The next city in the non-oncology field! Ascentage Pharma's EED inhibitor APG-5918 for the treatment of anemia indication IND was accepted by CDE

A biopharmaceutical company dedicated to the development of innovative drugs in the therapeutic areas of oncology, hepatitis B and aging-related diseases -- Ascentage Pharma (6855.
HK) announced on November 22 that the company's application for a new drug (IND) application for the treatment of anemia-related diseases by APG-5918, an innovative embryonic ectoderm development protein (EED) inhibitor, has been accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration, which will open the exploration
of non-oncology fields.
APG-5918 is the first original EED inhibitor in China to enter the clinical stage, and is simultaneously advancing clinical research
in China and the United States for the treatment of advanced solid tumors or hematologic malignancies.

This is a randomized, double-blind, placebo-controlled Phase I clinical trial to evaluate the safety and tolerability of APG-5918 in healthy adults and anemia subjects, as well as the initial efficacy
against anemia.
The study will include participants
with β-thalassaemia, renal anaemia and other related anaemias.

β-Thalassaemia is an inherited blood disease
with a wide global impact, a cumulative number of cases, and a serious threat to human health.
1-5% of the global population is carriers of β-thalassemia gene, of which about 2.
21% (95% CI: 1.
93~2.
48) in China, and it is especially common in southern regions ^[1].

Traditional therapies for β-thalassemia still have certain limitations, especially for transfusion-dependent patients, who are in a severe situation such as lack of treatment regimens, disease care and cost burden, and multiple factors make patients poor treatment compliance and generally low quality of life
.
According to statistics, 3.
9% of patients with the β-thalassemia gene are in low- or middle-income countries, so there is still a need to find better, more standardized, and easy-to-implement treatments for resource-poor countries ^[2].

Renal anemia refers to anemia that occurs due to absolute or relative insufficient production of erythropoietin (EPO) due to various renal diseases, and uremia toxins affecting erythropoiesis and its lifespan, which is prevalent in patients with chronic renal disease (CKD) and increases with the progression of CKD ^[3].

。 In addition to blood transfusions and iron therapy, guidelines recommend treatments such as erythropoietin (ESAs) and hypoxia-inducible prolyl hydroxylase inhibitors (HIF-PHI), which significantly reduce the number of transfusions and anemia-related symptoms in patients with CKD, but there are some safety concerns
.

APG-5918 is a novel potent and highly selective EED protein small molecule inhibitor with oral activity, which has a high binding affinity and has broad clinical application prospects
in hematological tumors, solid tumors and non-tumor indications by regulating tumor tissue epigenetics and tumor microenvironment.
APG-5918 can compete with histone H3 27th lysine trimethylation (H3K27me3) to bind EED protein, inhibit the methyltransferase activity of PRC2 complex, and relieve transcriptional inhibition of hemoglobin gene, thereby producing efficacy
in anemia diseases.

The results of preclinical studies showed that APG-5918 could significantly inhibit the level of H3K27me3 during erythroid differentiation of human CD34+ hematopoietic stem cells, dose-dependently upregulate the mRNA levels of γ-globino-coding gene (HBG) and β-globino-coding gene (HBB), and upregulate the expression levels of fetal hemoglobin (HbF) and total hemoglobin (Hb).
APG-5918 monotherapy had a dose-dependent anti-anemia efficacy in a rat model of adenine-induced renal anemia, and rat body weight and anemia-related blood routine parameters were significantly improved
after administration.
In the higher dose group, the anti-anemia effect was comparable to that of the clinical standard therapy EPO; After the combination of the medium dose group and EPO, the body weight and anemia-related blood routine parameters of rats could be further improved compared with the single-dose group, and by the end of the experiment, all blood routine parameters of rats in the combined group had recovered to the level of
the control group.

As of now, in addition to APG-5918, there are 4 EED inhibitors
in clinical development at the global level.
Among them, Fulcrum Therapeutics' FTX-6058 is currently the only small molecule EED inhibitor
in clinical phase I trials for non-tumor indications such as sickle cell anemia and β-thalassemia.

Professor Chen Ping, Deputy Director of the Institute of Thalassaemia Prevention and Treatment and Director of the Key Laboratory of Thalassaemia Prevention and Control of Guangxi Medical University, said: "There is a huge unmet treatment need for patients with β-thalassemia and renal anemia
.
APG-5918, which Ascentage Pharma is developing, is expected to provide a new treatment option
for the treatment of related anemia with a novel mechanism of action.
We look forward to providing safe and effective treatment options
for patients with anemia through solid and effective clinical data.
" "

Dr.
Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "APG-5918 is the first EED inhibitor in China, which has great clinical development prospects and value, and presents 'Best-in-class potential
' in related research.
We will accelerate the clinical development of APG-5918 for anemia-related indications and provide new treatment options
for patients in China and around the world.
" "

References

1.
Shang, Peng et al.
2017, Clinical Practice Guidelines for Genetic Diseases, Medical Genetics Branch, Chinese Medical Association, 2020

       2.
Thalassemia

3.
Chinese Medical Doctor Association Nephrology Physician Branch Guidelines Working Group 2021