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Orkambi™ For Cystic Fibrosis Before and After Lung Transplantation

A. Whitney Brown, MD

Adam B. Cochrane, PharmD, BCPS
Inova Fairfax Advanced Lung Disease & Transplant Program
Fairfax, VA, USA

Orkambi™ (lumacaftor 200 mg/ivacaftor 125 mg) was approved in the U.S. in July 2015 to treat cystic fibrosis (CF) in patients 12 years and older in patients who are homozygous for the most common CF mutation delF508. This genotype accounts for approximately half of the CF population in the U.S. and a large percentage of patients worldwide. Because lumacaftor/ivacaftor has not been extensively tested in CF patients other than those homozygous for the delF508 mutation, patients must have a confirmed genotype prior to starting treatment.

In two double-blind, placebo-controlled studies, CF patients with FEV1 40-90% predicted who received lumacaftor/ivacaftor, two pills every 12 hours, demonstrated a 2.6-4.0% absolute improvement in % predicted FEV1 compared to those who took placebo over the 24 week study period. There was also a significant reduction in the rate of pulmonary exacerbations and a trend toward improvement in body mass index for those on drug. The most common side effects of lumacaftor/ivacaftor were shortness of breath, upper respiratory tract infection, nausea, diarrhea, and rash.

Although this drug approval is exciting and sets the stage for a new era in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, the effects of this drug combination appear to be modest. To put this in context, lumacaftor (Kalydeco™) which is approved for the treatment of CF patients with one or more copies of G551D or eight other gating mutations showed a much more robust clinical effect in its phase 3 study. Treatment with lumacaftor for CF patients with one or more copy of G551D was associated with a 10.5% absolute improvement in % predicted FEV1 compared to placebo (both at 24 and 48 weeks). In addition, lumacaftor was associated with significant improvements in all key secondary endpoints -including fewer pulmonary exacerbations, weight gain (nearly seven pounds on average), and reduction in sweat chloride.

Although lumacaftor/ivacaftor for delF508/delF508appears to have less clinical benefit compared to lumacaftor for gating mutations, there is certainly enthusiasm for its use in delF508 homozygotes given the severity of this genotype and the inherent complexity of correcting its defects. The bottom line is that modulator therapy is much more challenging in this group than in other CFTR mutation classes.

Although lumacaftor/ivacaftor was not tested in patients with advanced CF or after lung transplantation, the potential use of this drug combination is of great interest to the lung transplant community. Patients, in particular, are likely to desire treatment with lumacaftor/ivacaftor given excitement over CFTR modulator therapy for this most common and most severe genotype. Despite the fact that the studies did not include patients with FEV1<40% predicted, it may be reasonable to extend treatment to advanced CF patients, even those awaiting lung transplantation, assuming there are no identified drug-drug interactions. Post transplantation, however, the use of lumacaftor/ivacaftor is fraught with issues due to its many drug-drug interactions with commonly used transplant medications.

The two components of Orkambi™ have different metabolism processes and drug/drug interaction profiles. Ivacaftor is a substrate of CYP3A which, when given as a single agent, is a weak inhibitor of CYP3A. The total adult daily dose of ivacaftor (Kalydeco™) is 300 mg.

Lumacaftor, on the other hand, is a strong inducer of CYP3A and results in "an internal drug-drug interaction" with ivacaftor and actually reduces ivacaftor levels. The fixed combination of Orkambi™ compensates for the strong inducer effect that lumacaftor has on ivacaftor with a total adult daily dose of 500 mg. The overall effect of the combination is a strong CYP3A induction. Lumacaftor has also been found to be an inducer and inhibitor of P-glycoprotein and in vitro has been found to be an inducer of CPY2B6, CYP2C8, CPY2C9, and CYP2C19.

The U.S. package insert of Orkambi™ advises against its use with CYP3A substrates (i.e. tacrolimus, sirolimus, and cyclosporine) with a narrow therapeutic index. In addition to a CNI or mTOR, most lung transplant recipients take a myriad of other medications with confounding interactions. Therefore, although tempting, combining lumacaftor/ivacaftor with a CNI or mTOR is likely to present considerable difficulties. To hit the highlights, the use of CYP3A inhibitors (such as azole anti-fungals) has no effect on lumacaftor, but significantly increases the exposure of ivacaftor. Lumacaftor/ivacaftor can reduce the exposure of and therefore the effectiveness of prednisone and methylprednisolone, therefore requiring higher doses of corticosteroids. Additionally, lumacaftor/ivacaftor can decrease the exposure and efficacy of proton pump inhibitors and H2 antagonists.

The list of concomitant medications investigated without drug interactions is short and includes among others, azithromycin, levofloxacin, ceftazidime, ciprofloxacin, and sulfamethoxazole/trimethoprim.

Without significantly changing standard immunosuppression and anti-infective regimens after transplant, lumacaftor/ivacaftor will be difficult to use after lung transplantation. One could argue that going to such trouble for a drug primarily focused on improving lung function and reducing CF pulmonary exacerbations is not worthwhile for patients whose CF lungs have already been replaced. In terms of its non-pulmonary effects, the modest improvement in BMI with lumacaftor/ivacaftor is not hugely compelling. While weight gain with this drug combination could reflect improved GI absorption due to normalized intestinal pH due to increased CFTR activity, it could also be a downstream effect of improved lung function and fewer pulmonary exacerbations. Thus, it is unclear if there would be any additional benefit of lumacaftor/ivacaftor given that this degree of weight gain occurs frequently in CF patients after lung transplantation. Other potential non-pulmonary benefits such as improvement in sinus symptoms, less episodes of distal intestinal obstruction syndrome, etc. have not been well investigated.

n summary, the use of Orkambi™ after lung transplantation requires further study given its multiple drug-drug interactions and the fact that it may offer little benefit outside of its pulmonary effects. With that being said, combination therapy with lumacaftor/ivacaftor represents the first of its kind and changes the landscape for a large percentage of patients with CF. As drug development gets more precise and sophisticated, newer generation combination CFTR modulators are likely to follow. Despite its limitations and unclear role after lung transplantation, the prospect of targeted CTFR therapy holds great promise as a key strategy to preserve lung function over the decades and postpone the need for lung transplantation for these young patients. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


  1. Orkambi® [package insert] Boston, MA: Vertex Pharmaceuticals Inc; 2015.
  2. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N Engl J Med 365; 18: 1663-1672.
  3. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med 373; 3: 220-231.

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