89bio, Inc. announced a successful end-of-Phase 2 Meeting with the U.S. Food & Drug Administration (FDA), supporting the advancement of pegozafermin into Phase 3 in NASH. The program will include two Phase 3 trials evaluating patients with NASH: ENLIGHTEN-Cirrhosis will enroll patients with compensated cirrhosis (F4) and ENLIGHTEN-Fibrosis will enroll patients with fibrosis stage F2-F3. The F2-F3 and the F4 trials are expected to initiate in the first quarter and the second quarter of 2024, respectively.

Initial scientific advice received from EMA was generally aligned with the feedback from the FDA. The planned ENLIGHTEN program will be comprised of two randomized, double-blinded, placebo-controlled Phase 3 trials, evaluating the efficacy and safety of pegozafermin in patients with NASH. ENLIGHTEN-Cirrhosis, in patients with compensated F4 NASH: The trial will evaluate the efficacy and safety of pegozafermin administered 30mg weekly.

Histology Portion: The primary endpoint will be regression of fibrosis from F4 to an earlier stage of fibrosis. This endpoint is planned to be assessed at 24 months, with the potential to assess it earlier based on the evolving clinical and regulatory landscape. This primary endpoint is intended to support a filing for accelerated approval in the United States and conditional approval in Europe in F4 patients.

Outcome Portion: Patients will continue to be treated in a blinded extension phase through clinical outcome events that are expected to be predominantly decompensation events. Alignment with the FDA on modified definitions of some of these events could allow the trial to reach the final number of events more quickly and therefore accelerate the timeline to trial readout. Positive results would support full approval in F4 patients and will also serve as confirmatory full approval in F2-F3 patients.

ENLIGHTEN-Fibrosis, in patients with F2-F3 NASH: The trial will evaluate the efficacy and safety of pegozafermin administered 30mg weekly and 44mg every-two-weeks. Histology Portion: The co-primary endpoints will be a one-point improvement in fibrosis with no worsening of NASH and NASH resolution with no worsening of fibrosis. These endpoints will be assessed at week 52 and are intended to support a filing for accelerated approval in the U.S. and conditional approval in Europe in F2-F3 patients.

Outcome Portion: Patients will continue to be treated in a blinded extension phase to measure clinical outcomes to support full approval in F2-F3 patients. The clinical outcome events are expected to be primarily due to progression to cirrhosis. Both ENLIGHTEN-Fibrosis and ENLIGHTEN-Cirrhosis will enroll a significant proportion of patients on stable doses of GLP-1 based therapies and data from these patients in the trials will evaluate the expected incremental benefit of adding pegozafermin to these therapies.

Both trials will employ the three-panel consensus biopsy reading methodology, which was successfully utilized in the ENLIVEN trial, for both baseline and primary endpoint biopsy reads. Patients will self-administer pegozafermin using the planned commercial liquid formulation delivered as a single subcutaneous injection. Pegozafermin is a specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21) being developed for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG).

FGF21 is an endogenous hormone that has broad effects such as regulating energy expenditure, glucose and lipid metabolism. In clinical trials, pegozafermin has demonstrated direct anti-fibrotic and anti-inflammatory effects on the liver, as well as reduced triglyceride levels, improved insulin resistance and glycemic control, and continued to demonstrate a favorable safety and tolerability profile. The FDA granted pegozafermin Breakthrough Therapy designation (BTD) for the treatment of NASH with fibrosis.

Pegozafermin is advancing into the Phase 3 ENLIGHTEN trial program for NASH and is being studied in the Phase 3 ENTRUST trial for SHTG.