Male CF Patient Homozygous For The CFTR Mutation, f508del

Adolescent pancreatic insufficient male CF patient homozygous for the most common CFTR mutation (F508del) with conserved pulmonary function (obtained by conventional pulmonary function testing), but poor nutritional status, chronic rhinosinusitis, chronic airway infection with P. aeruginosa and frequent hospital admissions (3-5/year) for IV antibiotic treatment of pulmonary exacerbations. Standard of care with daily treatments including inhaled rhDNase, inhaled antibiotics, hypertonic saline and chest physiotherapy with good adherence but no clinical improvement.

Considerations: 

• Are there guidelines which would influence your treatment of this patient?
• Does drug cost/reimbursement influence your treatment of this patient?
• What would you like to use/ what would you use to treat this patient?
• Would you recommend initiation with Ivacaftor/Lumacaftor (Orkambi TM) therapy for this patient?
  • How long would you treat before reassessing?
  • Which parameters would you use to assess potential therapeutic benefit?

Dr. Grasemann’s Recommendations:

• There is no “definitive solution” for this Case Study. Currently, there are no established guidelines on the use of CFTR targeting therapy in CF patients homozygous for the F508del mutation.
• Ivacaftor/Lumacaftor (Orkambi™) is a valid treatment choice. This combination therapy is approved in Canada, and stands as a “proof of concept” for the effectiveness of combination (corrector/potentiator) CFTR targeting therapies in CF.
• The efficacy of Ivacaftor/Lumacaftor was demonstrated in adolescents and adults homozygous for F508del, and a recent Canadian-lead phase 3 clinical trial by Felix Ratjen et al., also suggests improvement in lung function in treated CF children 6-10 years of age. This study used change in the lung clearance index (LCI) as primary endpoint.
• The degree of clinical improvement experienced by CF patients using Orkambi™ therapy may vary, however the fact that it is both effective (to some degree) and safe, seems consistent.
• Due to its proven capacity to reducing pulmonary exacerbation rate, I would consider OrkambiTM BUT cost and reimbursement can be limiting factors. Drug costs/reimbursement does influence the treatment of individual CF patients.
• I would like to use Ivacaftor/Lumacaftor therapy in this patient, however I am based in Toronto and Ontario’s provincial drug plan does not cover OrkambiTM.
• Reimbursement in Ontario is only available through private programs, which limits access.
• Once OrkambiTM therapy is initiated, the efficacy of the treatment should be reviewed, however
  • what is a reasonable treatment period to monitor effects on exacerbation rate?
  • what other parameters should be used to demonstrate therapeutic benefits in an individual patient?
• The Case Study illustrates how a lack of guidance and availability can impact treatment.

Moving Forward:

This case study illustrates that Ivacaftor/Lumacaftor combination therapy can be a treatment choice in CF patients homozygous for the most common CFTR mutation F508del; but can we access it, and how should we?

Current CFTR targeting therapies offer the opportunity of treating CF at the “source” i.e. the protein that causes the disease, and early treatment may help prevent the natural progression of the disease.

However, defining meaningful clinical endpoints to demonstrate efficacy of these therapies can be problematic in patients with early CF lung disease and minimal symptoms.

The lung clearance index (LCI), a measure of lung function obtained by multiple breath washout (MBW), is more sensitive to changes than conventional spirometry, but is a test that requires equipment not currently available in many CF centers.  Thus, while LCI may help to demonstrate effects of therapy on lung function in patients with CF, it’s accessibility is limited. Forced expiratory volume in 1 second (FEV1), which is broadly used to monitor CF lung disease however, is not sensitive enough to detect early changes, such as peripheral mucus plugging of airways, or subtle responses to therapies. Therefore, there is an ongoing need to develop easily administered, cost and time efficient tools to monitor disease progression in CFTR related respiratory diseases.

Though “innovation” is often associated with the development of novel therapies, the use of pre-existing treatments in new, more effective ways (or in different combinations) is also considered innovative.  There is concern that new beneficial agents will be inaccessible due to costs.  Cost is always a major factor in treatment initiation in Canada, with individual provinces and territories having different rules on reimbursement/funding.  CF treatment in Canada must remain both innovative and accessible.  There is a need to develop a guidance for the use of new therapies in CF patients.  The guidance would be developed by experts, based on experience and considering clinical trial data, helping to make CF treatment consistent in centers and provinces across Canada.

Insights Provided by Dr. Hartmutt Grasemann
CARE™ Respirology Faculty
The Hospital for Sick Children
Professor, University of Toronto