Tolerability data blunt Xenoport’s Tecfidera

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XenoPort has demonstrated the weaknesses of its strategy of repackaging old molecules, as well as showing that not every fumarate has Tecfidera-like potential in autoimmune disease.

A high incidence of diarrhoea in patients in a phase II psoriasis study will make a big task out of advancing XP23829 into phase III in either the skin disorder or the bigger prize of multiple sclerosis. While it was hoped that different pharmacokinetics to Tecfidera would reduce gastrointestinal side effects, the fact that the data suggest XP23829 is merely an equal shrinks its appeal as a next-generation oral agent.  

“It is what it is, and we don’t think it indicates that we’re any worse than Tecfidera,” XenoPort's chief executive, Ronald Barrett, said in a call with investors, on a day when shares sank 28% to $4.84.

Bigger fish

Although this was a trial in psoriasis, XenoPort positioned it as a proof-of-concept study for MS, a bigger indication and one in which oral agents are in demand. Novartis’s Gilenya and Biogen’s Tecfidera have paved the way on this front, and Xenoport had been hoping to outperform the latter agent, the biggest seller in this indication, on a superior dosing schedule.

The way to this was XenoPort’s technology for developing prodrugs of existing molecules in a bid to improve on safety and efficacy; its one marketed product, Horizant, is a version of Neurontin used to treat restless leg syndrome. It was hoped that XP23829, a reformulation of monomethyl fumarate, could deliver the active ingredient of Tecfidera more efficiently and allow for improved dosing and better tolerability.

Biogen has not tested Tecfidera in psoriasis, although as Fumaderm the molecule is used in this indication in Germany. An analysis from the UK National Health Service found data suggesting that Fumaderm was able to lower patients’ psoriasis area and index (PASI) scores from a mean baseline of 21.57 to 10.77 after 16 weeks.

Likewise, at an 800mg once-daily dose patients taking XP23829 saw a 48.2% reduction in PASI scores, and at a 400mg twice daily this was 50.7%. The diarrhoea rate was 40% and 39.6% respectively, higher than the 14% listed on Tecfidera's FDA label.

XenoPort executives did highlight a lower flushing rate for ‘829 compared with twice-daily Tecfidera. They also highlighted a subgroup analysis that found that patients naive to biologics like Humira scored better than those who had previously taken them – a 56.1% reduction in PASI score in the 800mg once-daily group and 59.1% with 400mg twice daily.

Setback

In most ways these results were worse than the worst-case scenario painted by analysts, who had expected that on safety and tolerability ‘829 would be the equal of Tecfidera (Event – XenoPort moves closer to its date with destiny, July 9, 2015). Nevertheless, executives spoke confidently of moving into phase III perhaps in both psoriasis and MS in 2016.

Notwithstanding Mr Barrett’s insistence that on safety ‘829 is the equal of Biogen’s blockbuster, more work will probably need to be done before then to address lack of tolerability, if not for regulators reviewing phase III design then at least for potential partners.

Another setback is not what XenoPort needed. Horizant does not look like it will ever become a huge seller, achieving $115m in sales in 2020, according to EvaluatePharma’s consensus. The company's last attempt to build the prodrug platform was a failure in MS spasticity and gastro-oesophageal reflux disease, and now investors are showing serious hesitation about the promise of ‘829.

The latest failure should also raise questions about the prodrug technology as XenoPort's foundation. The company has precious little to show for it, and its main success won approval in the smaller restless leg indication only after failing in diabetic neuropathic pain. There are certain efficiencies to be gained in repackaging established products, but the trick is to do better, and on this count XenoPort has now missed several times.

Trial ID NCT02173301

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @ByJonGardner on Twitter

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