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Cystic fibrosis and disease modification



Orkambi™ (a combination of lumacaftor and ivacaftor) is the first licensed cystic fibrosis transmembrane conductance regulator corrector/potentiator for use in cystic fibrosis patients who are homozygous for the Phe508del genetic mutation
Nicola Shaw BSc (Hons) Dip Clin Pharm MRPSGB
Advanced Clinical Pharmacist, Department of Respiratory Medicine/ Cystic Fibrosis Unit, St James University Hospital, Leeds, UK

In November 2015, the European Commission granted a marketing authorisation for Orkambi™ (Vertex Pharmaceuticals), a combination oral product containing lumacaftor and ivacaftor.1 It the first drug licensed for treating the cause of cystic fibrosis (CF) in people who have two copies of the genetic mutation Phe508del.2
A genetic disease
CF is a genetic disease that affects multiple organ systems, resulting in premature death. The average survival of the patient with CF in the UK is currently 41 years.3 The disease is characterised by pancreatic insufficiency and chronic airways infections, which can lead to loss of lung function and, eventually, respiratory failure.4
The genetic mutations that occur in CF cause a deficiency or a malfunction in the production of CF transmembrane conductance regulator (CFTR). The CFTR protein functions as a channel for the movement of chloride ions in and out of cells, which is important for the salt and water balance on epithelial surfaces. As a result of deficiency or lack of CFTR, there is a decrease in chloride conductance across the epithelial membrane accompanied by an increase in the uptake of sodium ions.
The increase in intracellular sodium and chloride concentrations leads an alteration in the osmotic balance; fluid then leaves the surface and moves into the submucosal space. This results in the production of abnormal sodium-rich, viscous mucus secretions. In turn, these viscous secretions cause inflammation and long-term infection.5
The Phe508del mutation is one of more than 2000 types of CFTR mutations reported to date.6 It is the most frequent mutation, with more than 43% of people with CF in Europe being Phe508del homozygous (that is, having two copies of Phe508del).7
Phe508del not only causes a processing defect that has a large impact on the protein levels at the epithelial membrane but also disrupts channel opening. The net effect is very little CFTR transport activity.8,9
Correction versus potentiation
Lumacaftor is a CFTR corrector and corrects the CFTR processing defect caused by the Phe508del genetic mutation and increases the amount of protein reaching the epithelial membrane.10
Ivacaftor is a CFTR potentiator, which increases the fraction of time that the CFTR channels are open. Ivacaftor has been licensed throughout the EU since July 2012 for use in patients aged six years and over with G551D gating mutations.11,12 This licence has since been extended to include other gating mutations, and the age of use has been lowered to include children aged two years and above.13–15
Earlier studies indicated that neither lumacaftor nor ivacaftor alone were effective in improving clinical outcomes in CF patients with the Phe508del mutation.16,17
However, a Phase II study suggested when used in combination, CFTR activity was increased sufficiently to show some clinical efficacy.18 This led to two Phase III trials – TRAFFIC and TRANSPORT – being conducted.19
Two Phase III multinational, placebo-controlled, double-blind trials were conducted to evaluate the efficacy of lumicaftor in combination with ivacaftor in patients with CF who were homozygous for the Phe508del and aged 12 years and over. In these trials, 1108 patients aged 12 years and over received at least one dose of Orkambi. A total of 369 patients received Orkambi (lumacaftor 400mg and ivacaftor 250mg every 12 hours), 369 patients received a lower dose of lumacaftor (600mg/day along with 250mg ivacaftor every 12 hours) and 370 patients received placebo for 24 weeks.
Improvements in forced expiratory volume in 1 second (FEV1) were seen from day 15 of treatment and maintained throughout the 24 weeks of treatment in both trials. The dosage used in Orkambi (lumacaftor 400mg/ivacaftor 250mg, 12-hourly) produced a difference in the mean absolute change in the percentage points of predicted FEV1 from baseline of 2.6 in the TRAFFIC study and 3 in the TRANSPORT study (p<0.001).
Over the 24 weeks, the rate of pulmonary exacerbations was lower in the lumacaftor/ ivacaftor group when compared to placebo. The rate ratio (lumacaftor 400mg /ivacaftor 250mg 12-hourly versus placebo) was 0.66 (p= 0.02) in TRAFFIC and 0.57 (p<0.001) in TRANSPORT. In pooled analysis, the rate of exacerbations in the lumacaftor 400mg/ivacaftor 250mg group was 39% lower than placebo. Additional analyses also revealed that the number of exacerbations requiring intravenous antibiotics and administration to hospital was reduced in the lumacaftor/ivacaftor-treated group compared with placebo.19
Dosing schedule 
The dose for adults and paediatric patients 12 years of age and older is two tablets taken orally every 12 hours with a fat-containing meal. Each tablet contains lumacaftor 200mg and ivacaftor 125mg. 
Lumacaftor has low aqueous solubility and exposure increased 1.6–2-fold when given with a fat-containing meal (for example, eggs, nuts, avocados, etc). When ivacaftor was given in combination with lumacaftor with a fat-containing meal, exposure increased by three-fold, in healthy volunteers.3
Dosing in renal impairment
Orkambi has not been studied in patients with renal disease. Lumacaftor is not extensively metabolised in humans, with the majority (51%) being excreted unchanged in the faeces. There was minimal excretion in the urine (<10%). Ivacaftor is mainly metabolised via oxidation and glucoronidation and approximately 88% is eliminated in the faeces after this metabolisation. There is minimal elimination of ivacaftor and its metabolites in the urine (approximately 7%).
Therefore, no dosage adjustment is required for patients with mild-to-moderate renal impairment. However caution is recommended in patients with severe renal impairment (creatinine clearance ≤30ml/min) or end-stage renal disease.3
Dosing in hepatic impairment 
No dose reduction is necessary for patients with mild hepatic impairment (Child-Pugh Class A); however, a dose reduction to two tablets in the morning and one in the evening is recommended (total daily dose lumacaftor 600mg and ivacaftor 375mg) for patients with moderate hepatic impairment (Child-Pugh Class B).
Studies have not been carried out in patients with severe hepatic impairment (Child-Pugh Class C) but it is thought that exposure will be higher than in patients with moderate disease. The risks versus benefits should be assessed for these patients. If treatment is indicated, a maximum dose of one tablet in the morning and one tablet in the evening (total daily dose lumacaftor 400mg and ivacaftor 250mg) should be used with caution.3
Drug–drug interactions
Effect on other drugs
Lumacaftor is a strong inducer of cytochrome P3A (CYP3A) and ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. When administered in combination, the net effect is thought to be strong CYP3A induction. Therefore the use of Orkambi with drugs metabolised by CYP3A could reduce their exposure. 
It is not recommended to use sensitive CYP3A substrates or substrates with a narrow therapeutic index in patients prescribed Orkambi.
Orkambi may also alter (increase or decrease) the exposure of CYP2C8 and CYP2C9 substrates, decrease the exposure of CYP2C19 substrates and substantially decrease the exposure of CYP2B6 substrates. 
Effects on Orkambi
When starting Orkambi treatment in patients taking strong CYP3A inhibitors such as itraconazole, a dose reduction to one tablet once a day for the first week of treatment is required. This is to allow for the steady state induction effect of lumacaftor to take place. However, if starting therapy with a strong CYP3A inhibitor in patients already established on Orkambi, no dose alteration is required.
Strong CYP3A inducers such as rifampicin have minimal effect on lumacaftor exposure but decreased the area under the curve of ivacaftor by 57%; therefore, co-administration is not recommended. However no dose adjustment is required when Orkambi is used alongside moderate or weak CYP3A inducers. Table 1 shows examples of CYP3A substrates.
Hormonal contraceptives
Orkambi can significantly reduce hormonal contraceptive exposure, thereby reducing their effectiveness. This applies to all forms of hormonal contraceptives: oral, injectable, transdermal and implantable. 
In clinical trials, 27% of women using hormonal contraceptives experienced menstruation-associated adverse reactions such as amenorrhoea, dysmenorrhoea and irregular menstrual cycle compared with 3% of women not using hormonal contraceptives.
Therefore hormonal contraceptives should not be relied upon as an effective method of contraception in patients taking Orkambi. Alternatives modes of contraception, such as barrier methods, should be used instead.3
Adverse reactions
The nature and incidence of adverse reactions experienced by patients taking Orkambi is obtained from the pooled analysis of TRAFFIC and TRANSPORT.19 Table 2 lists the adverse drug reactions.
Respiratory adverse events
Respiratory adverse events, such as dyspnoea and chest tightness, were reported more frequently in the lumacaftor/ivacaftor groups compared placebo (see Table 2). Two patients in the placebo group (one with dyspnoea and one with chest discomfort) and four patients in the lumacaftor 600mg/day group (two with dyspnoea and two with bronchospasm) had severe adverse reactions.
The majority of these reactions were mild to moderate in nature and were more common in patients with lower predicted FEV1 (29.6% and 37.7% among patients with ppFEV1 <70 and <40, respectively, compared with 21 % and 21.4% among the placebo-treated patients, respectively).
The majority of the respiratory adverse events occurred within the first week of treatment and generally resolved with in the first two to three weeks of treatment, usually without a need to stop or alter treatment. However, there is very little clinical experience in patients with a predicted FEV1%  <40 and additional monitoring of these patients during initiation of treatment is recommended.
There is also no experience of initiating treatment during a pulmonary exacerbation,  and is not recommended.3
Hepatobiliary adverse events
The incidence of elevation in alanine or asparte aminotransferase more than three times the upper limit of the normal range were observed in 5.2% of the lumacaftor/ivacaftor group compared with 5.1% in the placebo group.
Seven patients in the lumacaftor/ivacaftor group had serious liver-related events with elevated transaminases. Three of the seven patients also had elevation in total bilirubin. No serious liver adverse events were reported in the placebo group. After stopping or interrupting lumacaftor/ivacaftor therapy liver function improved, with liver function tests returning to baseline in six out of the seven patients.
Seven patients with pre-existing cirrhosis with or without portal hypertension were included in the two clinical trials TRAFFIC and TRANSPORT. Hepatic encephalopathy with worsening liver function (elevation in bilirubin, AST and ALT) was observed in one patient. This occurred within five days of starting treatment and resolved when treatment was stopped.
It is recommended that baseline liver function tests (ALT, AST and bilirubin) are obtained before the initiation of Orkambi therapy and three-monthly during the first year of treatment. This can be reduced to annually thereafter. In patients who have a history of elevations in AST, ALT or bilirubin, more frequent monitoring is recommended.
If patients develop elevations in AST, ALT or bilirubin during treatment, dosing should be stopped when: ALT or AST more than five-times the upper limit of normal if no elevation in bilirubin; ALT or AST more than three-times the upper limit of normal and bilirubin more than two-times the upper limit of normal.
When liver function tests return to normal, treatment with Orkambi should only recommence if benefits of treatment outweigh the risks.3
Orkambi is the first licensed CFTR corrector/potentiator for use in CF patients who are homozygous for Phe508del genetic mutation. Although a small improvement from baseline in ppFEV1 of 3% was observed in the clinical trials, this was maintained over 24 weeks. In addition, the rate of pulmonary exacerbations was 39% lower in the treatment group compared with placebo. The Committee for Medicinal Products for Human Use decided that although the beneficial effects were smaller than expected for a medicine that treats the mechanism of disease rather than symptoms, the effects were clinically relevant for patients with no alternative options.20
Support for the development of this article was provided by Vertex Pharmaceuticals
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  18. Boyle MP et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have Phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014;2:527–38.
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