Benzinga | Jul 28, 2021 08:04AM EDT

Vertex Reports Phase 2 Study Of Once-Daily Triple Combo Regimen For People With Cystic Fibrosis Met Primary Endpoint; Co. Plans To Initiation Phase 3 Trial In H2'21

- Phase 2 study met primary endpoint and all secondary endpoints -

- Phase 2 data demonstrated that a once-daily triple combination of VX-121/ tezacaftor/VX-561 has potential for enhanced clinical benefit compared to TRIKAFTA(r) (elexacaftor/tezacaftor/ivacaftor and ivacaftor) -

- Initiation of Phase 3 program expected in the second half of 2021 -

BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (NASDAQ:VRTX) today announced the company will initiate a Phase 3 development program for the new once-daily investigational triple combination of VX-121/tezacaftor/VX-561 (deutivacaftor) in the second half of 2021. The combination of VX-121/tezacaftor/VX-561 was first identified as having potential for increased efficacy based on its ability to drive higher levels of chloride transport compared to TRIKAFTA(r) (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in human bronchial epithelial cells in vitro. The combination of VX-121/tezacaftor/VX-561 was evaluated in a Phase 2 study in people with cystic fibrosis (CF) ages 18 and older with one F508del mutation and one minimal function mutation (F/MF) and in people with CF ages 18 and older with two F508del mutations (F/F). The regimen was generally well-tolerated, and the study met the primary efficacy endpoint of absolute change from baseline in ppFEV1 and all secondary efficacy endpoints including absolute change from baseline in sweat chloride concentration in both patient populations. Taken together, these data suggest the triple combination holds the potential to restore cystic fibrosis transmembrane conductance regulator (CFTR) function in people with CF to even higher levels than seen with other Vertex CFTR modulators and thereby provide enhanced clinical benefit.

"TRIKAFTA has demonstrated high levels of efficacy in people with CF who have at least one F508del mutation. However, we remain committed to continuing our efforts to maximize the benefit and convenience we can deliver for these patients," said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. "With this once-daily, next-in-class, triple combination regimen, our goal is to develop a more effective treatment regimen with the potential to restore CFTR function in people with CF to even higher levels than currently achievable."

Phase 2 Study Results:

Results from Phase 2 study of VX-121/ tezacaftor/VX-561 in adults with oneF508del and one minimal function mutation (F/MF). Results shown are mean absolute within-group change from baseline through Day 29*

ppFEV1 Sweat Chloride (Percentage (mmol/L) Points)

F/MF Treatment Group

+1.9 +2.3Placebo n=10 (p=0.5214) (p= 0.6198)

+4.6 -42.8VX-121 (5 mg qd)/tezacaftor (100 mg qd)/VX-561 (150 mg qd) Triple Combination Regimen n=9 (p=0.1253) (p <0.0001)

+14.2 -45.8VX-121 (10 mg qd)/ tezacaftor (100 mg qd)/VX-561 (150 mg qd) Triple Combination Regimen n=19 (p<0.0001) (p <0.0001)

+9.8 -49.5VX-121 (20 mg qd)/ tezacaftor (100 mg qd)/ VX-561 (150 mg qd) Triple Combination Regimen n=20 (p<0.0001) (p <0.0001)

Results from Phase 2 study of VX-121/ tezacaftor/VX-561 in adults with twoF508del mutations (F/F). Results shown are mean absolute within-group changefrom baseline (after 4-week run-in on tezacaftor/ivacaftor) through Day 29&#x2A;

ppFEV1 Sweat Chloride (Percentage (mmol/L) Points)

F/F Treatment Group

-0.1 -2.6Tezacaftor (100 mg qd)/ivacaftor (150 mg q12h) (active control) n=10 (p=0.9635) (p= 0.3633)

+15.9 -45.5VX-121 (20 mg qd)/ tezacaftor (100 mg qd)/VX-561 (150 mg qd) Triple Combination Regimen n=18 (p<0.0001) (p <0.0001)

&#x2A;The primary efficacy analysis is the mean absolute within-group changefrom baseline in ppFEV1 through Day 29 for any VX-121/tezacaftor/VX-561 dosegroup.

VX-561 was also evaluated in a dose-ranging monotherapy study. Complete data from the Phase 2 clinical study of VX-121/tezacaftor/VX-561 and the VX-561 Phase 2 monotherapy study will be presented at a later date.

About the Phase 3 Program

The Phase 3 program consists of two randomized, double-blind, active-controlled 48-week trials, which will evaluate the safety and efficacy of VX-121 (20 mg)/tezacaftor (100 mg)/VX-561 (250 mg) in comparison to TRIKAFTA(r) (elexacaftor/tezacaftor/ivacaftor and ivacaftor). The first study will enroll approximately 350 people with CF ages 12 years and older with one F508del mutation and one minimal function mutation (F/MF). The second study will enroll approximately 450 people with CF ages 12 years and older with two F508del mutations (F/F) or one F508del mutation and a second mutation responsive to CFTR modulators. The primary endpoint in both studies is the absolute change from baseline in ppFEV1, which will be analyzed for non-inferiority to TRIKAFTA. Both studies will also assess absolute change from baseline in ppFEV1 and sweat chloride for superiority to TRIKAFTA(r).

About VX-121/Tezacaftor/VX-561

In people with certain types of mutations in the CFTR gene, the CFTR protein is not processed and cannot move through the cell normally. This results in little to no protein at the cell surface. VX-121 and tezacaftor are designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the CFTR protein. VX-561 (deutivacaftor) is an investigational potentiator designed to keep CFTR proteins at the cell surface open longer to improve the flow of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways. The VX-121/tezacaftor/VX-561 program was granted Fast Track and Orphan Drug Designations from the U.S. Food and Drug Administration for the treatment of cystic fibrosis.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR TRIKAFTA(r) (elexacaftor/tezacaftor/ivacaftor and ivacaftor) TABLETS

What is TRIKAFTA?

TRIKAFTA is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or another mutation that is responsive to treatment with TRIKAFTA. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if TRIKAFTA is safe and effective in children under 6 years of age.

Patients should not take TRIKAFTA if they take certain medicines or herbal supplements, such as: antibiotics such as rifampin or rifabutin; seizure medicines such as phenobarbital, carbamazepine, or phenytoin; or St. John's wort.

Before taking TRIKAFTA, patients should tell their doctor about all of their medical conditions, including if they: have kidney problems; have or have had liver problems; are pregnant or plan to become pregnant because it is not known if TRIKAFTA will harm an unborn baby; or are breastfeeding or planning to breastfeed because it is not known if TRIKAFTA passes into breast milk.

TRIKAFTA may affect the way other medicines work, and other medicines may affect how TRIKAFTA works. Therefore, the dose of TRIKAFTA may need to be adjusted when taken with certain medicines. Patients should especially tell their doctor if they take: antifungal medicines including ketoconazole, itraconazole, posaconazole, voriconazole, or fluconazole; antibiotics including telithromycin, clarithromycin, or erythromycin.

TRIKAFTA may cause dizziness in some people