Ascentage Pharma submitted an IND application for the treatment of systemic lupus erythematosus with the Bcl-2 inhibitor APG-2575, which will open up the exploration of non-oncology fields

Ascentage Pharma (6855.
HK) announced on October 26 that it has officially submitted a new drug clinical trial (IND) application to the Center for Drug Evaluation (CDE) of the National Medical Products Administration, planning to carry out clinical research on APG-2575, a selective inhibitor of Bcl-2 under investigation, in the treatment of systemic lupus erythematosus (SLE), thereby opening up non-oncology exploration
。 As the second and first Bcl-2 selective inhibitor in China to enter the key registration clinical stage and have clear efficacy, APG-2575 has previously demonstrated good tolerability and efficacy
in clinical studies related to hematological tumors and solid tumors.

This is a randomized, double-blind, placebo-controlled Phase Ib/II clinical trial to evaluate the safety, pharmacokinetics and pharmacodynamics, and preliminary clinical efficacy
of APG-2575 in patients with mild to moderate SLE.

SLE is an autoimmune disease
that involves multiple systems, organs, and a variety of autoantibodies are produced.
The disease is mostly found in women of childbearing age, with a global prevalence of (4~25)/100,000, and the number of Chinese patients accounts for 1/4 of the world's [1], and the prevalence rate is as high as (30.
13~70.
41)/100,000.

SLE patients accumulate a large number of mature autoreactive B cells, which can be activated by autoantigens and cause autoimmune responses, which in turn affect multiple organs such as skin, kidneys, and heart[2].

At the same time, inflammatory cells such as plasmacytoid dendritic cells (pDC) and T cells promote SLE inflammation and autoimmune response
by secreting cytokines and activating B cells.

SLE is one of the autoimmune diseases that affect human health, but the development of new drugs to treat this disease is extremely difficult
.
At present, one of the major problems in the conventional treatment of SLE is the adverse reaction of drugs, especially long-term use of glucocorticoids can lead to serious side effects [3].

Treatment options are limited for patients who are
intolerant to or do not respond well to standard therapy.
In view of the high heterogeneity and complex pathogenesis of SLE, including B cell overactivation, T cell dysregulation, and excessive pDC INFα secretion [4]; At the same time, the high production cost of biomacromolecular targeted drugs, the limitations of immunogenicity after long-term administration, and non-oral drugs, it is difficult for existing bio-targeted drugs to meet urgent clinical needs
.

Current studies have found that the overexpression of the anti-apoptotic protein Bcl-2 is closely related to the occurrence of SLE, Bcl-2 overexpression mice show SLE-like symptoms, and a significant increase in Bcl-2 expression can be seen in lymphocytes of SLE patients [5].

Bcl-2 protein not only provides survival advantages for inflammatory cells such as T cells, B cells, and pDCs, but also confers resistance to commonly used glucocorticoid drugs in over-surviving inflammatory cells [6].

Therefore, selective Bcl-2 small molecule inhibitors, as a single drug or in combination with glucocorticoid drugs, can target a variety of pathogenic inflammatory cells at the same time, which may provide a new mechanism for the treatment of SLE and have broad application prospects
.

APG-2575 is a novel oral Bcl-2 selective small molecule inhibitor under development by Ascentage Pharma, which restores the programmed cell death mechanism (apoptosis) by selectively inhibiting Bcl-2 protein, thereby inducing apoptosis and achieving the purpose of
treating tumors and/or inflammatory diseases 。 Preclinical studies have shown that APG-2575 can competitively bind to Bcl-2 protein, destroy Bcl-2:Bim complex, and release Bim from Bcl-2:Bim complex, triggering downstream apoptosis signaling cascade, thereby inducing apoptosis of lymphocytes such as overproliferating T cells and B cells in the systemic lupus erythematosus model.
In the SLE mouse model, APG-2575 showed significant efficacy with a single agent and had a significant synergistic effect
in combination with hormonal drugs.

Dr.
Yifan Zhai, Chief Medical Officer of Ascentage Pharmaceutical, said, "APG-2575 is an important product under research in the field of apoptosis of the company, and it is also the second in the world and the first Bcl-2 selective inhibitor in China to enter the key registration clinical stage with clear efficacy, and has demonstrated good tolerability and effectiveness in relevant clinical studies in the field of hematological tumors and solid tumors, with 'Best-in-class potential
' 。 The preclinical research data of APG-2575 for the treatment of SLE further proves the clinical development potential of this variety, and we will actively promote the clinical development of this variety in the field of SLE and bring more treatment options
to patients in China and even around the world.
" "

References

[1] Chinese Medical Association Rheumatology Branch, 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus erythematosus.
Chinese Journal of Internal Medicine, 2020.
5: p.
13.

       [2] Lipsky, P.
E.
, Systemic lupus erythemotosus: an autoimmune disease of B cell hyperactivity.
Nature immunology, 2001.

       [3] Yildirim-Toruner, C.
and B.
Diamond, Current and novel therapeutics in the treatment of systemic lupus erythematosus.
J Allergy Clin Immunol, 2011.
127(2): p.
303-12; quiz 313-4.

       [4] Suarez-Fueyo, A.
, S.
J.
Bradley, and G.
C.
Tsokos, T cells in Systemic Lupus Erythematosus.
Curr Opin Immunol, 2016.
43: p.
32-38.

       [5] Ko, K.
, et al.
, Bcl-2 as a Therapeutic Target in Human Tubulointerstitial Inflammation.
Arthritis Rheumatol, 2016.
68(11): p.
2740-2751.

       [6] Manami, S.
, U.
Chifuyu, and S.
Noriyuki, Apptosis of lymphocytes induced by GC and relationship to therapeutic efficacy in patients with systemic lupus erythematosus.
Arthritis & Rheumatology, 1998.
41(5): p.
8.