Triple Combination Therapy for Cystic Fibrosis

Enrolling by invitation at 58 trial locations

Overseen By Medical Information

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Vertex Pharmaceuticals Incorporated

Disqualifiers: Hepatic impairment, Transplantation, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 96 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new triple combination treatment for cystic fibrosis to determine its long-term safety and effectiveness. The treatment combines three drugs—vanzacaftor, tezacaftor, and deutivacaftor—and evaluates their combined efficacy. Participants who completed a previous study with these drugs may be suitable for this trial. It specifically targets individuals managing cystic fibrosis who have participated in earlier related treatments. As a Phase 3 trial, it represents the final step before FDA approval, providing an opportunity to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that vanzacaftor/tezacaftor/deutivacaftor is likely to be safe for humans?

Research has shown that the combination of vanzacaftor, tezacaftor, and deutivacaftor (VNZ/TEZ/D-IVA) is generally safe for people with cystic fibrosis. In studies, patients tolerated this treatment well. Importantly, research involving children aged 6 to 11 indicated that taking this treatment once a day is safe and effective. While some side effects may occur, the overall safety is reassuring. Testing in even younger children suggests confidence in its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cystic fibrosis?

Researchers are excited about the Vanzacaftor/Tezacaftor/Deutivacaftor combination therapy for cystic fibrosis because it introduces a novel approach by targeting multiple defective proteins involved in the disease. Unlike many current treatments that address symptoms, this therapy directly targets the underlying cause, potentially improving lung function and quality of life. Moreover, its ability to cater to very young patients, including those under two years old, sets it apart by offering hope for earlier intervention and better long-term outcomes.

What evidence suggests that this treatment might be an effective treatment for cystic fibrosis?

Studies have shown that the combination of vanzacaftor, tezacaftor, and deutivacaftor is a safe and effective treatment for cystic fibrosis. This trial will evaluate this combination therapy, which improves the function of a protein called CFTR, often dysfunctional in people with cystic fibrosis. Research indicates that patients using this treatment experience fewer lung flare-ups and require fewer antibiotics. Initial findings also suggest that this therapy can benefit even young children. Overall, the evidence supports its potential to effectively manage cystic fibrosis symptoms. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for people with cystic fibrosis who finished treatment in a previous study (VX21-121-105). It's not open to those who've had organ transplants, cancer, drug intolerance during the prior study, or serious liver issues like cirrhosis with portal hypertension.

Inclusion Criteria

Participants who have completed study drug treatment in the parent study (VX21-121-105; NCT Number: NCT05422222)

Exclusion Criteria

You had a bad reaction to a drug in the previous study.

I have a history of organ transplant or cancer.

I have severe liver problems that could make taking new medications risky.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive VNZ/TEZ/D-IVA once daily at doses determined based on their age and weight

96 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Vanzacaftor/Tezacaftor/Deutivacaftor

Trial Overview The trial tests the long-term safety and effectiveness of a combination medication called vanzacaftor/tezacaftor/deutivacaftor (VNZ/TEZ/D-IVA) for individuals with cystic fibrosis.

How Is the Trial Designed?

Group I: VNZ/TEZ/D-IVA Experimental Treatment 1 Intervention

Part A: Participants (Cohort 1: 6 through 11 years of age (inclusive); Cohort 2: 2 through 5 years of age (inclusive) and Cohort 3: 1 to less than (\<) 2 years of age) will receive VNZ/TEZ/D-IVA once daily at doses determined based on their age and weight. The age range is based on date of informed consent in parent study. Part B: Participants in Cohort 1 who meet the eligibility criteria will receive VNZ/TEZ/D-IVA for an additional 96 weeks.

Who Is Running the Clinical Trial?

Vertex Pharmaceuticals Incorporated

Lead Sponsor

Trials

267

Recruited

36,100+

Dr. David Altshuler

Vertex Pharmaceuticals Incorporated

Chief Medical Officer since 2020

MD, PhD

Dr. Reshma Kewalramani

Vertex Pharmaceuticals Incorporated

Chief Executive Officer since 2020

MD, trained in internal medicine and nephrology

Published Research Related to This Trial

The triple combination therapy of elexacaftor-tezacaftor-ivacaftor has shown significant efficacy in improving lung function and survival rates in cystic fibrosis patients, particularly those with the p.Phe508del mutation, which is associated with poorer outcomes.

This review highlights the safety and effectiveness of these CFTR modulators, which work by correcting the misfolding of the CFTR protein, and discusses their regulatory approval and potential future research directions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elexacaftor-tezacaftor-ivacaftor: The new paradigm to treat people with cystic fibrosis with at least one p.Phe508del mutation. Gramegna, A., Contarini, M., Bindo, F., et al.[2022]

In a phase 3 trial involving 510 patients with cystic fibrosis, the combination of tezacaftor and ivacaftor significantly improved lung function, with an absolute increase in FEV1 of 4.0 percentage points compared to placebo (P<0.001).

The treatment also reduced the rate of pulmonary exacerbations by 35% compared to placebo, while showing a similar incidence of adverse events, indicating that it is both effective and safe for patients aged 12 and older with the CFTR Phe508del mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. Taylor-Cousar, JL., Munck, A., McKone, EF., et al.[2018]

In a study involving 16 patients with cystic fibrosis (PwCF) on Trikafta® therapy, downregulation of matrix metalloprotease 9 (MMP9) was observed in those who responded well to the treatment, suggesting it may serve as a biomarker for therapy efficacy.

The study indicates that the NF-kB pathway may regulate MMP9 levels, providing insights into the molecular mechanisms that could explain the variability in clinical responses to Trikafta®, which could inform future personalized medicine approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of Plasmatic Matrix Metalloprotease 9: A Promising New Tool for Understanding the Variable Clinical Responses of Patients with Cystic Fibrosis to Cystic Fibrosis Transmembrane Conductance Regulator Modulators. Capraro, M., Pedrazzi, M., De Tullio, R., et al.[2023]

In a study of 97 participants with cystic fibrosis homozygous for the Phe508del-CFTR mutation, tezacaftor/ivacaftor was found to be generally safe and well tolerated, with a lower incidence of respiratory adverse events compared to placebo (14.0% vs. 21.3%).

Tezacaftor/ivacaftor demonstrated efficacy by providing a mean improvement of 2.7 percentage points in forced expiratory volume (ppFEV1) from baseline, indicating it can be a beneficial treatment option for patients who previously experienced adverse effects from lumacaftor/ivacaftor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events. Schwarz, C., Sutharsan, S., Epaud, R., et al.[2022]

In a study of 48 adults with cystic fibrosis, treatment with tezacaftor-ivacaftor (TEZ/IVA) led to significant improvements in lung function (FEV1 increased from 66% to 72%) and reduced annual acute exacerbation rates after 6 months.

TEZ/IVA was found to be safe and well-tolerated, with only 6% of participants experiencing adverse events, indicating its potential as an effective treatment option for adults with cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data on the efficacy and safety of tezacaftor-ivacaftor in adults living with cystic fibrosis homozygous for F508del and heterozygous for F508del and a residual function mutation. Vincken, S., Verbanck, S., Braun, S., et al.[2023]

In a phase 3b trial involving 176 participants with cystic fibrosis homozygous for the F508del-CFTR mutation, the triple-combination therapy of elexacaftor, tezacaftor, and ivacaftor resulted in significant improvements in respiratory quality of life and lung function over 24 weeks, outperforming the dual therapy of tezacaftor and ivacaftor.

The treatment was found to be safe and well-tolerated, with most adverse events being mild or moderate, and only a small percentage of participants experiencing serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial. Sutharsan, S., McKone, EF., Downey, DG., et al.[2022]

Citations

1. thelancet.com thelancet.com/journals/lanres/article/PIIS2213-2600(24)00411-9/fulltext

Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor– ... These results show that vanzacaftor–tezacaftor–deutivacaftor treatment might lead to more people with cystic fibrosis attaining levels of CFTR function either ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39756425/

Vanzacaftor-tezacaftor-deutivacaftor for children aged 6-11 ... Vanzacaftor-tezacaftor-deutivacaftor has been shown to be a safe and effective, once-daily cystic fibrosis transmembrane conductance regulator (CFTR) modulator.

3. news.vrtx.com news.vrtx.com/news-releases/news-release-details/vertex-presents-new-data-across-portfolio-cystic-fibrosis

Vertex Presents New Data Across Portfolio of Cystic Fibrosis ... “Decreased Pulmonary Exacerbations and Lower IV Antibiotic Usage Following Vanzacaftor/Tezacaftor/Deutivacaftor Treatment in People with CF ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05844449?term=deutivacaftor%20AND%20tezacaftor%20AND%20vanzacaftor&rank=2

Evaluation of Long-Term Safety and Efficacy of Vanzacaftor ... The purpose of this study is to evaluate the long-term safety, tolerability, and efficacy of vanzacaftor / tezacaftor / deutivacaftor (VNZ/TEZ/D-IVA) in ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2213260024004077

Vanzacaftor–tezacaftor–deutivacaftor for children aged 6– ... Vanzacaftor–tezacaftor–deutivacaftor has been shown to be a safe and effective, once-daily cystic fibrosis transmembrane conductance regulator (CFTR) modulator.

6. alyftrekhcp.com alyftrekhcp.com/safety-profile

Safety Profile | ALYFTREK® (vanzacaftor/tezacaftor ... View information for healthcare providers about the overall safety profile of ALYFTREK and see information about adverse reactions. See Important Safety ...

7. thelancet.com thelancet.com/article/S2213-2600(22)00504-5/fulltext

Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor ... Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12126198/

Vanzacaftor–tezacaftor–deutivacaftor for children aged 6–11 ... Vanzacaftor–tezacaftor–deutivacaftor has been shown to be a safe and effective, once-daily cystic fibrosis transmembrane conductance regulator (CFTR) modulator.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/218730s000lbl.pdf

highlights of prescribing information - accessdata.fda.gov Vanzacaftor and tezacaftor are excreted into the milk of lactating female rats. Deutivacaftor has not been evaluated; however, ivacaftor is excreted into the ...