the fasted vehicle alone group. This comparison should not be considered valid however due to the fasting induced increase in recurrence. Vaginal swabs were collected from d35-53, the viral DNA was extracted, and real time quantative PCR was performed on the extracted samples. At present the data are incomplete due to an equipment problem but the available data are consistent with the recurrent data from the first treatment course and do not indicate a substantial impact of SCV-07. Preliminary values for the copies of viral DNA per milliliter that have not been fully quantified because of the equipment issue were determined for each vaginal swab, averaged by group and then were statistically compared. The current results indicate no significant difference was produced by SCV-07 in any of the groups, however these preliminary data require additional evaluations. The PCR data also was utilized to determine the frequency of viral shedding, and a significant difference (p<0.05) was observed for the Zovirax group compared to the no treatment group. These data are not effected by the equipment issue but require some additional analyses to be finalized. Additionally, comparison of the SC 100ug/kg + Zovirax group and the no treatment group showed a significant reduction in shedding frequency however no difference between the Zovirax alone group was observed. Collectively, the data indicate that with fasting with an oral SCV-07 delivery provides evidence of substantial therapeutic efficacy as measured by reduction of recurrent lesions in the HSV-2 guinea pig model.

Claims

1. A method of treatment or prevention of a genital viral infection in a subject comprising administering to said subject an effective amount of an immunomodulator compound of Formula A

(A)

wherein, n is 1 or 2, R is hydrogen, acyl, alkyl or a peptide fragment, and X is an aromatic or heterocyclic amino acid or a derivative thereof.

2. The method of claim 1 , wherein X is L-tryptophan or D-tryptophan.

3. The method of claim 1 wherein said compound is SCV-07.

4. The method of claim 1 wherein said genital viral infection is a papilloma virus infection.

5. The method of claim 4 wherein said genital viral infection is a human papilloma virus infection.

6. The method of claim 1 wherein said genital viral infection is a herpes virus infection.

7. The method of claim 6 wherein said infection is an HSV 1 virus infection.

8. The method of claim 6 wherein said infection is an HSV 2 virus infection.

9. The method of claim 1 wherein said compound is administered at a dosage within a range of about 0.1-10 mg.

10. The method of claim 1 wherein said compound is administered at a dosage within a range of about 0.1-1 mg.

11. The method of claim 1 wherein said compound is administered at a dosage within a range of about 0.01-100 micrograms per kilograms subject body weight.

12. The method of claim 1 wherein said compound is administered at a dosage within a range of about 0.1-10 micrograms per kilograms subject body weight.

13. The method of claim 12 wherein said compound is SCV-07.

14. The method of claim 4 wherein said compound is SCV-07.

15. The method of claim 5 wherein said compound is SCV-07.

16. The method of claim 6 wherein said compound is SCV-07.

17. The method of claim 7 wherein said compound is SCV-07.

18. The method of claim 8 wherein said compound is SCV-07.