The year of all hopes

By André Cantin, MD
Pulmonology department
Department of Medicine of the University of Sherbrooke
Written on January 2, 2018

Note
Kalydeco: ivacaftor
Orkambi: ivacaftor + lumacaftor
Symdeko: tezacaftor/ivacaftor + ivacaftor

The year 2017 was the year of great hope for all people living with cystic fibrosis. Research and clinical advances were summarized in the plenary session of the North American Cystic Fibrosis Congress held from November 2 to 4, 2017 in Indianapolis. You can watch this session (in English):

Two drugs are now approved by Health Canada for the treatment of people with cystic fibrosis and who have specific mutations. It is ivacaftor (trade name, Kalydeco) and the combination of ivacaftor and lumacaftor (Orkambi). There are several classes of mutations in the CFTR gene (Cystic fibrosis transmembrane conductance regulator) but classes 1, 2 and 3 are associated with the majority of the clinical manifestations of the disease (Figure 1). Class III mutations prevent the chloride ion transport channel from opening in affected cells. The use of ivacaftor in people with specific mutations, especially class III mutations (table 1) gives remarkable clinical improvements. This is a major scientific breakthrough that demonstrates the possibility of correcting the defect at the base of CF by giving a simple oral tablet. Unfortunately, less than 2% of people with CF in Quebec have these mutations, which severely limits the use of ivacaftor. On the other hand, nearly 89% of people with CF in Quebec have at least one copy of the class II mutation, F508del, and 50% have 2 copies (ie: they are homozygotes for this mutation). A class II mutation does not allow the CFTR protein to travel to the cell membrane to facilitate the transport of chloride ions. Several clinical studies have demonstrated modest benefits of Orkambi treatment in patients with 2 copies of F508del, but no beneficial effects have been noted in patients with only one copy of the mutation. Although modest, these improvements in the CFTR function give hope to people affected by CF, and an application to include Orkambi on the lists of medications reimbursed by the Quebec public insurance plan has been filed.

Following the opinion issued by members of the Drug Evaluation Committee for the purposes of inclusion in the drug lists, the National Institute for Excellence in Health and Social Services (INESSS) recommended that the Minister not register Orkambi in Quebec for the treatment of cystic fibrosis in individuals homozygotic for the F508del mutation of the CFTR gene. INESSS indicates that it does not recognize sufficient therapeutic value that could justify its registration. This is not a decision that is unanimous among expert CF clinicians in Quebec and elsewhere. However, it is possible to obtain reimbursement for Orkambi by the Exception Patients Program of the Quebec Health Insurance Board for people who meet certain criteria. In order to be eligible for reimbursement, you must have 2 F508del mutations, benefit from an optimal therapeutic regime to counter CF, and above all, demonstrate exemplary adherence to the therapeutic plan. This last criterion is essential not only to obtain reimbursement from Orkambi, but above all to ensure the best development for people with CF.

The effectiveness of the drugs available for the treatment of patients with at least one F508del mutation of the CFTR gene is limited by the fact that this mutation is linked to 3 defects in the protein. Ideally, a medication should correct each of these defects, otherwise it will be necessary to combine 3 drugs. The 3 defects are as follows: 1. the CFTR F508del protein is malformed and it is therefore destroyed before reaching the cell membrane where it should normally facilitate the passage of chloride ions, 2. once returned to the membrane, once returned to the membrane, the CFTR F508del remains closed and does not allow ions to pass through, and 3. The F508del protein that travels to the membrane is unstable and is removed from the membrane by protein quality control mechanisms. The first two defects are corrected by ivacaftor and lumacaftor (the 2 components of Orkambi). On the other hand, no drug on the market stabilizes the CFTR F508del protein once it is returned to the membrane. That is changing. Researchers have discovered a new class of molecules called next-generation correctors, which greatly increase the stability of CFTR F508del on the cell membrane and greatly increase the effectiveness of other agents such as ivacaftor and lumacaftor. A triple combination of drugs could therefore be a solution for individuals with CF and carriers of at least one CFTR F508del mutation.

When using more than one medication at a time, there is always a risk of harmful interactions between medications. Lumacaftor is metabolized by the liver and is particularly likely to induce undesirable interactions with other drugs. This is why an alternative that is less conducive to interactions is being sought to replace lumacaftor and allow the addition of a next-generation concealer. An important step in this direction has just been taken. Vertex recently completed a large study that showed that tezacaftor is equivalent in effectiveness to lumacaftor but with significantly less potential for interactions with other drugs. This is a key step in the development of new medications that could help the majority of patients with CF. Now the challenge is to find a next-generation concealer to add to the combination of ivacaftor and tezacaftor. This last step is in the process of being resolved.

In vitro studies have allowed researchers to discover several molecules of the next generation of correctors and to demonstrate a much greater correction of the function of CFTR F508del when added to the combination of ivacaftor and tezacaftor. These encouraging studies are now reflected in several clinical studies in patients with one or two F508del mutations. The results of these studies could be known within a year and, after that, lead to the marketing of a much more effective medication for the majority of individuals with CF.

Even if this exciting research delivers its promise, there will still be around 10% of people with CF who will not benefit from these pharmacological advances. On the other hand, a new field of research known as “CRISPR/Cas9” technology offers a lot of hope. It is a way of carrying out a specific repair of a genetic defect without replacing the gene. It's a bit like repairing an electronic chip on our hard drive instead of replacing the entire hard drive. This technology is making great strides forward and has demonstrated its effectiveness in several animal models. One of the challenges remains how to transport the corrective machinery inside the nuclei where the genetic baggage is located, but it is only a matter of time before practical solutions are developed to do so.

In summary, there have been a lot of therapeutic developments in CF in the last year with spectacular results. It is now possible for the majority of CF patients to hope that one day they will have access to a therapy that will transform their lives. On the other hand, until then, it will above all be necessary to work hard to maintain your state of health, which will necessarily require excellent adherence to good lifestyle habits and to the treatments prescribed by the members of your CF care team.

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