Liver worries sideline trials of new Vertex hep C drug

Gilead Sciences’ run of incredible luck continues. An FDA partial hold for safety reasons has afflicted yet another potentially competing compound, this time Vertex Pharmaceuticals’ VX-135, making Gilead’s $11bn sofosbuvir the only drug in its class in advanced clinical testing to have escaped safety worries so far.

Vertex is largely a cystic fibrosis player these days because of its breakthrough drug Kalydeco and follow-on candidates, but suffered at the hands of investors nonetheless, with shares falling 8% to $80.60 in early trading today. Trials are continuing in a low dose, but analysts reckon the hold will push out the potential launch of the NS5B inhibitor.

Another nuc knackered?

After market close yesterday, Vertex announced that the FDA had put a clinical hold on all US trials of the 200mg daily dose because of elevated liver enzymes detected in another trial. In a European phase II study of a 400mg dose in combination with ribavirin, one patient had grade 3, or moderate to severe, enzyme elevation. The Massachusetts group said the increased liver enzymes were reversible; no serious adverse events, cardiovascular issues, discontinuations or tolerability issues were identified when the nucleotide NS5B inhibitor was dosed at 100 and 200mg for 12 weeks in a European trial that has just concluded.

The NS5B inhibitor class, which includes Gilead’s sofosbuvir, has suffered mightily at the hands of the regulator, with Bristol-Myers Squibb writing off $2bn because of heart and kidney toxicity from BMS-986094 (Bristol-Myers setback another blow to hep C field, August 24, 2012) and Idenix shelving its candidate following the Bristol-Myers Squibb failure (Gilead’s sofo shines in hep C while Idenix’s nucs bomb, February 5, 2013).

Tests of VX-135, also known as ALS-2200, can continue at a 100mg dose in the US. Dosing at 100mg and 200mg is still ongoing in a New Zealand trial with the Bristol-Myers Squibb NS5A inhibitor daclatasvir.

Combination plays

Vertex was positioning VX-135 as a follow-up to its blockbuster pill Incivek, the first hep C treatment to improve on the longtime regimen of interferon and ribavirin. With more potent oral drugs like sofosbuvir on the verge of eclipsing the Incivek combination, sales forecasts have plummeted – last year is believed to have been its peak year, with sales of $1.16bn.

However, very few companies wholly own a combination that is believed to be able to take on the sofosbuvir and lepidasvir pairing that Gilead is expected to launch in 2014. AbbVie and Bristol-Myers are two, but companies operating in the wake of Gilead are experimenting with a number of non-exclusive combinations. This is especially true of Vertex, which has VX-135 in combination with Johnson & Johnson and Medivir’s simeprevir, as well as daclatasvir (EASL 2013 – In the shadow of Gilead, hep C progress continues, April 24, 2013). Vertex announced, however, that it had ceased a collaboration with GlaxoSmithKline’s phase II NS5A inhibitor GSK2336805.

For Vertex, meanwhile, the partial hold possibly removes one of the big catalysts to its shares for the autumn. Some data were expected at the American Association for the Study of Liver Disease meeting in Washington, DC, in November, at which time analysts might have begun forecasting sales.

However, until the safety clouds lift it seems likely that few will be willing to do that. ISI Group analyst Mark Schoenebaum estimated that it will take at least until the fourth quarter of 2013 to respond to the FDA’s clinical hold, adding crucial months to the development timeline.

Mr Schoenebaum described VX-135 as “injured, not dead.” But even so, it looks like it will fall another few months behind sofosbuvir, and that is time Vertex can ill afford.

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

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