Tech Sectors: Biotechnology: The Treatment of Palmar-plantar Erythrodysesthesia

With the introduction of anti-emetics, growth factors, and oral mucositis treatments, there has been increased focus on the integration of supportive and palliative oncology into the care of all cancer patients. An emerging segment of the approximately $10 billion supportive care oncology market relates to treatments for the cutaneous reactions arising from radiation therapy, chemotherapy, and even newer targeted agents such as inhibitors of the epidermal growth factor receptor (EGFR). These treatments can result in such undesirable effects in skin and appendages as xerosis, erythema, edema, papulopustular eruption, hair growth disorders, periungual and nail plate abnormalities, and pruritus.

Palmar-Plantar erythrodysesthesia (PPE), also known as hand-foot syndrome (HFS), is a relatively common dose-limiting side effect of cytotoxic chemotherapy—most frequently fluoropyrimidines, such as continuous infusion 5-fluorouracil (5-FU), and the oral 5-FU prodrug capecitabine. Fluoropyrimidines are among the most commonly used cancer chemotherapeutics nearly 50 years after their introduction. Fluoropyrimidines, alone or in combination therapy, are commonly used to treat cancers of the head and neck, breast, cervix, and gastrointestinal tract.

HFS is characterized by the progressive redness and cracking of the hands and feet. The severity of HFS is typically defi ned by three grade levels: Up to 60% of all capecitabine patients experience HFS, and up to 20% experience severe (Grade 3) HFS. According to the prescribing information for capecitabine, if Grade 2 or 3 HFS occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to Grade 1. Following Grade 3 HFS, subsequent doses of capecitabine should be decreased.

One company working to satisfy the unmet need for a treatment and preventative agent for HFS is VioQuest Pharmaceuticals (www. vioquestpharm.com/content/index.html), a New Jersey-based biotechnology company focused on developing treatments for both the molecular basis of cancer and side eff ects of treatment. The active ingredient for its drug candidate Xyfid™ is uracil, a naturally occurring substrate for enzymes, such as thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), that metabolize fl uoropyrimidines into toxic metabolites.

The addition of uracil to systemic fl uoropyrimidine treatment regimens, such as tegafur-uracil, or UFT, is well-established to signifi cantly diminish the incidence of HFS. Whereas such combination products have been licensed in Japan and much of Europe, they have not been approved for use in the United States due, in part, to FDA questions regarding the demonstrable non-inferiority of the combination drug compared with fluoropyrimidines alone.

In contrast to systemic exposure, topical application of uracil would potentially allow for the treatment and prevention of HFS without compromising the efficacy of systemic fluoropyrimidine therapy. In a small pilot study, Xyfid has been effective at preventing both the incidence and recurrence of dose-limiting HFS when applied topically. Plans are underway for a phase II trial of Xyfi d in this setting.

In the near-term, Xyfid may have a broader role in treating various dermatoses through its moisture barrier properties. A 510(k) application was submitted to the FDA on June 30, 2008. Michael D. Becker is president and chief executive officer of VioQuest Pharmaceuticals.