​How can Golly Pharma enter the oncology market?

On March 30, 2021, Gerry Pharmaceuticals (1672.
HK) announced its full-year results for 2020.
Among them, the lipid metabolism pathway represented by the FASN inhibitor series and the anti-tumor pipeline with PD-L1 small molecule oral inhibitors as the core are particularly important striking.

As an innovative drug company that has made great achievements in the field of antiviral (hepatitis B, HIV) and metabolic syndrome (NASH), how to enter the more competitive oncology field has become a market concern.

And what kind of increment will the current tumor research and development have with the addition of Songli? PART.
01 The tumor market has a bright future.
The research and development of drugs needs to be broken.
The Global Cancer Statistics Report (GLOBOCAN) shows that 19.
3 million new tumor cases will be reported in 2020, and the growth rate is obvious.
It is estimated that by 2040, the global new tumor cases will increase on the basis of 2020 47%, increasing to 28.
4 million cases.

Tumors have become the leading cause of disease-related deaths worldwide.

The pathogenesis of various types of tumors and the research and development of anti-tumor drugs have always been hot areas of medical research.
So far, more than 200 anti-tumor drugs have been approved for the market to treat about 40 tumor diseases.

However, data analysis of the US National Surveillance, Epidemiology, and Final Results (SEER) registry database shows that there is no obvious correlation between the 5-year survival rate of various types of tumor patients and the increase in the number of anti-tumor drugs approved for marketing.

The development of tumor therapy still depends on further exploration of tumor pathogenesis.

Looking for effective, low-toxicity, anti-tumor drugs or effective combination regimens with clear targets is the focus of current pharmacology and clinical therapeutics.

PART.
02 has a different vision and rushes into the blue ocean.
Researchers have discovered that as tumors develop, tumor cells can undergo energy metabolism remodeling.

Changes in metabolic pathways such as glucose metabolism, lipid metabolism and amino acid metabolism play a very important role in the occurrence, development and metastasis of tumors.

Tumor metabolic pathways play an important role in the treatment of tumors, and the research on tumor metabolic pathways has become a research hotspot in recent years.

Lipid metabolism in tumor cells has undergone specific changes, and these changes affect cell growth, proliferation, differentiation and migration.

Inhibiting fatty acid synthesis can weaken the ability of cell proliferation and survival, and fatty acid synthase (FASN) is the key to endogenous fatty acid synthesis in tumor cells.

In addition, it also mediates the signal transduction of the main carcinogenic pathways (including phosphatidylinositol 3'-kinase (PI3K/AKT) and extracellular regulatory kinase 1/2 (ERK1/2)) and regulates cellular mechanisms (including autophagy, DNA repair and lysosomal biogenesis gene transcription) are involved in the epithelial-mesenchymal transition and cell cycle regulation of tumors, and are closely related to the occurrence and development of tumors.

Therefore, inhibiting the overexpression of FASN not only selectively inhibits tumor cell proliferation and metastasis, and induces tumor cell apoptosis, but also has almost no effect on normal cells.

As a result, FASN inhibitors have become a key target for tumor therapy.

Figure 1 The molecular mechanism of FASN in tumor FAO: fatty acid oxidation; TFEB: transcription factor EB; PI3K/AKT: phosphatidylinositol kinase/protein kinase B; mTOR: mammalian target of rapamycin; Cav1: caveolin ; ATG1: Autophagy-related protein 1; ERK1/2: Extracellular signal-regulated kinase 1/2; PARP: Poly ADP-ribose polymerase; (Fatty Acid Synthase: An Emerging Target in Cancer.
Molecules 2020, 25, 3935 ; doi:10.
3390/molecules25173935) Gallite Pharmaceutical (1672.
HK), which focuses its attention on the field of tumor treatment, chose the first FASN inhibitor (ASC40) in its innovative drug development pipeline to treat glioblastoma as the treatment Breakthrough.

In the 2020 European Medical Oncology Conference (ESMO), a researcher-initiated application of the FASN inhibitor TVB-2640 (Gree code: ASC40) combined with bevacizumab for the treatment of glioblastoma II was announced Phase clinical results showed that the objective response rate (ORR) of the program reached 65%, of which the complete response rate (CR) was 20%, the partial response rate (PR) was 45%; the 6-month PFS rate was 47%, which was significantly better than Historical control (BELOB 16%, P=0.
01).

On March 30th of this year, when Gerry Pharmaceuticals announced its 2020 annual report, it announced that it would accelerate its investment in the field of oncology and plans to initiate a randomized, double-blind combination of ASC40 (TVB-2640) and bevacizumab in China.
, A placebo-controlled pivotal Phase II clinical trial, the trial population is the same as the US trial patient population (patients with first recurrence of high-grade astrocytoma).

Professor Li Wenbin, the deputy chairman and secretary-general of the Glioma Professional Committee, the director of the Cancer Comprehensive Treatment Center of Beijing Tiantan Hospital, Capital Medical University, and the main investigator of the Phase II clinical study in China, saw the ASC40 combined with bevacizumab in the United States.
The results of the Phase II clinical study are very exciting and indicate that for the treatment of glioblastoma, tumor metabolic pathway intervention and immunotherapy are the two most important research directions.

On the track of the development of innovative drugs for tumor treatment, compared with the increasingly fierce competition for homogeneity of PD-1/PD-L1, CD19, HER2, VEGF/VEGFR and other targets, the development of FASN inhibitors is only ASC40 The clinical phase of research has already begun, and Gale has clearly been in the first cohort for the research and development of innovative drugs for tumor lipid metabolism.

 Study indications, medication regimen, staging, study start date status NCT03808558 KRAS mutant non-small cell lung cancer ASC40 single-agent phase II 2019.
9.
11 recruiting NCT02223247 advanced solid tumor ASC40 single-agent phase I 2013.
11 completed NCT02980029 resectable colon cancer ASC40 single-agent phase I 2017.
1 recruiting NCT03179904 HER-2 positive advanced breast cancer ASC40 combined with paclitaxel + trastuzumab phase II 2017.
9 recruiting NCT03032484 high-grade astrocytoma ASC40 combined with bevacizumab phase II 2017.
5.
18 completed Table 1: TVB2640 (ASC40) Global Carry out a summary of clinical trials for tumor treatment.
The data comes from https://clinicaltrials.
gov.
With the in-depth study of tumor metabolism in recent years, it has been possible to distinguish the effects of different gene mutations in tumor cells on metabolic reprogramming, and then to find These driver mutation-related metabolism has metabolic weaknesses, and precise therapeutic interventions are required.

Expose non-small cell lung cancer strains with different gene mutations (EGFR, FGFR, KRAS, etc.
mutations) to a series of metabolic inhibitors.
Through the study of metabolomics and transcriptomics, the metabolic bias of different genotypes can be determined, such as EGFR activation promotes serine and nucleic acid synthesis, and FGFR activation enhances aerobic glycolysis and lactic acid cycle (Identification of metabolicvulnerabilities of receptor tyrosine kinases-driven cancer.
Nat Commun.
2019, 10(1):2701).

With the development of precision medicine, genetic testing of patients has become the norm.
According to the big data and laws of the sensitivity of different genotypes of tumors to metabolic pathways, the combined use of metabolic pathway regulation drugs can improve the therapeutic effects of existing targeted drugs.

With an in-depth understanding of the tumor microenvironment, opportunities for lipid metabolism pathways in tumor immunotherapy are gradually emerging.

In February 2021, the team of Professor Hongbo Chi from St Jude Children's Research Hospital in the United States published an article titled "Lipid signalling enforces functionalspecialization of Treg cells in tumours" on Nature and reported that FASN-mediated fatty acids are inhibited in the tumor microenvironment.
The synthetic pathway can inhibit the functional maturation of Treg cells, and reduce the suppression of Treg cells on immunotherapy without increasing the risk of autoimmune inflammation.

The study found that SREBP (sterol-regulatory-element-binding proteins) up-regulated the expression of Treg cells in tumors.

Loss of SREBP activity significantly inhibited tumor growth (Foxp3CreScapfl/fl test group, red curve, relative to Foxp3CreScap+/fl, black curve).

After using the PD-1 antibody in the SREBP activity-deficient group (Foxp3CreScapfl/fl+anti-PD-test group), the effect of PD-1 antibody in inhibiting tumors can be significantly improved.

Further studies have shown that in intratumoral Treg cells, SREBP can activate FASN-mediated fatty acid synthesis and mevalonate (mevalonate) two metabolic pathways.

Because of the lack of lipids in the tumor microenvironment, Treg cells rely on FASN for their own fatty acid synthesis to activate and mature, and help tumor cells escape immune surveillance.

Tregs in other organs can not rely on FASN for fatty acid synthesis.

Therefore, the use of FASN inhibitors can selectively inhibit Treg in the tumor, reduce immunosuppression, and further improve the effect of immunotherapy.

Figure 2 Inhibition of Treg lipid metabolism in tumors (red) combined with PD-1 antibody to inhibit tumor effects (Lipid signalling enforces functional specialization of Treg cells in tumours.
Nature.
Vol 591.
11 March 2021) PART.
03 Continued efforts to strategically deploy tumors Field According to the official announcement issued by Gallite, Gallite's tumor pipeline includes two mechanisms of tumor lipid metabolism and oral checkpoint inhibitors, and four drugs.

In addition to ASC40, which is about to launch a key phase II clinical study in China, it also includes a new generation of FASN inhibitor ASC60, and two self-developed oral PD-L1 small molecule inhibitors.

At the beginning of its debut, Gallée's tumor pipeline has a strong competitive advantage in the highly competitive tumor field.

Figure 3 Gale Tumor Lipid Metabolism and Oral Checkpoint Inhibitor Product Pipeline From the indications of Gale's pipeline deployment in the tumor field, the FASN series inhibitors are facing an out-and-out "blue ocean" market.

The "Guidelines for the Diagnosis and Treatment of Glioma" (2018 Edition) disclosed that the annual incidence of glioma in my country is about 5 to 8 per 100,000 people, but there is currently no standard for recurring glioma after standard treatment.

In addition to brain gliomas, FASN inhibitors are also expected to be used in non-small cell lung cancer, rectal cancer, breast cancer, prostate cancer and other solid tumors that highly express FASN during tumor progression.
The application market has great expansion.
space.

Moreover, FASN inhibitors mainly intervene in the lipid metabolism pathway of tumors, and have the basis for joint use with the current mainstream anti-angiogenesis (Angiogenesis), tumor-targeted therapy, and immunotherapy.

At present, many in vitro and animal experiments have shown that the combination of FASN inhibitors and other mechanisms can inhibit tumors more significantly than single drugs.

The Phase II data of the combined use of ASC40 and BEV also provide valuable clinical support for this direction.
If the FASN inhibitor series can be successfully commercialized, it can be combined with existing anti-tumor drugs with different mechanisms to obtain a broader business The Red Sea is not red in the transformation of space.

In addition, strong R&D execution is also the core element of Gerry's deployment of innovative drug research and development in the oncology field.

It took only 33 months for Gale to achieve the IND approval of a drug to the harvest of the new drug certificate.

Chairman Dr.
Wu Jinzi and CSO Dr.
Hanhan He have been deeply involved in the oncology field for many years, and they have the strategic vision and ability to lead R&D teams in the oncology market.

We look forward to Geli's continued efforts to advance FASN and even lipid metabolism pathway research to the commercialization stage as soon as possible, benefiting the majority of cancer patients.

Reference material: "New Points of Play" on the official website of Songli Pharmacy Pharmacy.
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