In the Phase 1 trial, 60 subjects were assigned to five cohorts of 12, and each cohort received one of four different formulations of XP23829 or placebo. Subjects received a single dose of XP23829 or placebo in both a fasted and fed state in a randomized order with a two-week period between dosing. All formulations of XP23829 were administered at a dose that was equivalent to 107 mg of MMF. Formulation 1 was a delayed-release formulation that was designed to suppress the release of XP23829 while in the stomach and then immediately release the drug upon entering the small intestine. Formulations 2, 3 and 4 were designed to delay and then slowly release XP23829.
All formulations of XP23829 produced MMF in the blood, while levels of intact XP23829 and the potential desmethyl-metabolite of XP23829 were below the limits of quantitation. The clearance of the promoiety, a pharmacologically inactive molecule that is also created in the enzymatic conversion of XP23829 to MMF, was rapid, with a half-life of about three hours.
As anticipated, when dosed in a fasted state, Formulation 1 produced a sharp peak in MMF blood levels and a PK profile that supports further evaluation for two- or three-times-a-day dosing. The maximum MMF concentrations after dosing Formulation 1 were lower and more variable when dosed with food.
Formulation 2 produced a total MMF exposure that was similar to that of Formulation 1, but with a lower maximum MMF concentration and a longer duration of exposure. The presence of food had minimal effect on the total exposure and PK profile of MMF. Given the duration of MMF exposure, the PK profile for Formulation 2 supports further evaluation as a once-a-day treatment. While Formulations 3 and 4 also produced sustained exposures of MMF, the total MMF exposures in blood were generally lower than Formulations 1 and 2.
XP23829 was generally well tolerated during the trial. All 12 subjects in each cohort completed both dosing periods. All adverse events were rated as mild. The only adverse events reported in more than one subject and more frequently for XP23829 than for placebo were flushing and "feeling hot." Of the 12 subjects in each cohort, the number of subjects reporting these adverse events was as follows:
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XP23829 is a fumaric acid ester compound that is a prodrug of MMF and for which U.S. Patent number 8,148,414 has been issued. Fumaric acid ester compounds have shown immuno-modulatory and neuroprotective effects in cell-based systems and preclinical models of disease. Dimethylfumarate (DMF), which is also a fumaric acid ester compound and a prodrug of MMF, has been shown to be effective in clinical trials in patients with RRMS and psoriasis. In XenoPort's preclinical animal studies that compared molar-equivalent doses of XP23829 to DMF, XP23829 demonstrated a greater degree of efficacy in both multiple sclerosis and psoriasis animal models. Toxicology studies conducted in two species showed that XP23829 caused less stomach irritation when compared to DMF.
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This press release contains "forward-looking" statements, including,
without limitation, all statements related to the clinical development
of XP23829 and the timing and results thereof; XenoPort's anticipated
future clinical trials of XP23829, and the number and timing thereof;
the potential suitability of XP23829 as a treatment for RRMS and/or
psoriasis, including the potential suitability of XP23829 as a
once-a-day treatment; and the therapeutic and commercial potential of
XP23829 and XenoPort's other clinical product candidates. 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
"anticipate," "believe," "could," "goal," "intends," "may," "possible,"
"potential," "suggest," "would" 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 and timing of clinical trials and other studies,
including the risk that success in preclinical testing and early
clinical trials do not ensure that later clinical trials will be
successful, and that the results of clinical trials by other parties may
not be indicative of the results in trials that
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