In the News – August 2013: Ivacaftor, lumacaftor, mannitol & nebulised amikacin

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CFTR Potentiator and Corrector Combinations
The main event of the European CF calendar, the 36th European CF Society conference, took place in Lisbon in June. This provided an opportunity for Vertex Pharmaceuticals to present some interesting data from early-stage in vitro studies which gave a sense of the theoretical potential of combinations of Ivacaftor, Lumacaftor (VX-809) and some of the second-generation correctors in pre-clinical development.

These tests showed that the combination of Ivacaftor and Lumacaftor in human lung cells with one copy of F508del and another mutation that does not respond to Ivacaftor restored CFTR function to 10% of normal. However, if the non-F508del mutation was G551D, the effect was to bring CFTR function up to 80% of the normal level equating to that of a carrier (i.e. absence of symptoms).

The combination of Ivacaftor and Lumacaftor in homozygous F508del cells restored CFTR function to 25% of the normal level but adding a second-generation corrector brought CFTR function up to 45% of the normal level equating to much milder CF. The same “triple” combination in cells with one copy of F508del and another mutation that does not respond to Ivacaftor restored CFTR function to almost 35% of normal which is also associated with much milder CF.

While these were early-stage experiments on human bronchial epithelial cells in the lab rather than clinical studies carried out in patients, they do confirm the theoretical potential of dual-corrector regimes in combination with Ivacaftor. Vertex has said its goal is to advance a second-generation corrector into clinical development by the end of 2014.

At the end of July, Vertex provided a detailed update on their clinical development programme. Headline data from the Phase 3 study evaluating Ivacaftor monotherapy in people aged six and older with at least one non-G551D gating mutation showed an average improvement of 14.2% in FEV1 through the 8-week treatment period. Additionally, treatment with Ivacaftor in this study resulted in statistically significant improvements in weight gain and in improvements in patient-reported quality of life. The safety and tolerability results observed in this study were consistent with those observed in prior Phase 3 studies of Ivacaftor monotherapy in people with CF who have the G551D mutation. Based on these results, Vertex plans to submit regulatory applications in the US and EU in the second half of 2013.

Two 24-week Phase 3 studies (TRAFFIC and TRANSPORT) of Vertex’s lead first-generation corrector, VX-809 or Lumacaftor, in combination with Ivacaftor are on-going in people aged 12 and older with two copies of F508del. TRAFFIC and TRANSPORT share the same study design. There have to be two Phase 3 studies to satisfy the technical requirements of the FDA but they are effectively two halves of the same study. The company expects to complete enrolment in these studies in the second half of 2013 and seek regulatory approval for this combination treatment in 2014, pending study results. Several UK hospitals are participating in one or other of these studies and the first two UK patients started on the trial at the end of July at Royal Devon & Exeter hospital.

Mannitol – paediatric investigation

Later in June, Pharmaxis announced that it has enrolled the first subject into its European paediatric clinical trial evaluating dry powder Mannitol (Bronchitol) in cystic fibrosis. The Phase 2 trial is a requirement of Bronchitol’s earlier European marketing approval for adults and, if positive, will form part of an application to extend this approval to treat children and adolescents in the EU with cystic fibrosis. The trial period is 27 weeks with Bronchitol being administered twice daily in approximately 160 patients aged 6 to 17 with cystic fibrosis and will assess improvements in lung function, treatment induced sputum weight and safety. The trial is taking place in Canada and seven countries in the EU.

Arikace – new inhaled antibiotic

On 1 July, Insmed reported headline results from its Phase 3 study of Arikace (inhaled liposomal amikacin) to treat Pseudomonas aeruginosa (Pa) in cystic fibrosis. The Phase 3 trial was an open-label, multi-centre, randomized study designed to assess the comparative safety and efficacy of Arikace and TOBI (inhaled tobramycin) in patients with CF and Pa. A total of 302 adult and paediatric CF patients with chronic Pa were randomized to receive 28-days of once-daily nebulised Arikace or twice-daily nebulised TOBI over a 24-week treatment period.

The primary endpoint was relative change in FEV1 measured after three treatment cycles, with each cycle consisting of 28 days “on” treatment and 28 days “off” treatment. The trial achieved its primary endpoint of non-inferiority to TOBI for relative change in FEV1 from baseline to the end of the study.
Secondary endpoints measured were relative changes in FEV1 at other time points, time to and number of pulmonary exacerbations, time to antibiotic rescue treatment, change in density of Pa in sputum, respiratory hospitalizations and changes in patient-reported Quality of Life. Overall, secondary endpoints showed comparability of once-daily Arikace compared with twice-daily TOBI consistent with the primary endpoint of the study. The safety profile of Arikace was comparable to TOBI, with adverse events consistent with those seen in similar studies and expected in a population of CF patients receiving inhaled antibiotics.

“Cystic fibrosis patients chronically infected with Pseudomonas aeruginosa are among the most heavily burdened patients when it comes to the number, frequency and types of treatments they need to take on a daily basis. The data from this study suggest that once-daily treatment with Arikace may provide a safe, effective and more convenient alternative to twice-daily TOBI treatment,” stated Diana Bilton, MD, Director of Adult CF Centre at the Royal Brompton Hospital in London, and the Principal Investigator of the study. “The hope of a once-daily treatment offers encouragement to cystic fibrosis patients suffering with Pseudomonas aeruginosa lung infections.”

Complete trial data will be reviewed in greater detail and is expected to be released at a scientific conference later this year. Insmed also intends to pursue publication of trial data in a peer-reviewed journal. The company later confirmed that it is on track for an EU regulatory submission in the first half of 2014 and that, subject to a positive review, it would expect Marketing Authorisation in late 2014 or early 2015.

by Oli Rayner, August 2013