UPDATE: Vertex beats own record in cystic fibrosis as next-gen treatment goes up against Trikafta

Set the bar and then beat it; that's what Vertex Pharmaceuticals has just done with a next-gen cystic fibrosis (CF) treatment.

The investigational treatment is a once-daily triple CFTR modulator regimen made up of vanzacaftor, tezacaftor and deutivacaftor, called vanza. This compares to Vertex’s own twice-daily Trikafta (elexacaftor/tezacaftor/ivacaftor), the first triple combination therapy to snag FDA approval for patients with the most common CF mutation, F508del. 

Vanza triple achieved the main goals across several phase 3 programs, demonstrating noninferiority against Trikafta for improving lung function and superiority to Trikafta in lowering levels of sweat chloride (SwCl), according to data shared Feb. 5 after market close.  

Based on the results, Vertex intends to file for approval in the U.S. and Europe for people with CF ages 6 years and older by mid 2024. The Boston-based company plans to use its FDA priority review voucher, which guarantees an expedited six-month review process in the U.S.

Using a 2025 model launch, William Blair analysts expect a peak revenue potential of $9.9 billion for vanza triple.

“With these results, we now know that the vanza triple has indeed surpassed the very high bar set by Trikafta in people with CF ages 6 and older,” Vertex CEO Reshma Kewalramani, M.D., said during a Feb. 5 quarterly earnings call. “And, by treating patients early with the vanza triple, we have the potential to possibly prevent systemic manifestations of CF in more people.” The new data come from three studies. The first were two double-blind 52-week trials—dubbed SKYLINE 102 and SKYLINE 103—that evaluated the efficacy of vanza triple head-to-head against Trikafta among people with CF ages 12 and up. Participants had at least one F508del mutation or a mutation responsive to triple combo CFTR modulators (CFTRm).

The investigational treatment met all primary and key secondary endpoints in the two SKYLINE trials. The main target of both studies was absolute change from baseline in percent predicted forced expiratory volume in one second through Week 24, a measurement that met statistical significance and showed that vanza is noninferior to Trikafta. 

A secondary endpoint in the SKYLINE trials measured change from baseline in SwCl through Week 24​ against Trikafta, finding that vanza triple was superior in reducing SwCl levels in both trials. Second and third key secondary endpoints, which were pooled across SKYLINE 102 and SKYLINE 103, found vanza triple achieved superiority in the proportion of patients with SwCl below 60 mmol/L (the diagnostic threshold for CF) and below 30 mmol/L (the carrier level threshold) compared to Trikafta.

“These results also reaffirm our conviction that continued investment in scientific and serial innovation will allow us to complete our journey to transform CF by bringing all eligible CF patients down to carrier levels of sweat chloride, where there are no manifestations of disease,” Kewalramani said.

For safety, the SKYLINE trials had adverse events that were generally consistent with the manifestation of CF. Most were mild to moderate, and the incidence of serious adverse events and adverse events that led to discontinuation were low and balanced across the vanza group and the Trikafta group. But, for both groups, 95% of patients experienced a treatment-emergent adverse event, with the most common being infective pulmonary exacerbation of CF.  

The third phase 3 program was a single-arm, 24‑week, open-label study called RIDGELINE 105 that assessed the vanza triple in children ages 6 to 11 with at least one mutation responsive to triple combination CFTRm.

The efficacy results were even more pronounced in this study, which met the main primary endpoint of safety, according to Vertex. Overall safety findings were similar to the12 years and older patient population.

The vanza triple treatment could be appealing to both patients who are currently being treated with Trikafta and those who have previously discontinued treatment, giving patients on Trikafta the chance to achieve even greater levels of CFTR function, Vertex Chief Operating Officer Stuart Arbuckle said on the earnings call.

The new CF data inch Vertex closer to its goal of launching five products by 2028. The company recently received two FDA approvals for CRISPR Therapeutics-partnered gene therapy Casgevy in transfusion-dependent beta thalassemia and sickle cell disease.

Vertex is also banking on VX-548, a non-opioid medicine designed to break into the blockbuster pain market. The therapy beat placebo on measures of pain intensity but failed to hit key secondary endpoints designed to show the med is more effective than Vicodin, a widely used painkiller, in a pair of phase 3 trials that read out last week. 

Editor's note: This article was updated at 9:45 a.m. ET on Feb. 6 to include analysis from William Blair.