Skip links

505(b)(2) Prodrug Fails Phase III Study

Development of drugs for new indications entails more risk of failure than simply changing formulations.  Just ask XenoPort, which announced May 19th that its prodrug of R-baclofen, arbaclofen placarbil,   failed to show efficacy in a Phase III clinical trial. Arbaclofen placarbil was being studied for multiple sclerosis-related spasticity. Racemic baclofen,  now generic, is indicated for treating muscle spasms, so it doesn’t seem to be a stretch to believe that it would be efficacious .  XenoPort based the prodrug on the active enantiomer, R-baclofen.  The prodrug approach was used to overcome some limitations of baclofen.  According to an abstract of a non-clinical pharmacokientic study, baclofen has

“a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter.”

 Interestingly, this non-clinical study demonstrated that in rats, dogs and monkeys, the prodrug was “rapidly converted to R-baclofen” and that “exposure to intact prodrug was low”.  Phase 1 human studies were reported:

“…included a total of over 250 healthy volunteers. The results of these Phase 1 clinical trials indicated that AP was well absorbed and rapidly converted to the R isomer of baclofen. Exposure to the intact Transported Prodrug was low compared to the level of R-baclofen produced at all dose levels. Comparison of these data with historical pharmacokinetic data for racemic baclofen suggests that AP taken twice a day should be associated with a decreased peak-to-trough ratio of R-baclofen blood levels over 24 hours compared to racemic baclofen dosed three or four times a day.”

This prodrug profile is one which the FDA considers eligible to be a pk-program-only if it was being developed for an approved indication.  As stated before, baclofen is used to treat MS-induced spasticity, so it unknown why this phase 3 trial failed.  I could not find any reports of a Phase 2 trial in MS-related spasticity; XenoPort has conducted Phase 2 trials in spinal cord injury and patients with GERD.