XenoPort Reports Results from a Phase 2 Clinical Trial of XP19986 as a Treatment for the Symptoms of Gastroesophageal Reflux Disease
XP19986 Monotherapy Generally Well Tolerated and Effective in Reducing Heartburn in GERD Subjects Previously Treated with Proton Pump Inhibitors
SANTA CLARA, Calif.--(BUSINESS WIRE)--Dec 2, 2008 - XenoPort, Inc. (Nasdaq:XNPT) announced today top-line results from a Phase 2 clinical trial that examined the ability of XP19986 (arbaclofen placarbil) extended-release tablets to reduce symptoms experienced by subjects with gastroesophageal reflux disease, or GERD. The primary analysis comparing XP19986 to placebo did not reach statistical significance. However, pre-defined subgroup analyses showed statistically significant benefits of XP19986 on a number of important parameters. XP19986 was generally well tolerated at all dose levels.
Ronald W. Barrett, Ph.D., XenoPort's chief executive officer, stated, “While we are disappointed that statistical significance in the primary analysis of this trial was not met, we are pleased that the subgroup analyses showed that XP19986 monotherapy was effective in reducing heartburn in GERD subjects who have previously experienced at least a partial response to proton pump inhibitors (PPIs). We are particularly encouraged by the results indicating that XP19986 appears to have acceptable tolerability for the GERD patient population. Effective treatment for GERD patients who remain symptomatic despite PPI therapy represents an important unmet medical need.”
The randomized, parallel-group, double-blind, placebo-controlled Phase 2 clinical trial enrolled 156 subjects at 16 sites in the United States. Enrolled subjects had reflux symptoms occurring at least three days a week and had either no history of taking PPIs (PPI NaÃ¯ve) or a history of at least a partial symptom response to PPI therapy (PPI Experienced). Enrolled subjects discontinued prior therapy for GERD other than rescue antacids. During the second week of a two-week washout period, baseline data regarding frequency and severity of GERD symptoms were recorded in an electronic diary as they occurred. Each subject who met the entry criteria was randomized to one of five treatment arms: placebo; three dose levels of XP19986 (20 mg, 40 mg or 60 mg) administered once a day in the morning; or XP19986 (30 mg) administered twice daily. PPI history was used as a stratification criterion during randomization. The treatment period was four weeks, which included an up-titration period. At the end of four weeks, subjects were tapered off treatment.
The primary efficacy analysis involved the difference in the change in total number of weekly heartburn episodes between the XP19986 dose groups and placebo through four weeks of treatment. Change in the total number of weekly heartburn episodes was analyzed using a repeated measures ANCOVA model. The primary efficacy analysis compared pooled XP19986 treatment groups (60 mg dosed once a day and 30 mg dosed twice a day; and 60 mg and 40 mg dosed once a day) with the placebo group and included both PPI Experienced and PPI NaÃ¯ve subjects. This analysis did not reach statistical significance.
The primary ANCOVA analysis indicated that the status of a subject as either PPI NaÃ¯ve or PPI Experienced had a significant impact on the outcome of the analysis (PPI history status by treatment group interaction term (p=0.02)). The prospective statistical analysis plan specified separate analyses of the PPI NaÃ¯ve and the PPI Experienced populations. In the PPI Experienced population, which represented 63% of all subjects, XP19986 demonstrated a significantly greater reduction in heartburn episodes compared to placebo for the 60 mg once-daily and the 30 mg twice-daily dosage groups using the repeated measures ANCOVA analysis (p=0.04 for both).
A number of pre-defined secondary analyses were conducted on subjects in the PPI Experienced population who completed four weeks of treatment. All XP19986 dose groups showed a greater adjusted mean percent reduction from baseline at week four in weekly heartburn episodes that was statistically significant compared to placebo. The adjusted mean percent change from baseline measured at week four for placebo, 20 mg, 40 mg and 60 mg dosed once daily and 30 mg of XP19986 dosed twice daily was -28%, -75%, -65%, -68% and -79%, respectively (p<0.01 for all XP19986 dose groups compared to placebo except for 40 mg (p=0.02); no correction for multiple comparisons).
In addition, a dose-dependent effect on the complete relief of heartburn symptoms during the last seven days of the four-week treatment period was observed for subjects in the PPI Experienced population (7%, 21%, 24%, 33% and 60% for placebo, 20 mg, 40 mg and 60 mg dosed once daily and 30 mg of XP19986 dosed twice daily, respectively). The comparison of the 30 mg twice-daily group with the placebo group was statistically significant (p=0.03; no correction for multiple comparisons).
XP19986 was generally well tolerated at all dose levels. There were no treatment emergent serious adverse events. Among all subjects receiving study medication, the most common adverse events for placebo, 20 mg, 40 mg and 60 mg dosed once daily and 30 mg of XP19986 dosed twice daily were somnolence, at rates of 3%, 3%, 12%, 16% and 13%, respectively, and dizziness, at rates of 10%, 10%, 6%, 13% and 20%, respectively. Most reported adverse events were mild or moderate in severity. Withdrawals due to adverse events were 6%, 0%, 3%, 9% and 10%, respectively.
“GERD is a common digestive system disorder that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Conventional treatments for GERD are not effective in all patients, and can lead to serious medical consequences in some patients,” said Nimish B. Vakil, M.D., FACG, Clinical Professor of Medicine at the University of Wisconsin Medical School and a principal investigator of the Phase 2 clinical trial. “This trial shows the potential of XP19986 in reducing heartburn in GERD patients who have previously taken PPIs. The favorable tolerability of XP19986 in this patient population is an important finding.”
Ronald W. Barrett, Ph.D., XenoPort's chief executive officer, added, “A primary goal of this trial was to advance our understanding of factors that may influence responsiveness to XP19986, since its mechanism of action differs from that of acid-suppressive agents. Based on the data we have reviewed to date, we believe we have already gained insights that will inform the design of our next trial, which will examine XP19986 in GERD subjects who continue to experience symptoms despite PPI therapy. We expect to provide an update on the next steps for the GERD development program in the first quarter of next year and to present additional results from this trial at a future medical conference.”
XP19986 (arbaclofen placarbil) is a Transported Prodrug of R-baclofen that is designed to engage natural nutrient transport mechanisms found on intestinal cell membranes, thereby gaining efficient entrance into the bloodstream. XP19986 is then rapidly converted by high-capacity enzymes to the parent compound and natural substances with favorable safety characteristics. The current sustained-release tablet formulation of XP19986 could enable convenient once- or twice-daily dosing of subjects in future clinical trials.
R-baclofen is an agonist of the target known as gamma amino-butyric acid(B), or GABA(B). A GABA(B) agonist has been approved for the treatment of spasticity and has been shown in clinical studies to have efficacy in a number of other therapeutic indications, including GERD and acute back spasms
GERD is a digestive system disorder affecting approximately 25% of the U.S. population. Normally, the lower esophageal sphincter (LES), a muscle that is located between the stomach and esophagus, prevents the reflux of stomach contents into the esophagus. In patients suffering from GERD, excessive transient LES relaxations (TLESRs) or a weak LES allow frequent passage of stomach contents into the esophagus, thereby causing the typical symptoms of heartburn and regurgitation. While GERD can cause discomfort and a diminished quality of life, inadequate treatment can lead to esophageal erosion, bleeding and potentially even cancer. Current treatment of GERD primarily involves suppression of acid secretion through the use of antacids and prescriptions drugs such as PPIs and H2 receptor antagonists. PPI therapy is the most efficacious and commonly used therapy to treat GERD. According to IMS Health, IMS Midas, over $25 billion worldwide was spent in 2007 on PPI therapeutics. While PPI therapy improves symptoms in the majority of GERD patients, an estimated 40% of patients on once-daily PPI therapy continue to experience breakthrough symptoms. There are no drugs currently approved to treat patients with PPI-refractory GERD.
Conference Call and Webcast Information
XenoPort will host a conference call at 8:30 a.m. Eastern Time today to discuss the Phase 2 clinical trial results. To access the conference call via the Internet, go to www.XenoPort.com. To access the live conference call via phone, dial 1-888-275-3514. International callers may access the live call by dialing 706-679-1417. The reference number to enter the call is 76269111.
The replay of the conference call may be accessed after 11:30 a.m. Eastern Time today via the Internet, at www.XenoPort.com, or via phone at 1-800-642-1687 for domestic callers, or 706-645-9291 for international callers. The reference number to enter the replay of the call is 76269111. Dial-in access to the replay of the call will be available for approximately one week, and the Internet replay of the call will be available for approximately one month following the live call.
XenoPort, Inc. is a biopharmaceutical company focused on developing a portfolio of internally discovered product candidates that utilize the body's natural nutrient transport mechanisms to improve the therapeutic benefits of existing drugs. XenoPort is developing its lead product candidate in partnership with Astellas Pharma Inc. and GlaxoSmithKline. GlaxoSmithKline is in the process of resubmitting to the FDA an NDA for this product candidate, known as Solzira™ in the United States, for the treatment of restless legs syndrome. XenoPort's product candidates are also being studied for the potential treatment of GERD, migraine headaches, neuropathic pain, spasticity related to spinal chord injury, acute back spasms and Parkinson's disease.
To learn more about XenoPort, please visit the Web site at www.XenoPort.com.
This press release contains “forward-looking” statements, including, without limitation, all statements related to our future clinical development program for XP19986 and the timing thereof; the therapeutic and commercial potential of XP19986; and the resubmission of the NDA for Solzira. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as “plan,” “will,” “expect,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon XenoPort's current expectations. Forward-looking statements involve risks and uncertainties. XenoPort's actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to the uncertain results of future clinical trials; XenoPort's ability to successfully conduct future clinical trials for XP19986; the uncertainty of the FDA approval process and other regulatory requirements; XenoPort's dependence on its current and additional collaborative partners; and the uncertain therapeutic and commercial value of its compounds. These and other risk factors are discussed under the heading “Risk Factors” in XenoPort's Quarterly Report on Form 10-Q for the quarter ended September 30, 2008, filed with the Securities and Exchange Commission on November 6, 2008. XenoPort expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the company's expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
XenoPort and Transported Prodrug are trademarks of XenoPort, Inc.
Solzira is a U.S. trademark of GlaxoSmithKline.
Contact: XenoPort, Inc.
Jackie Cossmon, 408-616-7220
Posted: December 2008