Last October, the U.S. Food and Drug Administration (FDA) approved Trikafta to treat cystic fibrosis (CF). The drug’s maker, Vertex Pharmaceuticals, was already riding high on clinical trial data showing that Trikafta had outperformed Symdeko, the company’s previous CF therapeutic, by producing a 10% increase in forced expiratory volume, a measure of lung function. Vertex must have been particularly gratified that the FDA’s decision came five months earlier than expected.

Now that Vertex is looking to move into new disease treatment markets, from alpha-1 antitrypsin deficiency (AATD) to muscular dystrophy to pain, the question on the minds of industry analysts is: Can Vertex extend its success beyond the cystic fibrosis space? Also worth pondering is a related question: Can other pharma companies learn anything from Vertex’ experience?

Qualified success

“This program has snowballed as the company has applied their chemistry capabilities to different elements and different approaches,” says Geoffrey Porges, a senior research analyst at SVB Leerink who has been following Vertex since 2003. But that doesn’t necessarily mean that it can be duplicated in other disease indications or settings.

Trikafta is a triple combination therapy of elexacaftor/ivacaftor/tezacaftor that is approved for patients age 12 and older that have at least one F508del mutation in the CF transmembrane conductance regulator or CTFR gene, making it suitable for 90% of the CF patient population. No overnight success, Trikafta built on the experience Vertex acquired with Symdeko, a combination of tezacaftor and ivacaftor, and Orkambi, a combination of ivacaftor and lumacaftor.

Whatever successes a company may find in the diligent labor of drug development, there is always some degree of luck in the formula, Porges notes, and in the case of Vertex and Trikafta, that good fortune came in the company’s 2001 acquisition of Aurora Biosciences, which was already working on cystic fibrosis.

“Vertex bought Aurora for totally different reasons,” he points out. “Vertex didn’t even know the CF thing was there.” Vertex’ acquisition of Aurora, then, was analogous to Merck’s acquisition of Schering-Plough. Schering-Plough’s immunotherapy pembrollizumab, also known as Keytruda, wasn’t even a consideration for Merck, but it has since become part of Merck’s core business.

So, a first principle for anyone looking to duplicate Vertex’ success, Porges gathers, is “always look very carefully in the bottom drawer when you close an acquisition.”

But if Vertex drew a lucky hand, the company “played it brilliantly,” Porges continues. “The company decided to really push all of its cash onto the table and go full steam. It was very impressive, and that’s what led to Trikafta. Trikafta in the hands of many companies might have taken another 5 to 10 years.” In Porges’ estimation, Vertex’ aggressive deployment of capital demonstrates a second principle for success.

This kind of investment is, in fact, part of Vertex’ core strategy, says company CEO Jeffry Leiden, MD, PhD. (Leiden will step down in favor of incoming CEO Reshma Kewalramani, MD, later this spring.) “If you’re serious about serial innovation, [you accept that] it is a risky process and that you have to invest a lot of money in it. We’re the only company in the industry that consistently spends more than 70% of our operating expense on R&D, not on sales and marketing.”

The importance of being committed to innovation is also appreciated by Vertex’ CSO, David Altshuler, MD, PhD. He cautions, however, that successful innovation means understanding the underlying biology of a disease and focusing on validated drug targets. “If you discover a medicine and you do everything right, but the target is wrong, it’s never going to succeed,” he says. “You’ll be racing toward a brick wall.”

So, the Vertex strategy to attack CF was to begin by really understanding the CFTR gene and the protein it expresses. The CTFR protein forms a sodium ion channel that normally embeds in cell membranes and helps transport sodium chloride to cell surfaces. When mutations in the gene lead to no production of CTFR proteins, or misfolded proteins that cannot reach the cell membrane and effectively transport sodium chloride to the surface of lung cells, there’s no salt to attract water to those cell surfaces. Mucus in the lungs grows thick, immobilizing cilia and attracting bacteria.

Trikafta works as a corrector to the misfolded CTFR protein, with elexacaftor and tezacaftor increasing protein transport to the cell surface, and with ivacaftor then increasing the probability of the protein acting properly as a sodium chloride channel, transporting more salt to the cell surfaces.

Validation: Targets, assays, and biomarkers

While developing Trikafta, Vertex spent time validating assays and biomarkers to make sure its drug candidates were the best candidates, according to Leiden and Altshuler. For instance, the company’s preclinical development team made use of human bronchial epithelial cells, which were donated by patients, instead of engineered tissue cultures.

“If you use the engineered cell lines, you just don’t find the kinds of medicines that we found,” Leiden insists. “You’ll never see us use engineered animal cells for our primary assays, and you’ll never see us put a lot of stake in animal models of disease if they’re not expressing the human gene.”

The validated assays helped Vertex select drug candidates out of the lab, Altshuler says, and the disease-specific biomarkers helped the company expedite clinical work. In the case of Trikafta, Vertex realized that since CF affects the cellular transport of sodium chloride all over the body, the company could give its drug to patients and measure changes in chloride levels in their sweat as a biomarker of drug action. “This biomarker,” Leiden says, “allowed us to see early on how well these molecules were working before committing into Phase III.”

It’s also what allowed Vertex to get Trikafta through Phase I and II trials within two years as opposed to three to five years, which is typical for most companies and most diseases, observes Hartaj Singh, a senior analyst with Oppenheimer & Co.

“Vertex went to the FDA, and the FDA said, ‘Well, okay, that’s interesting,’” Singh relates. In addition to having the biomarker, the company would still need to show that Trikafta actually improves lung function. The FDA did, however, say that Vertex could use sweat chloride to help speed through Phase I and Phase II trials. According to Singh, Vertex realized a time savings of about 50%.

Repeat performance

Can anyone, Vertex included, duplicate the company’s CF drug development process for drugs meant to treat other disease states? Vertex is certainly trying, according to Singh. Take AATD, for example. “It’s actually weirdly analogous to cystic fibrosis,” he says.

AATD occurs because a mutation in both copies of the AAT gene leads to a misfiled AAT protein that cannot leave the liver to serve a protective function in other organs such as the lungs, leading to emphysema and liver cirrhosis. Vertex’ Vx-814 is a small molecule that corrects the misfolding of AAT, theoretically allowing it to exit the liver and function properly.

Vertex should once again be able to show the FDA a biomarker of drug efficacy, Singh predicts, in this case levels of functional AAT protein in patient blood. “Hey, look at these blood plasma levels,” he imagines Vertex saying. “We can show that there’s a lot of functional protein in the blood, meaning not only are we folding correctly in the liver, but then it’s going into the blood.” Then Singh suggests that the FDA could respond as follows: “OK, here’s your proof-of-concept Phase II. Run like a Phase II/III on patients with the disease to actually show clinical efficacy.” Following this suggestion would take a year or two, Singh estimates.

A Phase II trial of Vx-814 in 50 patients began in January. At present, this trial has a target end date of November.

Although Singh is impressed with the Vertex strategy and with the team Leiden has developed at the company, he is also aware of how difficult it is to bring new, first-in-class drugs to market. (According to one study, just 12% of drugs entering clinical development make it to market.) Singh says he will reserve judgement until Vertex demonstrates a Trikafta-like success in a new disease space.

“Until the company can actually bring something like that to market in the next three to five years, I’m going to be skeptical,” he states. “I still believe in the vagaries of life on this planet. I think that still beats humans pretty consistently.”

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