Trikafta leads to clinical gains for 2 adults with rare M1101K mutation

Trikafta improves overall health of 2 Canadians with end-stage lung disease

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Six months of treatment with Trikafta (elexacaftor/tezacaftor/ivacaftor) significantly improved lung function and nutritional status in two adults with cystic fibrosis (CF) caused by the rare mutation M1101K, according to two cases described in Canada.

“Our cases not only demonstrate the therapeutic benefit of [Trikafta] in individuals with non-F508del variants, but also provide supporting data in the worldwide efforts to access [Trikafta] for individuals who would benefit from this therapy,” researchers wrote.

The study, “Elexacaftor-Tezacaftor-Ivacaftor in 2 cystic fibrosis adults homozygous for M1101K with end-stage lung disease,” was published in the journal Respiratory Medicine Case Reports.

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Mutations in the CFTR gene, which lead to a faulty or missing CFTR protein, are the cause of CF. The mutations might affect the protein’s production, trafficking, stability, or function, and lead to the accumulation of thick and sticky mucus in the body’s organs. It particularly affects the lungs, gastrointestinal tract, and pancreas.

CFTR modulator therapies increase the protein’s function, thus preventing mucus buildup and easing CF symptoms. Trikafta, a modulator therapy, can help to improve a patient’s lung function, nutritional status, and quality of life.

First approved for patients with at least one F508del mutation, the most common CF-causing mutation, Trikafta’s use was expanded to patients with other mutations. Preclinical studies have shown the benefit of Trikafta in patients with other CFTR mutations, including M1101K.

Rare M1101K variant found more prevalent in Canada

Although the M1101K variant is rare and found in 0.2% of CF patients worldwide, in Canada it is found in 1.7% of the patients, reaching even higher numbers in some rural communities.

“Approval for [Trikafta] use in those with M1101K is present in the United States, [but] the majority of countries including Canada have neither approval nor funding mechanisms for [Trikafta] use in nonF508del variants,” the researchers wrote.

Now, researchers in Canada described two cases of adults with CF who are homozygous for M1101K — meaning they have two copies of the mutation — with end-stage lung disease. The clinical condition of both patients improved after six months of Trikafta treatment, which was initiated through an Exceptional Drug Therapy funding program.

The first patient, a 28-year-old man, started Trikafta in December 2022. His medical history included airway infections with fungus, chronic lung infections with Pseudomonas aeruginosa, intermittent respiratory infection with Staphylococcus aureus, and CF-related diabetes.

Two years before starting on Trikafta, his percentage of predicted forced expiratory volume in one second (ppFEV1), which is a measure of lung function, was 22%, indicating severe obstruction in the lungs. During the year before treatment, his lung function had declined, leading to chronic low oxygen and pulmonary hypertension, and requiring five hospitalizations due to lung exacerbations.

Two weeks before starting Trikafta, his ppFEV1 was 10%, and he had lost 10% of his body weight in the previous month, despite receiving intravenous (into-the-vein) antibiotics and oxygen supplementation for over six weeks.

Within the first week of treatment with Trikafta, his sputum production improved, and he experienced less coughing and shortness of breath, which led to reduced oxygen supplementation and stopping his antibiotic therapy.

These cases show sustained clinical efficacy in a rare but important Canadian variant. Pulmonary and extra-pulmonary clinical improvements may still be safely achieved with [Trikafta] in end-stage lung disease.

Overall clinical status improved in first patient after 6 months on Trikafta

After six weeks on Trikafta, his ppFEV1 increased to 21%, and after six months his breathing improved, as well as his overall clinical status. The patient also reported reduced depression and anxiety scores.

The other patient in the report was a 35-year-old woman with a history of end-stage lung disease, chronic lung infections with P. aeruginosa and fungus, coughing up blood, and episodes of pancreatic infections and intestinal obstruction. She started Trikafta treatment in September 2022.

Two years before the treatment, her ppFEV1 was 46%, indicating moderate obstruction in the lungs. During the year before starting Trikafta, her lung function declined to a ppFEV1 of 27%, leading to chronic low oxygen levels requiring home oxygen supplementation, and six pulmonary exacerbations requiring antibiotic treatment.

After starting Trikafta, the patient experienced a rapid decrease in sputum production, coughing, and shortness of breath, and she stopped coughing up blood (episodes of hemoptysis). Her ppFEV1 increased to 33% at seven weeks, and to 38% six months after starting the treatment. Her overall health also improved.

“Our cases demonstrated increased ppFEV1 after the first month of [Trikafta] therapy and maintained ppFEV1 in the subsequent 6 months, with an absolute increase in ppFEV1 at 11% for both cases, despite advanced lung disease at baseline,” the researchers wrote.

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CFTR function reached near-normal levels in both patients

Moreover, CFTR function, measured by the sweat chloride test, which is a diagnosis method for CF as patients have high chloride levels, reached near-normal levels in both patients.

“Similar improvements were shown in studies in [people with CF] with F508del with advanced lung disease [receiving Trikafta],” the researchers noted.

Both patients also improved their nutritional status with Trikafta, as assessed by their body mass index (a measure of body fat based on height and weight).

Overall, treatment with Trikafta was found to be safe in both patients, with no adverse events reported during the six-month treatment period.

“These cases show sustained clinical efficacy in a rare but important Canadian variant,” the researchers concluded. “Pulmonary and extra-pulmonary clinical improvements may still be safely achieved with [Trikafta] in end-stage lung disease.”