Vertex Pharmaceuticals Inc. is targeting third quarter filings in the U.S. and Europe after reporting positive data from two phase III studies testing oral CFTR corrector tezacaftor (VX-661) plus approved CFTR potentiator Kalydeco (ivacaftor) in cystic fibrosis (CF), a combination expected to broaden the swath of patients eligible for therapy. More importantly, however, the solid phase III readouts for the EVOLVE and EXPAND studies bode well for the company's efforts to create a triple-combo regimen capable of benefiting nearly 90 percent of the overall CF population.
The ultimate goal, according to Jeff Leiden, Vertex's chairman, president and CEO, is to create "a combination of medicine that fundamentally alters the progression of the disease for all people" with CF.
To that end, EVOLVE and EXPAND serve largely as stepping stones – albeit important ones, as data, particularly from EXPAND, could help reach a group of CF patients currently without treatment options, while safety results offer greater confidence that a three-drug regimen could be clinically and commercially viable.
Much of the excitement centered on tezacaftor, which appears to have better safety and suggests better efficacy than lumacaftor, the drug that, along with ivacaftor, comprises Vertex's Orkambi, which gained first approval in 2015. Sales of Orkambi have been decent though not stellar – Cortellis Competitive Intelligence listed 2016 sales of $980 million – and its uptake in the market has been snagged by reimbursement and patient compliance issues.
EVOLVE and EXPAND data "confirmed our long held expectation that tezacaftor would prove to be both better, and better tolerated, than lumacaftor," wrote Leerink analyst Geoffrey Porges in a research note. "Tezacaftor also raises the bar for competitive entries, extends the patent horizon by a year or two and provides a solid foundation for the company's triple-combination program."
Wall Street clearly agreed with that enthusiastic outlook. Shares of Vertex (NASDAQ:VRTX) gained $18.34, or 20.5 percent, to close Wednesday at $108.01. Shares changed hands at eight times the normal volume.
In a conference call Wednesday morning, Leiden said Vertex designed the two phase III trials testing tezacaftor/ivacaftor (tez/iva) to answer three questions:
- 1. Do the studies support approval for use in CF patients with two copies of the F508del mutation?
- 2. Do they support approval for use in CF patients with one mutation that results in residual CFTR function and one copy of the F508del mutation?
- 3. Is the doublet efficacious and well-tolerated enough to warrant adding a third therapy to the mix?
"Based on the data, we believe that the answer to all three key questions is clearly yes," Leiden said.
EVOLVE, a randomized, double-blind, placebo-controlled study aimed at testing once-daily tezacaftor plus twice-daily ivacaftor in CF patients, 12 and older, with two copies of the F508del mutation, with a primary endpoint of absolute change in predicted forced expiratory volume in 1 second (ppFEV1). Through 24 weeks, the mean absolute improvement in ppFEV1 was 4 percentage points from baseline for those treated with tez/iva vs. placebo (p<0.0001).
Statistically significant improvements were seen in key secondary endpoints, too, namely a 35 percent reduction in the annualized rate of pulmonary exacerbations with the doublet therapy vs. placebo, a finding that was "especially encouraging," noted Jeff Chodakewitz, executive vice president, global medicines development and medical affairs, and chief medical officer.
The mean relative change in ppFEV1 through 24 weeks also hit statistical significance vs. placebo (p<0.0001), as did the change in Cystic Fibrosis Questionnaire-Revised (p < 0.0001). Change in body mass index showed only a slight difference between treatment and placebo (p = 0.4127).
The tez/iva combination was generally well-tolerated, and the rate of discontinuation due to adverse events was similar between the treatment and placebo groups. Of the 477 patients who completed the 24-week trial, 461 opted to enroll in a rollover study to receive combination treatment.
A readout of the EXPAND study, which enrolled CF patients 12 and older with one mutation that results in residual CFTR function and one copy of the F508del mutation, also yielded positive ppFEV1 results, with the tez/iva combination besting both placebo and ivacaftor monotherapy. Data from the eight-week, randomized, double-blind, placebo-controlled, crossover trial showed the mean absolute improvement in ppFEV1 was 6.8 percentage points from baseline for the tez/iva group vs. placebo (p < 0.0001) and 4.7 percentage points for those in the ivacaftor-only group vs. placebo (p < 0.0001). An additional pre-specified analysis showed that the tez/iva group had an improvement of 2.1 percentage points over the ivacaftor-only group (p < 0.0001).
Safety data were similar to what was seen in the EVOLVE study. Of the 235 patients who completed EXPAND, 227 chose to continue in a rollover trial to receive the combo treatment.
'HOW TO GET TO THE ENDGAME'
Vertex plans to submit regulatory applications in both the U.S. and Europe in the third quarter for tez/iva and is "certainly going to propose accelerated approval," said Chodakewitz.
For patients with one mutation that results in residual CFTR function and one F508del mutation, tez/iva could become the first treatment option. Worldwide, there are about 1,500 patients over the age of 12 who fall into that subset, according to Vertex. For patients with homozygous F508del mutations, the treatment could become an alternative for those who cannot tolerate Orkambi.
Credit Suisse analysts are modeling peak sales of tezacaftor totaling about $1 billion in 2023, "but this could be larger if patients switch from Orkambi to [tezacaftor] longer term," they noted. "Since we could see better compliance and persistence with [tezacaftor] vs. Orkambi, this could potentially also increase the market opportunity from the homozygous population."
In the meantime, Boston-based Vertex already has a clinical trial underway aiming to expand the doublet's use in patients, ages 6 to 11.
A separate phase III study also is ongoing testing tez/iva in CF patients with one copy of the F508del mutation and a second mutation that results in a gating defect in the CFTR protein. Last summer, the firm opted to stop a study testing the two-drug combo in patients with one copy of the F508del mutation and one copy of a mutation that results in minimal CFTR protein function following a futility analysis. (See BioWorld Today, Aug. 17, 2016.)
Since gaining approval of Kalydeco in 2012 – initially only for patients with the G551D mutation of the CFTR gene, or about 4 percent of the CF patient population – Vertex has worked to expand the patient base. Kalydeco's label now includes a host of CF gene mutations, including G1244E, G1349D, G178R, G551S, S1255P, S549N, S549R and R117H, and is used in patients 2 and older. Then came Orkambi, approved for patients 12 and older with homozygous F508del mutations, the largest CF subset. (See BioWorld Today, Feb. 1, 2012, and July 6, 2015.)
Currently, Vertex estimates about 29,000 patients worldwide are eligible for its CF treatments. Future label expansions – Orkambi for patients under 12 and Kalydeco for patients with residual function mutations – could raise the number as high as 44,000. After that, Vertex will try to reach up to as many as 68,000 – out of the estimated 75,000 CF patients worldwide – with triple-combination therapy.
Of the tez/iva readout, Leiden said, "basically it cements two legs of the stool," and called it a "de-risking event" for the triple-drug program.
"I think we have a high probability of success," he added. The company has four next-generation correctors in the clinic, two in phase II testing and two in phase I. "Now, it really becomes a matter of when, not if, we're going to be able to create such a triple combination, and I think the data that reads out in the second half of this year will be very informative in terms of picking one or more of those regimens to take into pivotal trials."
In October, Vertex disclosed plans to start two phase II studies with next-gen correctors VX-440 and VX-152 in combination with tez/iva.
The four-week VX-440 study is enrolling 40 CF patients who have one F508del mutation and one minimal function mutation and about 25 patients who have two copies of the F508del mutation. The two-week VX-152 study will enroll 35 patients with one F508del mutation and one minimal function mutation and 25 with homozygous F508del mutations. Data from both of those studies are expected in the second half of this year. (See BioWorld Today, Oct. 27, 2016.)
Phase I-stage next-gen correctors VX-659 and VX-445 also are progressing, with Vertex anticipating starting phase II development for one or both of those later this year.
As the firm continues collecting data, "we're getting a pretty clear vision on how to get to the endgame," Leiden said.
Analysts sound encouraged, as well. "We believe [tezacaftor] and especially the company's next-gen correctors (as part of a triple combination) have the potential – if successfully developed and approved – to drive substantial long-term upside in CF," wrote J.P. Morgan analyst Cory Kasimov. "We believe [Vertex's] prevailing dominance in the CF space, potentially meaningful bottom-line leverage and an advancing pipeline that could sustain its competitive position add to the company's overall strategic value."
For now, Vertex is well ahead of its chief potential competitor. Galapagos NV is working with Abbvie Inc. in an alliance to develop potentiators and correctors targeting the CF gene, also with the aim of creating a triple-combo therapy.
Credit Suisse analyst Vamil Divan noted that Vertex's success with the tez/iva trials "increases expectations for what [Galapagos] will need to deliver in terms of timelines and data for their triplet."
Galapagos has said it expects a triple-combo regimen to be tested in patients with the F508del mutation this year.