March 5, 2024

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Merck BTK inhibitor was suspended by FDA on Phase III trials

Merck BTK inhibitor was suspended by FDA on Phase III trials


Merck BTK inhibitor was suspended by FDA on Phase III trials

On April 13, the US Food and Drug Administration announced that it had partially suspended Merck’s phase III trials in Germany of the BTK inhibitor evobrutinib ( M2951) in the treatment of relapsing multiple sclerosis (MS).

Currently, the global phase III clinical development evaluation project of evobrutinib for the treatment of MS includes 2 pivotal phase III studies, EVOLUTION RMS1 (NCT04338022) and EVOLUTION RMS2 (NCT04338061).


Multiple sclerosis (MS), a chronic inflammatory central nervous system disease, is the most common non-traumatic, disabling neurological disease in young adults. It is estimated that approximately 2.8 million people worldwide are living with multiple sclerosis.

While symptoms can vary, the most common symptoms of MS include blurred vision, numbness or tingling in the extremities, and problems with strength and coordination. The relapsing form of multiple sclerosis is the most common.


Merck BTK inhibitor was suspended by FDA on Phase III trials



The regulatory order barred Merck from enrolling new patients in the trial and required it to stop dosing participants who had received evobrutinib for less than 70 days.

Both patients are currently asymptomatic and do not require hospitalization, Merck reported. After cessation of evobrutinib treatment, liver enzyme levels normalized.


Because the trial enrolled participants who had been exposed to study drug for more than 70 days, Merck does not anticipate that the clinical hold will impact the study’s timeline. Preliminary counts are scheduled for the fourth quarter of 2023.



Still, the company’s shares fell 7 percent on the Frankfurt stock exchange. Merck is also working with the U.S. Food and Drug Administration to determine the best regimen for evobrutinib.





Prospects and risks of BTK inhibitors


Evobrutinib, which crosses the blood-brain barrier, is an oral drug candidate that belongs to a class of drugs known as BTK inhibitors.


BTK (Bruton’s tyrosine kinase), Bruton’s tyrosine protein kinase, is a member of the Tec family of non-receptor tyrosine kinases, except T cells and natural killer cells, in all hematopoietic cells (such as B cells and myeloid cells) expressed in both.

BTK is a key molecule connecting B cell receptor (BCR) signaling, chemokine receptor signaling, and Toll-like receptor (TLR) signaling, and plays a key role in regulating B cells.

BTK can directly interact with five different molecules, which can promote cell proliferation, antibody secretion, and production of pro-inflammatory cytokines, etc., and then regulate B cell adhesion, migration, and tumor microenvironment.

Given its broad and critical physiological roles, BTK is an attractive therapeutic target for the treatment of autoimmune diseases and B-cell malignancies.


A total of five BTK inhibitors have been approved for marketing worldwide . Except for ibrutinib, the other four are second-generation BTK inhibitors, namely: AstraZeneca’s acatinib (Acalabrutinib, approved in 2017) ), BeiGene’s Zanubrutinib (approved in 2019), Ono/Gilead’s tirabrutinib (approved in 2020), InnoCare’s Orelabrutinib , approved in 2020).


Merck BTK inhibitor was suspended by FDA on Phase III trials


At present, the overall market size of BTK inhibitors has exceeded 10 billion US dollars. Among them, ibrutinib, which was launched in 2013, will have a global sales volume of 9.777 billion US dollars in 2021, and it is predicted that its sales will reach 13.6 billion US dollars in 2026.

It is a milestone product. Acatinib will rank second in terms of sales volume in 2021, with sales of US$1.238 billion; BeiGene’s Zanubrutinib, which was approved in November 2019, ranks third, tirabrutinib (tirabrutinib hydrochloride) and Obrutinib was launched late, and its sales contribution is relatively small in the BTK market.




In the field of multiple sclerosis, B TK inhibitors frequently hit the wall


In multiple sclerosis, targeting the BTK protein reduces levels of autoantibodies that attack the protective sheath of nerves, leading to better disease outcomes. The promise of BTK inhibitors in MS has attracted other biopharmaceutical companies, with Sanofi buying Principia Biopharma three years ago for $300 million. A year later, Biogen licensed the BTK inhibitor from China’s InnoCare Pharma. Novartis and Roche are also testing MS drugs. But safety concerns have led to limited success in the field.

Last month, Biogen terminated its partnership with InnoCare Pharma and returned the investigational BTK inhibitor orerabrutinib to its Chinese collaborator. The two companies previously signed a licensing agreement in July 2021, with Biogen paying $125 million up front and committing an additional $812.5 million in commercial and development milestones for MS and other immune disease research ,


Merck BTK inhibitor was suspended by FDA on Phase III trials

In December 2022, InnoCare announced that due to drug-related liver injury cases, the US Food and Drug Administration has suspended part of the clinical use of orerabrutinib.


Liver toxicity also caused problems with Sanofi’s BTK inhibitor tolebrutinib ( Tolebrutinib ) , and in June 2022, the US Food and Drug Administration (FDA) approved tolebrutinib (SAR442168) for multiple sclerosis (MS) and myasthenia gravis (MG) Phase 3 clinical studies are partially suspended.

Participants who have been in the trial for less than 60 days in the United States should suspend study drug. U.S. participants who completed at least 60 days in the trial should continue treatment.

The FDA’s action is based on the small number of cases of drug-induced liver injury seen in the Phase 3 study. Sanofi was also studying tolibrutinib for myasthenia gravis, but dropped that program in February.


Merck BTK inhibitor was suspended by FDA on Phase III trials


Whether BTK inhibitors can become a “game changer” for multiple sclerosis will take time to answer.








[1] FDA, citing safety concerns, places partial hold on Merck KGaA’s MS drug. 2023.4.13

[2] FDA pumps brakes on Sanofi’s $3.7B multiple sclerosis bet, imposing partial hold over liver injuries .2022.07.30

Merck BTK inhibitor was suspended by FDA on Phase III trials

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