NACF 2017: News in Respirology

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NACF 2017. P247. Efficacy and Safety of Tezacaftor/Ivacaftor in Patients Aged ≥12 Years with CF Homozygous for F508del-CFTR: A Randomized Placebo-Controlled Phase 3 Trial

 J. Taylor-Cousar, et al.


509 pts received ≥1 dose of tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (n=251) or placebo (PBO) (n=258). Baseline (BL) characteristics were well balanced between groups. There was a significant treatment effect favouring TEZ/IVA in absolute change in ppFEV1 (4.0 percentage points; 95% CI 3.1, 4.8; P<0.0001); a similar effect was seen in pts with ppFEV1 <40 at BL (TEZ/IVA [n=23] vs PBO [n=24]: 3.5 percentage points; 95% CI 1.0, 6.1; P=0.0070). Treatment differences for relative change in ppFEV1 and pulmonary exacerbations (Pex) (event rate, 0.64 vs 0.99; P=0.0054 [negative binomial regression]) met statistical significance while the comparison for change in BMI did not. Effects favouring TEZ/ IVA in CFQ-R and sweat chloride were nominally significant. In pts who had treatment-emergent adverse events (AEs), the majority were mild (TEZ/IVA 45.4% vs PBO 38.4%) or moderate (TEZ/IVA 36.3% vs PBO 45.3%); the most common were infective PEx (TEZ/IVA 29.9% vs PBO 37.2%), cough (26.3% vs 32.6%), headache (17.5% vs 14.3%), nasopharyngitis (16.7% vs 15.1%), and sputum increased (14.3% vs 16.3%). Predefined respiratory events occurred in 13.1% of pts in the TEZ/IVA arm and 15.9% in the PBO arm. Discontinuations due to AEs occurred in 2.8% (TEZ/IVA) and 3.1% (PBO) of pts; none were due to respiratory events. Serious AEs were reported in 12.4% (TEZ/IVA) and 18.2% (PBO) of pts, and no deaths were reported.


Significant improvements in ppFEV1, PEx rate, CFQ-R score (nominal), and sweat chloride (nominal) were observed with 24 wks of TEZ/IVA vs PBO. Treatment was well tolerated with few discontinuations due to AEs. Incidence of respiratory events was similar between PBO and TEZ/IVA, and none resulted in treatment discontinuation. These study results support the safety and efficacy of TEZ/IVA in pts with CF homozygous for F508del-CFTR.


NACF 2017. P273. Efficacy and Safety of Tezacaftor/Ivacaftor and Ivacaftor in Patients Aged ≥12 Years with CF Heterozygous for F508del and a Residual Function Mutation: A Randomized, Double blind, Placebo-Controlled, Crossover Phase 3 Study

 S. Rowe, et al.


Pts received tezacaftor (VX-661; TEZ)/ivacaftor (IVA) (TEZ/ IVA) (n=161), IVA monotherapy (n=156), or placebo (PBO) (n=161). Study baseline characteristics were balanced between groups (mean [SD] ages (y), 35.6 [13.5], 36.3 [15.2], and 32.6 [13.9] and mean [SD] baseline ppFEV1, 61.8 [14.9], 62.8 [14.6], and 62.1 [14.0] percentage points for TEZ/IVA, IVA, and PBO). Significant treatment effects were observed for TEZ/IVA and IVA in absolute ppFEV1 and CFQ-R respiratory domain score vs PBO. In addition, the treatment difference of absolute ppFEV1 between TEZ/IVA and IVA was statistically significant in favour of TEZ/ IVA. The majority of adverse events (AEs) were mild (TEZ/IVA 35.8%; IVA 35.0%; PBO 38.9%) or moderate (34.0%; 32.5%; 33.3%). The most common AEs (>10%) were infective pulmonary exacerbation of CF, cough, headache, and haemoptysis. No increase in respiration abnormal with TEZ/IVA was observed. No treatment discontinuations due to AEs were reported in the TEZ/IVA group vs 1.3% IVA and 0.6% PBO. Serious AEs were reported (TEZ/IVA 4.9%; IVA 6.4%; PBO 8.6%). No deaths occurred during the study.


Significant improvements in ppFEV1 and CFQ-R respiratory domain were seen with TEZ/IVA and IVA treatment vs PBO. Significant improvement in ppFEV1 was also seen with TEZ/IVA vs IVA. Treatments were well tolerated with no (TEZ/IVA) or few (IVA) discontinuations due to AEs. These findings support safety and efficacy of TEZ/IVA and IVA in pts with CF heterozygous for F508del and a second mutation resulting in CFTR residual function.


The two studies on tezacaftor-ivacaftor show that this combination therapy improves lung function (FEV1) and reduces exacerbation rate in CF patients with the most common genotype (Phe508del/ Phe508del) similar to lumacaftor-ivacaftor (OrkambiTM) but with better tolerability, and also improves lung function in patients with a residual function mutation, to a similar degree as ivacaftor monotherapy. Whether the combination of improved FEV1 and reduced exacerbation rate will result in greater treatment effects over time is unclear at this point though conceivable, as exacerbations contribute to a more rapid pulmonary function decline. Results from the open-label extension studies in which the majority of the study subjects were enrolled, may help clarify this in the near future.

While these studies demonstrate that CFTR modulating therapies have beneficial effects on some aspects of the disease, the clinical benefit of the current combination therapies for CF patients with the most common CFTR genotype (Phe508del/ Phe508del) falls within the range of established symptomatic therapies such as nebulized inhaled hypertonic saline or recombinant human DNAse. There is still an unmet need for truly effective new therapies to be developed for all individuals with CF. The complete study results on tezacaftor-ivacaftor combination therapy were recently published in the New England Journal of Medicine (Taylor-Cousar JL, et al., and Rowe SM, et al., N Engl J Med. 2017 Nov 3. [Epub ahead of print]), with an accompanying Editorial (Grasemann H, N Engl J Med. 2017 Nov 3. [Epub ahead of print]).

Whether new CFTR targeting combination therapies that are in the drug development pipeline, will ultimately result in clinically meaningful improvement of lung function and clinical status needs to be seen. Preliminary results presented by Dr. E. Tullis from Toronto suggest that the addition of a second corrector to corrector/potentiator combination regimens can result in improved efficacy of CFTR modulator therapy.

ATS 2017: News in Respirology - Cystic Fibrosis Case Study

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. 



  • 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

ATS 2017: News in Respirology - Asthma

ATS 2017. A4678 - Benralizumab Significantly Reduced Oral Corticosteroid Dosages and Asthma Exacerbation Rates for Patients with Severe, Uncontrolled Asthma: Results of the ZONDA Phase III Trial

P. Nair, MD, PhD, FRCP, FRCPC (Hamilton, ON, Canada) S. E. Wenzel, MD (Pittsburgh, PA, United States of America) K. Rabe, MD, PhD, FERS (Großhansdorf, Germany) A. Bourdin, MD (Montpellier, France) N. Lugogo, MD (Durham, NC, United States of America) P. Kuna, MD, PhD (Łódź, Poland) P. Barker, PhD (Gaithersburg, MD, United States of America) S. Sproule, PhD (Gaithersburg, MD, United States of America) S. Ponnarambil, MD (Cambridge, United Kingdom) M. Goldman, MD, PhD (Gaithersburg, MD, United States of America)

Results: Of 220 patients who were randomized and received treatment, 207 (94.1%) completed treatment. Benralizumab significantly reduced final OCS dosages by a median of 75% with the Q4W and Q8W regimens (p<0.001) compared with placebo (25%; table). The odds of a reduction in OCS dosage were 4.09-times greater (Q4W; p<0.001) and 4.12-times greater (Q8W; p<0.001) than with placebo. Benralizumab also significantly reduced annual asthma exacerbation rates by 55% (Q4W; p=0.003) and 70% (Q8W; p<0.001) vs. placebo, despite reduction in OCS dosages in the active treatment groups (table). Adverse events were numerically lower for the benralizumab Q4W and Q8W groups vs. placebo (68.1% and 75.3% vs. 82.7%, respectively). 

Conclusion: Benralizumab was well-tolerated and demonstrated significant, clinically relevant OCS-sparing benefits and asthma exacerbation rate reduction compared with placebo.


In this largest study to date of prednisone-dependent patients, benralizumab administered in dose of 30 mg SC every 8 weeks allowed the dose of prednisone to be reduced by up to 75% while still reducing exacerbations by 70% and preserving FEV1.  The odds of reducing prednisone was more than four-fold compared to placebo.  The magnitude of treatment effect was more than previously reported with mepolizumab.  It remains to be seen if the unique mechanism of action of antibody-dependent cytotoxic killing of eosinophils that express the IL-5 receptor leads to any long-term harmful consequences.

Provided by: Dr. Parameswaran Nair
CARE Respirology Faculty
Professor of Medicine, McMaster University
Staff Respirologist, St. Joseph’s Healthcare Hamilton

ATS 2017: News in Respirology - Cystic Fibrosis

ATS 2017. A4729 - Ivacaftor/Lumacaftor Improves Six Minute Walk Test Distance and Improves Lung Clearance Index and Functional Residual Capacity in Cystic Fibrosis Patients Homozygous for DF508 with Very Severe Lung Disease

P. A. Wark, MD, PhD (New Lambton, NSW, Australia), K. Cookson, B Nur (New Lambton, NSW, Australia), T. Thiruchelvenem, B Pharm (New Lambton, NSW, Australia), D. Dorahy, PhD (New Lambton, NSW, Australia), J. Brannan, PhD (New Lambton, NSW, Australia)

Conclusion: In subjects with severe lung disease treatment with Lumacaftor/Ivacaftor led to a significant improvement in 6MWT evident by 4 weeks, that continued to improve at 12 weeks. There was no improvement seen in FEV1, though the MBW demonstrates a change in LCI and a significant decline in FRC after 12 weeks of treatment.


Study by Wark et al indicates that combination Ivacaftor/Lumacaftor therapy improves functional residual capacity and six-minute walk test distance in patients homozygous for DF508 with severe lung disease (FEV1>40% predicted). Ivacaftor/Lumacaftor (Orkambi) therapy may lead to functional improvement by reducing airway mucus plugging and air trapping.  

Treatment paradigms for patients with CF have shifted with CFTR targeting therapies.  Some CFTR targeting therapies are already approved for clinical use (such as Orkambi) and others are in clinical or pre-clinical testing.  Unresolved issues for the treating physician include which criteria to use to select patients for these treatments and how to assess treatment success.  This will lead to more options and sequencing considerations.  However, fundamental/unresolved issues require attention from treating physicians, so that they may can have clarity when treating CF patients.  In order to frame this practically, a case follows.      

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


Press Release: CARE Congress on Biosimilars

On January 13th, 2017 CARE faculty specialists representing the fields of gastroenterology, hematology, oncology, respirology and rheumatology met to consider the integration of Biosimilars into the Canadian healthcare system.

Biosimilars are drugs that may replace expensive biologic drugs that are going off patent.  With biosimilars being relatively new to the Canadian landscape, there are also a number of questions/considerations on extrapolating data, interchangeability, immunogenicity, and systemic challenges (tracking and monitoring) that require attention.

Recognizing both the potential impact on the Canadian healthcare system and the importance of involving stakeholders, CARE faculty invited 16 speakers representing Canadian researchers, clinicians, Health Canada, public and private funding agencies, health economists, hospital pharmacists, nurses, advocacy groups, ethicists and legal experts to share perspectives, concerns, wants and needs.

An audience of 100+, representing the above named stakeholders, along with various levels of government, pharmaceutical companies and industry associations, listened in while speakers and assembled faculty discussed biosimilars from multiple perspectives.

The aim of this Congress is to increase collective understanding, consider education needs for specialists and assembled stakeholders, and ultimately refine a CARE guidance/position on Biosimilars.


CARE Faculty believes: 

  • Developing clinical practice through optimization of current therapies
  • Improving patient outcomes by developing innovative therapeutics
  • Ensuring access to quality care for all Canadians by the responsible and evidence-based use of treatment
  • Competition is welcomed to improve efficiency and access


CARE™ funding sources:

CARE™ receives unrestricted funding from multi-industry sponsors, institutions and associations. Content reflects the opinions, presentations and analyses of experts, investigators, educators and clinicians ("CARE Faculty"), whose activities, while independent, are commercially supported by the noted sponsor(s). Program content is developed independently of sponsor(s).


Background Steps that led up to this CARE™ Congress

  • CARE™ conducted needs assessments in oncology, hematology, rheumatology, and gastroenterology to understand current perceptions of biosimilars and their use in Canada
  • A multi-disciplinary group of CARE faculty members met October 27th, 2016 to discuss the various needs assessment data, and the impact biosimilars will have in Canada
  • There was consensus to host a larger meeting involving more stakeholders; CARE™ has worked to quickly assemble this Congress involving not only different specialties, but different stakeholder representatives.

For more information on the steering faculty, assembled CARE faculty, speaker list, or for questions/information needs regarding CARE, please contact Christina Lopes or Erica Duncan. 



  1. Hirsch BR, Lyman GH. Biosimilars: are they ready for primetime in the United States? J Natl Compr Canc Netw. 2011;9: 934–943
  2. Based on 2013 sales of biologics with patents expiring before 2021 (Remicade, Eprex, Aranesp, Levemir, Humira, Avastin, Enbrel, Lucentis, Rituxan, Gonal-F). IMS Health Canada - Canadian Drug and Hospital (CDH) Sales, December 2013, page 11

Click here to view more highlights from the CARE Congress on Biosimilars.

Insights on the NOR-SWITCH trial are now available! Hear from Canadian experts Drs. Brian Feagan & John Marshall

Biologic therapy has revolutionized the treatment of IBD and improved patient outcomes drastically. Many of the biologic therapies we routinely use are now or soon going off patent and competitive molecules, subsequent entry biologics (SEBs), are now being introduced. SEBs have potential implications for our own practices but also for how we manage our pharmacy budgets and how we deliver health care in Canada.

The NOR-SWITCH trial was a randomized, open-label trial studying a cohort of patients who were stable or in remission on the innovator biologic, infliximab (REMICADE®). Patients were randomized to either continue with infliximab or switch to a SEB version of infliximab (INFLECTRA® in Canada). This was a cross specialty trial that included patients from a variety of diagnoses, including: rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, UC, CD and chronic plaque psoriasis. Each group was followed for different endpoints over the course of the trial.

CARE Gastroenterology Faculty lead, John Marshall (McMaster University), sat down with Dr. Brian Feagan (Professor of Medicine at the University of Western) to critically assess this study and discuss how the results should be interpreted and applied in Canadian practice.


Interested in learning more? Join us at The CARE Congress on Biosimilars!

CARE Update: Fall 2016


CARE (Community, Academic, Research, Education) develops a number of educational initiatives throughout the year, designed to educate Canadian specialists on the latest news and developments in their respective fields, reflecting a national outlook but also recognizing regional considerations.

The CARE Faculty is comprised of leading Canadian specialists in a number of different disease categories, including (but not limited to): Gastroenterology, Rheumatology, Hematology, Oncology.

The CARE Faculty is excited to announce a number of new developments that have taken place so far this year. What follows is an update on the programs the CARE Faculty has developed in the last quarter of 2016, as well as upcoming CARE events.