How does the differentiation of the five new-generation BTK inhibitors that have been approved globally reflect?

Text|Pharmaceutical Mission Hills

Recently, the field of BTK targeted therapy has ushered in many developments

BTK is a proven target for B cell malignancies

Physiological function and disease of BTK

Bruton's tyrosine kinase (BTK) is a member of the TEC family of intracytoplasmic non-receptor tyrosine kinases

Especially in the activation, proliferation, survival and differentiation of B cells, BTK plays an important role

▲BCR receptor and Fcγ body (FcγR) signaling pathway (picture source: reference [1])

However, when BTK loses its effect, the BCR signal is insufficient to induce the differentiation of B cells, and may even cause serious immunodeficiency diseases such as X-linked agammaglobulinemia

Therefore, BTK has been regarded as a promising target in the treatment of hematological tumors and immune diseases

From one model in 20 years to one model in 1 year

Since BTK was first discovered in 1993, drug research on this target has not stopped

Ibrutinib, jointly developed by Johnson & Johnson and AbbVie, is the first BTK inhibitor approved for marketing

Since its first approval in 2013, Ibrutinib has been approved for the treatment of various blood diseases, as well as autoimmune-related diseases such as stem cell transplantation, post-transplant immune resistance and arthritis

However, long-term clinical data has found that the off-target effects of the first-generation BTK inhibitors can cause side effects such as atrial fibrillation and hypertension

Take Zebutinib independently developed by BeiGene as an example.

The other abutinib from Nuocheng Jianhua is also a new type of BTK inhibitor

It is worth mentioning that since 2017, 4 BTK inhibitors have been approved globally, and one BTK inhibitor has been produced every year on average

Overcoming drug resistance, non-covalent BTK inhibitors enter the late-stage clinical

Although five BTK inhibitors have been approved for marketing worldwide, and these drugs have shown excellent efficacy in the treatment of B-cell hematological cancers, they still have certain limitations

The main reason is that most of these BTK inhibitors adopt a covalent inhibition mechanism, and they irreversibly inhibit the activity of BTK by covalently binding to a target on BTK

This gave birth to a new generation of non-covalently bound BTK inhibitors

▲Schematic diagram of reversible BTK inhibitor binding to target (picture source: reference [3])

For example, LOXO-305, developed by Loxo Oncology, a subsidiary of Eli Lilly and Company, is a non-covalent BTK inhibitor.
The drug candidate is designed to overcome resistance to covalent BTK inhibitors
.
It has inhibitory activity against BTK C481 mutants, and its non-covalent inhibitory mechanism allows it to inhibit BTK activity even when the BTK turnover rate is high
.
Currently, LOXO-305 is conducting a phase 3 randomized trial in patients with mantle cell lymphoma
.

MK-1026 (ARQ 531) developed by ArQule is also an oral, potent and reversible BTK inhibitor.
It can not only inhibit wild-type BTK, but also C481S mutant of BTK
.
Therefore, MK-1026 has the potential to overcome tumor resistance to existing BTK inhibitors
.
In December 2019, Merck announced the acquisition of ArQule for US$2.
7 billion, thereby obtaining a variety of products including MK-1026
.
At present, this BTK inhibitor has been clinically approved in China and is in phase 2 clinical development globally
.

In China, Yehui Pharmaceutical has reached an agreement with Carna Biosciences in March 2020 to become the exclusive authorized company in Greater China for the new generation of non-covalently bound reversible BTK inhibitor BN102 (AS-1763)
.
BN102 is a new generation, potent, and strictly screened non-covalent binding reversible BTK inhibitor.
It has a strong inhibitory effect on wild-type BTK and C481S mutant BTK and has better selectivity.
It is expected Potentially better efficacy and less off-target toxicity
.
Currently, BN102 is undergoing animal experiments and preparation development stages before IND application
.

In addition, other reversible BTK inhibitors such as BMS-986142, PRN1008, ONO-4059 and other drugs are under clinical development
.

More new generations of BTK inhibitors are under development

Among the many new-generation BTK inhibitors under development, there is another class of eye-catching candidate products that are expected to overcome the blood-brain barrier
.
This is expected to provide potential treatments for patients with central nervous system diseases and brain injuries
.

For example, Nuocheng Jianhua’s abutinib, which has been approved for marketing, can penetrate the blood-brain barrier and have the potential to inhibit the function of B cells and myeloid cells in the central nervous system.
) Subtypes of disease progression provide beneficial clinical value
.
Currently, the product is conducting a phase 2 clinical study with placebo for patients with relapsing-remitting multiple sclerosis in many countries
.
In July of this year, Biogen obtained the exclusive global rights of abutinib in the field of multiple sclerosis through a cooperation with Nuocheng Jianhua
.

SAR442168, an oral BTK inhibitor that can cross the blood-brain barrier, obtained by Sanofi through the acquisition of Principia Biopharma, is expected to become a therapy that targets the origin of brain damage in MS patients to change the course of the disease
.
Currently, Sanofi has initiated an international multi-center phase 3 study in China to evaluate the efficacy and safety of SAR442168 in the treatment of primary progressive multiple sclerosis (PPMS)
.

Fenebrutinib, a reversible, non-covalent BTK inhibitor from Roche, is also an oral drug that can cross the blood-brain barrier
.
It not only inhibits the activation of B cells, but also inhibits the activation of myeloid cells including macrophages and microglia in the blood, thereby possibly reducing both acute and chronic inflammation in MS patients
.
At present, Roche has initiated two phase 3 clinical trials to evaluate the effects of fenebrutinib in patients with relapsed MS and primary progressive MS
.

In addition, many companies are also developing other new-generation BTK targeted therapies
.
For example, Hutchison Medicine's third-generation small molecule BTK inhibitor HMPL-760 has already submitted IND applications in China and the United States
.
This is a research, highly selective, and more effective candidate product, with higher activity against wild-type and C481S mutant kinases
.
Due to limited space, this article will not introduce other products under research one by one
.

From the development progress of different generations of BTK inhibitors, it can be seen that the new generation of BTK inhibitors must not only show good efficacy, but also be better in safety and tolerability
.
In addition to improving the specificity of covalent irreversible BTK inhibitors, the development of new reversible BTK inhibitors to overcome drug resistance, a new generation of products that can cross the blood-brain barrier, BTK targeted protein degradation agents, etc.
, are currently in this field A major research and development direction
.

We also expect that these continuously innovative BTK inhibitors can make more breakthroughs in clinical research, meet unfinished clinical needs as soon as possible, and allow more patients to benefit from this
.

references:

[1]Whang, Jennifer A.
; Chang, Betty Y.
(2014).
Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis.
Drug Discovery Today.
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021

[2]Gayko, U.
, et al.
, Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies.
Ann NY Acad Sci, 2015.
1358: p.
82-94.

[3] Discovery of new BTK inhibitors against rheumatoid arthritis [D].
East China Normal University, 2018.

[4] Huang Fei, Zhu Haijing, Zhou Xiang, Lu Tao, Jiao Yu, Tang Weifang.
Research progress of Bruton tyrosine kinase BTK and its inhibitors[J].
Journal of China Pharmaceutical University, 2014: 17-24.

[5] Loxo Oncology at Lilly Announces Updated Data from the Phase 1/2 BRUIN Clinical Trial for LOXO-305 in Mantle Cell Lymphoma and Non-Hodgkin Lymphomas at the American Society of Hematology (ASH) Annual Meeting.
Retrieved December 6, 2020, from https://investor.
lilly.
com/news-releases/news-release-details/loxo-oncology-lilly-announces-updated-data-phase-12-bruin

[6] Merck to Acquire ArQule, Advancing Leadership in Oncology.
Retrieved December 9, 2019, from https:// Sanofi brain-penetrant BTK inhibitor significantly reduced disease activity in Phase 2 trial in relapsing multiple sclerosis.
Retrieved 2020-04-23, from http:// brain-penetrant-BTK-inhibitor-significantly-reduced-disease-activity-in-Phase-2-trial-in-relapsing-multiple-sclerosis