Herpes zoster, also commonly known as shingles, is a neurological disorder caused by the reactivation of varicella zoster virus (VZV), the same virus that causes chickenpox. Based on recent research and publications, we estimate that there are over 4 million cases of shingles in the United States, Europe and Japan each year, of which more than half occur in the U.S.

The symptoms associated with shingles generally include localized lesions and pain. In many cases the patient may first notice localized prodomal pain; however, the first recognizable symptom of shingles is generally lesions that will continue to form for a week or two. These lesions generally follow the path of nerves that emanate from the spinal cord around the torso (thoracic); however, the infection is also commonly found on the face, neck, lower back and in certain cases, systemically. Within several weeks, the lesions in the infected areas will typically begin to heal, and these dermatological symptoms generally will resolve within a month or less. In rare instances, lesions may never appear, but pain will be present.

The pain associated with an episode of shingles is attributed to both the damage caused to the affected nerves by the replication of VZV and the inflammatory response associated with the infection. Pain symptoms are commonly described as a burning sensation, with bouts of stabbing and shooting pain, often set off by contact with the infected area. The majority of shingles patients experience such pain for several weeks in connection with their active infection, referred to as acute pain. For many patients, shingles-associated pain does not resolve when the lesions heal and the inflammation subsides, but, rather, continues for months, or possibly years. Persistent shingles-associated pain that lasts more than three to four weeks is referred to as sub-acute pain or neuralgia. Shingles-associated pain that persists more than three months is generally referred to as PHN, which is the most common and clinically relevant complication of shingles. Approximately 15-20% of all shingles patients experience PHN, although the incidence of PHN is more prevalent in patients over 50 years of age. Previous studies have established that additional risk factors for PHN include greater acute pain intensity, severity of the dermatological symptoms or lesions, and the presence and greater severity of a painful prodromal preceding the lesions or rash.

FV-100 is a bicyclic nucleoside analogue we are developing for the treatment of shingles and the reduction of shingles-associated pain and PHN. In pre-clinical studies, FV-100 has proven to be the fastest acting and the most potent antiviral agent with respect to inhibiting the replication of VZV.

We completed a Phase 2 clinical trial for FV-100 in December, 2010. This trial represented the first clinical trial of FV-100 in shingles patients. The Phase II trial was a well-controlled, double-blind study comparing two different dosing arms of FV-100 to an active control (valacyclovir). We enrolled 350 patients, aged 50 years and older, to one of three treatment arms: 200 mg FV-100 administered once daily; 400 mg FV-100 administered once daily; and 1,000 mg valacyclovir administered three times per day. In addition to further evaluating its safety and tolerability, the main objectives of the trial were to evaluate the potential therapeutic benefit of FV-100 in reducing the severity and duration of shingles-related pain, the incidence of PHN, and the time to lesion healing. Numerically favorable treatment differences, and in particular in those patients that received 400 mg FV-100, were observed for FV-100 as compared to valacyclovir for the primary endpoint of the study, which was the reduction in the severity and duration of shingles-associated pain over the first 30 days after lesion appearance. The treatment differences observed between either of the FV-100 treated arms and the valacyclovir-treated subjects for this primary endpoint were not statistically significant. There were also favorable treatment differences observed for key secondary pain endpoints, including the reduction in the severity and duration of shingles-associated pain over 90 days (a 14% relative reduction as compared to valacyclovir for 400mg FV-100) and the incidence of PHN (a 39% relative reduction as compared to valacyclovir for 400 mg FV-100). The secondary endpoints were not powered to demonstrate statistically significant treatment differences between the arms; however we believe these treatment differences are clinically meaningful. FV-100 was generally well tolerated at both dose levels, and demonstrated a similar adverse event profile as compared to valacyclovir.

In August 2011, we announced that we intend to file a protocol and other supporting documents, including a patient reported outcomes (PRO) dossier, to the FDA later this quarter for a proposed Phase 2b trial of FV-100 in order to obtain feedback from the FDA on the protocol, its PRO methodology, and a regulatory pathway that could potentially support an indication for the reduction of shingles-associated pain and/or the incidence of post-herpetic neuralgia (PHN). The proposed Phase 2b trial would include approximately 600 shingles patients with the primary endpoint being the time to resolution of clinically significant shingles-associated pain, and a key secondary endpoint being the reduction in the incidence of PHN. Subject to satisfactory regulatory review and feedback concerning these and other proposed clinical endpoints and their potential to support an indication for the reduction of shingles-associated pain and/or incidence of PHN, we will determine whether we will initiate the proposed Phase 2b study of FV-100 in 2012.