New drugs for cystic fibrosis: what’s next?


In the last 15 years, to its enormous credit the Cystic Fibrosis Foundation (CFF) has profoundly altered the drug discovery landscape in cystic fibrosis (CF). The CFF drive to both seed and subsequently fund drug discovery projects that would focus on repairing the faulty CF gene, CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), has ultimately lead to the registration of ivacaftor and lumacaftor (Vertex Pharmaceuticals). These are the first drugs that have been specifically designed as CFTR repair therapies. These drugs represent a significant milestone in the development of a cure for CF, but this is a complex disease characterised by numerous different mutations in the CFTR gene and approximately 50% of CF patients have mutations that are insensitive to these first generation therapies. So what is next in terms of therapies for CF patients? The North American Cystic Fibrosis Conference (NACFC) that was held in Phoenix, AZ last week (October 8-10 2015) highlighted many of the areas that hold promise for both near term and future delivery of medicines for these patients, but these do not come without new challenges and problems that will need solving.

The CFTR gene encodes a cAMP regulated anion channel that primarily conducts chloride and bicarbonate ions across mucous membranes including the lung and gut. Mutations in the CFTR gene can result in different protein phenotypes that range from no protein synthesis, through to reduced numbers of the channel at the plasma membrane or impaired opening of the channel. The net result of this is abnormal anion and therefore water secretion into these compartments which results in thick, sticky mucus which can block airways or the GI tract. In the airways this leads to recurrent infections and a slow, unrelenting destruction of the lungs.

The first of Vertex’s brace of CF drugs, ivacaftor, is termed a ‘potentiator’ as it improves the functioning of the protein by at least partially repairing its defective channel gating. This drug has shown remarkable efficacy in a subset of CF patients who have ‘gating mutations’ such as G551D and R117H but these patients represent only about 5-7% of the total CF patient population1. The majority of CF patients carry at least one copy of the F508del mutation which results in a misfolded protein that shows very low levels of expression at the plasma membrane and these patients need an additional drug called a ‘corrector’, a drug that will improve delivery of the mutated protein to the cell surface. Lumacaftor is the first CFTR corrector to be registered, and when combined with ivacaftor the pair do show clinical efficacy, albeit rather modest and only in patients carrying 2 copies of the F508del mutation2.

The mechanistic basis for CFTR potentiators (A) and correctors (B). From www.cftr.info

The mechanistic basis for CFTR potentiators (A) and correctors (B). From http://www.cftr.info

So there are at least 2 distinct challenges here: 1) the current first generation CFTR repair therapies need some improvements in clinical efficacy, and 2) what about the rest of the CF population (~50%) who still have nothing?

Improving clinical efficacy will need to be achieved through the development of new ‘stand-alone’ drugs as well as the rational use of combinations of CFTR repair agents. The CFF strategy to catalyse drug discovery has also had the effect of attracting a number of pharma and biotech into the area, buoyed by the early success of ivacaftor in the gating mutation patients. New companies equals new drugs with potentially better profiles when used as a single therapy, but perhaps more importantly when used in combination with drugs with additive or synergistic modes of action. The challenge however is recruiting the patients. CF patients are a well-motivated group who are willing to participate in trials, but they are relatively small in number. Furthermore, ivacaftor and lumacaftor represent a new ‘standard of care’ for the largest single population of CF patients (F508del homozygous) and testing new, potentially improved CFTR repair therapies on this background represents a challenge particularly as these 2 drugs will be formulated in combination (Orkambi) making withdrawal from one or the other very difficult. Questions have also been raised as to the suitability of ivacaftor as a potentiator of the F508del channel as chronic exposure of this form of the channel to ivacaftor can attenuate function3,4. The relevance of these preclinical observations can only be tested in the clinic with alternative potentiator molecules which do not share this putative negative pharmacology. But again, with ivacaftor and lumacaftor co-formulated as a single pill, this will be extremely difficult and may preclude F508del CF patients getting access to better, more effective treatments.

What about those CF patients not treated with current potentiators and correctors? Approximately 50% of CF patients have mutations that are insensitive to ivacaftor and lumacaftor, and in fact most of the pipeline of CFTR repair candidates which have been largely designed to repair F508del CFTR. Many of these patients have premature stop codon mutations which result in either no protein translation or truncated and inactive protein. Clinical trials with ataluren (PTC124), a candidate drug that was predicted to improve protein translation beyond the stop codons have been largely negative5 leaving an obvious gap in the CF portfolio. Early discovery work describing new premature stop codon mutation screens were reported at the NACFC 2015 last week and this will be an area of focus for years to come. The UK Gene Therapy Consortium reported back on the liposome formulated CFTR cDNA trial, re-emphasising the belief that there was a positive, albeit modest signal6. This group plans to study a higher dose of the liposome formulation and also have a viral-based delivery system as a backup program.

Of note at the NACFC 2015 was the relative absence of non-CFTR based discovery programs. The ivacaftor data in particular have instructed us that by improving mucosal hydration it is possible to enhance mucus clearance and reduce the frequency of exacerbations of CF lung disease. So why are there not more efforts to utilise alternative mechanisms to hydrate the airways? Do companies really not want to take the risk in a non-CFTR based mechanism? Is the allure of the now ‘clinically validated’ CFTR paradigm too strong? Or are those funding the research focused by the success of CFTR? The most advanced ‘CFTR-independent’ approach is that of Parion Sciences in collaboration with Vertex Pharmaceuticals who have P-1037, and inhaled ENaC blocker in Phase 1/2. Blocking ENaC activity in the airway will prevent sodium absorption out of the mucosa thereby maintaining hydration and mucus clearance. The key challenge with this approach is a target based side effect in the kidney but if this can be avoided, then ENaC blockers will represent a new target class that will be agnostic to the individuals CF mutation. Perhaps the most forward looking approaches in CF treatment relate to gene editing and stem cell therapies. The CFF are beginning to fund a bold initiative in these areas that if eventually successful will provide treatments for all CF patients. These are exciting technologies, but technologies that it will take years or even decades to translate from the lab into therapies.

Recent progress in drug discovery for CF highlights the tremendous potential for personalised medicine, whereby an individual’s particular mutation status will govern the selection of any given therapy or combination. However to get to this point solutions to some of the challenges highlighted above will need to be found. The financial implications for this path will also require further consideration. There was sharp criticism from many camps regarding the pricing point for ivacaftor and there will likely be a similar backlash regarding Orkambi. Competition in the field will force down prices, but to get to that point some of the problems with patient numbers and standard of care must be addressed. Concert Pharmaceuticals recent disclosure of a deuterated form of ivacaftor (CTP-656)7 will be an early test of how aggressively those already playing on the CF field will attempt to defend their turf…

Blog written by Henry Danahay

  1. Ramsey, BW et al. (2011) NEJM 365(18):1663-72
  2. Wainwright, CE et al. (2015) NEJM 373(3):220-31
  3. Cholon, DM et al. (2014) Sci Tansl Med 6(246):246
  4. Veit, G et al. (2014) Sci Transl Med 6(246):246
  5. Kerem, E et al. (2014) Lancet Respir Med 2(7):539-47
  6. Alton, EW et al. (2015) Lancet Respir Med 3(9):684-91
  7. Harbeson, S et al. (2015) Ped Pulmon 41(Supp):29
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