Vertex investors toast birth of the son of Orkambi

A double pivotal trial success with tezacaftor, a novel CFTR corrector, has given Vertex a neat follow-on to its blockbuster cystic fibrosis combination Orkambi, and should help it capture a greater market share of this respiratory disease.

Of course neither study compared the tezacaftor combo head to head against Orkambi, but on an across-trial basis efficacy looks marginally better, with safety – Orkambi’s main stumbling block – much improved. Moreover, the new combination bodes well for Vertex’s plans to cement its hold on cystic fibrosis with a triple combo.

The clinical success came shortly after Vertex’s latest empire-building move, when it bought Concert Pharmaceuticals’ CTP-656, a once-daily deuterium-modified version of its marketed monotherapy Kalydeco, for $160m. Vertex stock, which has fallen hard from its mid-2015 peak, was up 18% in early trade today.


Orkambi, which combines the CFTR potentiator Kalydeco with lumacaftor, is approved in cystic fibrosis patients who are homozygous for – in other words they have two copies of – the F508del mutation in the CFTR gene.

In Evolve, the first of the pivotal studies Vertex revealed yesterday, tezacaftor plus Kalydeco was tested in this same population, and compared against placebo. The novel combo beat placebo on the primary endpoint, with a four-point improvement in mean absolute FEV1 change at week 24 (p<0.0001).

This compares favourably with Orkambi’s historic 2.5 to 3.0-point improvement. The real benefit, however, was respiratory tolerability, a problem with Orkambi: 13% of tezacaftor plus Kalydeco patients suffered a respiratory adverse event, versus 16% of placebo recipients.

The historic comparison on respiratory AEs is 22% for Orkambi. Baird’s Brian Skorney said the apparent tolerability benefit should allow the new combo to capture a large percentage of Orkambi dropouts; some 20-30% of patients discontinue Orkambi early in therapy, often owing to bronchoconstriction, Vertex said on a call today.

... and Expanding use

That seems to take care of Vertex’s plan to broaden its presence in F508del homozygous patients. An added benefit could come courtesy of the second pivotal trial, Expand, in a new use, F508del heterozygotes, also known as patients with CFTR residual function.

Here the tezacaftor/Kalydeco combo was tested against placebo and against Kalydeco monotherapy. It showed a difference in FEV1 of 6.8 points versus placebo (p<0.0001), and of 2.1 points versus Kalydeco (p<0.0001).

Interestingly, Kalydeco monotherapy also beat placebo in these patients, with FEV1 difference of 4.7 points (p<0.0001). Vertex said it had already been in talks with the US FDA about expanding Kalydeco’s label to include F508del heterozygotes, though clearly its primary aim will be to seek approval here for the new combo; filings in both patient groups are expected in the third quarter.

Vertex's cystic fibrosis franchise expansion
Trade name Generic name(s) Mechanism Patient population Study detail Trial ID
Kalydeco ivacaftor CFTR potentiator Approved for pts with certain CFTR mutations
Orkambi ivacaftor + lumacaftor lumacafrot = CFTR corrector Approved for F508del homozygous pts
tezacaftor (VX-661) CFTR corrector F508del homozygous pts Kalydeco + tezacaftor combo (vs placebo) NCT02347657 (Evolve)
F508del heterozygous pts Kalydeco + tezacaftor combo (vs Kalydeco & vs placebo) NCT02392234 (Expand)
VX-152 Next-gen CFTR corrector F508del heterozygous pts Kalydeco + tezacaftor + VX-152 NCT02951195
VX-440 Next-gen CFTR corrector F508del heterozygous or homozygous pts Kalydeco + tezacaftor + VX-440 NCT02951182

As good as these data appear to be, there is a possible future boon for Vertex. Namely, they bode well for its triple combinations, which Mr Skorney described as the holy grail of cystic fibrosis therapy, possibly expanding reach into the remaining patients not genetically eligible for a current Vertex regimen.

This could also secure the lifecycle of Vertex’s cystic fibrosis franchise. The group is pursuing two triples, combining the tezacaftor/Kalydeco doublet with a next-generation corrector – either VX-152 or VX-440.

With phase II studies of both expected to read out in the second half of this year Vertex investors have a chance to forget their 2016 annus horribilis at last.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter

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