Safety Concerns Lead Merck and Enanta to Halt HIV and HBV Drug Development Programs

Compiled by Fan Dongdong

In the pharmaceutical R&D field, the path to an effective and approved drug is often paved with repeated failures. Not long ago, MSD and Enanta each terminated their HIV and HBV project developments due to safety risks.

Recently, the R&D of MSD's HIV project has suffered a major blow. After discovering a decrease in white blood cell counts among participants, the company announced the suspension of the development of its "very important" MK-8507 project. MSD has been committed to developing a once-weekly treatment regimen that combines MK-8507 with islatravir for HIV patients. However, in a Phase II trial, patients receiving the highest dose of MK-8507 were found to have reduced lymphocyte and CD4+ T-cell counts, which could potentially increase the risk of infections in these patients.

Although MSD quickly pointed out that MK-8507 was the cause, islatravir may have also played a role. When reviewing the results of previous islatravir trials used for pre-exposure prophylaxis (PrEP), higher doses of the drug did reduce patients' white blood cell counts but kept them "within the normal range." In two Phase III trials combining islatravir and doravirine administered once daily, the same decrease in cell count was observed among participants; however, each time this occurred, there was no increase in the patients' infection rates.

Currently, MSD has stopped dosing in the trial and will continue to monitor the 161 study participants. The company stated that it "remains confident in the overall development of islatravir" and will continue to develop the drug for its internal programs as well as its collaboration with Gilead. The two companies are combining Gilead’s lenacapavir and islatravir in an effort to create a long-acting cocktail therapy that can be administered both orally and via injection.

This combination therapy is designed as a once-a-week treatment, and if approved for marketing, it will greatly improve the convenience for HIV patients to take their medication. A Phase II study has already been launched this fall. The current HIV treatment regimen requires patients to take medication daily for life and strictly adhere to the treatment plan to be effective. This also leads to patients often missing doses or not fully complying with the treatment plan, resulting in the virus developing resistance to the treatment. Currently, in order to achieve this goal, MSD still needs to continue its efforts.

Besides MSD, another American company, Enanta, has also felt the sting of a failed HBV trial program. After the Phase I trial, this Massachusetts-based biotech company decided to pause the development of EDP-721 following safety signals observed in healthy participants; the drug is an oral hepatitis B virus RNA destabilizer.

However, this result is somewhat surprising because the drug had "demonstrated preclinical safety characteristics in comprehensive toxicology studies." Enanta CEO Jay Luly stated that patient safety is Enanta’s top priority, and therefore, Enanta decided to halt further development of this compound.

However, the company stated that it will continue to focus on developing a functional cure for patients with chronic hepatitis B and remains confident in its core product, the HBV inhibitor EDP-514, which demonstrated safe and potent antiviral activity in a Phase 1b study involving viremic and NUC-suppressed chronic HBV patients. The company’s previous work on HCV protease inhibitors was licensed to AbbVie, which received approval for it under the name Mavyret in 2019.

Just last month, Enanta discontinued two clinical-stage NASH treatment candidates under development, despite some promising results from the Phase IIb data. Moving forward, the company will shift its focus to advancing its HBV core inhibitor EDP-514. Positive data from the Phase Ib trial showed that the candidate was safe and well-tolerated, whether administered alone or in combination with NUC therapy. In the trial, EDP-514 demonstrated robust antiviral activity across all dose groups. The data supports a once-daily oral dosing regimen for the drug, which could also serve as a foundation for combination therapies aimed at achieving functional cures for patients with chronic HBV.

Reference Source:

1.Safety Signals Force Merck and Enanta to Scrap HIV and HBV Programs

2.Enanta dumps oral hep B program after safety warnings in early test