Orkambi’s Components Trigger Liver Enzyme That Decreases Its Ability to Fight CF, Study Finds

The two components of Orkambi act separately to trigger a liver enzyme that decreases the therapy’s ability to fight cystic fibrosis, a study reported.

Vertex Pharmaceuticals created Orkambi by combining ivacaftor and lumacaftor (VX-809). It addresses the underlying cause of the disease — a gene mutation that leads to a build-up of thick mucus in the lungs and other problems.

Researchers’ study about the liver enzyme problem appeared in the journal Drug Metabolism Letters. The title is  “Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor.”

The U.S. Food and Drug Administration approved Orkambi in September 2016 for children with CF, aged between 6 and 11, who have two copies of the F508del mutation in their CFTR gene. The European Commission approved it for the same group this year.

A number of red flags about Orkambi’s effectiveness have emerged since the approvals, however.

One concern is that the therapy’s “combination strategy may be limited due to antagonistic drug-drug interactions,” Elena K. Schneider, PhD, a research fellow at the University of Melbourne’s Department of Pharmacology & Therapeutics, said in a press release.

Schneider’s team has been looking at how ivacaftor and lumacaftor work in the body, as well as the workings of a CFTR regulator called tezacaftor (VX-661).

“Our lab is invested in shedding light on the pharmacology of cystic fibrosis transmembrane conductions regulator (CFTR) drugs,” said Schneider, the author of the study. “We have investigated potential cytochrome [protein] interactions of ivacaftor, its major metabolites lumacaftor and tezacaftor.”

Ivacaftor is broken down into two main components in the liver — an active metabolite called hydroxymethyl-ivacaftor (M1) and an inactive one called ivacaftor-carboxylate (M6). The enzymes CYP1A2 and CYP3A4 play the main role in breaking down ivacaftor.

The researchers decided to see how the two ivacaftor metabolites, and lumacaftor and tezacaftor, affected liver enzymes.

Their key finding was that ivacaftor-M6 and lumacaftor trigger the CYP3A4 liver enzyme.

This leads to patients who receive Orkambi having significantly less ivacaftor in their system, reducing the treatment’s effectiveness against CF, the researchers said.

Schneider said the results underscore the urgency of developing more effective CF therapies.