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Vertex Completes NDA on CF Drug for G551D Mutation, Releases Data on Other Targeted CF Therapies


By Molika Ashford

Vertex last month submitted new drug applications to the US Food and Drug Administration and the European Medicines Agency for Kalydeco, a CFTR potentiator that showed promising results in two clinical trials this year for cystic fibrosis patients harboring the G551D mutation.

Last week, the company reported data from its primary phase III trial, STRIVE, in the New England Journal of Medicine and also presented final results from a phase III study of Kalydeco (ivafactor, previously called VX-770) in children between six and eleven years old at the North American Cystic Fibrosis Conference.

Additionally, Vertex released early data at the conference from a phase II study evaluating a combination of VX-770 with another experimental drug, VX-809, to treat patients with the much more common F508del mutation.

While only four percent of CF patients are G551D mutated, 90 percent carry at least one copy of the F508del mutation, which has motivated researchers to investigate additional drugs that might prove effective in this larger patient group. In earlier studies, F508del patients showed no benefit from VX-770, so Vertex is now evaluating the CFTR corrector VX-809 as well another CFTR corrector, VX-661, in those patients, Eric Olson, vice president of the CF franchise at Vertex, told PGx Reporter this week.

While trials for these other treatments are still in early stages, the company hopes it is close to an approval for VX-770 in the US and Europe so that the drug can begin benefitting those CF patients who do carry a G551D mutation.

Vertex and the CF Foundation jointly discovered the mechanism underlying VX-770, which is the first drug to target an underlying genetic defect of cystic fibrosis rather than its symptoms. The foundation is funding Vertex's development of the drug and has provided $75 million to the company for CF research (PGx Reporter 3/23/2011).

Bonnie Ramsay, associate director of the cystic fibrosis clinic at Seattle Children's Hospital and the principal investigator on the STRIVE trial, told PGx Reporter that she considered the results "extraordinarily impressive."

"Because I've been involved in CF research for many, many years, I tend to be a very conservative person. But these were eye-popping results," she said.

Ramsey runs the CF Foundation's therapeutics development network. While most of the top-line data from the STRIVE trial was presented earlier this year (PGx Reporter 3/23/2011), she said that the full report published in NEJM offers important additional details.

For example, the report details more recently completed subgroup analyses, which demonstrate that the effect of VX-770 wasn't skewed by a concentration of response in any one clinical subset.

"The subgroup analysis is very important because if you look back at the development of other [CF therapies] … often there was a subgroup that really sort of pulled the whole population," she said. "For example, in [a previous trial for the antibiotic tobamycin], it was the adolescents who had this remarkable improvement, so that had an impact on the overall findings."

In STRIVE, "it's quite striking that it's significant from the most severely involved to the mildest, the youngest to the oldest. It was really surprising to me to see that you had so much consistency and it was all significant across … age, geographic distribution, illness severity, and gender," she said.

All patients in the STRIVE trial were 12 or older and had a G551D mutation on at least one CFTR allele. Overall, the 77 patients given VX-770 had 10.5 percentage points greater lung function over the 48-week STRIVE trial than the 68 placebo-group patients. They also gained more weight, had a 55 percent reduction in the risk of pulmonary problems requiring antibiotics, and their sweat chloride levels — a marker of CFTR protein dysfunction — dropped by approximately 50 mmol per liter.

One element that STRIVE did not really assess was the microbiologic impact of VX-770 therapy, Ramsey said, adding that the CF Foundation plans to conduct an independent observational study to collect baseline and follow-up data on the microbiology of patients taking the new drug, along with additional markers of their airway function.


In addition to the publication of STRIVE, Vertex also released final results at the North American Cystic Fibrosis Conference from a second Phase III study, ENVISION, which evaluated VX-770 in 52 children between the ages of 6 and 11 with at least one copy of the G551D mutation. Of the study population, 26 subjects received the potentiator and 26 received placebo in 150 mg single-tablet doses every 12 hours.

Patients on VX-770 showed "rapid, significant and sustained improvements in lung function throughout the 48-week study," Vertex said in a statement.

Through week 48 the treatment group gained 13 pounds on average compared to 6.8 lbs for the placebo-treated patients. By the second week of the trial, children treated with VX-770 experienced an average reduction in sweat chloride of approximately 53 mmol per liter; and through week 48, the average reduction rose to 56 mmol per liter. Children in the placebo group experienced an average reduction of only 3 mmol per liter.

Along with the final ENVISION data, Vertex also released some initial results last week from another trial called PERSIST, a 96-week open-label follow-up study of safety and durability of treatment with VX-770 in the adolescents and adults who participated in STRIVE.

Analysis presented at the meeting included data from 144 STRIVE participants, of whom 77 were treated with VX-770 and 67 received placebo.

In PERSIST, positive changes in lung function in those from the STRIVE treatment cohort were sustained through another 12 weeks for a total of 60 weeks of treatment, the company wrote. "In addition … when people treated with a placebo during the STRIVE study rolled over to PERSIST and began receiving [the drug], the improvements in lung function through week 12 were similar to those observed among people treated … in the first 12 weeks of STRIVE."

Patients who received placebo during STRIVE showed a 10.9 percent absolute change in lung function in the first 12 weeks of PERSIST, while patients who were treated throughout the 60 weeks of both trials showed an 11.6 percent absolute improvement, the company reported.

According to Olson, Vertex plans next year to start a study of VX-770 in children aged two to five years with G551d mutations. This may shed some light on whether the drug might be able to halt deterioration of lung if used earlier in life.

Recent research has been able to detect lung damage in children with CF as young as "one year or less," he said. "We don't know until we test the drug in that age group what the long-term benefit will be from treating early. But certainly there is a lot of excitement and interest in testing this drug in younger patients."

Additionally, Vertex plans to study next year whether VX-770 also has an effect on other CFTR gating mutations aside from G551D, Olson said.

VX-809 and VX-661

Vertex also presented data at the conference from the first part of an ongoing Phase II study, which suggests that treatment with a combination of VX-770 and VX-809 — an experimental Vertex drug that acts on a different CFTR protein dysfunction — may improve outcomes for people with the most common CF mutation, F508del. Approximately 90 percent of people with CF have at least one copy of the F508del mutation, and about 48 percent have two copies.

The G551D mutation is known as a gating defect, preventing CFTR proteins from unfolding properly at the surface of cells, but is only present in approximately four percent of patients. VX-770, a CFTR potentiator, acts to keep CFTR channels in the cell surface open longer.

But for patients with the F508del mutation, in which CFTR proteins do not reach the cell surface in normal amounts and don't function properly when they get there, CFTR potentiation alone does not appear to work. VX-809 (and another compound VX-661 also in development at Vertex) are CFTR correctors, aiming to increase the proteins' function by increasing the movement of CFTR to the cell surface, according to Vertex.

"Since [f508del] is the most predominant mutation, we wanted a definitive answer [as to] whether VX-770 would work in that group or not, so we did a study there and it turned out it did not work in that group," Olson said. A previous Phase II trial using VX-809 by itself also didn't work, he said, so that formed the basis for the company's combination strategy.

Ramsey said it is likely that VX-770 will need to be used with added correctors in patients with F508del mutations, possibly even with more than one corrector.

"It’s a very complicated process because the protein has to be folded properly, has to be tracked up to the surface, has to bind and then open up," she said.

"We've figured out how to do the last step, which is how you open up or potentiate. But now they're working on the correctors, how to get it folded and up to the surface."

Vertex presented full data from the first part of the phase II combined therapy study last week. During the 21-day study, 62 patients 18 and older with two copies of the F508del mutation were divided into three arms and given placebo or VX-809 alone for two weeks, followed by a combination of VX-809 and VX-770 or a placebo combination for another seven days.

Data showed that there was a nearly two-fold greater reduction in sweat chloride between day 14 and day 21 when VX-770 was added to VX-809 compared to those who continued to receive VX-809 alone, the company reported.

Patients in the non-placebo arms showed a sweat chloride reduction of 4.21 mmol per liter in the first two weeks. The arm with an added dose of 150 mg of VX-770 in the final week had an additional 2.24 mmol per liter reduction, and the arm with a higher 250 mg added dose showed a further reduction of 9.1 mmol per liter, for a total of 13.17 mmol per liter.

Eight of the 17 patients with evaluable data in the larger-dose arm "had a reduction of sweat chloride that exceeded 15 mmol per liter, while four of these 17 patients had a reduction of sweat chloride that exceeded 20 mmol per liter," Vertex wrote.

According to Vertex, the second part of the trial, now enrolling patients, will evaluate dosing of VX-809 alone for four weeks followed by a combination of the two drugs for four weeks. Olson said the study will evaluate multiple dose levels of VX-809, some higher and of longer duration than those studied in the trial's first section.

Primary goals are to evaluate safety and tolerability and the effect of the combination on CFTR function as measured by sweat chloride, the company said. Lung function will also be measured as a secondary endpoint.

According to Olson, Vertex also anticipates starting a study next year for the other CFTR corrector, VX-661, first looking at the compound alone, and then, based on results, potentially combining it with VX-770, as well.

Ramsey said that the drop in sweat chloride in the first part of the VX-809 trial was much lower than in STRIVE. "Of course the big question always is, how much change in sweat chloride do you need to have? It was about a third of what was seen in the G551D [trial] so it's probably not going to be as dramatic an effect," she said.

"On the other hand, I think it's a very important step forward, because … we know for some of the milder CF mutations, those patients' sweat chlorides are a little bit lower: instead of in the 100 [mmol per liter] range [they are] in the 80 [mmol per liter] range. And even that small difference has a significant impact on the morbidity and lifespan of those patients," she said. "[Sometimes up to] a decade longer."

This means that even small increments are likely to have some impact, she said. "Is it a cure? Probably not, but it probably will be beneficial."

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at mashford [at] genomeweb [.] com.

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