Merck Returns Rights to NASH Drug Candidate MK-3655 to NGM Bio

On February 28, NGM Bio disclosed in its 2022 annual report that Merck & Co., Inc. had decided to terminate the Phase IIb study of MK-3655 (NGM313) for the treatment of non-alcoholic steatohepatitis (NASH). By the end of April 2023, Merck will return the licensing rights acquired in 2018 for MK-3655 and its related compounds, at which point NGM Bio will fully own the program.

MK-3655 is an investigational monoclonal antibody that activates the β-Klotho/FGFR1c receptor complex, intended for the treatment of NASH and type 2 diabetes. It binds to β-Klotho and selectively activates the FGFR1c receptor-mediated signaling pathway without activating FGFR2c, FGFR3c, or FGFR4. Phase I studies have demonstrated that MK-3655 has the potential to serve as a once-monthly injectable insulin sensitizer.

MSD registered the Phase IIb study (NCT04583423) of MK-3655 for pre-cirrhotic NASH patients on Clinicaltrials.gov in 2020. This is a randomized, double-blind, placebo-controlled study, recruiting a total of 328 patients and is scheduled to be completed on April 13, 2023.

This study aims to evaluate the impact of three doses (low, medium, high) of MK-3655 (subcutaneous injection, once every 4 weeks) compared to placebo on the proportion of patients who achieve NASH resolution without worsening of fibrosis after 52 weeks. In addition, the primary endpoints also include the proportion of patients experiencing adverse events and the proportion of patients discontinuing treatment due to adverse events. One of the secondary endpoints is the mean percentage change in liver fat content from baseline at 24 weeks.

NGM Bio stated that Merck's decision to terminate the study was based on its interim analysis of liver fat reduction at Week 24, and was not related to safety issues.

▌MSD and NGM Bio's 8-Year Friendship

The origin of the relationship between MSD and NGM Bio dates back to 2015, when the two parties entered into a broad strategic collaboration. Under this agreement, NGM Bio led the research and development of existing preclinical drug candidates. After the completion of proof-of-concept clinical trials, MSD had the option to obtain the global exclusive license for all drug candidates arising from this partnership. In addition to a $94 million upfront payment and the purchase of $106 million worth of NGM Bio stock, MSD committed to providing NGM Bio with up to $250 million in funding over the initial five-year collaboration period.

In 2019, the two parties announced that Merck & Co., Inc. had exercised the option in the cooperation agreement reached in 2015, obtaining the global exclusive rights for the development, production, and commercialization of MK-3655 and related compounds, for which NGM Biopharmaceuticals received a payment of 20 million US dollars.

In 2021, Merck & Co., Inc. (MSD) and NGM Bio revised their original collaboration agreement, extending the partnership term until March 2024 but narrowing the scope of collaboration to focus on developing therapies for retinal, cardiovascular, and metabolic diseases, with MK-3655 and NGM621 being the key highlights of the collaboration.

Notably, NGM621, the complement C3 monoclonal antibody that Merck & Co., Inc. had high hopes for, failed in a Phase II study in 2022, missing the primary endpoint of reducing the lesion area in geographic atrophy. Following this news, the stock price of NGM Biopharmaceuticals, Inc. plummeted by 70% on the same day.

▌Pharmaceutical Giants Battle in the NASH Field

Since the beginning of this year, several pharmaceutical giants seem to have developed second thoughts about the NASH field.

According to the latest pipeline disclosed in the financial report, Eli Lilly has removed the Phase II clinical program of ketohexokinase (KHK) inhibitor for NASH and diabetes. This is the second setback for Eli Lilly regarding KHK inhibitors, as the first KHK candidate drug disappeared from the company’s pipeline in October 2021.

In February this year, after a strategic R&D portfolio review, Johnson & Johnson decided to return all rights to the RNA interference (RNAi) therapy ARO-PNPLA3 to Arrowhead.

ARO-PNPLA3, developed using Arrowhead's proprietary TRiM platform, aims to reduce the liver expression of patatin-like phospholipase domain-containing protein 3 (PNPLA3) for the treatment of NASH. PNPLA3, as a driver of liver fat accumulation and damage in patients carrying the common I148M mutation, has strong genetic and preclinical validation.

Going back in time, there are also many failures of pharmaceutical giants in the NASH field. In 2019, two Phase III studies of Gilead's ASK1 inhibitor selonsertib ended in failure.

Similar to Eli Lilly, Pfizer also stumbled with a KHK inhibitor. In 2021, after completing Phase II research, Pfizer removed PF-06835919 from its NASH pipeline.

Although NASH research and development has amassed countless failures like a black hole, some companies are still persisting...

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