Vertex pushes ahead on cystic fibrosis franchise


The first drugs to receive breakthrough designations from the FDA, Vertex Pharmaceuticals’ Kalydeco and VX-809, have been readied for two pivotal trials that will see a test of the latter part of the combination at the highest doses investigated in phase II studies.

News that the pairing will go forward should steady investors’ nerves, as it is accompanied by long-awaited disclosure of positive phase II data on the highest dose of ‘809. The more positive news emerging on Vertex's all-important cystic fibrosis franchise should help rebuild some of the faith lost when the Massachusetts group botched a data release last year (Vertex data blunder punctures high risk cystic fibrosis candidate, May 29, 2012).

Break on through

Vertex shares rose 6% to $46.66 in early trading today after yesterday’s post-market announcement. It was probably good enough news earlier this year that the FDA had designated the combination a breakthrough therapy – but news on the trial design is clearly cheering investors.

The new “breakthrough” category, permitted in the 2012 PDUFA update, requires a greater level of interaction between companies and FDA staff in trial design, which could eliminate much of the uncertainty surrounding regulatory submissions (PDUFA V nears final act, May 31, 2012).

In addition, as breakthrough designation is restricted to treatments that address serious and life-threatening conditions, it allows drug developers to streamline clinical trials to minimise the number of patients exposed to placebo or potentially less effective treatments.

Thus, with announcement of the final design, the combination is expected to report data from the new 24-week trials early next year, and with fast-track designation a part of the breakthrough therapy programme there could be a launch in early 2015.

Allowing the 400mg twice-daily dose to go forward in addition to the once-daily 600mg means the chances of success are “unchanged to slightly higher”, UBS analyst Matthew Roden wrote. What probably relieved investors more than anything was the fact that the newly disclosed data for the twice-daily 400mg dose look "generally similar” to 600mg, in the words of ISI Group analyst Mark Schoenebaum – with the caveat that the data from the 400mg arm are not placebo-adjusted.

However, the data avoided a disappointing scenario in which the 400mg arm showed no activity, something that had been feared because Vertex had not released that result yet.


As a monotherapy, Kalydeco was one of the big drug launches of 2012, bringing in $172m in 11 months of sales last year (Liftoff for 2012’s big drug hopes, January 24, 2013). However, it is effective only in those with the G551D mutation, representing just 5% of CF patients.

Franchise expansion hopes rest on the fate of ‘809 and phase II VX-661, both effective in patients with two copies of the F508del mutation, or about half of all CF patients. The differences in patient population relate to the mechanism of action: Kalydeco acts to maximise the function of a defective protein called cystic fibrosis transmembrane conductance regulator (CFTR), necessary to regulate cellular chloride and sodium content, while ‘809 and ‘661 correct faulty CFTR.

With the drastic falloff in forecasts for hepatitis C antiviral Incivek, the CF franchise is looming ever larger for Vertex. Current EvaluatePharma forecasts suggest that Kalydeco-‘809 sales will account for $2.28bn in 2018, or 96% of Vertex's total sales. That is a picture that could change with phase II success for ‘661, as analysts begin to make estimates on the compound.

Given the history of missteps in advancing this franchise – and huge ones they were – Vertex needs to avoid putting a foot wrong as ‘809 reaches the pivotal stage. If it executes well, it might be able to open the next chapter in its history at about the same time the current one closes.

Trial  Trial ID
Phase II study of VX-809 alone and in combination with VX-770 in cystic fibrosis patients homozygous or heterozygous for the F508del-CFTR mutation NCT01225211

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

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