Vertex and Treating CF: 3 Disease-modifying Therapies Make Leap from Lab to Patients

Editor’s Note: This is the second of a four-part series looking at Vertex Pharmaceuticals and its “all in for CF” approach. Here, we detail the steps that made three disease-modifying oral treatments for cystic fibrosis possible.

Kalydeco (ivacaftor), as Vertex‘s cystic fibrosis potentiator came to be known, was a small molecule compound that posed big questions upon its discovery in the mid-2000s.

Should researchers go ahead and test it in those few patients — about 3 percent worldwide — with a rare gating mutation known as G551D?

Should they plow on in pursuit of a paired corrector, a double combination that might treat many more — some 40 percent — with the F508 deletion mutation?

These weren’t minor considerations. No disease-modifying therapy existed in 2005 to strike at the underlying cause of cystic fibrosis (CF), a progressive mutation-driven disease that takes hold at birth and continues its damaging toll for life.

Paul Negulescu, a senior vice president at Vertex and CF research team leader. (Photos courtesy of Vertex Pharmaceuticals)

“This really good-looking compound” made company scientists wonder — as Paul Negulescu, leader of Vertex’s CF research team and now a senior vice president, put it — “can you restore the function of CFTR in a person? … And if you do, what sort of clinical response do you see?”

The ultimate decision to bring ivacaftor into a Phase 2 safety and tolerability study (NCT00457821) in 39 gating mutation patients in 2007 was a good one — serendipitous, even.

Ivacaftor surpassed all best hopes, becoming “a landmark study in the field,” Negulescu said in an interview with Cystic Fibrosis News Today.

Two Phase 3 trials — STRIVE (NCT00909532) and ENVISION (NCT00909727) — followed, and would be instrumental in Kalydeco’s approval. Results were impressive across-the-board, including significant and sustained improvements in sweat chloride levels (a measure of the CFTR protein’s performance), lung function (measured using FEV₁, or forced expiratory volume in one second), and weight gain.

Data extended to a subsequent open-label extension study, PERSIST (NCT01117012), proved these gains were sustained, and included an absolute increase in FEV₁ of 9.4 percentage points in adolescents and 10.3 points in adults at week 96, according to published results.

The U.S Food and Drug Administration (FDA) approved Kalydeco for gating mutation patients ages 6 and older in January 2012; Europe followed suit six months later, and Canada in November.

Since then, Kalydeco’s use has been expanded to CF patients with a gating mutation as young as 12 months old in the U.S. and patients as young as 2 in Europe and Australia.

Reshma Kewalramani, Vertex’s chief medical officer.

Approval requests are in for those 12 to 24 months old in the U.S. and Europe based on an ongoing Phase 3 trial called ARRIVAL (NCT02725567), said Reshma Kewalramani, Vertex’s chief medical officer. Kalydeco’s testing is continuing in infants enrolled in this study.

Expanding access to younger patients is especially important to Vertex, which believes its disease-modifying treatments work against CF progression,  Kewalramani said. The earlier patients start using them, the less damage they sustain.

Data from a large-scale, real-world registry study presented at a June science conference support Kalydeco’s benefits. Here, treated CF patients — 635 on the therapy for five years in the U.S., and 247 for four years in the U.K. — were compared to age-, sex-, and disease severity-matched untreated patients (more than 1,200 in each country). Kalydeco use resulted in lower risks of mortality, transplants, hospitalization, and pulmonary flares.

To date, this treatment is FDA-approved for 38 known CF-causing mutations.

“Kalydeco showed that, for a particular set of mutations in the CFTR gene, a small molecule could boost their function to a level where they’d have a very substantial clinical benefit both short term and long term,” said David Altshuler, Vertex’s chief science officer.

A disease-modifying treatment was indeed possible for CF. Now, all Vertex needed to do was make a combination treatment — ivacaftor plus a corrector — for the many more patients whose CFTR protein may never reach a cell’s surface, like those with F508del mutations.

Double combinations arrive

CF can result from many variations in the CFTR gene; in fact, 374 known mutations are considered the most common. But it is a recessive disease, meaning that both gene copies, one inherited from each parent, have to be defective. One healthy CFTR gene is enough to remain symptom-free.

To Vertex, that meant we “just need to boost one gene copy,” Altshuler said. It also meant a double combination treatment because many common mutations, like F508, involved CFTR proteins that can neither unfold to get to the channel membrane nor work once there. A corrector works to fix the protein’s structure and movement; a potentiator works to increase its activity as a channel in transporting ions through the membrane.

David Altshuler, Vertex’s chief scientific officer.

“We know that single therapy with ivacaftor was very effective — it’s probably still one of the more effective treatments that we’ve had,” said Edith Zemanick, a pediatric pulmonologist at Colorado Children’s Hospital and an investigator for Vertex CF trials. But “for most patients, given their genotype … [a] single therapy is not going to work. It’s not going to be effective enough.”

Even as Kalydeco was heading into clinical trials in 2007, Vertex hit upon a potential corrector — lumacaftor — that could be paired with ivacaftor for those with F508 deletion mutations.

Later trials did test that combo, called Orkambi, paving the way for FDA approval for patients 12 and older in 2015, and later in younger groups — reaching those as young as 2 in August 2018.

But for all the potential seen in Orkambi — with efficacy and safety shown in two Phase 3 trials, TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949) — it wasn’t on the level of Kalydeco. It was a stopgap corrector, and one with limitations.  

“We got our first medicine for the largest population of CF patients, those with two copies of [F508del],” Negulescu said, but “it had some challenges as a combination therapy because it has some drug-drug interactions. It wasn’t an ideal compound as the basis for combination therapies.”

As one researcher with no connection to Vertex explained in a 2018 published study, Orkambi appears to have problems with how it is metabolized in the body.

Ivacaftor is broken down by liver enzymes, wrote Elena K. Schneider, PhD, a research fellow at the University of Melbourne’s Department of Pharmacology & Therapeutics, and lumacaftor seems to stimulate the activity of these enzymes, speeding this process. In other words, lumacaftor works to diminish ivacaftor’s effectiveness.

Not surprisingly, while Kalydeco’s approval was swift — one of the fastest in FDA history — Orkambi continues to face hurdles. Approved across the EU by the European Medicines Agency (EMA) in January 2018 for F508del patients starting at age 6, its inclusion in the subsidized health systems of specific EU countries has depended on negotiations about its cost.

Like Kalydeco, which carried an annual list price of $311,000 in 2017 according to Forbes, Orkambi is costly at $272,000 a year. That price has met resistance in some countries, and still blocks Orkambi’s inclusion in the U.K. health system.

Patients, however, are pushing for its approval, and for that of a newer double combination corrector — tezacaftor — paired twice with ivacaftor to create Symdeko (known as Symkevi in Europe).

Vertex’s “Cell Daycare,” where cells isolated from human lungs are stored and developed.

Tezacaftor (VX-661) plus ivacaftor showed superiority to ivacaftor alone in two Phase 3 studies, EVOLVE (NCT02347657) and EXPAND (NCT02392234), both in how it interacts with other compounds (drug-to-drug interactions) and in treating EVOLVE patients with one F508 mutation and one “residual function” mutation, which causes inadequate transport of salts (sodium and chloride) and water from cells.

Benefit was again seen in lung function — a “clinically important” increase of four or more points in 65 percent of Symdeko-treated patients in EVOLVE under the CFQ-R respiratory domain score — and in lower sweat chloride concentrations, fewer pulmonary flares, and evidence of better pancreatic health, according to published data.

Because tezacaftor showed clear evidence that it could play well with others, it also became the corrector of choice for a new generation of CF-targeted treatments, and that’s a “really important element,”  said Kewalramani. Tezacaftor in the form of Symdeko is “two-thirds of our triple combination” treatments now either in or readying for clinical trials, she said.

With Kalydeco, Orkambi, and Symdeko approved and available to many, Vertex has therapies able to treat about half of all people living with CF. With the next-generation triple combinations underway — mostly tezacaftor and ivacaftor plus a new corrector — that number may leap to 90 percent.

“These are really the first treatments to impact the underlying cause of CF,” said Zemanick, the Colorado pulmonologist. “And that’s what’s so exciting about the triple combinations” — the possibility of “almost 90 percent of people with CF having a modulator that’s hopefully effective.”

Another big plus, she added, is benefit from “essentially pills twice a day — oral tablets twice a day, generally. Compared to what people with CF do right now, it’s not adding a lot of treatment burden.”

Next: Testing begins on next-generation correctors and triple combinations, and Vertex explores the possibility of gene editing for CF.