TECHNOLOGY & PIPELINE

SoloVir™ ETS Acyclovir

The ideal treatment for herpes labialis will rapidly deliver an antiviral medication directly to the dermal layer of the skin in sufficient amounts to block viral replication before significant tissue damage has occurred. This would also prevent the virus from spreading and would reduce much of the pain and social embarrassment associated with infection. Clinical research demonstrates that the efficacy of antiviral drugs is linearly related to the concentration of the drug in the dermal layer of the skin where the herpes virus replicates during an episodic recurrence. SoloVir™ ETS, Transport’s lead product, delivers high concentrations of acyclovir directly to the epidermal/dermal junction, the precise site of HSV replication in a single 10-minute treatment. This approach addresses the challenge of rapidly achieving concentrations of drug in the skin necessary to inhibit viral replication and achieve improved clinical outcomes. In addition, Transport’s product requires only one 10-minute application, compared with multiple doses of oral drugs or multiple daily applications of topical anti-viral formulations for several days.

Product Highlights

• Delivers orders of magnitude more acyclovir directly to impacted skin area than currently available oral or topical anti-viral treatment options.
• Requires one painless, 10-minute treatment application.

Proprietary Acyclovir Formulation

Creams and ointments for topical drug delivery are typically oil-in-water emulsions, formulated to contain large amounts of drug to create a depot on the surface of the skin. These creams and ointments are intended for repeated application over a period of time and are formulated at a neutral pH to prevent skin irritation during prolonged exposure. Many drugs, like acyclovir, are relatively insoluble at pH 7. Transport has developed a proprietary acyclovir gel formulation that has been optimized for iontophoretic delivery and takes advantage of the increased solubility of acyclovir at high pH. In vitro and in vivo drug delivery models demonstrate that iontophoretic application of Transport’s 5 percent acyclovir gel formulation delivers orders of magnitude more acyclovir compared to passively applied topical 5 percent acyclovir cream. In Transport’s gel formulation, all of the acyclovir is fully solubilized and ionized, and thus immediately available for iontophoretic delivery. Acyclovir at high pH carries a negative charge and the drug is actively delivered via electrorepulsion at the cathode electrode contained in the drug cartridge.

SoloVir™ electrokinetic transdermal system (ETS)

The goal of Transport’s SoloVir™ Electrokinetic Transdermal System (ETS) is to rapidly and painlessly move the drug from the surface of the skin, as with creams and patches, into the epidermis, creating an intradermal drug depot. Transport’s ETS saturates the stratum corneum and epidermis with drug in a single, short treatment, delivering large amounts of drug to the dermal-epidermal interface, the site of activity for most dermal conditions. As a result, high levels of drug are immediately available without significant systemic exposure, and the intradermal depot provides continuing drug exposure hours after the initial treatment, decreasing or eliminating the need for subsequent treatments. The graphics below illustrate the difference between traditional topical dermal drug treatments and Transport’s intradermal drug depot effect.

Traditional dermal drug depot on skin surface. Drug slowly penetrates skin through passive diffusion. Arrow vectors represent movement of drug.

SoloVir™ ETS Clinical Path

Phase 2 Program
October 2007: Transport completed a Phase 2 study, TPI-H-221, to examine the safety and efficacy of SoloVir™ ETS in subjects with recurrent herpes labialis. The study was designed to determine the optimum treatment protocol based upon the immediate delivery of a large bolus of acyclovir into the skin during a herpetic episode, i.e. whether treatment at the prodrome, erythema, or papule/edema stage, on day one of the herpetic episode, was significantly better than placebo. TPI-H-221 was a multi center, randomized, double blind, patient-initiated, placebo-controlled study and enrolled approximately 260 subjects. Patients were randomized in a 1:1:1 ratio into one of three treatment groups: treatment with active gel followed by treatment with placebo gel; treatment with placebo gel followed by treatment with active gel; or treatment with placebo gel followed by treatment with placebo gel.

Primary efficacy in this study was measured by duration of the herpetic episode.  Prevention of progression to classical lesion, time to complete healing, and duration of pain were key secondary endpoints.  Patients were randomized into one of three iontophoretic treatment groups: two active arms and one placebo arm.  Treatment phase ended after at least 80 patients in each treatment group had experienced a herpetic episode and received either drug or placebo treatment.  SoloVir™ ETS, an iontophoretic device with pre-loaded drug cartridges containing a proprietary five-percent acyclovir gel formulation, was employed in this study.  The small size and portability of SoloVir™ ETS allowed patients to treat themselves immediately at the first signs and symptoms of a herpetic lesion with a single, ten-minute iontophoretic application of either active acyclovir gel or placebo gel.  A second, investigator-supervised treatment followed 6 – 18 hours later in the clinic.

Data from this Phase 2 clinical study indicate that treatment at the erythema or papule/edema stages resulted in a statistically significant and clinically meaningful effect on the herpetic episode. Subjects treated at the prodrome stage did not see a statistically significant benefit.  In particular, the study demonstrated a 79 percent increase in aborted lesions (43% active; 24% placebo; p= 0.03; active n= 61; placebo n= 72) in SoloVir™ ETS treated subjects versus placebo.  These subjects also experienced a 3.5 day reduction in time to complete healing (p= 0.015).  Furthermore, this study demonstrated a statistically significant and clinically meaningful reduction in duration and severity of pain.  SoloVir™ ETS was shown to be well tolerated with a compliance rate greater than 98 percent and with no serious adverse events reported related to study drug in all groups.

The results from this study confirmed the positive results from Transport’s previous Phase 2 study with its prototype electrokinetic system and an approved topical acyclovir cream formulation.  That earlier study was a 200-patient, double blind, placebo-controlled trial that demonstrated, in subjects who treated at either the erythema or papule/edema stage, a one and a half day (35 hour) reduction in the intent-to-treat population median time to healing in the active treatment group, as compared to the placebo group (113 hours versus 148 hours; p=0.02); (Clinical Infectious Disease v. 43, p.460, published August 15, 2006).

Phase 1 Studies
SoloVir™ ETS/Acyclovir Gel
February 2007: Transport announced preliminary results from a Phase 1 safety and pharmacokinetic study with its SoloVir™ ETS. The TPI-H-111 study, which was conducted in 32 normal volunteers, was the first clinical application of the new SoloVir™ ETS combination product featuring single-use drug cartridges containing Transport’s novel, 5 percent acyclovir gel formulation. The four treatments administered over two days were well tolerated by all subjects, with no significant skin irritation and few, mild adverse events. In addition, the portable, ergonomically designed SoloVir™ ETS was easily used by all subjects and performed as specified during 128 uses. The pharmacokinetic analysis indicated that SoloVir™ ETS achieved skin concentrations of acyclovir in excess of 200 ug/ml; more than 100 times greater than can be achieved with a 1 gram dose of currently marketed Valtrex®. This study validated SoloVir™ ETS and demonstrated that the proprietary technology could deliver a large bolus of drug directly to the target tissue in a simple, painless, convenient and patient-friendly manner.

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