Retlirafusp alfa

On September 19, 2024, the National Medical Products Administration (NMPA) accepted Hengrui Pharmaceutical's marketing authorization application for the Class 1 new drug Retlirafusp-α Injection (SHR-1701). The application seeks approval for its use in combination with Fluorouracil  and platinum-based drugs for the first-line treatment of locally advanced unresectable, recurrent, or metastatic gastric and gastroesophageal junction adenocarcinoma. About Retlirafusp-αRetlirafusp-α is a bispecific fusion protein targeting both PD-L1 and TGF-βRII. It works by promoting the activation of effector T cells and effectively improving immunomodulation in the tumor microenvironment, thereby enhancing the immune system's ability to kill tumor cells. In November 2020, Hengrui reached an agreement with South Korea's DONG-A ST Co., Ltd. (hereinafter "Dong-A"), licensing the SHR-1701 project to Dong-A for a total transaction amount of $139.27 million, while also securing a share of the sales revenue. Dong-A holds exclusive rights for clinical development, manufacturing, and marketing of SHR-1701 in South Korea and is authorized to develop and market SHR-1701 for all human diseases. Recently, Hengrui presented the Phase 3 clinical trial data of SHR-1701 combined with chemotherapy versus placebo combined with chemotherapy for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJA) as a first-line treatment at the 2024 European Society for Medical Oncology (ESMO) conference. The primary endpoints were overall survival (OS) in PD-L1 CPS≥5 and intention-to-treat (ITT) populations. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Stratification factors included PD-L1 expression (composite positive score CPS≥5 vs. <5), ECOG performance status (0 vs. 1), and peritoneal metastasis (presence vs. absence). The results showed: ·In the PD-L1 CPS≥5 population, the median OS (mOS) was 16.8 months in the SHR-1701 group compared to 10.4 months in the placebo group, achieving statistical significance. ·In the ITT population, the mOS was 15.8 months for the SHR-1701 group versus 11.2 months for the placebo group, also achieving statistical significance. ·In the PD-L1 CPS≥5 population, the median PFS (mPFS) was 7.6 months for the SHR-1701 group versus 5.5 months for the placebo group. The confirmed ORR was 56.5% for the SHR-1701 group compared to 32.7% for the placebo group, a difference of 23.8%. The DoR was 10.2 months versus 5.1 months, respectively. ·In the ITT population, the mPFS was 7.0 months for the SHR-1701 group compared to 5.5 months for the placebo group. The confirmed ORR was 53.4% for the SHR-1701 group versus 32.8% for the placebo group, a difference of 20.6%. The DoR was 8.5 months versus 5.3 months, respectively. Beyond gastric cancer, Hengrui is also developing SHR-1701 for indications such as lung cancer, colorectal cancer, and nasopharyngeal carcinoma. An Ib/III phase clinical study for cervical cancer showed that SHR-1701 combined with platinum chemotherapy and BP102 for first-line treatment achieved an ORR of 77.4% and a DCR of 93.5% (compared to an ORR of 68% for the FDA-approved first-line therapy "K drug + chemotherapy ± bevacizumab" for PD-L1 positive recurrent or metastatic cervical cancer), demonstrating its potential to challenge the K drug! On PD-L1/TGF-βRII DrugsTransforming Growth Factor-Beta (TGF-β) is known to promote tumor progression by stimulating epithelial-mesenchymal transition within the tumor microenvironment, inducing angiogenesis, activating cancer-associated fibroblasts, and suppressing the immune response. Its role is linked to resistance against PD-(L)1 antibodies. The dual-targeted PD-(L)1/TGF-β therapy can simultaneously block the TGF-β-mediated downstream tumor activation pathways and PD-1-mediated tumor immune escape, achieving a dual anti-tumor effect. Currently, Hengrui's SHR-1701 is the only PD-(L)1/TGF-β bispecific antibody that has submitted a global marketing application. In addition, Merck’s bintrafusp alfa (M7824) has advanced to Phase III clinical trials, while most other candidates are still in Phase I or Phase I/II stages. On First-Line Treatment for Gastric CancerGastric cancer is a prevalent solid tumor in China, with limited systemic treatment options for advanced stages, leading to short survival periods and significant unmet clinical needs. In China, current treatments for advanced gastric cancer include chemotherapeutic agents, immune checkpoint inhibitors, and anti-angiogenic drugs. Combination chemotherapy based on fluorouracil and platinum is one of the first-line treatment protocols for advanced gastric cancer, but the long-term survival benefits of chemotherapy alone are limited. Monotherapy with immune checkpoint inhibitors has shown suboptimal efficacy for treating gastric cancer. Consequently, the combination of immune checkpoint inhibitors with chemotherapy has emerged as the new first-line treatment standard for patients with advanced gastric cancer. On Jiangsu Hengrui PharmaceuticalsLast month, Jiangsu Hengrui Pharmaceuticals released its financial results for the first half of 2024: the company achieved a revenue of 13.601 billion RMB, representing a year-on-year increase of 21.78%. Notably, revenue from innovative drugs reached 6.612 billion RMB, marking a 33.25% year-on-year growth, with external licensing revenue amounting to 160 million euros. For 2024H1, the net profit attributable to shareholders was 3.432 billion RMB, showing a year-on-year increase of 48.67%; the net profit excluding non-recurring gains and losses was 3.490 billion RMB, up by 55.58% year-on-year.  Since the implementation of centralized procurement in 2021, the company's semi-annual revenue had not surpassed the 2021 peak of 13.3 billion RMB; this outstanding performance indicates that the company has finally overcome the impact of centralized procurement and re-entered a period of high growth. The company continues to refine its established technology platforms, which encompass chemical pharmaceuticals (including peptides and PROTACs), mono/bispecific antibody drugs, ADC drugs, small nucleic acids, radiopharmaceuticals, multispecific antibodies, and bispecific ADC platforms. Additionally, it has begun to develop new molecular model platforms such as PDC, AOC, DAC, and mRNA, while continuously expanding into structural biology and AI drug development platforms. Currently, 18 innovative drug products and indications are in the NDA stage, with over 10 compounds in the ADC pipeline. Furthermore, the company's innovative drugs have achieved significant progress in international markets, becoming a secondary growth engine. To date, Jiangsu Hengrui Pharmaceuticals has out-licensed 11 innovative drug projects, with a total overseas contract value of $10.35 billion, including $315 million in upfront payments. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

At the end of October, Hengrui and Merck reached a transaction cooperation totaling 1.4 billion Euros, with an initial payment of 160 million Euros. The transaction mainly includes Hengrui's independently developed PARP1 inhibitor HRS-1167 and Claudin-18.2 antibody-drug conjugate (ADC) SHR-A1904. The distribution ratio of the initial payment between small molecules and large molecules was not disclosed in the transaction. Considering the current research popularity of ADC, SHR-A1904 should have a higher proportion. Search for the transaction record of HRS-1167 in the Synapse databasePrior to this, Hengrui's overseas cooperation projects included SHR0302, SHR1459, Apatinib, Carrelizumab, Pyrotinib, and SHR1701, among others. The small molecule with the highest upfront payment was EZH2 inhibitor SHR2254, which Hengrui licensed out in February of this year for an upfront payment of $11 million. After all, SHR2254 is already in Phase I/II clinical trials, so the upfront payment naturally wouldn't be low. SHR2254 is indicated for the treatment of conditions including B-cell lymphoma, peripheral T-cell lymphoma, prostate cancer, and solid tumors, among others. This time raising the upfront payment record to 160 million Euros is of milestone significance for Hengrui. What insights can we gain from this? HRS-1167 is a small molecule drug, with PARP1 as its target. PARP1 is a protein associated with DNA repair and cell apoptosis, playing a crucial role in tumor development. Therefore, HRS-1167 is widely used in the field of tumor treatment. At present, HRS-1167 is undergoing phase 1 clinical trials for solid tumors. Solid tumors are a common type of tumor, including lung cancer, breast cancer, colorectal cancer, and so on. By targeting PARP1, HRS-1167 may be able to interfere with the DNA repair mechanisms of tumor cells, leading to the death or inhibition of tumor cell growth. With further research and clinical trials, HRS-1167 is hoped to provide a new treatment option for cancer patients. Search for patents associated with HRS-1167 in the Synapse databaseIn the Synapse database, search for HRS-1167 and find two groups of patents applied for by Hengrui, which are CN115403595A and WO2022247816A1. The WO patent also has a Taiwanese homologous patent, TW202313630A. The drugs protected by these patents may all contain HRS-1167.  On May 24 and 27, 2021, Hengrui respectively initiated temporary applications for two patents, and obtained the corresponding patents for molecular formulas and compounds. It is clear which patent is more important. It is considered by the author that HRS-1167 is more likely to be the structure of Example 2 in WO2022247816A1.  In the WO patent, the Compound of Example 2 significantly inhibits recombinant PARP1 activity (IC50 = 11 nM), which is more selective than recombinant PARP2 (IC50= 1779 nM). In the Cell Titer-Glo assay, it showed anti-proliferative activity against human breast cancer MDA-MB-436 and colon cancer DLD-1 cells with knocked out BRCA2 (IC50 values of 1 and 2.5 nM respectively), and no significant activity against wild-type DLD-1 cancer cells (IC50>250 nM).  WO2022247816A1 includes 10 examples and corresponding isomers. CN115403595A includes 4 examples and related isomers. Timeline of Two Hengrui Patents and Possible Lead Molecule StructuresThese two patents are both fast follows on AstraZeneca's PARP1 inhibitor AZD5305. Hengrui has once again maximized benefits by minimizing costs (with the synthesis of 14 examples). It is also worth admiring AstraZeneca's strong research and development prowess in PARP inhibitors. Additionally, AstraZeneca also has another brain-penetrating PARP1 selective inhibitor AZD9574, the structure of which was first revealed at the 2022 ACS Spring Meeting. It is believed that Hengrui should also have a strategic layout in the same field. The structure of AZD9574The preclinical in vivo pharmacokinetic (PK) characteristics of AZD5305 were measured in mice, rats, dogs, and cynomolgus monkeys. The compound AZD5305 has a very low plasma clearance (CLp) of 0.23, 1.1, 0.33, and 0.84 mL/min/kg respectively in mice, rats, dogs, and monkeys, while the steady-state volume of distribution (Vss) is 0.17, 0.38, 0.30, 0.38 L/kg. The plasma half-life is 8.0, 4.6, 10, and 7.1 hours respectively. The oral bioavailability of AZD5305 is very high in all species, consistent with low hepatic clearance and high absorption rates. With a relatively low unbound clearance rate, coupled with high potency, it is expected that the effective in vivo doses can be reduced. Optimization and partial in vivo data of AZD5305However, the current clinical trials have not revealed the dosage of AZD5305. The clinical registration information updated in July 2023 only includes two items: NCT05938270 and NCT05797168. Among them, NCT05797168 is a phase I/IIa study of AZD5335 as a monotherapy and in combination with anti-cancer drugs for the treatment of solid tumor patients. AZD5335 is AstraZeneca's FRα ADC drug, with AZD5305 being used as a combination drug. NCT05938270 also involves combination use with darolutamide. Moreover, the patent WO2023089527 includes an embodiment of the anti-tumor effect of AZD5305 combined with the TROP-2 ADC drug DS-1062. Patent WO2022074617 introduces the combination use of AZD5305 and DS8201. In AstraZeneca's public pipeline, AZD5305 does not seem to be given enough attention. Based on the previous analysis, the likely structure of HRS-1167 is the molecular structure presented in Embodiment 2 of WO2022247816A1. The difference between this molecule and AZD5305 is merely the attachment of a 6-membered oxygen ring, and derivation of one of its isomers. Some preclinical data disclosed in the patent suggest that this series likely holds potential benefits over AZD5305.  This strategy of design is not uncommon, as evidenced by the KRAS inhibitor that Jinfang Pharmaceuticals transferred to Cinda. However, whether the advantages displayed in preclinical stages can effectively translate into clinical benefits is always filled with unknowns.