Symdeko for Cystic Fibrosis

Overseen By Heather Hathorne, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Alabama at Birmingham

Must not be taking: Antibiotics, Steroids, others

Disqualifiers: Smoking, Transplant, Cirrhosis, ESRD, others

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

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 32 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how certain drugs might help individuals with specific genetic mutations linked to cystic fibrosis (CF). Researchers are testing treatments such as Symdeko (a combination of tezacaftor and ivacaftor), Ivacaftor, and Orkambi to assess their impact on the function of CFTR, a protein involved in CF. Individuals with cystic fibrosis and a mutation that might respond to these drugs could be suitable candidates, particularly if they have managed the condition without recent severe flare-ups. As a Phase 1 trial, the research focuses on understanding how the treatment works in participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but it excludes those taking medications with significant drug interactions with CFTR modulators. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have used the medications Symdeko, Ivacaftor, and Orkambi to treat certain types of cystic fibrosis (CF). Symdeko has been tested in over 1,000 patients and is generally well-tolerated, with most people not experiencing serious side effects. It is approved for patients aged 6 and older with specific gene mutations. Ivacaftor aids CF patients with a different type of mutation, and research shows it improves lung function and is safe for many. Orkambi combines two drugs to assist patients with two copies of a specific mutation. Studies in both young children and older patients have shown it is generally safe.

These treatments have been tested in various patient groups, and results indicate they are mostly well-tolerated. Prospective trial participants should remember that while side effects can occur, they are often manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for cystic fibrosis because they offer targeted approaches based on specific genetic mutations. Symdeko and Orkambi are both CFTR correctors, which help correct the malfunctioning protein caused by cystic fibrosis mutations. Ivacaftor, on the other hand, is a potentiator that enhances the function of the CFTR protein, especially for mutations similar to the wild type. Unlike standard treatments that may not account for individual genetic differences, these treatments are tailored to the patient's specific mutation, potentially leading to more effective and personalized care. This precision in targeting the underlying genetic causes of cystic fibrosis is what makes these treatments stand out.

What evidence suggests that this trial's treatments could be effective for cystic fibrosis?

In this trial, participants will receive one of the following treatments: Symdeko, Ivacaftor, or Orkambi. Research has shown that Symdeko, a combination of tezacaftor and ivacaftor, can significantly improve lung function in people with cystic fibrosis. Studies have found that it enhances lung performance, lowers sweat chloride levels, and improves quality of life. Ivacaftor alone has also proven effective, with evidence showing it reduces lung issues and hospital visits for cystic fibrosis patients. Clinical trials have demonstrated that Orkambi, which combines lumacaftor and ivacaftor, benefits patients with certain genetic mutations by improving lung function and reducing disease severity. All these treatments aim to enhance lung health and overall well-being in cystic fibrosis patients. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with Cystic Fibrosis, aged 6 or older, who have specific CFTR mutations that might respond to certain drugs not yet approved for their condition. They must be on a stable CF treatment and able to give consent. People can't join if they have severe liver or kidney disease, had an organ transplant, are currently in another drug study, smoked recently, or take medications that don't mix well with the trial drugs.

Inclusion Criteria

I am 6 years old or older.

My CFTR mutation could improve with specific approved treatments.

My cystic fibrosis lung treatment has not changed recently.

Exclusion Criteria

I cannot use CFTR modulators due to conditions like advanced cirrhosis or ESRD.

I am not taking any medications that interact badly with others.

You have smoked cigarettes within the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive off-label CFTR modulators such as Symdeko, Orkambi, or Ivacaftor based on their CFTR mutation response

32 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Symdeko

Trial Overview

The trial is testing Symdeko in patients with Cystic Fibrosis who have certain genetic mutations. It's designed to see if this medication can help even though it's not officially approved for these particular mutations.

How Is the Trial Designed?

Group I: Symdeko Experimental Treatment 1 Intervention

Patients who have a mutation that responds to a CFTR corrector from in vitro study will be given Symdeko, depending on the in vitro response pattern

Group II: Orkambi Experimental Treatment 1 Intervention

Patients who have a mutation that responds to a CFTR corrector from in vitro study will be given Orkambi, depending on the in vitro response pattern

Group III: Ivacaftor Experimental Treatment 1 Intervention

Patients who have mutation response to a potentiator of CFTR function will be given Ivacaftor monotherapy.. Patients with a mutation equivalent to wild type will be given Ivacaftor.

Symdeko is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Symdeko for:

• Cystic fibrosis in people ages 12 and older with certain mutations in the CFTR gene

Approved in Canada as Symdeko for:

• Cystic fibrosis in people with certain mutations in the CFTR gene

Approved in European Union as Symkevi for:

• Cystic fibrosis in people with certain mutations in the CFTR gene

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

George Solomon

Lead Sponsor

Trials

1

Recruited

500+

Published Research Related to This Trial

In a study of 101 cystic fibrosis patients treated with elexacaftor-tezacaftor-ivacaftor, participants reported significant improvements in respiratory symptoms, sleep quality, and overall well-being within just a few months of treatment.

Patients experienced a notable reduction in treatment burden and expressed renewed physical strength and self-confidence, leading to better life planning, although some had concerns about body image and treatment dependency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung disease. Martin, C., Burnet, E., Ronayette-Preira, A., et al.[2022]

Elexacaftor/tezacaftor/ivacaftor, a triple-combination therapy, showed potential benefits for a 37-year-old cystic fibrosis patient with chronic lung allograft dysfunction, including improved pancreatic function and quality of life, despite no change in lung function as measured by forced expiratory volume.

The treatment was well-tolerated with no significant side effects, although careful monitoring of renal function and immunosuppressant levels is necessary, indicating that this therapy may be beneficial for select patients awaiting lung retransplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elexacaftor/Tezacaftor/Ivacaftor as a Bridge to Lung Retransplant in a Recipient With Cystic Fibrosis. FitzMaurice, TS., Nazareth, D., Iyer, K., 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 3 study involving 168 participants with cystic fibrosis who were heterozygous for the F508del-CFTR mutation, tezacaftor/ivacaftor did not show significant improvement in lung function (ppFEV1) or other key health measures after 12 weeks, leading to the study's termination for futility.

Despite the lack of efficacy, tezacaftor/ivacaftor was found to be generally safe and well tolerated, with a safety profile consistent with previous studies in cystic fibrosis patients aged 12 and older.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations. Munck, A., Kerem, E., Ellemunter, H., et al.[2021]

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]

CFTR modulators, like tezacaftor/ivacaftor, represent a significant advancement in treating cystic fibrosis by targeting the underlying genetic defect, with promising results from pivotal clinical trials.

Tezacaftor/ivacaftor has a better safety profile compared to lumacaftor/ivacaftor and is effective for a wider range of CFTR mutations, paving the way for future therapies that could benefit most cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tezacaftor and ivacaftor for the treatment of cystic fibrosis. Paterson, SL., Barry, PJ., Horsley, AR.[2021]

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]

Elexacaftor/tezacaftor/ivacaftor is safe and well tolerated in individuals with moderate hepatic impairment, as shown in a study involving 22 subjects (11 with hepatic impairment and 11 healthy controls) over a 10-day period.

The pharmacokinetics of the drug were affected by hepatic impairment, necessitating a dose reduction for these patients, as the drug's levels were significantly higher in those with liver issues compared to healthy individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Study to Assess the Safety and Pharmacokinetics of Elexacaftor/Tezacaftor/Ivacaftor in Subjects Without Cystic Fibrosis With Moderate Hepatic Impairment. Viswanathan, L., Bachman, E., Tian, S., et al.[2022]

Elexacaftor-tezacaftor-ivacaftor is a newly approved triple-combination therapy for cystic fibrosis that significantly improves lung function, quality of life, and reduces exacerbations in patients aged 12 and older with at least one F508del mutation in the CFTR gene, surpassing existing treatments.

While the therapy shows promising efficacy, common side effects include rash and headache, and liver function monitoring is advised; however, about 10% of the cystic fibrosis population remains ineligible for this or any CFTR modulation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy. Ridley, K., Condren, M.[2020]

A 7-year-old boy with cystic fibrosis experienced a severe skin reaction to the CFTR modulator elexacaftor/tezcaftor/ivacaftor (Trikafta), highlighting the potential for adverse reactions to these important medications.

Desensitization was successfully implemented, allowing the patient to continue treatment, which underscores the importance of managing drug reactions to maintain access to essential therapies for cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

If At First You Don't Succeed, Trikafta Again. Loyd, I., Papac, N., Hirshburg, J., et al.[2022]

Elexacaftor/tezacaftor/ivacaftor therapy significantly reduced sweat chloride levels by an average of 59.3 mmol/L in children with cystic fibrosis, indicating improved chloride transport and potential for better lung function.

After 3 months of treatment, there was a notable increase in pulmonary function (11.4% improvement in FEV1) and nutritional status (0.31 increase in BMI-z score), with these benefits sustained at 6 months, demonstrating both efficacy and safety in a real-world setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-life impact of highly effective CFTR modulator therapy in children with cystic fibrosis. Olivier, M., Kavvalou, A., Welsner, M., et al.[2023]

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