UPDATED: FDA review challenges Vertex on crucial cystic fibrosis combo data

FDA reviewers plan to put Vertex's ($VRTX) cystic fibrosis team to the test on Tuesday, when outside experts will gather to offer their opinion on the treatment. In a review of the biotech's data for its closely watched combination therapy for CF, the reviewers raised doubts about the efficacy of the drug, posing a direct challenge to a program that is crucial to Vertex's future.

The data for the combo, now dubbed Orkambi, demonstrated a "small but statistically significant" improvement in a key measure for lung function used to assess the drug, according to the agency. But what they didn't prove, the FDA reviewers added, is that the experimental add-on lumacaftor made a significant contribution to the outcome.

Comparing the data for the combo, a match of Vertex's Kalydeco (ivacaftor) and lumacaftor (VX-809), "raises 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 LUM/IVA combination studies, would the treatment effects for ivacaftor alone also have been significant, especially in relation to improvements in lung functions and reductions in CF pulmonary exacerbations," according to the review.

The review also highlighted mixed results for the secondary endpoints in the study, with unsuccessful outcomes on weight and quality of life assessments.

That all may sound somewhat ominous, but it wasn't enough to shake the confidence of a number of analysts who follow the company.

The conclusions may "make for bad headlines," writes UBS biotech analyst Matthew Roden, "but do not represent significant fundamental risk, in our view. 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 in next week's AdComm and therefore are buyers of VRTX shares."

And, in fact, Vertex shares were up a bit in midmorning trading.

Kalydeco's arrival marked a major breakthrough for a small group of patients who share the G551 genetic mutation. But they represent only about 4% of the U.S. market. Vertex, which charges $311,000 for the drug, has heralded its combo as a major new hope for patients with the much more common F508del mutation. And its fortunes hinge on its success with this combo.

FDA reviews are often meant to challenge drugmakers, looking for weak spots in a company's case that an FDA panel can explore. But the FDA also is known for keeping an open mind on such challenges, particularly where patients have no other drugs to turn to.

Barring a major safety problem, such drugs are often green-lighted in order to give physicians a chance to use something to stop disease, and that perspective may prove to be Vertex's trump card.

- here's the review (PDF)