By the time GSK sealed the deal on Bellus Health in April, the U.K. pharma knew exactly what not to do with the phase 3 chronic cough program. The company had watched Merck & Co. struggle with a rival med called gefapixant, taking notes.
“When we were doing due diligence on acquiring camlipixant we looked at Merck’s program and it was pretty clear there was a number of things that we could build into our phase 3 program to reduce and actually avoid all the problems they’d had,” GSK’s Chief Commercial Officer Luke Miels told Fierce Biotech in an interview.
Now, after closing the $2 billion deal in June, GSK is showcasing the phase 3 camlipixant program and ready to replace Merck as the market leader. Two studies called CALM-1 and CALM-2 are currently enrolling now. While GSK has a long history in respiratory diseases, chronic cough is new territory—but somehow, still fits in nicely with GSK’s portfolio.
“Typically when you've got an R&D portfolio, you want to be entering some novel areas that you maybe have not had history there. You need to do that to evolve your portfolio,” Miels said. “I led the deal to acquire camlipixant. That was a core element.”
Gefapixant and camlipixant are both P2X3 antagonists that act on a peripheral nervous system receptor that triggers neuronal hypersensitization and is linked to the urge to cough. It’s believed that by preventing stimulation of P2X3, the therapies can reduce the severity and frequency of cough.
Merck is technically closer to market. However, gefapixant suffered a major setback earlier in November when an FDA advisory committee recommended against approval. In a 12-1 vote, the committee questioned whether the evidence clearly showed that the therapy made a difference in reducing cough frequency.
But being first, Merck also had to contend with the fact that the FDA had no regulatory precedent in the indication. The agency noted it had “limited experience with the endpoints used in this program.” So Merck, and now GSK, are treading new regulatory ground. The FDA has not officially ruled on gefapixant but is expected to do so by Dec. 27.
In explaining why GSK is “more confident” in camlipixant, Miels stressed that this is a real, chronic and extremely difficult condition. To bring Bellus under GSK’s wing, Miels himself dove into learning about what these patients deal with every day. The official name is chronic refractory cough and it's characterized by a person who is coughing for more than eight weeks.
“I got very engaged. When you read the disruption to these people’s lives—a typical patient is middle-aged, female, 50 to 65, coughing around 500 times a day,” Miels said. Around 50% have urinary incontinence and over 50% experience depression because of “societal aesthetics” and personal relationship challenges, which Miels said has worsened since COVID.
Gefapixant is approved under the brand name Lyfnua in the EU, Japan and Switzerland, leaving the world’s biggest markets wide open for GSK to play with. The Big Pharma identified several ways to prime the clinical program for success during due diligence.
First off, the program has a central adjudication that ensures patients in the trial are in fact experiencing chronic refractory cough. Then, the trial is enrolling only the most severe patients.
“Because as you get to lower cough rates, it can be a bit idiosyncratic as to what's the mechanism causing the cough, whereas patients with more severe high cough frequency typically are those that have cough generated via the neuropathic pathway, which is where camlipixant works,” Miels explained.
Third, the phase 3 study features a six-week placebo washout period, where patients are taken off any other cough treatments. “So you get a true placebo effect,” Miels said. Merck’s study did not have this protocol, he pointed out.
The phase 3 trial was designed in close coordination with the FDA given the uncertainty the agency had about the first effort to get a chronic cough medicine approved, Miels said.
“There are advantages in coming second and we’ve heavily built the phase 3 program based on what the agency valued,” Miels said.
GSK has also acted to ensure the software they use to count the coughs in the study is shored up, because this caused a major delay for Merck last year. The FDA rejected gefapixant in January 2022 due to the cough counting system used in a phase 3 test for the drug. While the measure was changed, the FDA still flagged issues with whether the submitted cough count data truly proved clinical meaningfulness.
“We've been able to learn what issues Merck had with the cough software because these people wear these devices that count the number of coughs for up to a year and they're constantly recording,” Miels said.
Another thing that’s different with GSK’s program is the molecule itself. Miels said that camlipixant is much more selective to the P2X3 target, meaning fewer side effects. As a result, GSK can use the maximum dose.
“If you look at Merck’s product gefapixant, it's more promiscuous and also is able to target a sibling receptor which is called P2X2. And the problem with P2X2 is it's present in the tastebuds,” Miels said.
This causes a metallic or bitter taste in the mouth, with some patients losing their sense of taste entirely, which was something the FDA flagged in its briefing documents for the advisory committee meeting. The side effect was experienced by 65% of subjects receiving 45 mg and prompted discontinuation of treatment for 14% of patients.
Another issue with taste disturbance is that it can unblind the study, as patients who experience this side effect know they have received the study drug. Camlipixant, meanwhile, has shown lower taste disturbance and no discontinuations.
Miels again noted that these patients are quite desperate for relief from their condition and doctors also want to have an option to offer that truly works. GSK looked at market research in its due diligence efforts that polled doctors on whether they are happy with the options available to them.
“Three percent cite 'yes' and 97% are very unhappy with the options that they have,” Miels said.