NGM's Aldafermin Becomes Latest NASH Failure as it Misses Mark in Phase IIB

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NGM Biopharmaceuticals aldafermin failed to hit its primary endpoint in the company’s Phase IIb ALPINE 2/3 trial for non-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis.

NASH, a form of fatty liver disease in people who drink little or no alcohol, has been a tough nut to crack, with several high-profile failures in recent years. 

The ALPINE 2/3 study evaluated 171 patients with biopsy-confirmed NASH with stage 2 or 3 liver fibrosis (F2/F3). Patients received either 0.3 mg, 1 mg or 3 mg doses of aldafermin once a day via subcutaneous injections and were compared to placebo. 

The trial failed to hit the primary endpoint of a dose response showing improvement in liver fibrosis by greater than or equal to 1 stage with no worsening of NASH at week 24. It did achieve statistical significance compared to placebo on some secondary endpoints, including NASH resolution at the 3 mg dose and multiple non-invasive measures of NASH, including liver fat content reduction at the 1 mg and 3 mg doses.

Aldafermin is an engineered analog of the human hormone FGF19.

“These results are certainly disappointing, particularly given the dire unmet need in this patient population,” said David J. Woodhouse, chief executive officer of NGM. “The lack of significant fibrosis improvement was unexpected given the consistency of histology findings previously seen with aldafermin in our adaptive four-cohort Phase II study. 

"However, in line with the data from that study, ALPINE 2/3 achieved statistical significance on multiple non-invasive measures of NASH at the two higher doses," Woodhouse continued. "That said, given the failure to meet the primary endpoint, we have decided to shift resources that had previously been reserved for a Phase III F2/F3 NASH development program toward advancing our other programs.”

That pipeline includes NGM621, an anti-complement C3 antibody in Phase II studies for geographic atrophy; NGM120, a GFRAL antagonistic antibody in Phase II for metastatic pancreatic cancer and cancer-related cachexia; and NGM707 and NGM438, anti-ILT2-ILT4 and LAIR1 myeloid checkpoint candidates, respectively. Both of those compounds are expected to start Phase I trials for advanced solid tumors this year. 

In addition, Merck is progressing its Phase IIb trial of MK-3655, an FGFR1c/KLB agonistic antibody for NASH, which NGM discovered via a collaboration with Merck.

Woodhouse added, “NGM is a markedly different company than when we initiated ALPINE 2/3 in May 2019, when our clinical-stage pipeline consisted primarily of liver and metabolic programs. Over the past two years, we have steadily expanded that pipeline with programs generated from our productive in-house discovery engine, and today we are also an ophthalmology and oncology company with four Phase II programs underway. We look forward to advancing our clinical programs and moving additional programs into the clinic, supported by our cash balance that was in excess of $300 million at the end of the first quarter.”

In mid-2020, France’s Genfit reported that its drug elafibranor failed a Phase III trial in NASH. The year before, Gilead Sciences selonsertib flunked a Phase III trial. Gilead’s firsocostat and cilofexor were also unsuccessful in NASH. Boehringer Ingelheim and Pharmaxis’ BI 1467335 also failed in trials.

For quite some time, the leading company in the NASH race was Intercept Pharmaceuticals and its drug obeticholic acid (OCA). In June 2020, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) rejecting their application. The CRL stated that it could not be approved because of uncertainty about the efficacy of the treatment. There were also concerns over the risk-benefit profile for the drug.

NGM Bio took a hard hit at today’s news, with shares dropping 48.73% in premarket trading.

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