May 24, 2021 07:00 AM EDTUpdated 07:59 AM R&D
NGM concedes key failure for their lead NASH drug, closing the door on a pivotal followup — and asking analysts to look past the wreckage into the pipeline
John Carroll
Editor & Founder
Amber Tong
Senior Editor
A little more than a year ago NGM whipped up considerable enthusiasm for its anti-fibrotic NASH drug aldafermin based on a cohort of patients who showed a marked response to the treatment. But its great expectations — backed by some enthusiastic analysts — failed to pan out at the primary endpoint in the crucial Phase IIb that followed among people with with stage 2 or 3 fibrosis. And while another trial in more severely afflicted patients is continuing, NGM is taking its $400 million in cash reserves and shifting focus to the rest of the pipeline, ending any hopes for a pivotal in this group — and blasting the beliefs they had inspired earlier.
NGM CEO David Woodhouse isn’t applying any spin on the data. The primary — an improvement in fibrosis with no worsening of NASH among the 107 patients taking a 0.3 mg, 1 mg or 3 mg dose — flopped badly, with a p-value of 0.55. The 1 mg dose fell behind the placebo as well as the 0.3 group, while undercutting expectations of efficacy overall. There was a significant improvement in NASH resolution (at the 3 mg dose) and “multiple non-invasive measures of NASH,” including liver fat content reduction, reductions in the liver enzymes ALT and AST; and-reductions in Pro-C3, a biomarker of fibrogenesis.
But that wasn’t good enough to stake a Phase III pivotal roll of the dice on.
“It is disappointing for not only us but for patients too,” Woodhouse told me in a late-night preview of the readout this morning. “There’s a big unmet need with nothing available for treatment. What we see here is that there continues to be activity and consistency around many of the things we measure around NASH. This key endpoint, that seems to be quite a variable endpoint.” It’s early days for NGM with the data, he added, and this was a well conducted trial, but: “It does seem like this variability around this endpoint didn’t work in our favor.”
NASH is an incredibly complicated disease, he adds, involving patients with a host of problems. “This is a really difficult disease to measure progression and reverse of; there’s a frustration being beholden to the biopsy,” says Woodhouse, when a combination of noninvasive measures could be used — but need to be validated.
Looking at the percentage of patients who saw their fibrosis improve by at least 1 stage without worsening of NASH, the biotech reported 31% and 30% response rates for the 0.3 mg and 3 mg groups, respectively. But among the middle, 1 mg dose cohort, only 15% reached that threshold — an even smaller percentage than placebo (19%). The four groups each had similar numbers of patients.
The data look similarly messy across secondary endpoints. The key figure that carried statistical significance involved the observation that 22% of patients who received aldafermin 3mg achieved NASH resolution with no worsening of fibrosis. None of the doses spurred both fibrosis improvement and NASH resolution in a large enough number of patients.
In addition to biopsies, investigators also reviewed biomarkers measured by non-invasive means, and noted a reduction in liver fat at the 1mg and 3mg doses.
Analysts had painted this one as a key catalyst for the stock $NGM, making this a painful morning for the biotech. Its shares plummeted 51% ahead of the bell on Monday. That’s a wipeout of more than $1 billion in market cap.
While investors and analysts have been zeroing in on NGM’s NASH program, though, the company has been steadily building a pipeline with new drugs aimed at cancer and ophthalmology — arenas where they hope to do better.
That pipeline includes several drugs now in human trials. One of the top drugs in that category is NGM120, a cancer therapy that is being tested for pancreatic cancer and cachexia — a wasting disease that afflicts patients.
NGM707, meanwhile, blocks 2 receptors in the tumor microenvironment, looking to improve immune responses by inhibiting both the ILT2 and ILT4 receptors. And there’s a drug called NGM621 that blocks complement C3, targeting geographic atrophy with a potential dosing regimen of every 8 weeks.
NASH drugs in general have been under a considerable cloud. The field, which kept collecting sizable venture checks betting on a comeback after repeated disappointments, saw the two leading biotech efforts implode up close, with Genfit failing a closely-watched Phase III and Intercept getting unexpectedly slapped down at the FDA after submitting positive results on one of two primary endpoints (notably, Intercept’s drug did help patients improve fibrosis, making it the lone winner in the late-stage race). Both, like NGM, signaled that they will be getting out of NASH altogether — even as earlier-stage players carry on with their pipeline while bigger ones like Gilead and Novo Nordisk team up to try a combo approach following stinging setbacks.
NGM had sold their 2019 IPO on the notion that the anti-fibrotic NASH drug — formerly NGM282, a take on human hormone FGF19, which researchers had explored for its ability to diminish liver fat content and quell bile acid — could be a game-changer in the field.
One good thing the execs can say about it now is that it looks safe: Only 2% of patients in each of the three arms dropped out of the trial because of a treatment-released adverse event, compared to 5% for placebo. While one patient died in the 1mg arm 30 days after the last aldafermin dose, the site investigator concluded it was unrelated to the therapy.
