New Drug for Cystic Fibrosis

Lumacaftor/Ivacaftor (Orkambi) Just Approved for Cystic Fibrosis

Ask any pediatrician why they like their job, and you'll likely hear the following: Kids get better.  And it's true ... many of the most ill kiddos go on to live happy and healthy lives.  Fortunately, children are resilient and survive grave disease, the severity of which would kill many adults.  For years, however, cystic fibrosis (CF) was the exception to this general rule. 

Once upon a time, most children with CF died during childhood.

  But thanks to advances in the treatment of cystic fibrosis, including better supportive and multidisciplinary care, people with CF are living well into middle age (50s).

One recent advance in the treatment of CF is the July 2015 approval of a drug combo called lumacaftor/ivacaftor (Orkambi) by the FDA for the treatment of children aged 12 and older with a homozygous (two-copy) gene mutation (deletion) in F508del.  What makes lumacaftor/ivacaftor special is that the homozygous F508del mutation affects almost 45 percent of people with CF worldwide.  In other words, lumacaftor/ivacaftor has the potential to help lots of people.

Although a rare disease, CF affects about 30,000 Americans and 80,000 people worldwide.  In fact, CF is the most common fatal genetic disease in Caucasians.  As you may be aware, CF results in thick mucus buildup which plugs up the lungs, sinuses, gastrointestinal tract and sex organs.

  Blockage caused by mucus results in infertility, trouble breathing and digestive problems (think steatorrhea or bulky, oily stool). 

Because of the buildup of mucus in the lungs, people with CF often experience respiratory infections which require antibiotics.  Furthermore, because mucus clogs up the pancreas in those with CF and messes with pancreatic enzymes, diabetes secondary to insulin deficiency and beta-cell dysfunction also result.

Cystic fibrosis also causes sweat to become salty and messes with body salts causing dehydration and electrolyte imbalances which can lead to fatigue, weakness, drops in blood pressure and even death. 

Here is a list of treatments for CF:

  • chest physical therapy (chest clapping to loosen mucus)
  • exercise (also to loosen mucus)
  • antibiotics (think respiratory infections commonly caused by P. aeruginosa)
  • bronchodilators
  • anti-inflammatory medications

More recent CF therapies target mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR) protein.  Specifically, in people with the F508del mutation, there is abnormal folding and trafficking of CFTR protein to the epithelial cell membrane.  Thus, limited amounts of protein make it to the cell surface in people with this mutation.  Lumacaftor/ivacaftor is a combination of two small proteins that aim to correct the dysfunction in CFTR.

In Phase 3 clinical trials, lumacaftor/ivacaftor increased %FEV between 2.6 and 4 percent during a period of 24 weeks.

  Of note, forced expiratory volume or FEV is a measure of lung function.  (People with CF have impaired FEV because they can't breathe as well.)  Additionally, this drug combination also decreased the number of pulmonary exacerbations or temporary increases in disease severity by about 33 percent depending on the treatment arm of the study.  

Many people hail the FDA approval of lumacaftor/ivacaftor and hope the drug will also help people with other CFTR mutations.  However, some experts are more reserved in their optimism for several reasons.  First, the improvement in lung function in people with heterozygous F508del mutation taking this drug is modest and no different from drugs that target the CFTR mutation downstream like DNAase, nebulized antibiotics and azithromycin.  Second, the reduction in pulmonary exacerbations is modest, too.  Third, lumacaftor/ivacaftor is a combination of two drugs and such polypharmacy can increase the number of adverse effects.  Specifically, some experts are worried about incidents of chest tightness and bilirubin elevations observed during trials.  Fourth, it's unclear how this drug combination affects sweat chloride levels or other biomarkers.  Fifth, despite receiving orphan drug designation by the FDA, this drug could end up costing a lot of money.

If you or a loved one suffers from certain types CF, the approval of lumacaftor/ivacaftor is good news.  This breakthrough is another step forward in our quest to treat a disease that once killed during childhood.  However, more research needs to be done before we fully understand this drug's efficacy and potential for adverse effects. 

Selected Sources

Article titled "Measurements of Functional Responses in Human Primary Lung Cells as a basis for Personalized Therapy for Cystic Fibrosis" by NT Awatade and co-authors published in eBioMedicine in 2015.  Accessed on 8/11/2015.

Article titled "Lumacaftor/ivacaftor for patients homozygous for Phe508del-CFTR: should we curb our enthusiasm" by AM Jones and PJ Barry published in BMJ in 2015.  Accessed on 8/11/2015.








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