[116] New drug for cystic fibrosis: Regulatory approval, clinical uncertainty?

[116] New drug for cystic fibrosis: Regulatory approval, clinical uncertainty?

A new drug for cystic fibrosis (CF) that combines lumacaftor and ivacaftor (Orkambi), was approved by Health Canada (HC) in 2016 to treat people age 12 and older with the most frequent CF genetic mutation: homozygous F508 deletion of the cystic fibrosis transmembrane regulator (CFTR) gene. This affects 50% of the Canadian CF population.

In CF, mucus membranes do not release an adequate amount of moisture, therefore respiratory and other secretions are thick and sticky. This leads to an increase in respiratory infections, scarring, and deterioration in lung function, as well as pancreatic insufficiency and inadequate nutrition.

Current therapy includes both pharmacotherapy (antibiotics, mucolytics, pancreatic enzymes) and physiotherapy. These therapies are critical to reducing the frequency and severity of lung infections and slowing the deterioration in lung function. As a result of these therapies, Canadian CF patients now have a median survival of over age 50.1

Lumacaftor/ivacaftor (LUM/IVA) attempts to modulate the cellular dysfunction caused by a specific gene mutation. Lumacaftor is understood to ‘correct’ the misfolding of the CFTR protein caused by the F508del gene mutation, while ivacaftor is understood to ‘potentiate’ a gating mechanism at the cell surface.

The basis for regulatory approval

Regulatory approval2 was based on the findings of two studies that randomized 750 subjects, age 12 years and older, to placebo or the recommended dose of LUM 400 mg / IVA 250 mg administered every 12 hours for 24 weeks.3,4 Participants were eligible for enrolment if they had stable mild to moderate disease. Both study groups received current therapy as per their usual routine or as needed to treat pulmonary exacerbations.

The primary efficacy outcome was the average change in the ‘percent predicted forced expiratory volume in the first second of expiration’ (ppFEV1) as measured by spirometry at 16 and 24 weeks. The ppFEV1 improvements of 2.6% and 3.0%, although statistically significant, were short of the 5% change that investigators designing the trials saw as clinically significant.5 Of the five secondary outcomes, statistically significant improvements were not replicated in both trials (Table 1). Perhaps most relevant to treatment of CF, neither trial showed a statistical difference in the outcomes: quality of life or number of pulmonary exacerbations per year.

Clinical uncertainty

A survival benefit was not demonstrated in regulatory trials required by HC. Nevertheless, CFTR modulating therapies like LUM/IVA have generated considerable excitement because they build on emerging scientific knowledge of how CFTR mutations affect the functioning of mucus membrane cells. Another important and as yet unanswered question in the regulatory trials is whether LUM/IVA eliminates or modifies the exhaustive daily therapeutic programs undergone by CF patients.

Disease progression in CF patients is well understood6 with optimal current clinical therapy in persons with mild to moderate CF. FEV1 as well as ppFEV1 are valid disease progression markers although unreliable measures of symptoms.

Disease progression, including mortality can be measured in clinical studies, but the trials need to be much longer than the 24 weeks required by the regulators. Randomized controlled trials of 3 years duration have been conducted for other therapeutic interventions in CF.7 A recent observational study offers some evidence to clinicians regarding LUM/IVA performance outside of a clinical trial. In a cohort of 116 patients followed for 11 months after initiating LUM/IVA treatment, 46 (39.7%) reported adverse effects related to LUM/IVA: 38 (32.7%) had pulmonary adverse effects and 20 (17.2%) discontinued treatment. Individuals with a ppFEV1 of ≤ 40% had proportionally higher rates of adverse effects and discontinuation.8 This lower quality evidence demonstrates a higher rate of drug intolerance than seen in the RCTs and suggests that people with more severe disease are more likely to discontinue the drug due to adverse effects.


  • Lumacaftor/ivacaftor (Orkambi) is a new combination drug for the treatment of cystic fibrosis.
  • Health Canada granted regulatory approval for this drug combination based on two 24-week placebo-controlled studies showing a 3% improvement with the drug in a lung function test (ppFEV1).
  • There is insufficient evidence at the present time that lumacaftor/ivacaftor improves quality of life, morbidity or mortality in patients with cystic fibrosis.

Table 1: LUM/IVA findings at recommended dose for people with homozygous F508del CFTR mutations

Secondary efficacy outcomes reported at 24 weeks

Trial 1 3

(n = 374)

Trial 2 4

(n = 376)

Relative change in ppFEV1 – percent change relative to the baseline FEV1 NS

Statistically significant

Absolute change in body mass index (BMI)
a measure of nutritional status

Statistically significant

Absolute change in CFQ-R respiratory domain score
a measure of quality of life
Response rate – relative change in % of patients with a ≥ 5% relative change in ppFEV1 NS

Statistically significant
OR 2.4; 95% CI 1.5-3.7

Number of pulmonary exacerbation events per year NS


CFQ-R = Cystic Fibrosis Questionnaire – Revised || NS = not statistically significant

The draft of this Therapeutics Letter was submitted for review to 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

The Therapeutics Initiative is funded by the BC Ministry of Health through a grant to the University of BC. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
ISSN 2369-8691 (Online) <||> ISSN 2369-8683 (Print)


  1. The Canadian Cystic Fibrosis Registry. 2016 annual data report. 2016. https://www.cysticfibrosis.ca/uploads/2016%20Registry%20Annual%20Data%20Report_2.pdf [Accessed 20 Dec 2018]
  2. Health Canada. Summary basis of decision (SBD) for Orkambi. 2016. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00294#AClinBasisHeader [Accessed 20 Dec 2018]
  3. Vertex Pharmaceuticals Incorporated. A study of lumacaftor in combination with ivacaftor in cystic fibrosis subjects aged 12 years and older who are homozygous for the F508del-CFTR mutation (TRAFFIC). 2015. https://clinicaltrials.gov/ct2/show/NCT01807923/ [Accessed 20 Dec 2018]
  4. Vertex Pharmaceuticals Incorporated. A study of lumacaftor in combination with ivacaftor in cystic fibrosis subjects aged 12 years and older who are homozygous for the F508del-CFTR mutation (TRANSPORT). 2016. https://clinicaltrials.gov/ct2/show/NCT01807949/ [Accessed 20 Dec 2018]
  5. UK National Institute for Health and Care Excellence. Committee papers. Lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation. Technology appraisal guidance [TA398]. 2016. https://nice.org.uk/guidance/ta398/documents/committee-papers/ [Accessed 20 Dec 2018]
  6. Adler FR, Liou TG. The dynamics of disease progression in cystic fibrosis. PloS One. 2016; 11(6):e0156752. DOI: 10.1371/journal.pone.0156752
  7. Schneiderman-Walker J, Pollock SL, Corey M, et al. A randomized controlled trial of a 3-year home exercise program in cystic fibrosis. The Journal of Pediatrics. 2000; 136(3):304-10. DOI: 10.1067/mpd.2000.103408
  8. Jennings MT, Dezube R, Paranjape S, et al. An observational study of outcomes and tolerances in patients with cystic fibrosis initiated on lumacaftor/ivacaftor. Annals of the American Thoracic Society. 2017; 14(11):1662-6. DOI: 10.1513/AnnalsATS.201701-0580C
  • Giorgio Karam
    Posted at 18:06h, 28 December Reply

    It should be noted that, in both trials, patients on Orkambi had fewer pulmonary exacerbations than those on placebo, 0.7 per year vs. 1.14 per year, rate ratio 0.61, p < 0.001 (see Table 2 of the NICE clinical effectiveness report), but because it was the last of several secondary endpoints and earlier endpoints were not statistically significant, it could not be reported as statistically significant and cannot be considered confirmatory evidence (hierarchical testing of endpoints, a way of controlling for spurious statistical significance due to multiple testing).

    That said, the FDA did write in its summary review (p.19) that: "The numerical beneficial effect on pulmonary exacerbations places the improvement in FEV1 in context, as it suggests that the numerically small but statistical significant improvement in FEV1 is a meaningful clinical benefit." This is even though the FDA statistical review said that the improvement in FEV1 was "small with unclear clinical relevance."

    In contrast, another CFTR modulator, Symdeko, had a similar finding as in the Orkambi trials: exacerbation rate ratio 0.65, p = 0.005. But in the Symdeko trial, pulmonary exacerbations as an outcome was the second of the secondary endpoints (rather than the last of several as with Orkambi). Because all prior outcomes were statistically significant, the result for Symdeko is statistically significant as well.

  • Carolyn Green
    Posted at 16:09h, 31 January Reply

    We appreciate your well informed response and website http://www.students4bestevidence.net. Debates about statistical and clinical significance are not easily resolved without further data. Moreover the important issues are not statistical but rather relating to disease progression like the lack of demonstrated improvement in quality of life or reduction in the need for intensive treatment with other medications and therapies. Comparative trials are needed to show at least a relative morbidly benefit versus other therapies.
    The exacerbation data also has several limitations:
    1. Data for pulmonary exacerbation are limited by the relatively short duration of the trials.
    2. To support an exacerbation claim evidence needs to be replicated in 48 week trials (US Food and Drug Administration, 2015a).
    3. The event rate calculation per year assumes that the rate of pulmonary exacerbation is constant for the entire 1 year period which may not be true.

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