A new treatment for cystic fibrosis (CF), Orkambi, has recently gained media attention as a result of the National Institute for Health and Care Excellence (NICE) committee’s decision to not fund the drug through the NHS (Cystic Fibrosis drug Orkambi decision ‘a death sentence’, BBC Online). At an annual cost of >£100,000 per patient, the positive effects of the drug on disease exacerbations and lung function were not considered by NICE to be cost effective. So what does the near future hold in terms of new therapies in CF and will therapies for patients with rare mutations benefit from the current wave of pharma interest?
The last decade has seen significant advances in the hunt for new therapies to treat cystic fibrosis (CF). Since the cloning of CFTR, the gene which is mutated in CF, the mechanisms which lead to such a devastating lung disease have come into greater focus and the first drug treatments, designed to repair the basic defect have shown efficacy in the clinic. Vertex’s Kalydeco (ivacaftor), a drug which potentiates the chloride channel activity of CFTR, has shown significant benefit in CF patients with so-called ‘gating mutations’1 in the channel which account for approximately 10% of the 120,000 patients globally. As a mono-therapy, ivacaftor does not however show any benefit in CF patients carrying the most common mutation, F508del. The F508del mutation prevents the channel being trafficked to the cell membrane, so for a CFTR potentiator such as ivacaftor to work a 2nd drug, a CFTR corrector is required to rescue membrane insertion. To this end, Vertex have developed lumacaftor, a drug that facilitates F508delCFTR trafficking to the plasma membrane (a CFTR corrector)2. The combination of lumacaftor with ivacaftor (Orkambi), as described above, has shown some clinical improvement in CF patients homozygous for F508delCFTR (approximately 50% of the CF population), although the magnitude of benefit has fallen somewhat short of the impressive ivacaftor and in recognition of this 2nd generation ‘correctors’ are in development. Vertex have advanced two new correctors (VX152, VX440) and Galapagos are pushing GLPG2222, GLPG2737 and GLPG2857.
Central to the efficacy of these CFTR repair therapies is their ability to restore anion secretion into the airway lumen which serves to draw in water and hydrate the thick, sticky CF mucus thereby improving its ability to clear bugs out of the lungs. However, a number of other CFTR-independent mechanisms are at play in the airway epithelium which can also improve the hydration status of the mucus. Clearly there is not yet the same weight of clinical validation that a CFTR-independent based therapy will show efficacy in patients, however, these types of therapies will offer the potential to treat all CF patients, irrespective of their particular CFTR mutation. Furthermore, these therapies are anticipated to be used in combination with CFTR repair approaches, where available, with anticipated additive or perhaps synergistic activity.
One of these CFTR-independent targets is the epithelial sodium channel, ENaC. ENaC is responsible for absorbing fluid out of the airways and blockers of this channel have been shown to improve mucociliary clearance in the clinic3. Vertex/Parion have VX-371, an inhaled ENaC blocker in a Phase 2 study in CF patients in combination with Orkambi. When used as a monotherapy in a short Phase 2 CF study, VX-371 failed to show any signs of efficacy. This may have been due to the short duration of the study (14 days) but it was also suggested that the efficacy of an ENaC blocker may be limited if there is inadequate anion secretion. Putting a plug into an empty bath tub will not help it fill up unless the taps are switched on! Data reported at the NACFC 2016 seemed to support this notion illustrating that the combination of VX-371 with Orkambi enhanced mucosal hydration and ciliary beat frequency in primary cultures of CF-derived bronchial epithelial cells4.
As well as CFTR, there is an additional anion secretory pathway in the human airway epithelium, often called the ‘alternative’ chloride conductance. This chloride conductance is regulated by calcium and termed the Calcium Activated Chloride Conductance, CaCC. The human airway CaCC was identified as TMEM16A in 2008. This CFTR-independent pathway for anion and thereby fluid secretion into the airway appears to have been somewhat overlooked in the ‘pharma clamour’ for CFTR regulators but its importance should not be underestimated. CF patients are born with dysfunctional CFTR but despite this they maintain some degree of mucociliary and cough clearance, that is the lungs manage to provide anion and fluid secretion from somewhere. Mother Nature has installed a back-up mechanism, the alternative chloride conductance, that is capable of sustaining mucus clearance even in the absence of CFTR. However, this mechanism is clearly not sufficient to maintain long-term health and eventually the lungs succumb. So from a therapeutic perspective, can we utilise this alternative chloride conductance? Actually, we are already doing it, albeit subconsciously. We now understand that CF patients gain significant benefits from regular exercise5 and one of the mechanisms believed to drive this is the alternative chloride conductance. During exercise, our rate and depth of breathing increases which induces an increase in calcium levels in the epithelium through a purinergic, P2Y-receptor mediated mechanism6. This elevation of calcium increases CaCC activity and thereby enhances anion and fluid secretion into the airway boosting mucus clearance; an important mechanism to ensure our lungs clear the extra burden of microorganisms that come with the extra volumes of inspired air on exertion. So could we harness this mechanism and use it as a basis for a completely novel drug therapy for CF? With the identity of the CaCC known to be TMEM16A it is now possible to find compounds that will potentiate the activity of the channel. In essence, a TMEM16A ‘potentiator’ will sensitise the channel to intra-cellular calcium levels thereby maintaining it in an activated state for longer, enabling an enhanced fluid secretory response. As with an ENaC blocker, this approach will be agnostic to the CF patient’s mutation and will therefore be suitable for all patients. Furthermore, additive or synergistic effects with CFTR repair therapies as well as ENaC blockers would be anticipated.
Looking ahead to the near term, advances in pharmacotherapy for CF patients are going to continue to be largely based around CFTR-repair, focusing on the 50% of the population who are homozygous for the F508del mutation. We will eagerly await data to understand whether Orkambi does influence the natural history of the disease whilst testing the next generation of ‘corrector’ molecules, hoping for a breakthrough in clinical efficacy. In parallel, CFTR-independent therapies hold significant promise as both combinations for existing therapies, but importantly also as stand-alone treatments in their own right.
- Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-72
- Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP; TRAFFIC Study Group.; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-31
- Hirsh AJ. Altering airway surface liquid volume: inhalation therapy with amiloride and hyperosmotic agents. Adv Drug Deliv Rev. 2002;54(11):1445-62.
- Haberman, R, Ling M, Thelin W, van Goor, F, Higgins M, Jain M. Preclinical evidence for adding ENaC inhibition to corrector/potentiator therapy (lumacaftor/ivacaftor combination therapy) in cystic fibrosis. Ped Pulm. 2016;S45:216 (abstract)
- Hebestreit H. Exercise in cystic fibrosis. In: Cystic Fibrosis ed. Mall M, Elborn JS. European Respiratory Society Monograph 2014
- Button B, Okada SF, Frederick CB, Thelin WR, Boucher RC. Mechanosensitive ATP release maintains proper mucus hydration of airways. Sci Signal. 2013;6(279):ra46.
Blog written by Henry Danahay