More data backs Orkambi benefit in cystic fibrosis

Vertex is just a few weeks away from hearing the FDA's verdict on its cystic fibrosis (CF) therapy Orkambi, so the publication of clinical trial data in a prestigious journal comes at an opportune time.

Orkambi is a combination of two drugs – lumacaftor and ivacaftor – designed to overcome the underlying molecular defect that causes the symptoms of CF in around 45 per cent of patients with the disease.

The drug is targeted specifically at CF patients carrying two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Defects in CFTR function lead to an over-production of mucus-like secretions in the lungs, pancreas, liver and intestine that causes the characteristic symptoms of CF.

Ivacaftor was approved by the FDA in 2012 as a monotherapy – under the Kalydeco brand name – but is suitable for only around 4 to 5 per cent of CF patients, specifically those with the Gly551Asp mutation, so the combination with lumacaftor dramatically increases the proportion of patients eligible for treatment.

The odds are already stacked in favour of approval following an FDA advisory committee verdict earlier this month that the therapy is safe and effective in CF patients aged 12 and up and should be approved for sale in the US.

Now, two pivotal trials that underpin Vertex' marketing application for Orkambi in the US, the TAFFIC and TRANSPORT studies, have been published in the New England Journal of Medicine (NEJM).

Taken together, the two trials suggest that Orkambi improves lung function in CF patients who are homozygous (have two copies) of the Phe508del mutation, improving lung function by 2.6 to 4.0 per cent over the course of 24 weeks, a period in which most CF patients would be expected to show some evidence of a decline in function.

Moreover, treatment with the drug product reduced the rate of pulmonary exacerbations such as infections by between 30 and 39 per cent, with fewer cases of hospitalisation and less use of intravenous antibiotics compared to placebo.

The therapy also had an acceptable side-effect profile, according to the authors of the report, who note that more than 93 per cent of patients completed therapy with Orkambi across the two trials.

The FDA is due to deliver a verdict on Orkambi by 5 July. If it follows its panel's advice, Vertex could have a product with upwards of $5 billion a year in peak sales potential, according to analysts at RBC Capital Markets.

Robert Beall, chief executive of the CF Foundation in the US, said the publication of the data "is a powerful validation that this drug is an important new CF treatment."

Meanwhile, in an editorial accompanying the NEJM report Pamela Davis of Case Western Reserve University School of Medicine in the US said that, despite some drug interactions between the two drug components that have pared down their combined efficacy, Orkambi represents "the beginning of effective therapy for cystic fibrosis associated with the most common mutant form of CFTR."

For Vertex, approval of a blockbuster candidate would mark a dramatic reversal of fortune for the company, which once made massive sales from hepatitis C virus therapy Incivek (telaprevir) but saw its revenues dwindle as doctors and patients waited for the approval of a new generation of therapies such as Gilead Science's Sovaldi (sofosbuvir). Vertex eventually withdrew Incivek from sale last October.