US regulators have questioned the clinical validity of Vertex’ cystic fibrosis combo Orkambi, which targets the most common form of the genetic condition, ahead of an advisory committee meeting this Tuesday (May 12). 

Vertex is developing the Orkambi - a combination of Kalydeco (ivacaftor), which is already on the market for various rare CF mutations, and experimental drug lumacaftor - for patients who carry two copies of the Fdel508 genetic mutation, affecting around 8,500 (over 12’s) in the US and 12,000 in Europe.

But in documents posted to the Agency’s website ahead of the meeting, reviewers said the data raise the question whether lumacaftor contributes any added benefit over that of ivacaftor alone, and “begs the question if an ivacaftor alone arm were included [in the combination studies], would the treatment effects for ivacaftor alone also have been significant”.

Overall the data demonstrate that, compared to placebo, the combo had a “small but significant effect” in improving lung function (as measured by ppFEV1), but some secondary targets - relating to quality of life and body weight - were not met, the documents note.

Meaningful improvement?

Clinical trials showed absolute improvements in lung function of between 2.6 and 4.0 percentage points from baseline compared to placebo and, while this may seem small, Vertex has long argued that if this effect is sustained long-term it could make a real difference to patents, given that, on average, those with two copies of the F508del can currently expect to lose nearly two percent of their lung function each year.

Analysts also seems unperturbed by the development, as did Vertex’ stock. UBS biotech analyst Matthew Roden believes the conclusions “do not represent significant fundamental risk”. 

“The FDA is questioning [1] the clinical meaningfulness of the combo in Fdel508, [2] whether ivacaftor alone would be sufficient for Fdel508, and [3] whether an additional trial of ivacaftor +/- lumacaftor should be conducted. In our view, there are relatively easy answers to all these questions, hence we have a lot of confidence in a positive vote,” he said, as reported by FierceBiotech.