“The New CF Therapies: Who Will Benefit?” was the title of the presentation given by Dr. Michael Boyle at the 32nd Kit Taylor Lecture on Tuesday, May 8, 2012. While some caution is still necessary, Dr. Boyle reported on the promising results from recent drug trials.
The topic of the lecture was consistent with Dr. Boyle’s experience and expertise. In addition to being the director of the Adult Cystic Fibrosis Program at Johns Hopkins University, he is also affiliated with the Cystic Fibrosis Foundation. He is active in CF related research including his role as a lead investigator for the current trials for the Vertex ivacaftor, VX-809 and VX-661 products.
Dr. Boyle provided some background before delving into the new therapies. He started with a summary of statistics that demonstrate the progress that has been made in treating CF. Today, the median survival age is 38 years old – a significant gain over the pre-teen expectancy at the time Kit Taylor was diagnosed in 1958. He also noted that 2012 is projected to be a milestone year when the number of adult CF patients exceeds the number of pediatric patients.
Dr. Boyle then presented an overview of the physiology of CF as a basis for understanding the new therapies. CF results from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene controls production of the CFTR protein which regulates the chloride (and maybe other) channels in epithelial cells that line the passageways of the lungs, pancreas, and other organs. The primary focus is on the lung epithelial cells since reduced lung function is the most critical symptom of CF.
Defects in the CTFR gene interfere with the transport of chloride ions through the cells which, in turns disrupts the flow of water to the cell surface. The inadequate supply of water results in thick mucus that impedes the clearing of the lungs and promotes bacterial infections.
Over 1,500 mutations have been identified that produce the range of dysfunctions presented as cystic fibrosis. These mutations have been categorized into five general classes that describe the nature of the dysfunction. The classes, dysfunction and rate of occurrence in the CF population are as follows:
| Most severe
| | | Least severe |
Class I Class II Class III Class IV Class V |
Defective synthesis Defective processing Defective regulation Defective conductance Reduced synthesis |
12% 87% 4% 4% 4% |
Note, the percentages represent the portion of the CF population that have at least one gene in the class. Since a patient may have two different mutations, the numbers total more than 100%.
With Class I mutations, the cells do not produce the CFTR protein. The CFTR protein is produced in Class II mutations; however, the protein does not reach the cell surface. In each of the remaining classes, the protein does reach the cell surface but does not function at expected levels.
While the genetic defect is a significant factor in lung function, it is not the sole contributor. Dr. Boyle offered the following “formula:” lung function = genes + environment + stochastic. He noted that, in addition to the CFTR gene, other mitigating genes can influence lung function. The stochastic element represents the unknown or unexplained variations in lung function for CF patients.
Environmental factors include exposure and treatments. Exposure to second-hand smoke has been shown to have a strong negative impact on CF lung function. Studies have also shown a correlation between lung function and latitude; that is, CF patients in northern states show better lung function and later pseudomonas colonization than patients in southern states. In addition, more aggressive treatment (e.g., tune-ups at lower thresholds and longer tune-ups) and higher treatment compliance correlate with better lung function.
Dr. Boyle demonstrated the importance of environmental factors with a display of lung function statistics for a set of identical twins. Given their identical genetic make-up, the similarity in lung function test results was no surprise. However, those results diverged after the twins moved apart; into different living environments.
Dr. Boyle transitioned to his discussion of new treatments by noting that we have reached the point in time where, rather than addressing symptoms, treatments are targeting the root defects of CF. Almost 20 years ago, the Kit Taylor Lecture series hosted Dr. Francis Collins, a key member of the team that discovered the CFTR gene. In his presentation, he predicted that the discovery would some day lead to treatment of the underlying defect – that day has arrived.
Dr. Boyle first discussed ivacaftor (also known as Kalydeco or VX-770) which was approved by the FDA on January 31, 2012. Ivacaftor works on the CFTR protein to improve the transport of chloride through the ion channel. The results exceeded expectations: on average, patients experienced a 10% increase in lung function within two weeks and that improvement was sustained throughout the period of treatment. Patients using ivacaftor also experienced 55% fewer exacerbations and measurable weight gain. The sweat chloride concentration was also below the level used for CF diagnosis. Like icing on the cake, there do not appear to be any significant side effects from the treatment.
There is no denying the importance – and hope – of the ivacaftor treatment, but some significant hurdles remain:
- Ivacaftor was developed and approved for patients with the G551D mutation, a Class III defect. Therefore, approximately 4% of the CF community will now be given access to this product.
- Ivacaftor has been approved for patients who are six or more years old. It is expected that further work will be done to develop a formulation appropriate for younger patients.
- Ivacaftor improves the patient’s current lung function but does recover capacity lost due to scarring or other lung damage. This highlights the need to initiate treatment as soon as possible to minimize the risk of tissue damage.
- Given the small target population compared to the huge research investment, ivacaftor will cost about $300,000 a year.
Dr. Boyle then discussed two branches that research will take to build on the success from ivacaftor. One path will be investigation of the effectiveness of ivacaftor in dealing with other mutations. While it was developed specifically for the G551D mutation (a Class III defect), there is hope that ivacaftor will work on other Class III mutations, such as G551S. Further, ivacaftor improves the functionality of CFTR proteins that have reached the surface of the epithelial cells; therefore, research will also be conducted to test its application in addressing mutations in Class IV and Class V.
The second avenue of research will address Class II mutations; particularly, ∆F508, the most prevalent mutation. Although the CFTR gene produces the protein in Class II mutations, the protein does not reach the cell surface. Therefore, ivacaftor – which improves the function of the protein – alone cannot produce the results it did for G551D patients. To overcome this challenge, ivacaftor is being tested in combination with two other drugs (VX-809 and VX-661) which are designed stimulate the delivery of the CFTR protein to the cell surface.
Interim results have been very promising, such that Vertex (the pharmaceutical company producing the drugs) recently issued a press release. This news has been widely reported including articles in Nature, Business Week and The New York Times. Two members of the audience volunteered that they had participated in the Rochester trials for the ∆F508 treatment and reported that they were pleased with their results. Dr. Boyle urged caution in drawing conclusions from the trial outcomes until the data is fully analyzed.
If the apparent success of the treatment for the Class II mutations holds true, therapies will be available for a large majority of the CF community. An even greater challenge lies ahead for those with Class I mutations since the underlying defect is the failure to produce the CFTR protein.
During his discussion of the evolving therapies, Dr. Boyle emphasized the importance of CF patients knowing their particular mutation(s) or genotype(s). Since the new therapies are targeted at specific defects, the patient’s genotype will be crucial in selecting the best CFTR treatment. Identifying the genotype is also useful in adjusting other treatments. In recognition of this development, the Cystic Fibrosis Foundation announced the Mutation Analysis Program (MAP) which offers free genotyping to cystic fibrosis patients.
As usual, the Kit Taylor Lecture was very informative. Yet, this year’s discussion was quite special given the promise demonstrated by the ivacaftor trials.