Vertex’s new dilemma: With more positive PhIII data on hand, which of their promising combos should go to the FDA, EMA?

Vertex $VRTX has a pleasant dilemma on its hands.

The big biotech reported that its Phase III trial for a cocktail used to treat cystic fibrosis has come in with positive results for VX-445, tezacaftor and ivacaftor.

In fact, they’re almost identical to the Phase III results they got for VX-659 combined with tezacaftor and ivacaftor. And that means the jury on which triple will head to regulators on both sides of the Atlantic is still out.

Now the executives at Vertex say they’ll wait for 24-week data due on both late-stage combinations in Q2, then decide which will get pitched to the FDA and EMA. Bottom line:

Data from a pre-specified interim analysis of the Phase III study in people with one F508del mutation and one minimal function mutation showed a mean absolute improvement in ppFEV1 of 13.8 percentage points from baseline at week 4 of treatment compared to placebo (p<0.0001). In the Phase 3 study in people with two F508del mutations, the addition of VX-445 in patients already receiving tezacaftor and ivacaftor resulted in a mean absolute improvement in ppFEV1 of 10.0 percentage points from baseline at week 4 of treatment compared to the control group in whom placebo was added to tezacaftor and ivacaftor (p<0.0001).

VX-659 was credited with a 14% placebo-adjusted improvement from baseline in FEV1 for patients with one F508del mutation and one minimal function mutation, with a clear score on the p value (p<0.0001). In a separate Phase III patients homozygous for the F508del mutation already taking Symdeko saw an average 10% improvement with VX-659 added on.

Cue the enthusiastic response from analysts. Noted SVB Leerink’s Geoffrey Porges:

This triple data is, if anything, even better than the previously released VX-659 triple results, and in our view effectively guarantees the launch, approval, commercialization and adoption of one of these combinations, with resulting multi-billion dollar sales to Vertex (regardless of the UK’s intransigence). ​

Reshma Kewalramani

“Both the VX-659 and VX-445 triple combination regimens showed highly consistent and significant improvements in lung function across our Phase III programs, underscoring the important clinical benefit that a triple combination regimen may provide to patients with two F508del mutations and to those with one F508del and one minimal function mutation,” said Vertex CMO Reshma Kewalramani. “We look forward to submitting global regulatory applications for one of these triple combination regimens for both patient populations later this year.”

Vertex has acquired quite a cheering section among analysts covering the market, with many seeing the company stepping up with a triple that can significantly broaden their market share.

Once approved — if the optimists are correct — Vertex will also throw their combo into the battle over access in Europe. Several single payer systems, most notably the UK, have bucked at the price of their bestseller Orkambi. But CEO Jeff Leiden has waged a PR war against his pricing foes, adamantly seeking more than what NICE and others are willing to pay. 

That showdown will come to a head tomorrow, as Vertex execs square off with public health officials in a high profile, head-to-head battle over the price. The triple can only add more heat to the already fetid confrontation that has now lingered for 3 years, with patients caught in the middle.

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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