XenoPort Announces Positive Results of a Phase 1 Clinical Trial of XP21279
Ronald W. Barrett, Ph.D., XenoPort's chief executive officer, stated, "We believe that this clinical trial serves as a solid proof of concept for XP21279. We will use these results to help optimize the formulation, with the goal of providing a relatively constant exposure to L-Dopa when XP21279 is dosed twice a day. We believe that an optimized formulation of XP21279 could provide therapeutic benefits to patients with Parkinson's disease, particularly in avoiding periods of 'wearing-off,' or the return of symptoms, that occur during the day with oral L-Dopa therapy."
Phase 1 Clinical Trial Results
The double-blind, placebo-controlled, single-dose Phase 1 clinical trial was designed to assess the safety and PK of a prototype, sustained-release formulation of XP21279 administered with carbidopa and to compare its PK profile to that of Sinemet (L-Dopa/carbidopa). Twelve healthy subjects participated in the three-period study. During the first two periods, nine subjects received two 250 mg XP21279 tablets, which have the capability to release 216 mg-equivalent of L-Dopa, and Lodosyn (two 25 mg of carbidopa tablets) under fasted and fed conditions. Three subjects received placebo under fasted and fed conditions. In the third period, all subjects received Sinemet (two 100 mg L-Dopa/25 mg carbidopa tablets) administered with food in an open-label manner. All subjects also received Lodosyn every 12 hours on the day prior to each treatment and the 12 hours after treatment. Blood and urine were collected to determine the PK profile of XP21279, L-Dopa, L-Dopa metabolites and carbidopa.
The PK results for L-Dopa in blood for the nine subjects who received active treatment were as follows:
-- For Sinemet (fed), the mean time to peak concentration (Tmax) for L-Dopa was 2.1 hours. The ratio of the maximum concentration (Cmax) to the mean concentration at 12 hours (C12) was 39.7.
-- For XP21279 (fed), the mean Tmax was 4.3 hours. The ratio of Cmax to C12 was 4.2. The area under the curve, or AUC, of L-Dopa in blood after XP21279 administration was 57% relative to the AUC produced by Sinemet.
-- For XP21279 (fasted), the mean Tmax was 2.6 hours. The ratio of Cmax to C12 was 10.5. The AUC of L-Dopa in blood after XP21279 administration was 37% relative to the AUC produced by Sinemet.
No intact XP21279 was detected in blood under fed or fasted conditions. Reported adverse events were low in frequency and mild in intensity.
These results are consistent with XP21279 being released from the prototype formulation in a controlled manner, resulting in sustained absorption from the gastrointestinal tract followed by complete conversion to L-Dopa. A lower Cmax to C12 ratio in a single-dose study would predict reduced fluctuations in L-Dopa blood levels with repeated twice-a-day dosing.
Dr. Barrett added, "Symptom control and side effects remain significant problems for existing oral L-Dopa products. Published studies have shown clinical benefits when L-Dopa was delivered in a continuous manner (either intravenously or intraduodenally), resulting in lower fluctuations in L-Dopa blood levels throughout the day. Based on these initial results with XP21279, we are optimistic that XP21279 can produce a better PK profile than existing oral L-Dopa therapies. We plan to work toward optimizing the formulation of XP21279 later this year and hope to begin a clinical trial in Parkinson's disease patients in 2009."
Dr. Barrett continued, "More generally, we are particularly pleased that our first three Transported Prodrug product candidates, XP13512, XP19986 and now XP21279, have each shown superior human PK profiles compared to its respective parent drug. We believe that this clinical success reflects positively on our technology platform and our prospects for further advancements in our research and development programs."
XP21279 is a new chemical entity that is a Transported Prodrug of L-Dopa. XP21279 is designed to engage natural nutrient transport mechanisms located throughout the length of the gastrointestinal tract and then be rapidly converted to L-Dopa by the body's naturally occurring endogenous enzymes. In addition to L-Dopa, the metabolic breakdown products of XP21279 are substances with favorable safety characteristics.
About Parkinson's Disease
Parkinson's disease is a motor system disorder that results from the loss of dopamine-producing nerve cells in the brain. Dopamine is naturally produced by the body and is responsible for smooth, coordinated function of the body's muscles and movement. When approximately 80% of dopamine-producing cells are damaged, the symptoms of Parkinson's disease appear. The primary symptoms of Parkinson's disease are tremor or shaking, slowness of movement, rigidity or stiffness and difficulty with balance. Approximately 1% of the U.S. population over 65 years old has been diagnosed with Parkinson's disease. At present, there is no cure for Parkinson's disease, but a variety of medications provide relief from the symptoms. L-Dopa acts to replenish dopamine in the brain. It is usually administered with benzerazide or carbidopa, or a combination of carbidopa and entacapone, which delays the premature conversion of L-Dopa to dopamine in peripheral tissues. Another class of drugs, called dopamine agonists, mimics the role of dopamine in the brain. In spite of their wide use, both L-Dopa and dopamine agonists remain suboptimal in treating the symptoms of Parkinson's disease.
XenoPort, Inc. is a biopharmaceutical company focused on developing a portfolio of internally discovered product candidates that utilize the body's natural nutrient transporter mechanisms to improve the therapeutic benefits of drugs. Its development and commercialization efforts are currently focused on potential treatments of central nervous system disorders. XenoPort's most advanced product candidate, XP13512, has successfully completed three pivotal trials in its Phase 3 clinical program for the treatment of moderate-to-severe primary restless legs syndrome, and has successfully completed a Phase 2a clinical trial for the management of post-herpetic neuralgia. XenoPort has also reported positive results from a Phase 2a clinical trial of its second product candidate, XP19986, in patients with gastroesophageal reflux 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 XenoPort's future clinical development of XP21279 and the timing thereof; the therapeutic and commercial potential of XP21279; the suitability of XP21279 as a treatment for Parkinson's disease; formulation plans for XP21279; and our future clinical trials. 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 "believe," "plan," "will," "potential," "may," "can," "goal," "hope," "optimistic" 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, the ability of XenoPort to successfully optimize the formulation of XP21279 to improve its PK properties; the ability of XenoPort to successfully conduct clinical trials for XP21279 and the uncertainty of the timing and results thereof; the uncertainty of the FDA approval process and other regulatory requirements; and the uncertain therapeutic and commercial value of XenoPort's compounds. These and other risk factors are discussed under the heading "Risk Factors" in XenoPort's Annual Report on Form 10-K for the year ended December 31, 2007, filed with the Securities and Exchange Commission on February 22, 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 U.S. trademarks of XenoPort, Inc.
Jackie Cossmon, 408-616-7220
Posted: March 2008