Cystic Fibrosis Research: Major Advances and Persistent Challenges in 2015

By Dr. André Cantin, pneumologist
Sherbrooke University Hospital Center

The 29th Annual North American Cystic Fibrosis Conference took place in October 2015 in Phoenix, Arizona. It was an opportunity for many scientists and clinicians around the world to share their discoveries and to establish new collaborations for the advancement of research in basic sciences and clinical applications. One of the major themes that emerged from this conference was the strengthening of clinical research collaborations with people with cystic fibrosis. It turns out that cystic fibrosis is a particularly variable disease, both in terms of its clinical expression and in terms of the composition of genetic abnormalities. However, the new drugs developed for cystic fibrosis are specific to particular mutations, which requires the international community to establish collaborations in order to accelerate the discovery of new effective products adapted to the genetic particularity of each individual (personalized medicine).

The discovery with the most clinical impact in 2015 was that of clinical data related to the partial correction of the CFTR defect in the population with two F508d mutations, which is the most common defect that affects 50% of people with cystic fibrosis in North America (Figure 1). A combination of two drugs, Lumacaftor and Ivacaftor, known by the trade name Orkambi, is available on the American market. This new drug allows the two chemical molecules to work in synergy while Lumacaftor promotes the progression of the abnormal protein towards the cell membrane and Ivacaftor (Kalydeco) activates the opening of the CFTR once this protein is located in the membrane. Clinical research involving more than a thousand patients over a period of 24 weeks demonstrated a modest but significant improvement in the sweat test as well as several clinically relevant parameters such as respiratory function, weight gain, and an approximately 50% decrease in the number of respiratory exacerbations. This last data is particularly relevant in the clinic because we know that the number of respiratory exacerbations is strongly associated with the speed of the decline in respiratory capacity. The side effects of Orkambi are relatively mild and, interestingly, one of the drug side effects includes changes in bowel habits, while patients who were previously constipated report more frequent bowel movements and sometimes complain of diarrhea. This adverse drug effect could be directly related to a partial correction of the defect in chloride transport in the intestine. Everyday clinical experience with this new drug is very limited as it is not yet approved in countries other than the United States and the drug has only been on the American market for a few months. Preliminary data suggests that its clinical effectiveness is still noticeable by users.

Three major challenges remain with this new drug to treat patients with two F508d mutations. First, the molecular effectiveness of the drug is still very limited if we rely on the sweat test correction which is only 11%. A correction of 50% or more would be desirable in order to reverse the majority of symptoms and clinical manifestations of cystic fibrosis. Second, before the medication can be prescribed, it must be approved by government drug regulators such as Health Canada. The assessment done prior to the approval of a new drug includes an analysis of benefits versus adverse drug effects. Health Canada is currently studying this file in order to decide on the possible approval of Orkambi in Canada. The third challenge, and not the least, is getting individuals and families living with cystic fibrosis reimbursed for the high cost of medication. At USD$710 per day in the United States (according to The Associated Press — November 2015), Orkambi is not cheap. Any new drug developed for a rare disease involves very high costs, because the amount of investment required to bring new molecules to the market remains the same regardless of the frequency of the disease for which the drug is being developed. On the other hand, since the pool of people with a rare disease is by definition very small, companies that have invested in the development of a molecule specific to this disease must recover the costs of this investment by predicting that there will be no sales volumes comparable to those of products developed for common conditions such as high blood pressure or hypercholesterolemia. This is a challenge not only for families dealing with cystic fibrosis, but for all individuals in society. We need to demonstrate social solidarity within a sustainable financial framework, as we are all likely to be treated for a rare disease at some point in the future.

The effectiveness of new drugs aimed at treating the basic defect in cystic fibrosis remains suboptimal and several clinical research studies are in progress in order to evaluate new molecules, which is particularly true for people who are homozygotes (two identical mutations) for the F508d mutation. Two major international studies are underway to study a new generation of improved molecules that could prove to be better than Orkambi. In addition, there is ongoing international research to study Ataluren in people with cystic fibrosis with a class I mutation, a mutation that prematurely blocks the transcription of the gene encoding the CFTR protein.

Several nutritional intervention projects are in progress. The link between nutritional defect and excessive inflammation in patients with cystic fibrosis is increasingly recognized. There is a deficiency of certain essential fatty acids in the membranes of people with cystic fibrosis and the deficiency of these essential fatty acids, including some omega-3 oils, could be a factor promoting inflammation. Clinical research to restore a favorable membrane lipid profile and thus counter the inflammation caused by cystic fibrosis is under development in Montreal, Sherbrooke and elsewhere in the world. If you are interested in participating in a clinical research project, you are encouraged to discuss it with your clinic director or with the staff at your cystic fibrosis clinic. These professionals are very familiar with the various research programs.

Finally, all participants in the North American Cystic Fibrosis Congress were able to benefit from a plenary session that focused entirely on the psychological well-being, depression and anxiety associated with cystic fibrosis. These elements that were previously rarely discussed have now become priority topics for scientists and clinicians associated with various cystic fibrosis clinics around the world. It is recognized that this sometimes overlooked aspect is particularly important in the overall care offered in cystic fibrosis clinics.

In summary, the North American International Cystic Fibrosis Congress was one of those that disclosed the largest amount of new information that could allow health professionals to hope to truly change the course of the disease in patients with cystic fibrosis. We all left Phoenix excited but realistic, while recognizing the significant amount of work we still need to do before seeing these promises translate into improved quality of life for each individual in all of our cystic fibrosis clinics.

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