NGM Biopharmaceuticals Inc. wowed investors with positive preliminary top-line results from the 24-week double-blind, randomized, placebo-controlled fourth cohort of an adaptive phase II study testing aldafermin in nonalcoholic steatohepatitis (NASH), and shares of the South San Francisco-based firm closed at $18.87, up $2.68, or 16.5%, after trading as high as $22.95.
“Even taking out the time factor we’ve treated, which is shorter than other agents, we’re showing an effect that is at the top of the industry,” CEO David Woodhouse said during a conference call with investors, adding that the data make “a good argument that we may be able to run a shorter pivotal trial,” though the company “just received the data and [we] need to think about all the different levers we have to run a thoughtful but quick as possible” registrational experiment, he said.
The study measured the efficacy, safety and tolerability of 1-mg aldafermin in patients with biopsy-confirmed disease and stage 2 or 3 liver fibrosis (F2, F3). Formerly known as NGM-282, the lead candidate is an engineered variant of the human hormone FGF19 in the works as a once-daily therapy. NGM’s fourth cohort was powered to demonstrate the effect of drug treatment vs. placebo on the primary endpoint of change in absolute liver fat content (LFC), which achieved statistical significance. The study measured secondary and exploratory endpoints of liver histology and biomarkers of disease activity, many of which rang the bell, too, NGM said. Interim results were disclosed in October 2019.
Enrolled were 78 patients, randomized 2-to-1 to receive once-daily aldafermin 1 mg (n=53) or placebo (n=25). The primary endpoint was the treatment effect on absolute LFC as measured by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) compared to placebo at 24 weeks, with a ≥5% absolute LFC reduction identified as clinically meaningful. Secondary and exploratory endpoints included relative changes in LFC, biomarkers of liver function and effect on liver histology. Patients were also evaluated at week 30 following six weeks off treatment for safety and non-invasive measures.
Biopsies were done at baseline screening and at the end of 24 weeks of treatment and were read using the NASH Clinical Research Network criteria by one central, independent hepatopathologist who was blinded to patient and treatment assignment. Per protocol, liver biopsy data were analyzed using the “liver histologic population," defined as the subset of enrolled patients who had valid, non-missing biopsy data at both baseline and week 24 (n=72). Six patients (three in the aldafermin arm and three in the placebo arm) withdrew prior to the week 24 biopsy for reasons not due to adverse events (AEs) related to treatment.
Histology results revealed that treatment with aldafermin led to clinically meaningful improvements at 24 weeks vs. placebo in fibrosis and in resolution of NASH. Treatment with aldafermin 1 mg resulted in a fibrosis improvement of ≥1 stage with no worsening of NASH in 38% of patients compared to 18% in the placebo arm. Twenty-four percent of patients in the aldafermin treatment arm achieved the endpoint of resolution of NASH with no worsening of liver fibrosis as compared to 9% on placebo – and 22% of those in the aldafermin treatment arm vs. none in the placebo arm achieved the composite endpoint of both fibrosis improvement and resolution of NASH, which was statistically significant. Draft guidance by the FDA indicates that each of those is an acceptable endpoint for potential accelerated approval in a future pivotal bid. Chief Medical Officer Hsiao Lieu said that “with the robustness of these data, we definitely will take this and go back to the FDA and other regulators and have a meaningful discussion on how to move forward in a timely manner.”
Patients treated with aldafermin also turned up statistically significant improvements in each of the nonalcoholic fatty liver disease activity score (NAS) components: steatosis, lobular inflammation and hepatocellular ballooning. A statistically significant proportion of patients in the aldafermin treatment arm (62%) gained a two-point improvement in total NAS without worsening of fibrosis, compared to the placebo arm (9%).
“It’s not just liver-fat reduction, which is clearly a driver of disease and important, but there are other mechanisms going on,” CEO Woodhouse said. “As we theorized at our 12-week data, there seemed to be enough heading in that direction that this was possible. We were quite encouraged to see that the effect of the drug is being read out not just on fibrosis reversal but on NASH resolution.”
Aldafermin was generally well-tolerated with no study withdrawals due to AEs as compared to one withdrawal due to an AE in the placebo arm. The most common AEs (>10% in either treatment arm) in the study (diarrhea, headache, abdominal distension, nausea, fatigue, diabetes mellitus and peripheral edema) were primarily mild to moderate and occurred with comparable frequency in the aldafermin and placebo arms. None of the reported serious AEs (two in the aldafermin arm and three in the placebo arm) was deemed related to treatment by the site investigator. Patient-reported outcomes were not tracked. “Going forward, this is something we are thinking of,” Lieu said. “We have ongoing dialogue with our site investigators to understand the AE profile in real time.”
Ongoing is the phase IIb Alpine 2/3 study to assess the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg of aldafermin compared to placebo in patients with biopsy-confirmed NASH and F2-F3 liver fibrosis. NGM expects to sign up about 150 patients, with data expected in the first half of 2021. “We could move forward with 1 mg, but it’s interesting to think about what 3 mg may be able to do at 24 weeks,” Woodhouse said. The company also plans to kick off the phase IIb Alpine 4 trial testing aldafermin in NASH patients with F4 liver fibrosis and well-compensated cirrhosis, in the first half of 2020.
Meanwhile, Wall Street speculated about the meaning of the latest results from NGM for Akero Therapeutics Inc., also of South San Francisco, which is developing the FGF21 analogue AKR-001 in NASH. J.P. Morgan analyst Eric Joseph said in a report that “notwithstanding mechanistic differences between FGF19 and FGF21 agonism,” NGM’s first placebo-controlled histological findings in the FGF space “are de-risking for the longer-term clinical implications for AKR-001 into its series of phase IIa readouts.” These are due in the first half of 2020, including MRI-PDFF data in the first quarter and histological results in responders during the second quarter. Shares of Akero (NASDAQ:AKRO) closed at $24.15, up $1.56.