CFTR Modulators
CF Modulator therapies, like Trikafta, have been a game changer for cystic fibrosis treatment. We’ve compiled some information about the different types of CFTR modulator therapies available today.
What are CFTR modulators and how do they work?
Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies work to correct the malfunctioning protein made by the CFTR gene. There are a few different CFTR modulators available that target specific mutations.
In people with CF, mutations in the CFTR gene result in either a defective protein being produced or no protein at all. The CFTR protein regulates the proper flow of water and chloride in and out of cells lining the lungs and other organs. A defect in this protein results in a buildup of thick, sticky mucus, which can lead to infections in the lungs and damage to the pancreas. It can also lead to problems in other parts of the body. CFTR modulator therapies, such as Trikafta, are designed to help the malfunctioning protein work better
Cystic Fibrosis Canada is currently advocating for access to CF modulator therapies for all who can benefit, including people with responsive rare CF mutations.
What modulators are available?
There are four CFTR modulators approved for sale in Canada. Three of these – Kalydeco, Orkambi and Trikafta - are publicly funded, some with restrictions. One modulator - Symdeko – is only available through some private insurance plans.
Kalydeco (ivacaftor) is the first-generation modulator, treating between 4-5% of the Canadian cystic fibrosis population. Kalydeco is approved for treatment of cystic fibrosis for those 2 months of age and older who have one of the following mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. Kalydeco is available through some public and private drug plans, in some cases only for certain mutations. In other countries the list of mutations approved for Kalydeco is different. For example, in the United States Kalydeco is approved for use in people with any of 97 different CF mutations. All mutations approved for Kalydeco in Canada have also been shown to respond to Trikafta, but that drug is not yet approved to treat these mutations in Canada.
Orkambi and Symdeko
Orkambi (lumacaftor and ivacaftor) and Symdeko (tezacaftor and ivacaftor) are second-generation modulators. Orkambi can treat the approximately 50% of the Canadian cystic fibrosis population that carry two copies of the most common CF mutation (F508del) and is approved by Health Canada for use in people age 1+. Orkambi is funded by some public and private drug programs with limitations. Health Canada has approved Symdeko for people age 12+ with two copies of the F508del mutation, or one copy of F508del and one copy of any of the following mutations: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T. No public drug plans fund Symdeko, but some private drug programs do. People over the age of 2 who are indicated for Orkambi and Symdeko are also indicated for Trikafta. Those 1-2 years of age on Orkambi may transition to the more effective Trikafta once they reach 2 years of age.
Trikafta
Trikafta (elexacaftor, tezacaftor and ivacaftor) is a third-generation modulator and is approved by Health Canada for the approximately 90% of the Canadian cystic fibrosis population, aged two years and older over the age of 2 who have at least one copy of F508del mutation. Trikafta is also approved by Health Canada for 152 additional rare mutations for the same age group, as of July 2024. aged two years and older.
Currently, Trikafta is funded through all of Canada’s provincial, territorial and federal public drug programs for those aged two six and older with at least one F508del mutation. As of July 2024, the funding of Trikafta for the additional 152 rare mutations approved, is being assessed by Canada’s Drug Agency (CDA), and is becoming available in some jurisdictions for the 2 to 5-year-old age group.
Trikafta is a triple combination therapy, adding?elexacaftor?to?tezacaftor?and?ivacaftor?to target CFTR protein defects caused by the F508del mutation or another mutation responsive to the drug. Canadian research published in the Journal of Cystic Fibrosis demonstrates that access to Trikafta in 2021 would result in profound health benefits for Canadians living with cystic fibrosis. By 2030, Trikafta could reduce the number of people living with severe lung disease by 60% and reduce the number of deaths by 15%.
The findings show a significantly slower disease progression with an 18% increase in people with mild lung disease and 19% fewer hospitalizations or home intravenous antibiotics for pulmonary exacerbations. The estimated median age of survival for a child born with cystic fibrosis would increase by 9.2 years.
Trikafta FAQ
Which cystic fibrosis mutations can benefit from Trikafta?
Clinical trials for Trikafta were initially conducted in people with at least one copy of the F508del mutation. and this is the only mutation that Health Canada has approved for this drug. Trikafta has been shown in laboratory studies, and through real world evidence in CF patients to be effective in many more mutations. With this evidence behind it, Trikafta is now approved for 152 mutations in addition to the most common mutation, F508del. In the United States, for example, Trikafta is approved for 177 mutations, including F508del. Despite this evidence, in Canada Trikafta currently remains approved by Health Canada for only F508del. If the indication were expanded to all of these 177 mutations, an additional approximately 200 Canadians could benefit from this life changing drug. In other countries other mutations beyond this list of 177 have been shown to benefit, and expanding access to these mutations would help even more Canadians. There remains many CF mutations that are unknown to respond to Trikafta, and there are select mutations that have been proven to not benefit from the drug.
Is Trikafta more effective than earlier generation cystic fibrosis gene modulator therapies?
Yes, and significantly so. On average, Trikafta use leads to a 14% increase in lung function over the untreated baseline. In clinical trials of the triple combination therapy, people with two copies of the F508del mutation had a 10% increase in lung function on average compared to treatment with Symdeko (that already provides a 4% increase over baseline), and people with a single copy of F508del had, on average, more than a 14% increase in lung function compared to treatment with the placebo.
For source information pls see: VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles | NEJM
And Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele | NEJM
Will everyone who takes Trikafta see significant improvement?
Cystic fibrosis is a heterogenous disease, people living with CF have individualized experiences with the disease and therefore, individual responses to Trikafta will vary. Many people on Trikafta have experienced a dramatic increase in lung function while others have experienced a more moderate increase or no significant change in lung function. As a heterogenous disease, the response to Trikafta will be individual and as such, those who demonstrated a more muted improvement in lung function may have seen improvements in other areas that are equally as important to consider, such as in BMI or overall quality of life.
It is also important to note that some people may feel side effects while taking Trikafta, including rash, headache, changes to their mental health and abdominal pain. In all cases, Cystic Fibrosis Canada encourages patients to discuss how they are responding to Trikafta with their clinics.
Modulator Consensus Guidelines
CF Canada has worked alongside clinicians across Canada to develop guidelines on the initiation, discontinuation and monitoring of CFTR modulators such as Trikafta. View them here.
How can I access Trikafta?
Accessing Trikafta is dependent upon your mutation, age and your location in Canada. To learn more about how to access Trikafta in Canada we recommend speaking with your clinic team.
