A Phase 2, Muti-Center Study of Repeat Dosing of Squaric Acid Dibutyl Ester in Subjects With Herpes Labialis

Primary oral infection with the herpes simplex virus (HSV) typically occurs at a young age,
is asymptomatic, and is not associated with significant morbidity. After primary oral
infection, HSV may persist in a latent state in the trigeminal ganglion and later reactivate
as the more common herpes labialis, or "cold sores." Common triggers for reactivation are
well known and include ultraviolet light, trauma, fatigue, stress, fever, inflammation, and
menstruation. These lesions affect up to 45 percent of the U.S. population. They classically
manifest as a well-localized cluster of small vesicles along the vermilion border of the lip
or adjacent skin. The vesicles subsequently rupture, ulcerate, and crust within 24 to 48
hours. Spontaneous healing occurs over seven to 10 days.

In immunocompetent patients, herpes labialis usually is mild and self-limited. However, pain,
swelling, and cosmetic concerns may prompt physician consultation. Orally administered
antiviral agents, such as acyclovir (Zovirax) or valacyclovir (Valtrex), have a modest
clinical benefit if initiated during the prodrome. Topical treatment with 1% penciclovir
cream (Denavir) may reduce healing time and pain slightly, even if initiated after the
prodrome. However, reduction in healing time with systemic or topical agents is modest.

Squaric acid dibutyl ester (SADBE) is a topical immunotherapeutic agent used in the treatment
of verruca vulgaris and alopecia areata. During a recent FDA Compounding Advisory Committee
Meeting, it was recommended that squaric acid dibutylester be included on the list of bulk
drug substances allowed for use in compounding under section 503A of the Federal Food, Drug,
and Cosmetic Act. And SADBE has now been so listed under section 503A.

A study completed by Lee et al of 29 patients with recalcitrant warts demonstrated complete
clearance in 69% of patients with application every 2-4 weeks. Silverberg et al showed a
complete clearance in 58% of patients (n=61) when SADBE was applied 3 times weekly. A
placebo-controlled clinical study completed at Massachusetts General Hospital showed that
squaric acid prevented recurrence of herpetic lesions. The effect of SADBE of delaying new
herpes labialis outbreaks was highly significant (p<0.01) as compared to placebo.

Primary Objective: To assess local and generalized adverse events with repeat topical
application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent
herpes labialis (4 or more episodes in the previous 12 months).

Secondary Objective: To assess efficacy of repeat topical application of 2% and 0.5% SADBE in
the prevention of herpes labialis episodes.

Inclusion Criteria:

1. Age ≥ 18 and ≤ 65

2. Clinical diagnosis of herpes labialis, which may be made at the screening visit based
on the patient's self-reported history of symptoms. An active herpes labialis outbreak
at the time of entry into the clinical trial will neither be required nor will be an
exclusion criterion.

3. Self report having four (4) or more episodes of herpes labialis in the past 12 months.

Subjects will NOT be told that four-or-more episodes in the previous 12 months is the
entry criterion. Subjects will be asked "How many separate episodes of cold sores have
you had in the previous 12 months?" They will be included if they give an answer of
four or more and excluded if they give an answer of three or fewer.

4. At least half of the subject's episodes of the previous 12 months should be vesicular
in nature and at least half preceded by prodromal symptoms. Prodromal symptoms may
include tingling, itching, burning or pain before the development of a herpetic
lesion.

Exclusion Criteria:

1. Pregnant or lactating females.

2. Current or recurrent non-herpetic infection or any underlying condition that may
predispose to infection or anyone who has been admitted to the hospital due to
bacteremia, pneumonia or any other serious infection in the last 12 months.

3. Therapy with glucocorticoid or immunosuppressants at time of recruitment or within
past 4 weeks prior to the screening visit, or at any time during the study (including
inhaled corticosteroids for asthma), except for topical steroids in sites other than
face.

4. History of malignancy (except patients with surgically cured basal cell or squamous
cell skin cancers).

5. History of organ transplantation.

6. HIV-positive status determined by history at screening or known history of any other
immunosuppressive disease.

7. Severe co-morbidities (CHF [NYHA class II or worse], MI, CVA or TIA) within 3 months
of screening visit, current unstable angina pectoris or oxygen-dependent severe
pulmonary disease.

8. Known hypersensitivity to Dimethyl sulfoxide (DMSO).

9. Any condition judged by the investigator to cause this clinical trial to be
detrimental to the patient.

10. Subject is currently enrolled in another investigational device or drug trial(s), or
subject has received other investigational agent(s) within 28 days of the screening
visit.

11. Previous exposure to SADBE (squaric acid or squaric acid dibutyl ester).

12. Subject has an abnormal skin condition (e.g., acne, eczema, rosacea, psoriasis,
albinism, or chronic vesiculo-bullous disorder) that occurs in the area ordinarily
affected by herpes labialis

13. Subject has an abnormal skin condition (e.g., eczema, rosacea, psoriasis, albinism, or
chronic vesiculo-bullous disorder) that occurs in the inner aspect of either upper arm
(the area where drug will be applied).

14. Subject has had a vaccine for either HSV-1 or HSV-2.

15. Subject has had treatment with anti-viral therapy (including ABREVA) within 2 weeks
before first dose of SADBE or at any time during the study.