Vertex Stuck Between A Good Place And A Better Place

Two three-drug regimens for cystic fibrosis hit their primary endpoints in both heterozygous and homozygous patients, with good safety and tolerability, which analysts say increases the likelihood one of them will obtain approval.

Vertex Pharmaceuticals Inc. may not yet have certainty on which of two three-drug combination regimens for cystic fibrosis it will file for approval in the US and Europe, but it at least has options. A second three-drug combo hit the primary endpoints in a pivotal Phase III study a few months after its first trio did the same, and now Vertex says it will wait for 24-week data to decide which regimen it will file for approval.

On March 6, the Boston specialty pharma revealed that a combination of next-generation CFTR (cystic fibrosis transmembrane conductance regulator) corrector VX-445 with the components of its marketed two-drug therapy Symdeko (ivacaftor/tezacaftor) met the primary efficacy endpoint for lung function improvement in both patient cohorts of a Phase III study. In November, it reported nearly identical efficacy findings for a three-drug combo of another CFTR corrector, VX-659, plus Symdeko and said it would wait for data from the second trial to decide which was the better candidate for filing. (Also see "Vertex's CF Three-Drug Combo Excels In Phase III, But Filing Depends On Second Regimen's Results" - Scrip, 29 Nov, 2018.)

“Not only did all studies meet their primary endpoint, but the similarity in the four-week lung function data between the Phase III triple combo studies, evaluating either VX-445 or VX-659 in combination with tezacaftor and ivacaftor, has pushed Vertex to look for differentiating signals in the final 24-week data that will become available for the winning drug in the second quarter,” Datamonitor Healthcare Senior Analyst Pamela Spicer told Scrip. “This shouldn't have a major impact on the company's initial plans to submit an NDA by mid-2019, now the third quarter, to get a triplet to CF patients by 2020.”

In a pre-specified interim analysis, patients with one F508del mutation in the CFTR gene and one minimal function mutation (heterozygous patients) showed a mean absolute improvement in percent predicted forced expiratory volume at one second (ppFEV1) after four weeks treatment with the VX-445 triplet of 13.8 percentage points from baseline compared to placebo. The VX-659 three-drug regimen yielded a 14-point mean absolute improvement in ppFEV1 compared to placebo.

The efficacy data in homozygous patients (those with two F508del mutations) was also extremely similar in the two studies. Patients showed a 10-percentage point mean absolute improvement from baseline with the VX-445 regimen in the four-week interim look, compared to 9.9 points in the four-week interim look with the combo containing VX-659.

Vertex said the regimen containing VX-445 was well tolerated and showed an approvable safety profile. Of note, all treatment-arm and placebo-arm patients from both cohorts of the study agreed to participate in an open-label extension study with VX-445/Symdeko.

Now, Vertex says it is going to wait until it has a full 24-week dataset for both the VX-659 and VX-445 combination regimens before it decides which one to file for approval in the US and EU. This decision slightly sets back its timeline for a filing at the US FDA; where Vertex previously guided to a mid-2019 filing, it is now targeting third quarter 2019 for the filing. It still expects to file one of the regimens for approval in Europe during the fourth quarter. Further, given the strength of the data seen so far, Vertex says it will seek approval in heterozygous and homozygous patients concurrently with whichever regimen it picks.

Setting A High Bar For CF Competition

Analysts were largely impressed with the data. SVB Leerink analyst Geoffrey Porges wrote in a March 6 note that “this 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.” The latest results “further place Vertex in the driver’s seat” in CF, with potential competitors years behind, he added.

SVB Leerink projects an early 2020 launch of whichever regimen moves forward with $400m in first-year revenue, increasing to $5.2bn in 2024. Consensus estimates project $800m in sales in 2020 and $4.8bn in 2024, the note states.

Jefferies analyst Michael Yee revised his previous prediction that Vertex was likely to file the combo including VX-659 due to the better safety profile seen in Phase II. Now, both regimens are equally in play, he said on March 6.

“With the data looking similar between the two regimens to date, we think it is a prudent move by the company to wait for more data in Q2, given they will have a better picture of the efficacy and safety profile of the drugs at that point,” Yee said.

The data indicate that either triple regimen could improve upon lung-function improvement of roughly 4% with Symdeko or Vertex’s previously approved doublet Orkambi (ivacaftor/lumacaftor) to about 14%. While this will cannibalize the earnings of those two products, it also “creates a huge barrier to entry [for competitors] given the enhanced safety/efficacy profile of both triples,” Yee added.

Datamonitor’s Spicer noted that Vertex estimates approval of a triplet regimen would enable it to reach about 68,000 CF patients worldwide, encompassing about 90% of the global patient population. “This approval would not only allow Vertex to hit its goal of expanding to new CF patients, but the impressive efficacy data will prompt current patients to use the new triple combo,” she said. “Competitors will now need to beat the double-digit percent improvement from baseline in lung function in order to challenge Vertex' dominant spot in CF.” (Also see "Vertex Set To Dominate Cystic Fibrosis Market For The Next Decade" - Scrip, 24 Sep, 2018.)

William Blair analyst Katherine Xu said one competing data readout to keep an eye on is the Phase II proof-of-concept data expected this quarter from Proteostasis Therapeutics Inc. with its proprietary triplet of CFTR correctors PTI-808, PTI-801 and PTI-428. (Also see "Finance Watch: The Curious Case Of Proteostasis' Short Attack" - Scrip, 22 Mar, 2018.)

Xu pointed out that in a prior study, a two-drug regimen of PTI-808 and PTI-801 yielded a mean absolute improvement in ppFEV1 in homozygous patients of 6%-8%, “seemingly comparable to or better than Symdeko.” PTI-428 is added as an amplifier compound to the doublet, and Xu said if Proteostasis can achieve at least a 10-percentage point improvement in ppFEV1 in both heterozygous and homozygous patients, its triple regimen “will be viewed as competitive to Vertex.”