XenoPort, Inc. (Nasdaq: XNPT) announced today that it had reached agreement with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for a pivotal Phase 3 clinical trial of arbaclofen placarbil (AP), previously known as XP19986, as a potential treatment of spasticity in multiple sclerosis (MS) patients. An SPA is a written agreement with the FDA on the design, including the scope and size of the patient population, the efficacy endpoints and safety assessments, the duration of treatment and the statistical analysis plan, of a pivotal Phase 3 trial to support an efficacy claim in a New Drug Application (NDA).
In addition, XenoPort reported that it has completed an End of Phase 2 meeting with the FDA regarding the additional studies required to enable submission of an NDA for AP as a treatment for spasticity. The FDA indicated that the Phase 3 pivotal trial that is the subject of the SPA and these additional studies could form the basis of an NDA to be filed under Section 505(b)(2), which allows reference to published literature and the FDA's previous finding of safety and effectiveness for baclofen, a drug that has been approved by the FDA for the alleviation of signs and symptoms of spasticity in individuals with MS or spinal cord injury.
Ronald W. Barrett, chief executive officer of XenoPort, stated, "We are pleased to reach agreement with the FDA on the design of our Phase 3 trial as well as the other clinical and non-clinical studies required for filing an NDA for AP as a treatment for spasticity. We were very encouraged by our previous Phase 2 study of AP that evaluated spasticity in spinal cord injury patients and hope to see similar positive results in MS patients, who we believe are still underserved by current treatments for spasticity."
XenoPort plans to initiate the pivotal Phase 3 clinical trial that is the subject of the SPA later this quarter. The trial will be a multi-center, randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of AP as a treatment for spasticity in MS patients. XenoPort expects to enroll approximately 200 subjects in this trial, which will be conducted in the United States. Eligible subjects will be randomized to one of four arms: 15 mg, 30 mg or 45 mg of AP or placebo dosed twice daily with food. The entire treatment period will be 13 weeks.
There will be two co-primary endpoints for the trial. The first co-primary endpoint will be the change from baseline in maximum Ashworth Scale score assessed six hours after morning dosing at week 10. The maximum Ashworth score is determined by the muscle group with the highest Ashworth score at baseline. At baseline, subjects must have a maximum Ashworth score of two or greater. The second co-primary endpoint will be the score on the 7-point Patient Global Impression of Change (PGIC) scale at week 10. The analysis of the co-primary endpoints will examine the change in maximum Ashworth score and the PGIC score after at least eight weeks of stable dosing at the fixed dose to which the subject is randomized. The co-primary endpoints will be analyzed independently, both using observed case data and utilizing a mixed models repeated measures analysis.
In addition to this Phase 3 efficacy trial, per the guidance that it received from the End of Phase 2 meeting, XenoPort also plans to conduct additional studies that are intended to be part of the NDA. Subjects who complete the 13-week pivotal Phase 3 efficacy trial will have the option to enter a six-month, open-label safety study of AP. Together, these trials are intended to provide nine months of AP exposure for at least 100 MS patients, as requested by the FDA. XenoPort will also conduct a Phase 1 study in healthy subjects that is designed to demonstrate that R-baclofen exposure associated with the maximum potential clinical dose of AP does not exceed those exposures produced by the highest approved dose of racemic baclofen (20 mg dosed four times daily). In addition, XenoPort plans to conduct two clinical pharmacology trials to evaluate the effect of food on AP pharmacokinetics in healthy subjects and to evaluate pharmacokinetics of AP in subjects with renal impairment.
XenoPort intends to submit to the FDA, as soon possible, its completed cardiovascular safety study (Thorough QTc study) and an analysis of the exposures for intact prodrug and R-baclofen achieved in non-human species in completed toxicology and carcinogenicity studies relative to the exposures in humans at the proposed clinical doses. The FDA has agreed to provide feedback in a timely manner on these submissions. If additional studies are required after such FDA review, XenoPort believes these studies could be completed prior to the completion of the six-month, open-label safety study.
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