Available online at www.sciencedirect.com
ScienceDirect Where are we with transformational therapies for patients with cystic fibrosis? Kris De Boeck1 and Jane C Davies2 The disease cystic fibrosis (CF) is caused by a disturbance in the synthesis or function of the CFTR anion channel. Several types of small molecules geared to overcome the underlying defect in specific patient groups are in the clinical pipeline. Two drugs have obtained regulatory approval. The potentiator ivacaftor brings major clinical benefit in patients with CFTR protein expression at the cell membrane; the combination ivacaftor plus corrector lumacaftor brings a modest benefit for patients homozygous for the most common mutation F508del. The busy drug pipeline puts pressure on the finite CF patient population. Improving CFTR function in patients has at times yielded unexpected findings. The initial success with ivacaftor has set high expectations, has pushed drug prices sky high and has resulted in inequity in drug access. Addresses 1 Pediatric Pulmonology, University of Leuven, Leuven, Belgium 2 Imperial College London and Royal Brompton & Harefield Foundation Trust, London SW3 6LR, UK Corresponding authors: De Boeck, Kris (christiane.deboeck@uzleuven. be), Davies, Jane C ([email protected])
Current Opinion in Pharmacology 2017, 34:70–75 This review comes from a themed issue on Respiratory Edited by David N Sheppard, Hugo R de Jonge and Christine E
http://dx.doi.org/10.1016/j.coph.2017.09.005 1471-4892/ã 2017 Elsevier Ltd. All rights reserved.
Introduction Cystic Fibrosis (CF) is a disease of ion channels. The primary defect is in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an anion channel protein in epithelial cell membranes. CFTR mutations will lead to a defect in the quantity and/or function of the CFTR channel [1]. Depending on the underlying defect there is need for small molecules called correctors to increase CFTR expression at the cell membrane and/or small molecules called potentiators to enhance the function (‘gating’) of the CFTR channel (see Table 1). Therapies with read-through molecules aim to overcome premature stop codon mutations. CFTR stabilizers increase the protein residence time at the cell membrane. CFTR amplifiers stabilize the nascent CFTR Current Opinion in Pharmacology 2017, 34:70–75
mRNA and hence open the potential for more efficient protein translation to be then corrected or potentiated. At least half of the patients carry 2 different CFTR mutations on their CF alleles. In addition, most CFTR mutations lead to a combination of defects: production, function as well as residence time at the cell membrane are impacted. Hence combination therapies to overcome these several defects must be developed. This article gives a state-ofthe-art overview of small molecules to improve CFTR function, with a focus on recent clinical trials and lessons learned. For a more extensive discussion of this rapidly evolving area, we refer to previous reviews [2,3,4,5].
Current state of affairs So far ivacaftor (TMKalydeco) and the combination lumacaftor plus ivacaftor (TMOrkambi), developed by Vertex Pharmaceuticals, are licensed for clinical use [6,7]. These drugs are in general well tolerated although side effects occur in some patients such as elevated liver enzymes (both drugs), possible lens opacities (Kalydeco), shortness of breath (on initiation of Orkambi), slight increase in blood pressure (Orkambi) [https://www. medicines.org.uk/emc/medicine/27586 and https://www. medicines.org.uk/emc/medicine/31534]. Kalydeco is approved for use in patients older than 2 years who have at least one class III mutation (associated with defective channel opening [1]); on average, this is around 5% of the CF population worldwide, although there are large inter-country differences [8]. Kalydeco leads to an approximate 10% predicted absolute rise in forced expiratory volume in 1 second (FEV1) and an impressive decrease in sweat chloride concentration (50 mmol/L) [6,7,9,10]. Patients have fewer pulmonary exacerbations, a marked weight gain and report a better quality of life. The treatment benefit is sustained and the longterm benefits become apparent: less frequent Pseudomonas infections, slower decline in lung function, longer survival and less need for lung transplant [11,12]. Kalydeco is also approved for patients with the class IV mutation R117H that is associated with residual CFTR function [1]. In these patients, the benefit is modest and mainly observed in adults [13]. Orkambi has been approved for patients homozygous for the F508del mutation aged at least 12 years (by the European Medicines Agency) or 6 years (Food and Drug Administration in the USA). Almost 50% of patients worldwide are homozygous for F508del, but again with large inter-country differences [8]. Treatment with Orkambi in F508del homozygous patients results in 3% improvement in FEV1 and a 35% decrease in pulmonary exacerbations [7]. There is www.sciencedirect.com
Where are we with transformational therapies for patients with cystic fibrosis? De Boeck and Davies 71
Table 1 Terminology used to describe small molecules designed to overcome defects in the synthesis or function of CFTR. Therapy type
Aim
Mutation class targeted
Administration route
Stage of development
Correctors
Improve mutant CFTR trafficking and folding
Class II
Oral
Potentiators
Increase mutant CFTR channel opening
Class III (Class IV, Class V)
Oral
Amplifiers
Increase mRNA stability
All
Oral
Stabilizers
Increase protein residence time at cell membrane
All
Oral
Preclinical (after failure of cavosonstat)
Read-through compounds
Overread premature stop codons during translation
Class I
Oral
Preclinical (after failure of ataluren)
-F508del -Splicing mutations
-Inhalation -Most likely inhalation
-In clinical trial -Preclinical
Antisense oligonucleotides
Lumacaftor in use; Next generation correctors in clinical trial Ivacaftor in use; Alternative potentiators in clinical trial In clinical trial
Many CFTR mutations have characteristics of more than one mutation class. Mutation class defects include: class I failure of synthesis (mainly large deletions or premature stop codons mutations); class II defective folding or trafficking (F508del, many missense mutations); class III defective channel opening (specific missense mutations with retained trafficking to cell membrane; mutant CFTR protein rescued by corrector therapy); class IV defective conductance (R117H, some missense mutations); class V decreased normal protein synthesis (mostly splicing mutations); class VI decreased protein stability at the cell membrane (specific mutations and mutant protein rescued by correctors).
some indication that the drug decreases lung function decline [14]. In children aged 6–11 years, lung clearance index, a sensitive measure of ventilation homogeneity, improved by 1 unit and sweat chloride concentration decreased on average by 25 mmol/L but was highly variable [15]. Tezacaftor (Vertex Pharmaceuticals) is an F508del corrector with improved pharmacokinetic properties. Although not yet published, clinical trial data have been press-released showing that the combination of tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) given for 24 weeks to more than 500 patients homozygous for F508del older than 12 years resulted in a 4% predicted improvement in FEV1, a 35% decrease in pulmonary exacerbations, a significant improvement in body mass index as well as in the patient reported outcome ‘CFQ-R’ [http://investors.vrtx. com/releasedetail.cfm?ReleaseID=1019156]. Although the improvements seen with 1 corrector (lumacaftor or tezacaftor) plus a single potentiator (ivacaftor) are significant, the combination of 2 correctors with different mechanisms of action appears to be needed to induce a robust improvement in F508del protein folding and trafficking and obtain a much improved expression of F508del CFTR at the cell membrane [16]. In Ussing chamber studies on human bronchial epithelial cells [HBE] triple combination with either VX152 or VX-440 (Vertex Pharmaceuticals) improved chloride transport to respectively 75% and 68% of normal in F508del/ F508del HBE and to about half that in F508del/minimal function HBE’s [17]. These results in F508del/F508del HBE are even superior to the ex vivo efficacy of ivacaftor in G551D/F508del HBE (48% of normal) [17]. And indeed, the results of the phase 2 trial (4 weeks intake of VX-440 plus ivacaftor and tezacaftor) show a 10–12% improvement in FEV1 in F508del/minimal function patients compared to www.sciencedirect.com
placebo. Homozygous F508del patients were first treated with ivacaftor/tezacaftor and on addition of VX-440 a further 10% improvement in FEV1 was seen. Patients reported a marked improvement in wellbeing, and sweat chloride dropped significantly. The combination treatment was overall well tolerated and safe (http://investors.vrtx.com/ releasedetail.cfm?ReleaseID=1033559). Vertex Pharmaceuticals has alternative second generation correctors in the phase 1 clinical pipeline, including VX-659. Galapagos/Abbvie have similar triple combinations (first and second generation correctors, C1 and C2, plus potentiators) under development but their program is less advanced: C1 GLPG2222 and potentiator GLPG1837 are in phase 2 clinical trials and C2 GLPG2737 is in phase 1 [http://www.glpg.com/clinical-pipelines]. Several backup compounds are in the preclinical phase. Additional companies that are developing CFTR modulators include Flatley Discovery Lab, Proteostasis, Novartis, Genzyme, Pfizer and Reata. QR010 is being developed by ProQr Therapeutics. Through an as yet incompletely understood mechanism, the small chemically modified RNA oligonucleotide inserts the 3 deleted bases in the F508del-CFTR mRNA. Although to be used via inhalation, the biodistribution and long half-life in mice suggest the potential of a systemic treatment benefit [http://www.asgct.org/ the-vector/volume-1-issue-17-july-2015/meeting-center/ gene-modulation-and-editing-for-lung-disease]. In an open label study of nasal administration of QR010, the CFTR function measured via nasal potential difference test improved in patients homozygous for F508del [18]. Safety and efficacy of single and multiple ascending doses of QR010 via inhalation are currently being tested. Current Opinion in Pharmacology 2017, 34:70–75
72 Respiratory
A major challenge is the development of small molecule therapies for patients with class I mutations; 10% of patients with CF have a premature stop codon mutation on one of their alleles [8]. Ataluren is a ‘read-through drug’ with conditional approval (EMA) for patients with Duchenne’s muscular dystrophy caused by a premature stop codon. In patients with CF and a premature stop codon, ataluren showed promise in an open label phase 2 trial [19]. In the subsequent phase 3 trial, the primary outcome of improving FEV1 was not met in the global analysis although in a post hoc analysis, stabilization of FEV1 was seen in the subset of patients not using an inhaled aminoglycoside [20]. However, the company has recently announced that a confirmatory phase 3 study including only patients not inhaling aminoglycosides failed its primary endpoint (http://ir. ptcbio.com/releaseDetail.cfm?ReleaseID=1015471). The search for more efficient read-through drugs thus continues. Currently marketed drugs were tested for read-through capacity in preclinical models and several seemed to be effective at suppressing nonsense mutations [21] although these remain to be tested in the clinic. Riociguat, a stimulator of soluble guanylate cyclase developed by Bayer is another, possible low hanging fruit. This drug is marketed for patients with pulmonary hypertension and is currently being tested for its efficacy to improve CFTR function in patients homozygous for the F508del mutation (https://clinicaltrials.gov/ct2/ show/NCT02170025?term=riociguat&cond=Cystic +Fibrosis&rank=1). Cavosonstat developed by Nivalis Therapeutics (in the meantime acquired by Alpine Immune Sciences) is a CFTR stabilizer aiming to increase CFTR protein residence time at the cell membrane. By inhibiting S-nitrosoglutathione reductase (GSNOR) cavosonstat increases intracellular levels of GSNO that plays a critical role in modulating protein function through S-nitrosylation. In in vitro cell systems, this promotes CFTR maturation and membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators. Although safe and well tolerated [22], addition of cavosonstat in patients taking Orkambi did not provide additional benefit. PTI-428 developed by Proteostasis is a ‘CFTR amplifier’, a compound that somehow stabilizes nascent mRNA to increase efficiency in CFTR translation that can then be further corrected or potentiated. Evaluations of safety, tolerability, pharmacokinetics, and efficacy of PTI-428 in adults with CF are ongoing [23]. Especially in Europe, drug approval and licensing does not necessarily equate to drug availability; drug reimbursement is the competence of the national health authorities. Due to its high efficacy and despite its very high cost, reimbursement of Kalydeco has been granted Current Opinion in Pharmacology 2017, 34:70–75
in western European countries. The uptake of Orkambi has been much slower. It is at present available in a minority of European countries and often on a named basis program only. Even in North-America, at the end of the first year on the market, only 42% of the 8895 eligible patients were reported to be on the treatment [24]. Another item for concern is the low adherence to the highly efficacious drug Kalydeco — only 61% — in a small group on patients with CF monitored electronically [25]. Adherence decreased over time. There was no correlation between adherence monitored electronically (61%), by refill history (84%) or self-report (100%). So, in summary, the last few years have seen extremely encouraging progress and the pipeline is currently very full, but significant challenges remain. For the second half of this review, we will consider the lessons learned, outstanding questions and areas of unmet need. Whilst we do not have answers to many of these issues, we wish to provide our personal opinions and some food for thought.
What lessons have we learned? The trial landscape is becoming increasingly complex
The phase III trials of ivacaftor were extremely easy to enrol, as patient enthusiasm was enormous: the phase II trial data were exciting, compelling and unrivalled by anything else in the field. Indeed, the very large phase III studies of Orkambi, enrolling between them over 1000 patients globally, were also conducted in a remarkably short period of time. It is possible that this ‘honeymoon’ period, if not over, will only be short-lived from now. For all sorts of reasons, it will likely be challenging to recruit gating mutation patients to trials of new potentiators or combinations: many of them feel their lives have been transformed by Kalydeco. They have returned to work, started families, or may simply feel, as described by one of our patients, that they are no longer ‘defined by having CF and want to forget about it’. Some of those who helped develop ivacaftor may be experiencing ‘trial fatigue’, whereas others willing to participate may be too well, with an FEV1 above the usual cut-off of 90%; alternative inclusion criteria for these patients may therefore be essential. One particular issue of concern is the requirement by some regulatory agencies of a placebo arm or prolonged washout period; it is clear that patients’ health will decline off ivacaftor, so we consider it crucial that washout periods are limited and that alternatives to conventional placebo-controlled designs are explored. Although Orkambi is not yet established as standard of care in many European countries, a substantial proportion of US patients are taking this drug, so these issues will come more and more to the fore in the development of combination treatments also. Finally, the future will require us to develop better outcome measures than FEV1. Although capable of demonstrating the efficacy described, it has limitations in early life and in www.sciencedirect.com
Where are we with transformational therapies for patients with cystic fibrosis? De Boeck and Davies 73
patients with well-preserved respiratory health. Additional outcome measures such as lung clearance index [26,27] and imaging (CT [28] and MRI [27,29]) are being increasingly explored and, with sufficient validation, may provide extremely useful alternatives. We must manage expectations
[a] Ivacaftor in patients with CF and gating mutation set the benchmark very high: It seemed intuitive that it would be easier to target correctly-localised CFTR with drugs that improve function than correct absent or mislocalised protein. This has indeed been borne out in trials, with the lung function improvements in patients with CF who carry a gating mutation on ivacaftor being around 10% and closer to 3% in F508del homozygous subjects receiving Orkambi. Interestingly, the difference in reduction of exacerbation frequency was less dramatic and furthermore, longer-term data, albeit not from a placebo-controlled trial but based on propensity-matched registry data, would appear to suggest that the chronic effects on rate of lung function decline may also be similar. Whilst continuing to strive for the most efficacious drugs, we should be careful not to fall into the trap of overvaluing short-term, large impact interventions. The inclusion of long-term monitoring periods to examine a drug’s potential for disease modification may be enlightening. [b] Failure is still possible at a late development stage: The recent announcement that the read-through agent, ataluren, had failed to meet primary and secondary endpoints in a second phase 3 trial has been a major blow. Results from phase 2 trials had been somewhat patchy with at least one study not showing the expected nasal potential difference measurement changes, but others were extremely encouraging. The first phase 3 trial, a large, multicentre, global endeavor failed to show a statistically significant difference between treated and placebo groups, but did show a trend favoring active treatment. Based on knowledge of the mechanisms of action of ataluren and aminoglycosides at ribosomes, there was a predefined plan to examine any impact of inhaled aminoglycosides: here, there appeared to be a compelling signal favoring ataluren-treated patients who were not receiving tobramycin, in both FEV1 and pulmonary exacerbation rates. We would applaud the decision of PTC to seek confirmation of such post hoc results by conducting a follow-on trial, the results of which, to the surprise of many investigators, were negative. Whilst a major disappointment, the results underscore the importance of rigor in drug testing, even at late stages of development. Even supposedly ‘irreversible’ disease might be amenable to improvement
Systemic drugs have a major benefit over those topicallyadministered in their potential for multi-organ benefit. The improvements in weight observed in the early www.sciencedirect.com
ivacaftor trials were surprising in their magnitude, and likely related to gut bicarbonate secretion aiding absorption [30]. By contrast, there was probably no initial expectation that pancreatic exocrine dysfunction could be reversed, as the organ’s destruction happens extensively in the pre-natal period. The KIWI trial, an openlabel study of ivacaftor in children 2–5 years of age provided the first chink in this assumption, around one third of pancreatic insufficient children demonstrating faecal elastase (FE) levels of >200 after 24 weeks of treatment [31]. FE is now included in a second trial in this age group [clinicaltrials.gov NCT02742519] and another in even younger infants and toddlers [clinicaltrials.gov NCT02725567]. Future trial design should be creative, to capture all of the potential benefits of new agents, and not focus simply on airways disease.
Even the most effective drug is of no use if patients cannot access it
We currently have a serious issue of inequity of access; this is not a problem purely related to developing countries, but one that is happening in our own healthcare systems. CF centres who have played important roles in the development of a new drug find themselves unable to prescribe it now licensed. Even the schemes whereby trial participants continue to receive drug thereafter have been criticised by CF patients who have perhaps not had the same opportunities to enrol in trials in the first place. The expanded N. American and European Trials Networks and new initiatives such as the UK CF Trust’s Clinical Trials Accelerator Platform [https://www. cysticfibrosis.org.uk/news/announcing-the-new-clinicaltrials-accelerator-platform], are seeking to address some of these access problems. However, the impact of costs seems unlikely to melt away as a problem; whilst the rise in numbers of pharma companies seeking to develop CFTR modulators is extremely welcome, whether this will impact significantly on licensed product costs remains to be seen. We need to work hard as a CF community to continue to push for widespread and equitable access as new drugs are developed.
Conclusion The current pipeline of therapies that improve the underlying CFTR dysfunction in patients with CF is very busy. Since most mutations cause different defects in CFTR protein synthesis or function and since at least half of the patients with CF have 2 different mutations, combining corrective strategies may prove most effective in the long term. Important lessons have emerged from the clinical drug development phase: the complexity of testing new CFTR modulator therapies in the context of access to Kalydeco and Orkambi; the design of trials in young children; the need for long term follow up to value the full impact of Current Opinion in Pharmacology 2017, 34:70–75
74 Respiratory
CFTR modulator therapies; the importance of monitoring access to approved therapies for all patients with CF.
Conflict of interest statement Nothing declared.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevı´nek P, Griese M, McKone EF, Wainwright CE, Konstan MW et al.: A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011, 365:1663-1672. First landmark paper proving the effectiveness of oral small molecule therapies in patients with CF.
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Wainwright CE, Elborn JS, Ramsey BW et al.: Lumacaftor– ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015, 373:220-231.
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De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L: The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros 2014, 13:403-409. The relative frequency of different mutation classes differs greatly, depending on the region of the patients being studied.
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Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K et al.: Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013, 187:1219-1225.
10. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M: Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014, 13:674-680. 11. Rowe SM, Heltshe SL, Gonska T, Donaldson S, Borowitz D, Gelfond D et al.: Results of the G551D observational study: the effect of ivacaftor in G551D patients following FDA approval. Pediatr Pulmonol 2013, 48:278. 12. Sawicki GS, McKone EF, Pasta DJ et al.: Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med 2015, 192:836-842. Longterm treatment with CFTR potentiatos in patients with gating mutation leads to improved survival. 13. Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M, VX11-770-110 (KONDUCT) Study Group: Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a doubleblind, randomised controlled trial. Lancet Respir Med 2015, 3:524-533. Current Opinion in Pharmacology 2017, 34:70–75
14. Konstan M, McKone E, Moss R, Marigowda G, Cooke J, Lubarsky B, Rubin J et al.: Evidence of reduction in annual rate of FEV 1 decline and sustained benefits with lumacaftor and ivacaftor (lum/iva) in patients with CF homozygous for F508del-CFTR. Pediatr Pulmonol 2016, 51 (S45):S260. 15. Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M, VX13-809-011 Part B Investigator Group: Lumacaftor/ivacaftor in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR. Am J Respir Crit Care Med 2017, 195:912-920. 16. Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A et al.: Mechanismbased corrector combination restores DF508-CFTR folding and function. Nat Chem Biol 2013, 9:444-454. 17. Grootenhuis P, Van Goor F, Hadida S, Burton B, Young T, Selkirk J, Chen W, Zhou J, Yu H, Negulescu P: Discovery and biological profile of next-generation CFTR correctors. Pediatr Pulmonol 2016, 51(S45):S263. 18. Sermet-Gaudelus I, Nichols D, Nick JA, De Boeck K, Clancy JP, Solomon GM, Rowe SM et al.: Open-label, exploratory study to evaluate the effects of QR-010 on nasal potential difference (NPD) in subjects with cystic fibrosis who are homozygous or compound heterozygous for the DF508 CFTR mutation. Pediatr Pulmonol 2016, 51(S45):S485. 19. Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M et al.: Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008, 372:719727. 20. Kerem E, Konstan MW, De Boeck K, Accurso FJ, SermetGaudelus I, Wilschanski M, Elborn JS, Melotti P, Bronsveld I, Fajac I et al.: Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebocontrolled phase 3 trial. Lancet Respir Med 2014, 2:539-547. 21. Mutyam V, Du M, Xue X, Keeling KM, White EL, Bostwick JR, Rasmussen L, Liu B, Mazur M, Hong JS et al.: Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations. Am J Respir Crit Care Med. 2016, 194:1092-1103. 22. Donaldson SH, Solomon GM, Zeitlin PL, Flume PA, Casey A, McCoy K, Zemanick ET, Mandagere A, Troha JM, Shoemaker SA et al.: Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DELCFTR. J Cyst Fibros 2017. pii: S1569-1993(17)30016-4. 23. Mouded M, Layish D, Sawicki GS, Milla C, Flume PA, Tolle J, Vansaghi L, Watson C, Munoz B, Bhalla A: Phase 1 initial results evaluating safety, tolerability, PK and biomarker data using PTI-428, a novel CFTR modulator, in patients with cystic fibrosis. Pediatr Pulmonol 2016, 51(S45):S262. 24. Sawicki GS, Fink A, Hamblett NM: Uptake of lumacaftor– ivacaftor use among eligible CF patients in the US in 2015. Pediatr Pulmonol 2016, 51(S45):S382. 25. Siracusa CM, Ryan J, Burns L, Wang Y, Zhang N, Clancy JP, Drotar D: Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor. J Cyst Fibros 2015, 14:621-626. 26. Davies J, Sheridan H, Bell N, Cunningham S, Davis SD, Elborn JS, Milla CE, Starner TD, Weiner DJ, Lee PS, Ratjen F: Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013, 1:630-638. 27. Stahl M, Wielpu¨tz MO, Graeber SY, Joachim C, Sommerburg O, Kauczor HU, Puderbach M, Eichinger M, Mall MA: Comparison of lung clearance index and magnetic resonance imaging for assessment of lung disease in children with cystic fibrosis. Am J Respir Crit Care Med 2017, 195:349-359. 28. Loeve M, Krestin GP, Rosenfeld M, de Bruijne M, Stick SM, Tiddens HA: Chest computed tomography: a validated www.sciencedirect.com
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surrogate endpoint of cystic fibrosis lung disease? Eur Respir J 2013, 42:844-857. 29. Altes TA, Johnson M, Fidler M, Botfield M, Tustison NJ, LeivaSalinas C, de Lange EE, Froh D, Mugler JP 3rd: Use of hyperpolarized helium-3 MRI to assess response to ivacaftor treatment in patients with cystic fibrosis. J Cyst Fibros 2017, 16:267-274. 30. Gelfond D, Heltshe S, Ma C, Rowe SM, Frederick C, Uluer A, Sicilian L, Konstan M, Tullis E, Roach RN et al.: Impact of CFTR modulation on intestinal ph, motility, and clinical outcomes in patients with cystic fibrosis and the G551D mutation. Clin
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Transl Gastroenterol 2017, 8:e81 http://dx.doi.org/10.1038/ ctg.2017.10. 31. Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Robertson S, Green Y, Cooke J et al.: Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016, 4:107-115. First study in preschool children demonstrating the complexity of clinical trials in this age group.
Current Opinion in Pharmacology 2017, 34:70–75
ScienceDirect Where are we with transformational therapies for patients with cystic fibrosis? Kris De Boeck1 and Jane C Davies2 The disease cystic fibrosis (CF) is caused by a disturbance in the synthesis or function of the CFTR anion channel. Several types of small molecules geared to overcome the underlying defect in specific patient groups are in the clinical pipeline. Two drugs have obtained regulatory approval. The potentiator ivacaftor brings major clinical benefit in patients with CFTR protein expression at the cell membrane; the combination ivacaftor plus corrector lumacaftor brings a modest benefit for patients homozygous for the most common mutation F508del. The busy drug pipeline puts pressure on the finite CF patient population. Improving CFTR function in patients has at times yielded unexpected findings. The initial success with ivacaftor has set high expectations, has pushed drug prices sky high and has resulted in inequity in drug access. Addresses 1 Pediatric Pulmonology, University of Leuven, Leuven, Belgium 2 Imperial College London and Royal Brompton & Harefield Foundation Trust, London SW3 6LR, UK Corresponding authors: De Boeck, Kris (christiane.deboeck@uzleuven. be), Davies, Jane C ([email protected])
Current Opinion in Pharmacology 2017, 34:70–75 This review comes from a themed issue on Respiratory Edited by David N Sheppard, Hugo R de Jonge and Christine E
http://dx.doi.org/10.1016/j.coph.2017.09.005 1471-4892/ã 2017 Elsevier Ltd. All rights reserved.
Introduction Cystic Fibrosis (CF) is a disease of ion channels. The primary defect is in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an anion channel protein in epithelial cell membranes. CFTR mutations will lead to a defect in the quantity and/or function of the CFTR channel [1]. Depending on the underlying defect there is need for small molecules called correctors to increase CFTR expression at the cell membrane and/or small molecules called potentiators to enhance the function (‘gating’) of the CFTR channel (see Table 1). Therapies with read-through molecules aim to overcome premature stop codon mutations. CFTR stabilizers increase the protein residence time at the cell membrane. CFTR amplifiers stabilize the nascent CFTR Current Opinion in Pharmacology 2017, 34:70–75
mRNA and hence open the potential for more efficient protein translation to be then corrected or potentiated. At least half of the patients carry 2 different CFTR mutations on their CF alleles. In addition, most CFTR mutations lead to a combination of defects: production, function as well as residence time at the cell membrane are impacted. Hence combination therapies to overcome these several defects must be developed. This article gives a state-ofthe-art overview of small molecules to improve CFTR function, with a focus on recent clinical trials and lessons learned. For a more extensive discussion of this rapidly evolving area, we refer to previous reviews [2,3,4,5].
Current state of affairs So far ivacaftor (TMKalydeco) and the combination lumacaftor plus ivacaftor (TMOrkambi), developed by Vertex Pharmaceuticals, are licensed for clinical use [6,7]. These drugs are in general well tolerated although side effects occur in some patients such as elevated liver enzymes (both drugs), possible lens opacities (Kalydeco), shortness of breath (on initiation of Orkambi), slight increase in blood pressure (Orkambi) [https://www. medicines.org.uk/emc/medicine/27586 and https://www. medicines.org.uk/emc/medicine/31534]. Kalydeco is approved for use in patients older than 2 years who have at least one class III mutation (associated with defective channel opening [1]); on average, this is around 5% of the CF population worldwide, although there are large inter-country differences [8]. Kalydeco leads to an approximate 10% predicted absolute rise in forced expiratory volume in 1 second (FEV1) and an impressive decrease in sweat chloride concentration (50 mmol/L) [6,7,9,10]. Patients have fewer pulmonary exacerbations, a marked weight gain and report a better quality of life. The treatment benefit is sustained and the longterm benefits become apparent: less frequent Pseudomonas infections, slower decline in lung function, longer survival and less need for lung transplant [11,12]. Kalydeco is also approved for patients with the class IV mutation R117H that is associated with residual CFTR function [1]. In these patients, the benefit is modest and mainly observed in adults [13]. Orkambi has been approved for patients homozygous for the F508del mutation aged at least 12 years (by the European Medicines Agency) or 6 years (Food and Drug Administration in the USA). Almost 50% of patients worldwide are homozygous for F508del, but again with large inter-country differences [8]. Treatment with Orkambi in F508del homozygous patients results in 3% improvement in FEV1 and a 35% decrease in pulmonary exacerbations [7]. There is www.sciencedirect.com
Where are we with transformational therapies for patients with cystic fibrosis? De Boeck and Davies 71
Table 1 Terminology used to describe small molecules designed to overcome defects in the synthesis or function of CFTR. Therapy type
Aim
Mutation class targeted
Administration route
Stage of development
Correctors
Improve mutant CFTR trafficking and folding
Class II
Oral
Potentiators
Increase mutant CFTR channel opening
Class III (Class IV, Class V)
Oral
Amplifiers
Increase mRNA stability
All
Oral
Stabilizers
Increase protein residence time at cell membrane
All
Oral
Preclinical (after failure of cavosonstat)
Read-through compounds
Overread premature stop codons during translation
Class I
Oral
Preclinical (after failure of ataluren)
-F508del -Splicing mutations
-Inhalation -Most likely inhalation
-In clinical trial -Preclinical
Antisense oligonucleotides
Lumacaftor in use; Next generation correctors in clinical trial Ivacaftor in use; Alternative potentiators in clinical trial In clinical trial
Many CFTR mutations have characteristics of more than one mutation class. Mutation class defects include: class I failure of synthesis (mainly large deletions or premature stop codons mutations); class II defective folding or trafficking (F508del, many missense mutations); class III defective channel opening (specific missense mutations with retained trafficking to cell membrane; mutant CFTR protein rescued by corrector therapy); class IV defective conductance (R117H, some missense mutations); class V decreased normal protein synthesis (mostly splicing mutations); class VI decreased protein stability at the cell membrane (specific mutations and mutant protein rescued by correctors).
some indication that the drug decreases lung function decline [14]. In children aged 6–11 years, lung clearance index, a sensitive measure of ventilation homogeneity, improved by 1 unit and sweat chloride concentration decreased on average by 25 mmol/L but was highly variable [15]. Tezacaftor (Vertex Pharmaceuticals) is an F508del corrector with improved pharmacokinetic properties. Although not yet published, clinical trial data have been press-released showing that the combination of tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) given for 24 weeks to more than 500 patients homozygous for F508del older than 12 years resulted in a 4% predicted improvement in FEV1, a 35% decrease in pulmonary exacerbations, a significant improvement in body mass index as well as in the patient reported outcome ‘CFQ-R’ [http://investors.vrtx. com/releasedetail.cfm?ReleaseID=1019156]. Although the improvements seen with 1 corrector (lumacaftor or tezacaftor) plus a single potentiator (ivacaftor) are significant, the combination of 2 correctors with different mechanisms of action appears to be needed to induce a robust improvement in F508del protein folding and trafficking and obtain a much improved expression of F508del CFTR at the cell membrane [16]. In Ussing chamber studies on human bronchial epithelial cells [HBE] triple combination with either VX152 or VX-440 (Vertex Pharmaceuticals) improved chloride transport to respectively 75% and 68% of normal in F508del/ F508del HBE and to about half that in F508del/minimal function HBE’s [17]. These results in F508del/F508del HBE are even superior to the ex vivo efficacy of ivacaftor in G551D/F508del HBE (48% of normal) [17]. And indeed, the results of the phase 2 trial (4 weeks intake of VX-440 plus ivacaftor and tezacaftor) show a 10–12% improvement in FEV1 in F508del/minimal function patients compared to www.sciencedirect.com
placebo. Homozygous F508del patients were first treated with ivacaftor/tezacaftor and on addition of VX-440 a further 10% improvement in FEV1 was seen. Patients reported a marked improvement in wellbeing, and sweat chloride dropped significantly. The combination treatment was overall well tolerated and safe (http://investors.vrtx.com/ releasedetail.cfm?ReleaseID=1033559). Vertex Pharmaceuticals has alternative second generation correctors in the phase 1 clinical pipeline, including VX-659. Galapagos/Abbvie have similar triple combinations (first and second generation correctors, C1 and C2, plus potentiators) under development but their program is less advanced: C1 GLPG2222 and potentiator GLPG1837 are in phase 2 clinical trials and C2 GLPG2737 is in phase 1 [http://www.glpg.com/clinical-pipelines]. Several backup compounds are in the preclinical phase. Additional companies that are developing CFTR modulators include Flatley Discovery Lab, Proteostasis, Novartis, Genzyme, Pfizer and Reata. QR010 is being developed by ProQr Therapeutics. Through an as yet incompletely understood mechanism, the small chemically modified RNA oligonucleotide inserts the 3 deleted bases in the F508del-CFTR mRNA. Although to be used via inhalation, the biodistribution and long half-life in mice suggest the potential of a systemic treatment benefit [http://www.asgct.org/ the-vector/volume-1-issue-17-july-2015/meeting-center/ gene-modulation-and-editing-for-lung-disease]. In an open label study of nasal administration of QR010, the CFTR function measured via nasal potential difference test improved in patients homozygous for F508del [18]. Safety and efficacy of single and multiple ascending doses of QR010 via inhalation are currently being tested. Current Opinion in Pharmacology 2017, 34:70–75
72 Respiratory
A major challenge is the development of small molecule therapies for patients with class I mutations; 10% of patients with CF have a premature stop codon mutation on one of their alleles [8]. Ataluren is a ‘read-through drug’ with conditional approval (EMA) for patients with Duchenne’s muscular dystrophy caused by a premature stop codon. In patients with CF and a premature stop codon, ataluren showed promise in an open label phase 2 trial [19]. In the subsequent phase 3 trial, the primary outcome of improving FEV1 was not met in the global analysis although in a post hoc analysis, stabilization of FEV1 was seen in the subset of patients not using an inhaled aminoglycoside [20]. However, the company has recently announced that a confirmatory phase 3 study including only patients not inhaling aminoglycosides failed its primary endpoint (http://ir. ptcbio.com/releaseDetail.cfm?ReleaseID=1015471). The search for more efficient read-through drugs thus continues. Currently marketed drugs were tested for read-through capacity in preclinical models and several seemed to be effective at suppressing nonsense mutations [21] although these remain to be tested in the clinic. Riociguat, a stimulator of soluble guanylate cyclase developed by Bayer is another, possible low hanging fruit. This drug is marketed for patients with pulmonary hypertension and is currently being tested for its efficacy to improve CFTR function in patients homozygous for the F508del mutation (https://clinicaltrials.gov/ct2/ show/NCT02170025?term=riociguat&cond=Cystic +Fibrosis&rank=1). Cavosonstat developed by Nivalis Therapeutics (in the meantime acquired by Alpine Immune Sciences) is a CFTR stabilizer aiming to increase CFTR protein residence time at the cell membrane. By inhibiting S-nitrosoglutathione reductase (GSNOR) cavosonstat increases intracellular levels of GSNO that plays a critical role in modulating protein function through S-nitrosylation. In in vitro cell systems, this promotes CFTR maturation and membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators. Although safe and well tolerated [22], addition of cavosonstat in patients taking Orkambi did not provide additional benefit. PTI-428 developed by Proteostasis is a ‘CFTR amplifier’, a compound that somehow stabilizes nascent mRNA to increase efficiency in CFTR translation that can then be further corrected or potentiated. Evaluations of safety, tolerability, pharmacokinetics, and efficacy of PTI-428 in adults with CF are ongoing [23]. Especially in Europe, drug approval and licensing does not necessarily equate to drug availability; drug reimbursement is the competence of the national health authorities. Due to its high efficacy and despite its very high cost, reimbursement of Kalydeco has been granted Current Opinion in Pharmacology 2017, 34:70–75
in western European countries. The uptake of Orkambi has been much slower. It is at present available in a minority of European countries and often on a named basis program only. Even in North-America, at the end of the first year on the market, only 42% of the 8895 eligible patients were reported to be on the treatment [24]. Another item for concern is the low adherence to the highly efficacious drug Kalydeco — only 61% — in a small group on patients with CF monitored electronically [25]. Adherence decreased over time. There was no correlation between adherence monitored electronically (61%), by refill history (84%) or self-report (100%). So, in summary, the last few years have seen extremely encouraging progress and the pipeline is currently very full, but significant challenges remain. For the second half of this review, we will consider the lessons learned, outstanding questions and areas of unmet need. Whilst we do not have answers to many of these issues, we wish to provide our personal opinions and some food for thought.
What lessons have we learned? The trial landscape is becoming increasingly complex
The phase III trials of ivacaftor were extremely easy to enrol, as patient enthusiasm was enormous: the phase II trial data were exciting, compelling and unrivalled by anything else in the field. Indeed, the very large phase III studies of Orkambi, enrolling between them over 1000 patients globally, were also conducted in a remarkably short period of time. It is possible that this ‘honeymoon’ period, if not over, will only be short-lived from now. For all sorts of reasons, it will likely be challenging to recruit gating mutation patients to trials of new potentiators or combinations: many of them feel their lives have been transformed by Kalydeco. They have returned to work, started families, or may simply feel, as described by one of our patients, that they are no longer ‘defined by having CF and want to forget about it’. Some of those who helped develop ivacaftor may be experiencing ‘trial fatigue’, whereas others willing to participate may be too well, with an FEV1 above the usual cut-off of 90%; alternative inclusion criteria for these patients may therefore be essential. One particular issue of concern is the requirement by some regulatory agencies of a placebo arm or prolonged washout period; it is clear that patients’ health will decline off ivacaftor, so we consider it crucial that washout periods are limited and that alternatives to conventional placebo-controlled designs are explored. Although Orkambi is not yet established as standard of care in many European countries, a substantial proportion of US patients are taking this drug, so these issues will come more and more to the fore in the development of combination treatments also. Finally, the future will require us to develop better outcome measures than FEV1. Although capable of demonstrating the efficacy described, it has limitations in early life and in www.sciencedirect.com
Where are we with transformational therapies for patients with cystic fibrosis? De Boeck and Davies 73
patients with well-preserved respiratory health. Additional outcome measures such as lung clearance index [26,27] and imaging (CT [28] and MRI [27,29]) are being increasingly explored and, with sufficient validation, may provide extremely useful alternatives. We must manage expectations
[a] Ivacaftor in patients with CF and gating mutation set the benchmark very high: It seemed intuitive that it would be easier to target correctly-localised CFTR with drugs that improve function than correct absent or mislocalised protein. This has indeed been borne out in trials, with the lung function improvements in patients with CF who carry a gating mutation on ivacaftor being around 10% and closer to 3% in F508del homozygous subjects receiving Orkambi. Interestingly, the difference in reduction of exacerbation frequency was less dramatic and furthermore, longer-term data, albeit not from a placebo-controlled trial but based on propensity-matched registry data, would appear to suggest that the chronic effects on rate of lung function decline may also be similar. Whilst continuing to strive for the most efficacious drugs, we should be careful not to fall into the trap of overvaluing short-term, large impact interventions. The inclusion of long-term monitoring periods to examine a drug’s potential for disease modification may be enlightening. [b] Failure is still possible at a late development stage: The recent announcement that the read-through agent, ataluren, had failed to meet primary and secondary endpoints in a second phase 3 trial has been a major blow. Results from phase 2 trials had been somewhat patchy with at least one study not showing the expected nasal potential difference measurement changes, but others were extremely encouraging. The first phase 3 trial, a large, multicentre, global endeavor failed to show a statistically significant difference between treated and placebo groups, but did show a trend favoring active treatment. Based on knowledge of the mechanisms of action of ataluren and aminoglycosides at ribosomes, there was a predefined plan to examine any impact of inhaled aminoglycosides: here, there appeared to be a compelling signal favoring ataluren-treated patients who were not receiving tobramycin, in both FEV1 and pulmonary exacerbation rates. We would applaud the decision of PTC to seek confirmation of such post hoc results by conducting a follow-on trial, the results of which, to the surprise of many investigators, were negative. Whilst a major disappointment, the results underscore the importance of rigor in drug testing, even at late stages of development. Even supposedly ‘irreversible’ disease might be amenable to improvement
Systemic drugs have a major benefit over those topicallyadministered in their potential for multi-organ benefit. The improvements in weight observed in the early www.sciencedirect.com
ivacaftor trials were surprising in their magnitude, and likely related to gut bicarbonate secretion aiding absorption [30]. By contrast, there was probably no initial expectation that pancreatic exocrine dysfunction could be reversed, as the organ’s destruction happens extensively in the pre-natal period. The KIWI trial, an openlabel study of ivacaftor in children 2–5 years of age provided the first chink in this assumption, around one third of pancreatic insufficient children demonstrating faecal elastase (FE) levels of >200 after 24 weeks of treatment [31]. FE is now included in a second trial in this age group [clinicaltrials.gov NCT02742519] and another in even younger infants and toddlers [clinicaltrials.gov NCT02725567]. Future trial design should be creative, to capture all of the potential benefits of new agents, and not focus simply on airways disease.
Even the most effective drug is of no use if patients cannot access it
We currently have a serious issue of inequity of access; this is not a problem purely related to developing countries, but one that is happening in our own healthcare systems. CF centres who have played important roles in the development of a new drug find themselves unable to prescribe it now licensed. Even the schemes whereby trial participants continue to receive drug thereafter have been criticised by CF patients who have perhaps not had the same opportunities to enrol in trials in the first place. The expanded N. American and European Trials Networks and new initiatives such as the UK CF Trust’s Clinical Trials Accelerator Platform [https://www. cysticfibrosis.org.uk/news/announcing-the-new-clinicaltrials-accelerator-platform], are seeking to address some of these access problems. However, the impact of costs seems unlikely to melt away as a problem; whilst the rise in numbers of pharma companies seeking to develop CFTR modulators is extremely welcome, whether this will impact significantly on licensed product costs remains to be seen. We need to work hard as a CF community to continue to push for widespread and equitable access as new drugs are developed.
Conclusion The current pipeline of therapies that improve the underlying CFTR dysfunction in patients with CF is very busy. Since most mutations cause different defects in CFTR protein synthesis or function and since at least half of the patients with CF have 2 different mutations, combining corrective strategies may prove most effective in the long term. Important lessons have emerged from the clinical drug development phase: the complexity of testing new CFTR modulator therapies in the context of access to Kalydeco and Orkambi; the design of trials in young children; the need for long term follow up to value the full impact of Current Opinion in Pharmacology 2017, 34:70–75
74 Respiratory
CFTR modulator therapies; the importance of monitoring access to approved therapies for all patients with CF.
Conflict of interest statement Nothing declared.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Current Opinion in Pharmacology 2017, 34:70–75
