May is Cystic Fibrosis (CF) Awareness Month. CF is a multi-organ genetic disease that particularly affects the lungs, which see a gradual decline in their function due to cycles of infection and chronic inflammation. The disease has a 1%-2% mortality rate, with approximately half of Canadians dying from CF before they reach the age of 35.
By Philip Fine

Dr. John Hanrahan

Clapping on a child’s chest to release the disease’s telltale thick mucus is a long standing treatment for Cystic Fibrosis (CF). It does help, but discoveries in biomedical research are now leading to the development of new therapeutics which can target the molecular defect.

The first such drug developed by Vertex Pharmaceuticals Inc. called Kalydeco is remarkably effective, but only for 3% of people with CF.   “It provides a 10-per-cent improvement in lung function, which is life changing” says Dr. John Hanrahan, Cystic Fibrosis Canada Researcher and Professor in the Department of Physiology at McGill University, who lays out some of its pros and cons.

Quebec has yet to add Kalydeco to its list of medications covered by the Public Prescription Drug Insurance Plan, presumably due to its cost, which is approximately $300,000 a year per patient. Nevertheless Quebec has been generous in granting exceptional reimbursement to the small number of patients who benefit from the drug, and most provinces and Yukon also provide coverage automatically.

While there are patients who respond well to this medication, it does not work when given alone to those carrying the most common CF gene mutation.

The problem lies in the fact that the most common gene mutation, delta F508, causes multiple defects in the gene product, and Kalydeco targets only one of them. “With delta F508 we need to increase opening of the defective ion channel, and also correct its folding and delivery to the cell surface” says Dr. Hanrahan.

A drug for this more common mutation called Orkambi has been developed but unfortunately its effects are less dramatic than those of Kalydeco. Bouts of infection are less frequent, but only about 25 per cent of the patients have significant improvement in their lung function, making the decision to fund Orkambi with public-health dollars more difficult.

“There’s currently no objective way to identify those who will, or will not, benefit from Orkambi, and therefore no rational basis for withholding the medication” says Dr. Hanrahan, who is also affiliated with the Research Institute of the McGill University Health Centre.

Hanrahan’s lab is in the Cystic Fibrosis Translational Research Centre (CFTRc), a McGill research centre in the Faculty of Medicine. The acronym CFTRc is a word play on the name of the molecule at the heart of their academic work, the Cystic Fibrosis Transmembrane conductance Regulator. The centre includes David Thomas, Larry Lands, Gergely Lukacs and about 20 other researchers who try to understand the molecule and develop new therapies. “On the academic side we want to understand how CFTR and CF drugs work, and on the commercial side we want to develop new candidate drugs which can help people with CF.”

Promising lead molecules were developed in the centre last year by a startup company called Traffick Therapeutics, co-founded by David Thomas and John Hanrahan, and they are presently being developed further by Vertex for possible combination with their own drugs.

Hanrahan follows the basic science and many clinical trials taking place around the world and, despite the current obstacles for Orkambi, he is optimistic for those dealing with CF. “What’s exciting is that there are many academic groups and companies working on this, and there are many drugs in the pipeline. The goal is to have all people with CF benefit regardless of their mutation, and as more drugs become available it may be possible to choose the most effective one for individual patients. This, along with competition, may also bring drug costs down to where they can be covered by public drug plans.”

May 19, 2017