While keeping eye on snap NASH OK, Inventiva tests out alternative PhIII path

As promising late-stage data reinvigorate the NASH drugs after years of setbacks, one player is changing up its Phase III plans to capitalize on what it sees as a new regulatory approach at the FDA.

Inventiva, which kicked off its Phase III NATiV3 study for lanifibranor in 2021, had originally designed a two-part study where part one would support accelerated approval with data from 900 patients and part two would follow 2,000 patients for up to seven years. While part one will continue as planned, Inventiva is now replacing part two with a new, separate Phase III trial that will enroll around 800 patients and last for about three years.

If successful, Inventiva expects the second Phase III trial to support full approval.

The changes follow a consultation with the FDA, Inventiva said in a press release Wednesday, which it requested after the agency in 2021 shared its thinking on evaluating potential NASH treatments. The FDA, in that communication, said that it would consider full approval based on Phase III results “using a histology surrogate endpoint in patients with NASH and a Phase III clinical outcome trial in patients with NASH and compensated cirrhosis.”

Part one of the NATiV3 study, Inventiva noted, should provide the data on liver histology from tissue biopsies. Enrollment is set to be completed in the second half of 2023, and patients are to be followed for 72 weeks.

New Phase III

Meanwhile, the new Phase III will recruit patients with NASH and compensated cirrhosis — a bigger group than what’s envisioned in the original part two, which would’ve only enrolled patients with F2 and F3 fibrosis.

Inventiva said it’s also adding a placebo-controlled exploratory cohort of around 200 patients with NASH and fibrosis who were screened but deemed not eligible for part one. Data from this group, including results from non-invasive tests, may contribute to the safety database requirement to support an accelerated approval filing, according to the company.

Michael Cooreman

Patients in both Part 1 and the exploratory cohort will be offered to participate in a new 48-week treatment extension study.

“Not only are Inventiva’s changes to the trial design expected to provide an opportunity for patients enrolled in the placebo arm to access a lanifibranor treatment arm, but also the changes are designed to reduce the number of biopsies,” CMO Michael Cooreman said in a statement.

A chronic disorder characterized by the buildup of fat in the liver, NASH is increasingly prevalent in Western populations, with some warning that it will become the leading cause of liver transplants. But it is notoriously challenging to treat and multiple drugs have failed to make a difference — and at the same time, the standards for diagnosis and measuring clinical benefit remain in debate.

When the FDA rejected Intercept’s obeticholic acid for NASH back in 2020 — a big setback for the field — Intercept CEO Mark Pruzanski criticized regulators’ “apparently still-evolving expectations.” Others have argued that the requirements for biopsies make clinical development overly burdensome for both drug developers and patients.

Recently, Madrigal and Akero both reported positive data with their respective drugs, with Madrigal shooting for accelerated approval in 2023 and Akero spotlighting a histology endpoint that it said came from the FDA’s draft guidance.

Inventiva said it does not expect the trial design modifications to have a significant impact on its budgeting for the accelerated approval.

fda