Cystic fibrosis: searching for a breakthrough

There are exciting years ahead for the treatment of cystic fibrosis (CF). This inherited autosomal recessive genetic disorder has proven to be incredibly tough for drug developers, with research efforts hampered by the formidable scientific challenges involved.


There are exciting years ahead for the treatment of cystic fibrosis (CF). This inherited autosomal recessive genetic disorder has proven to be incredibly tough for drug developers, with research efforts hampered by the formidable scientific challenges involved.

CF affects around one in every 3,000 newborns, with approximately 75,000-100,000 patients worldwide. These are most commonly those of northern European descent.

Progress in the last few decades has had a marked impact on the life expectancy of CF patients. In the 1960s, median survival for those born with CF was around ten years, with few surviving into their teenage years. Today, average life expectancy can be as high as 50 years in countries that provide access to today’s most advanced treatments.

CF treatments: the waiting game

CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which codes for the CFTR protein. This protein’s role is to facilitate the movement of chloride ions in and out of cells to balance salt and water on exocrine epithelial surfaces, an important function for organs such as the lungs and the pancreas. CF occurs when a baby inherits abnormal copies of the CFTR gene from both parents, which results in a dysfunctional chloride channel and a resulting inhibition of sodium and water across epithelial cells.

The disorder leads to the creation of thicker-than-normal mucus, which causes obstructions in the lungs and increases the liklihood of bacterial infections. Alongside shortness of breath and recurrent infections, CF patients may also be faced with a varied array of other symptoms, from poor growth and weight gain to digestive issues and potential infertility in males.

Until relatively recently, treatment options were limited to the mitigation of individual symptoms, such as inhaled antibiotics to tackle infections in the lungs. However, the CFTR gene responsible for the disorder was identified in 1989, which opened up the possibility for new gene therapies to address the root cause of CF, rather than just treating the symptoms.

"The CFTR gene responsible for the disorder was identified in 1989, which opened up the possibility for new gene therapies to address the root cause of CF."

Still, it has been a long wait for patients in the CF community, as effective CFTR-based treatments are only now beginning to arrive and there is still much work left to do to improve their efficacy. In an emotive 2015 editorial for Cystic Fibrosis News Today, PhD student and CF patient Stephen Shannon equated the experience of waiting for a CF breakthrough to a Latin phrase, dum spiro spero, which translates to, “while I breathe I hope”.

Shannon wrote: “This past year has been the first time I have allowed myself to begin to hope that my life can be different than it is now.

“Now more than ever, the words ‘Dum spiro spero’ [represent] the strength that is carried in each of us who suffer from this disease. And with each of these therapies that is developed, our breath becomes deeper and our hope stronger.”

Vertex dominant in CFTR

In the last five years or so, a new crop of CFTR-regulating drugs has begun to hit the market. These therapies are designed to correct the function of defective CFTR protein translated from a mutated CFTR gene. The first such drug to arrive on the scene was Kalydeco (ivacaftor), developed by Boston-based Vertex Pharmaceuticals, with a $150m philanthropic investment from the Cystic Fibrosis Foundation.

Kalydeco was hailed as a wonder drug upon its approval by the US Food and Drug Administration (FDA) in 2012, as it was the first treatment to directly target the gene mutations responsible for CF. The drug works as a CFTR potentiator, improving the transport of chloride through the ion channel by binding directly to the channels and improving the liklihood that they will stay open. The treatment has shown broad efficacy in CF patients who are suited to the drug, with trials showing significant improvements in lung function, decreases in the frequency of pulmonary exacerbation, and greater weight gain when compared to placebo.

In many ways, Kalydeco represents a milestone for personalised medicine and a clear indication of the pharmaceutical sector’s direction in terms of tailoring treatments to patients’ genetic profiles. But, as much as drugs such as Kalydeco have opened up the possibilities of personalised medicine, the specificity of tailored drugs brings complications for the treatment of a condition that can potentially be caused by thousands of CFTR gene mutations. Kalydeco, for example, is only effective in patients who have one of around ten mutations (primarily G551D), which represents only 4%-5% of the total CF community.

Combination therapies

As a result, Vertex has been working to develop combination therapies to increase the proportion of the patient population for who CFTR-based treatment would be effective. Orkambi, a combination of ivacaftor and lumacaftor, was approved by the FDA in July 2015. It is effective in a much higher proportion of the CF community, as more than half of CF patients globally have two copies of the F508del mutation that is targeted by the treatment.

At the end of March, Vertex announced positive results from two Phase III clinical trials (EVOLVE and EXPAND) of its tezacaftor/ivacaftor combination, which met its primary endpoints in lung function improvement in both studies. In the same month, the company acquired investigational drug CTP-656 from Concert Pharmaceuticals for up to $250m, adding this deuterated form of ivacaftor to Vertex’s options for future drug combinations.

These breakthrough innovations come at a high cost at a time when drug pricing is very much under the spotlight, particularly in the US. List prices for Kalydeco run to around $300,000 a year. While this is not unusual for a treatment that has been granted orphan and breakthrough drug designations, it received strong criticism from many in the medical community. A 2013 editorial in the Journal of the American Medical Association described the price as 'exorbitant'. The cost also denied or delayed access under public healthcare systems in Canada, Europe, and elsewhere.

The UK’s National Institute for Health and Care Excellence (NICE) rejected the use of Orkambi on the NHS, prompting campaigns from charities and patient groups keen to see negotiations bring the drug into use on the health service.

ProQR’s RNA-based approach

Vertex is not the only company looking to pursue innovative means of rectifying CFTR processes. In the Netherlands, ProQR Therapeutics is working on a ribonucleic acid (RNA) centric approach to restoring CFTR function by targeting the messenger RNA (mRNA) in CF patients who have the common F508del mutation. This first-in-class RNA-based oligonucleotide (QR-010) would be administered via a nebuliser and delivered as a mist inhaled directly into the lungs. It is designed to bind to defective CFTR mRNA and restore proper function.

The treatment is still in the early stages of development, but in October last year ProQR announced the results of a proof-of-concept study where QR-010 met its primary endpoint of making a statistically significant improvement to nasal potential difference (NPD) in ten CF patients who were homozygous for the F508del mutation.

"These breakthrough innovations come at a high cost at a time when drug pricing is very much under the spotlight."

ProQR CEO Daniel de Boer said: “Confirming QR-010's ability to improve CFTR function in homozygous [F508del] patients is a strong validation of the preclinical evidence and reinforces our belief that QR-010 can make a transformative difference in the lives of CF patients."

As much as CFTR modulators look to be the next step in CF treatment, drug developers in other areas are seeking to provide incremental improvements and new options for patients to mitigate their symptoms. The market for pancreatic enzyme replacement therapies (PERT) is a crowded one, with pancreatic enzyme combinations available from the likes of AbbVie (Creon), Johnson & Johnson (Pancreaze), and Digestive Care (Pertzye). These pancreatic enzyme products are used to treat exocrine pancreatic insufficiency (EPI) associated with CF.

Other CF advances

Even in a market as saturated as PERTs, there is still room for innovation. Anthera Pharmaceuticals recently announced results from its Phase III SOLUTION non-inferiority clinical study, which found that the company’s new PERT Sollpura (liprotamase) had efficacy comparable to Johnson & Johnson’s Pancreaze in terms of weight and height maintenance.

However, Sollpura has the potential to become the first approved PERT that is neither porcine-derived nor enterically coated. With the ability to dissolve the medication in liquid or reduce the number of capsules that need to be taken, paediatric patients could have much less trouble taking the drug, improving adherence to treatment. The drug could also provide an alternative for patients who do not react well to porcine-derived PERTs. Anthera started screening patients for Phase III trial RESULT in May, and expects to produce top-line results by late 2017 or early 2018.

More CF innovations are in the pipeline. Montreal-based Laurent Pharmaceuticals, for example, got the go-ahead from the FDA and Health Canada in April to move forward with its Phase II trial of LAU-7b, an investigational drug that could become the first anti-inflammatory treatment indicated for CF.

The drug is intended to activate the resolution phase of the inflammatory response, potentially addressing chronic inflammation without inducing immune-suppression. Unlike some CFTR-based therapies, which are targeted at specific genetic mutations, introducing a novel anti-inflammatory to CF patients could bring more universal benefits to the treatment population.

The last few decades have been a long slog for a patient population that is in desperate need of more effective therapies. But with the wave of iterative improvements and innovative new drugs on the market and in the pipeline today, it looks as though CF patients can finally look forward to a dramatically improved treatment landscape on the horizon. CF remains one of the Western world’s most pernicious and stubborn chronic illnesses, but to paraphrase Stephen Shannon, drug developers are in a better position than ever to deepen the breath and strengthen the hope of all those who suffer from it.