ASCO presentation further demonstrates life-saving promise of chemo antidote

WELLSTAT INVESTIGATIONAL DRUG SHOWS LIFE-SAVING POTENTIALIN TREATING TOXICITY OF WIDELY USED CANCER CHEMOTHERAPY

Presentation At ASCO Annual Meeting Will Report On Data

For Uridine Triacetate To Reverse 5-FU Overexposure

Gaithersburg, MD -- May 20, 2010 – Wellstat Therapeutics announced today that the company’s investigational drug uridine triacetate has further demonstrated its life-saving potential in treating patients overexposed to the widely used cancer chemotherapy 5-fluorouracil (5-FU), according to clinical data to be presented June 7 at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.1

The National Institutes of Health estimate that 275,000 patients in the United States undergo 5-FU therapy annually, and 1,300 die from 5-FU overexposure resulting from accidental overdoses or poor drug clearance.2 While no antidote for 5-FU overexposure has been approved by regulatory authorities, uridine triacetate (formerly known as vistonuridine) has been made available to physicians for emergency use. 3

Wellstat’s poster presentation at ASCO will report on 37 cases of 5-FU overexposure treated with uridine triacetate. In all of these cases, the patients recovered from the overexposure, even though a fatal outcome for at least 27 of them would have been predicted by the dose and rate of 5-FU administration. In one extreme case, the patient survived after receiving a 5-FU dose 10 times higher than intended (10,000 mg in three hours instead of 1,000 mg in one hour). In all cases, the emergency treatment commenced as rapidly as possible after 5-FU overexposure (within 8 to 96 hours), depending on the timing of the request to Wellstat and the location of the treatment site. Among the patients receiving uridine triacetate, a few experienced mild nausea and three of these patients had one episode of vomiting each that may have been associated with uridine triacetate.

In contrast to these observations, the presentation reports data from a review of cases in which patients did not receive uridine triacetate but had received 5-FU overdoses of a similar magnitude to those in the uridine-triacetate-treated group.4 In this comparator group, 32 of the 36 patients died. The cases were reported by the Institute for Safe Medication Practices Canada, the FDA MAUDE database, and other sources.5

“Since our first report on uridine triacetate at ASCO in 2009, the number of patients treated with this investigational antidote has more than doubled,” said Michael Bamat, Vice President, Research and Development, Wellstat. “At ASCO in 2010 we can report on this broader experience, which provides additional evidence in support of the life-saving potential of uridine triacetate in treating 5-FU overexposure.”

Wellstat plans to seek regulatory approval of uridine triacetate in the US, Europe, and other regions. Uridine triacetate has been granted orphan-drug status by the FDA and the European Commission.

Accidental overdose versus drug clearance

All of the emergency-use cases to be reported at ASCO resulted from accidental overdoses of 5-FU, usually due to misprogrammed or malfunctioning infusion pumps used to administer the drug. But another common cause of overexposure is thought to be poor drug clearance: a genetic variation in certain patients results in deficient levels of an enzyme essential for 5-FU metabolism, dihydropyrimidine dehydrogenase (DPD). Patients deficient in DPD may experience severe 5-FU toxicity even when 5-FU is administered in standard doses. It is estimated that people with complete or partial DPD deficiency make up 0.1% and 3% of the population, respectively.

In an additional abstract published at ASCO, Wellstat will report data from a preclinical study examining the role of uridine triacetate in reversing 5-FU toxicity due to DPD deficiency.6 Results of this study showed that a standard anti-cancer dose of 5-FU was lethal in mice pre-treated with a DPD inhibitor, then administered 5-FU, and then treated with placebo only. But when, in similarly pre-treated mice, 5-FU administration was followed by uridine triacetate, all mice given uridine triacetate within 24 hours survived. After 24 hours, survival continued to correlate with time of uridine-triacetate administration, survival rates being higher among mice given uridine triacetate in earlier time periods. Uridine triacetate thus may be beneficial in DPD-deficient patients if they are identified and treated soon enough after they receive 5-FU.

“Preclinical investigation enables us to examine questions outside the practical and ethical constraints of the clinical emergencies for which uridine triacetate has been provided,” said Reid von Borstel, Vice President, Discovery Research, Wellstat. “And the preclinical evidence supports what we would assume—that uridine triacetate could be beneficial in treating cases of DPD deficiency as well as accidental overdose, and that the sooner treatment begins, the better.”

5-FU

In use as a cancer drug for decades, 5-FU is a mainstay of various treatment regimens for solid tumors including those of the colon, stomach, esophagus, breast, and head and neck. The drug is most commonly administered by infusion pump at or near what is considered the maximum tolerated dose. Yet many patients do not receive optimally effective treatment with 5-FU because of concerns about dose-limiting toxicity and individual variation in 5-FU metabolism.7

Expected side effects of 5-FU include myelosuppression (a reduction in white-blood-cell counts and thus increased risk of infection), diarrhea, nausea, vomiting, and mucositis (a painful inflammation of the mucous membranes lining the digestive tract). Overexposure to 5-FU can lead to severe myelosuppression, gastrointestinal hemorrhage, septic shock, multiple organ failure, and death.

The incidence of 5-FU overexposure is low though difficult to quantify. Overexposure may result despite careful selection of patients and adjustment of dose, both because the effective dose must often be close to a toxic dose and because patients vary in their capacity to break down 5-FU and eliminate it from the body.

About uridine triacetate

Uridine triacetate, formerly known as vistonuridine, is an orally active prodrug of uridine, meaning that uridine triacetate is converted to uridine in the body. Once uridine triacetate is converted to uridine, it reduces the incorporation of 5-FU metabolites into the genetic material of non-cancerous cells. Because of the poor bioavailability of oral uridine, however, and because of complications associated with intravenously administered uridine, uridine itself is not a clinically viable treatment for 5-FU overexposure. Uridine triacetate delivers about eight-fold more uridine into the bloodstream than does oral administration of uridine.

Wellstat is also investigating the potential use of uridine triacetate when given after 5-FU administration to cancer patients to achieve higher, more effective doses of 5-FU while preserving an acceptable margin of safety.

Uridine triacetate does not have marketing approval for any indication.

About Wellstat Therapeutics Corporation

Wellstat Therapeutics Corporation, a privately held biopharmaceutical company in Gaithersburg, Maryland, is dedicated to the discovery, development, and commercialization of innovative therapeutics that expand the frontier of modern medicine. The company focuses on oncology, metabolic disorders including diabetes, and neurometabolic disorders.

Wellstat Therapeutics is part of the Wellstat group of companies, which are developing therapeutics, vaccines, and point-of-care diagnostics.

Notes to editors:

1 Bamat MK, Tremmel R, O’Neil JD, von Borstel R. Uridine triacetate: An orally administered, life-saving antidote for 5FU overdose.

2Federal Register/Vol. 73, No. 129, July 3, 2008.3The emergency use of an investigational drug requires an Investigational New Drug (IND) submission to the Food and Drug Administration. The usual procedure has been to contact the manufacturer and determine whether the drug can be made available under an IND.

4Whether or not an antidote for 5-FU overexposure is available, various types of supportive care may be provided, such as growth factors to stimulate blood-cell production and antibiotics.

5Institute for Safe Medication Practices Canada. Fluorouracil Incident Root Cause Analysis. May 22, 2007. http://www.cancerboard.ab.ca/NR/rdonlyres/2FB61BC4-70CA-4E58-BDE1-1E54797BA47D/0/FluorouracilIncidentMay2007.pdf.

6von Borstel R, Tremmel R, O’Neil JD, Saydoff J, Bamat MK. Uridine triacetate for lethal 5FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency.

7Gamelin E, Delva R, Jacob J, et al. Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer. (2008) J. Clin. Oncol. 26:2099-2105.

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Posted: May 2010