With positive phase III data in hand from its next-generation corrector, VX-659, Vertex Pharmaceuticals Inc. was in a no-lose situation as it released data from the cystic fibrosis (CF) phase III studies for its other next-generation corrector, VX-445.

Vertex didn't exactly win, either. In fact, it was basically a dead heat between the two drugs, leading the Boston-based company to push back a final decision on which regimen to submit to regulators until it sees longer-term data from the studies that should be available in the second quarter of this year.

"Both VX-659 and VX-445 regimens have highly favorable efficacy and safety profiles and are potentially transformative for the treatment of CF. The decision of which asset to submit for approval is critical, and we want to carefully review all the data available for these regimens to ensure we make the best decision for patients," Reshma Kewalramani, executive vice president and chief medical officer at Vertex, told BioWorld.

Investors didn't seem particularly excited about waiting for a decision on which regimen to advance. Shares of Vertex (NASDAQ:VRTX) closed down $6.69, or 3.6 percent, to $181.11 on Wednesday.

In a phase III study of 402 CF patients with one F508del mutation and one minimal function mutation, treatment with VX-445 in combination with tezacaftor and ivacaftor for four weeks produced a mean absolute improvement in percent predicted forced expiratory volume in one second (ppFEV1) of 13.8 percentage points from baseline compared to placebo (p<0.0001).

By comparison, data released in November showed VX-659, tezacaftor and ivacaftor produced a mean absolute improvement in ppFEV1 of 14 percentage points from baseline to week four of treatment compared to placebo in the same population of 380 CF patients (p<0.0001).

The 0.2-percentage-point difference might seem to slightly favor VX-659, but the 13.8 vs. 14 comparison is for numbers relative to placebo. In the VX-659 study, the group who got placebo did a little worse, so looking at the within-group improvement, VX-445 actually has a slight edge, with a mean absolute within-group improvement in ppFEV1 of 13.6 percentage points from baseline to week four, compared to a 13-percentage-point improvement for VX-659.

The top-line data from a second set of phase III studies of patients with two F508del mutations who were already taking tezacaftor and ivacaftor, which Vertex markets as Symdeko, was even more similar (identical in fact). In both studies, adding VX-445 or VX-659 to tezacaftor and ivacaftor for four weeks produced a mean absolute improvement in ppFEV1 of 10 percentage points compared to patients taking placebo added to tezacaftor and ivacaftor (p<0.0001 for both studies).

Looking at the within-group numbers for the patients with two F508del mutations, VX-445 had a slight advantage with a mean absolute within-group improvement of 10.4 percentage points, compared to an improvement of 10.2 percentage points for VX-659.

"Bigger picture, both of the triple combinations continue to look very strong vs. existing therapies and what we've seen out of competitor programs to date, and the data today leave us incrementally more confident that the company's dominance in the CF space will continue," J.P. Morgan analyst Cory Kasimov concluded of the data for both regimens.

Safety data – at least what was released by Vertex – wasn't any help in deciding a winner, either. Both regimens were only described as "well-tolerated" without any report on the frequency of adverse events.

"We believe that additional disclosure for safety and tolerability for VX-445, as well as VX-659, will occur, potentially at a major medical meeting," Leerink analyst Geoffrey Porges wrote, hypothesizing that data could be presented at the North American Cystic Fibrosis Conference, which starts at the end of October.

Waiting for 24-week data

Vertex plans to wait for more data before making a final decision about which regimen to take forward. The studies in patients with one F508del mutation and one minimal function mutation are still ongoing with another data readout at 24 weeks where Vertex will look at key secondary endpoints, including the number of pulmonary exacerbations, change in sweat chloride, change in patient-reported outcomes as measured by the respiratory domain score of the Cystic Fibrosis Questionnaire-Revised and change in body mass index, among others.

After reviewing the 24-week data and making a final decision about which regimen to take forward, Vertex plans to submit an NDA with the FDA in the third quarter of 2019 with the submission of an MAA in Europe expected in the subsequent quarter.

The timeline is a slight delay from Vertex's previous guidance to file an NDA "no later than mid-2019."

"This seems a small price to pay, in terms of time, for a major investment such as the triple launch," Leerink's Porges opined.

On the plus side, the delay will allow for simultaneous submissions for both indications. "Because these submissions will include the final 24-week data, Vertex will seek approval for patients ages 12 and older with one F508del mutation and one minimal function mutation and for patients with two F508del mutations concurrently," Vertex's Kewalramani said.

Around 27 percent to 30 percent of CF patients have one F508del mutation and one minimal function mutation, offering a substantial new market for Vertex to capture. In patients with two F508del mutations, the new triple combination will likely replace Symdeko, which itself has had a solid launch, logging $796 million in sales in its first 10.5 months on the market.