Consistent phase III cystic fibrosis (CF) data for a combination regimen of Vertex Pharmaceuticals Inc.'s VX-809 (lumacaftor) and Kalydeco (ivacaftor) offered marked improvements in lung function, and hit multiple secondary endpoints, driving the Boston-based company's stock up by 40 percent Tuesday.

The statistically significant results showed that all four treatment arms in TRAFFIC and TRANSPORT hit the primary endpoint of mean absolute change from baseline in percent predicted forced expiratory volume in one second (FEV1) compared to placebo. Vertex plans to submit regulatory filings in the U.S. and Europe in the fourth quarter, and if all goes as planned, a launch could come as early as the second half of 2015.

Investors responded with enthusiasm. The stock (Nasdaq:VRTX) climbed 40.4 percent, or $26.92, to close Tuesday at $93.53.

While the Street estimates pricing, upon approval, of between $150,000 and $175,000, about half of what Kalydeco costs, analysts from Cowen and Co. and RBC Capital Markets LLC expected it to be higher. Cowen's Phil Nadeau and Mark Frahm estimated a $5.5 billion CF product franchise for Vertex by 2018, with about 5,000 patients on Kalydeco and 17,000 on lumacaftor/ivacaftor, assuming a price of about $250,000 per patient per year. RBC's Michael Yee put peak sales at $4.5 billion, with U.S. pricing around $225,000 for the combination.

Yee called the data a "solid win," mentioning in a research note that potential competition is lagging. "The big picture that investors should remember is this is a major improvement for sick CF patients (typically kids), and all our doc feedback is that, if the drug is FDA approved, the patients will get access to it."

CF, one of the most common autosomal recessive diseases, affects about 75,000 people in North America, Europe and Australia, many of whom spend two hours a day on treatments to clear their lungs of sticky mucus. They lose on average 2 percent of lung function a year, and the median age of death is the mid-to-late 20s.

Vertex's combination treatment joins a corrector (lumicaftor) and a potentiator (ivacaftor) to target the 22,000 people ages 12 and older with the most common form of CF, those who have two copies (homozygous) of the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene.

In addition to improvements in lung function, the combination regimen showed benefits in body mass index and a reduction in pulmonary exacerbations, a common CF event that often results in hospitalizations.

"For these patients, every improvement that they have in lung function, and every day that they don't spend in the hospital and every pound they gain is meaningful both to them and to their families," said Vertex president and CEO Jeff Leiden on a conference call, "and that's why we're so pleased with the results and so eager to get this medicine to the patients who are waiting for it."

Vertex is working to provide the therapy on a compassionate use basis prior to approval. With a new drug application in the U.S. and a marketing authorization application in Europe slated for the fourth quarter, as an FDA breakthrough therapy, analysts expect a drug launch as early as the second half of 2015.

'VERY STRONG RISK-BENEFIT PROFILE'

Nearly identical studies, TRAFFIC and TRANSPORT enrolled more than 1,100 patients across 200 sites, and each consisted of two treatment groups of lumicaftor given at 600 mg daily or 400 mg every 12 hours, plus 250 mg of ivacaftor every 12 hours, compared to a placebo group. The primary endpoint was assessed by the average change in lung function at weeks 16 and 24.

In TRAFFIC, the 600-mg and 400-mg groups displayed an absolute treatment difference of 4 and 2.6 percentage points (p = 0.0004), and a relative difference of 6.7 percent and 4.3 percent (p = 0.0007), respectively. In TRANSPORT, the absolute treatment difference was 2.6 and 3 percentage points, and the relative difference was 4.4 percent and 5.3 percent.

Pooled data from both trials evaluated absolute FEV1 over time.

"The combination treatment arms separate from the placebo arm by the first measurement at week two and sustain a separation throughout the study period," said Jeff Chodakewitz, Vertex's senior vice president and chief medical officer. "In fact, each measurement from each of the four active treatment arms within the study at weeks two, four, eight, 16 and 24, shows statistically significant mean, absolute and relative improvements in lung function, both within group and vs. placebo."

The combination regimen hit several secondary endpoints, including mean relative change from baseline in FEV1, with twice as many treated patients achieving a 5 percent and 10 percent improvements compared to placebo patients. Five percent improvement was seen in 46 percent of 600-mg patients, 39 percent of 400-mg patients and 22 percent of placebo patients. A 10 percent improvement was seen in 27 percent of 600-mg patients, 24 percent of 400-mg patients and 13 percent of placebo patients.

A body mass index secondary endpoint showed that treated patients gained about 1.5 pounds more over 24 weeks, compared to placebo. Treated patients also showed a 39 percent to 61 percent reduction in pulmonary exacerbations that required hospitalizations, and a 45 percent to 56 percent reduction in events requiring intravenous antibiotics. Even when divided by subgroup, improvements were seen across the board, according to age, gender, geography, baseline FEV1 status, baseline CF medications and those with Pseudomonas aeruginosa infection.

The only secondary endpoint for which statistically significant changes were not consistently observed was patient-reported respiratory symptoms as part of the CF questionnaire-revised (CFQ-R). In a research note, Wells Fargo Securities analyst Brian Abrahams said the endpoint is "less important, as it is a subjective and potentially less reliable measure."

In terms of safety, the combination regimen was generally well tolerated, with adverse events occurring in the first week of treatment. The most common were infective pulmonary exacerbation, cough, headache and increased sputum. A total of 4.2 percent (31) of treated patients discontinued treatment due to adverse events, compared with 1.6 percent (six) of placebo patients.

"We think we've got a very strong benefit-risk profile, which translates into a high-value medicine for people with CF," said Vertex's chief commercial officer, Stuart Arbuckle. Looking ahead toward a potential approval of the combination regimen, the company will not need to expand its sales force in the U.S. and northern Europe, Arbuckle said – Kalydeco first received approval for CF in early 2012 – but he expects to build a bigger footprint in other parts of Europe, as well as Latin America and Brazil. (See BioWorld Today, Feb. 1, 2012.)

Soon, Vertex hopes to have results of the heterozygous study portion of the combination therapy, and it plans to start dosing in patients ages 6 to 11. A phase II trial is enrolling and dosing homozygous patients with another corrector, VX-661, plus ivacaftor, with data expected early next year. Vertex said it believes it may become part of a triple-drug regimen, as it has shown two advantages over VX-809: better lung penetration, and no decline in FEV1 when used as a monotherapy, as was seen in a phase II trial with VX-809.