Kalydeco Packaging

Source: Vertex Pharmaceuticals.

Back in 2012, Vertex Pharmaceuticals (NASDAQ:VRTX) changed thousands of lives when it won approval to market Kalydeco to treat cystic fibrosis patients in the U.S. and EU. Cystic fibrosis, or CF, can be caused by one of many mutations along the CFTR gene. The trouble is, the therapy was initially approved for one specific mutation in the CFTR gene -- G551D -- leaving the vast majority of patients untreated.

Kalydeco's label now includes 10 specific mutations, but the big expansion came with the approval of combination therapy Orkambi. This combination of ivacaftor -- Kalydeco's active ingredient -- and lumacaftor is indicated for treatment of patients with two copies of the most common mutation, F508del, representing an estimated 8,500 of the 30,000 people in the U.S. living with the disease.

Orkambi is a huge improvement, but it still leaves the majority of CF patients untreated. The potential is not lost on two companies trying to unseat Vertex from its CF throne: Concert Pharmaceuticals (NASDAQ:CNCE) and Galapagos NV (NASDAQ:GLPG).

Deuterium, where's my hydrogen?
Concert is a clinical-stage pharmaceutical company founded on the premise that substituting a compound's hydrogen atoms for deuterium can improve safety and efficacy. 

Deuterium

Source: Wikimedia Commons.

While deuterating existing compounds sounds like another flashy gimmick, the data so far is compelling. Earlier this month, Concert presented results from a 10-patient trial with CTP-656, a deuterated analog of Kalydeco. Patients receiving just 75mg of CTP-656 had higher plasma concentrations after 12 and 24 hours than patients receiving a 150mg dose of Kalydeco.

If these results can be repeated in larger trials, and the company doesn't get bogged down with a flurry of lawsuits, this improved profile could eventually pressure Kalydeco sales. Before you get too excited, it's important to remember that Kalydeco alone treats just a small subset of the overall CF population. Also, those results are from healthy volunteers, so we know nothing of CTP-656's efficacy in CF patients.

An improved pharmacokinetic profile should also improve the drug's efficacy, but we won't know for quite some time. Concert is going forward with another phase 1 trial in healthy volunteers, and we can expect those results in the first half of next year.

Class 3 contender
While Concert advances heavy hydrogen, Belgium's Galapagos also has a CF candidate in development. Analysts might be focused on the company's ill-fated rheumatoid arthritis partnership with AbbVie, but Vertex investors will want to keep an eye on its CF program.

Galapagos is developing GLPG1837 for treatment of patients with class 3 mutations -- a subset representing between 2% and 3% of the CF population. The company recently posted top-line results from a phase 1 trial that suggest the drug is safe and well-tolerated even at high doses. Like Concert's candidate, GLPG1837 was tested on healthy volunteers. Unlike Concert, however, Galapagos intends to begin a phase 2 study with actual CF patients before the end of the year.

Double entry
Both Concert and Galapagos are well behind Vertex, and it looks like the Cambridge company is about to widen the gap even further. Vertex just moved two next-generation correctors into clinical development that could more than double its CF franchise.

At a recent conference, Vertex announced it would advance VX-152 and VX-440 into clinical development. While Kalydeco is a potentiator that improves the ability of CFTR to function at the cell surface, it isn't much help if the protein never makes it there. This is where the new correctors come into play. Like lumacaftor -- the other active ingredient in Orkambi -- these two are designed to get CFTR to the cell surface where it can do its job.

What makes these compounds exciting is that they could speed Vertex toward its goal of treating the vast majority of CF patients. When applied to cell cultures in triple combinations -- VX-152/VX-661/Kalydeco and VX-440/VX-661/Kalydeco -- they have been shown to improve CFTR function in human cells with just one copy of the F508del mutation. Since an estimated 90% of CF patients have at least one copy of of the F508del mutation, eventual approval of just one of these combinations would create an enormous opportunity.

It's important to point out that Vertex's new correctors haven't been tested in CF patients yet. But with Galapagos and Concert at roughly the same stage with their first CF candidates, I'd say Vertex is in little danger of losing its market position soon.

In the first half of this year, Kalydeco brought in $285 million. When the company reports third-quarter earnings on Oct. 28, it will be able to include nearly two months of U.S. Orkambi sales as well. As exciting as those figures are, they would look weak in comparison to a combination therapy indicated for 90% of CF patients. Just one of the two triple therapies needs to win approval to make this happen. This is why I'll be watching their development very closely.

Cory Renauer has no position in any stocks mentioned. The Motley Fool recommends Vertex Pharmaceuticals. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.