Lumacaftor-ivacaftor (Orkambi) for cystic fibrosis: behind the 'breakthrough'.

Lumacaftor-ivacaftor (Orkambi) was recently approved by the Food and Drug Administration (FDA) in the USA to treat patients at least 12 years old who have cystic fibrosis due to two copies of the F508del (Phe508del) mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lumacaftor-ivacaftor has been designated a ‘breakthrough’ and is slated to cost $259 000 per year per patient, but close scrutiny of the data behind this new medication reveals modest improvements in outcomes that are not exclusively benefited by lumacaftor-ivacaftor, and the $259 000 cost is questionable and problematic. Providers considering this therapy should have a candid and easily-understandable discussion with their patients about what the data show for lumacaftor-ivacaftor so their patients can make an informed decision about taking it. This article aims to help this process. Introduction The Food and Drug Administration (FDA) recently approved lumacaftor 200 mg-ivacaftor 125 mg (Orkambi) to treat patients at least 12 years old who have cystic fibrosis (CF) due to two copies of the F508del (Phe508del) mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The FDA press release noted: “Orkambi was studied in two double-blind, placebo-controlled clinical trials [with a combined total] of 1108 participants. In both studies, participants with CF who took Orkambi, two pills taken every 12 hours, demonstrated improved lung function compared to those who took placebo”. These trials, known to the FDA as 809-103 and 809-104, were also published in the New England Journal of Medicine (NEJM) shortly after being considered at the 12 May 2015 Pulmonary-Allergy Drugs Advisory Committee Meeting of the FDA. The Phe508del mutation is the most common genetic mutation resulting in CF, accounting for roughly half of all cases of CF. Since CF is rare, this drug was granted ‘orphan drug’ status, thus conferring certain benefits for the manufacturers, Vertex Pharmaceuticals (Vertex). It was also given a ‘breakthrough therapy’ designation. Looking at the FDA press release, one sees suggestions of a ‘breakthrough therapy’ with “two doubleblind, placebo-controlled clinical trials [demonstrating] improved lung function compared to those who took placebo”. What exactly did these trials find, though? The evidence Effect on lung function Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT) both ran for 24 weeks, and the primary efficacy outcome for both was absolute change from baseline to week 24 in the percentage of predicted forced expiratory volume in 1 s (ppFEV1) as assessed by a mixed-effects model for repeated measures analysis (with treatment, visit and treatment-by-visit interaction as the fixed effects, and adjustments for sex, age group at baseline (<18 vs ≥18 years old) and ppFEV1 severity group at screening (<70% vs ≥70%)). Each study compared two doses of lumacaftor-ivacaftor against placebo to assess change beyond placebo, and absolute change in ppFEV1 was used to infer improvement in lung function. Using the effect estimates to derive a range of potential improvement, lumacaftor-ivacaftor improved ppFEV1 anywhere from 2.5–2.6% (lower bound) to 4.0–4.1% (upper bound) depending on the dose used, the study being considered, and if correcting for inconsistencies (note this uses the effect estimates only and not their associated confidence intervals (CIs)). Pooling the studies yielded an improvement of 2.8–3.3%. Vertex recommends 400–250 mg q12h, which would mean the estimate of absolute improvement in ppFEV1 would be between 2.6% and 3.0% (TRAFFIC, 2.6%; TRANSPORT, 3.0%; pooled, 2.8%). How much is that worth to a patient with CF? The undeniably small improvement in ppFEV1 seems unconvincing with respect to providing clinically-meaningful benefit. This is corroborated by the marginal and ultimately non-significant changes in the patient-reported Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores for the recommended dose. For some, however, perhaps any degree of improvement is ‘worth it.’ So, again, how much is it worth? The answer would have to be $259 000 a year, because Vertex plans to charge this much. Secondary outcomes Although the improvement in ppFEV1 might be of questionable benefit, there were a number of secondary outcomes, and perhaps considering these might change the overall appraisal. A key consideration with secondary outcomes is preventing type I error, and in an effort to do so, the authors prespecified a simple Bonferroni-adjusted p value threshold, yielding α=0.025 (0.05/2, accounting for testing two doses). The authors also prespecified a hierarchical testing paradigm where key secondary outcomes were prioritised and a given secondary outcome was considered significant if its p value was less than 0.025 and all preceding secondary outcomes also had a p value less than 0.025. If a given secondary outcome had a p value greater than 0.025, the testing hierarchy broke at that level, and that outcome and all subsequent outcomes were considered non-significant. Cystic Fibrosis Questionnaire-Revised Change in CFQ-R respiratory domain score was one of the secondary outcomes in TRAFFIC and TRANSPORT. The CFQ-R respiratory domain is a scale from 0 to 100 with higher scores indicating better patient-reported Editor’s choice Scan to access more free content 10.1136/ebmed-2015-110325 Department of Physician Assistant Studies, East Carolina University, Greenville, North Carolina, USA Vidant Medical Center, Greenville, North Carolina, USA Correspondence to: Professor Martin Mayer, Department of Physician Assistant Studies, College of Allied Health Sciences, 4310N Health Sciences Building, Mail Stop 668, East Carolina University, Greenville, NC 27858-4353, USA; [email protected] Evid Based Med June 2016 | volume 21 | number 3 | 83 Perspective group.bmj.com on August 27, 2017 Published by http://ebm.bmj.com/ Downloaded from