Pharma Frontiers: Daily Digest of Global Pharmaceutical News – Sep 3

1.Hengrui Pharmaceuticals’ HER2 ADC Proposed for Priority Review

On September 2, the official website of the CDE (Center for Drug Evaluation) indicated that Hengrui Pharmaceuticals' HER2 ADC, SHR-A1811 (Resankrutuozumab for Injection), is proposed to be included in the priority review process. This drug is intended for the treatment of adult patients with locally advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC) who have previously received at least one systemic therapy. SHR-A1811 consists of Trastuzumab, a cleavable linker, and the topoisomerase I inhibitor payload SHR169265. The payload SHR169265 not only exhibits higher membrane penetration ability but also significantly enhances cytotoxic effects. More importantly, the drug features an innovative chiral cyclopropyl design between the linker and the toxin, which greatly improves the chemical stability of the drug, effectively controls the precise release of the toxin, and significantly reduces early release-related side effects.

2.EU Approves Braftovi+Mektovi Targeted Combination Therapy

Pierre Fabre Laboratories recently announced that the European Commission (EC) has approved the expansion of the Braftovi (encorafenib) and Mektovi (binimetinib) combination therapy to include the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring the BRAF V600E mutation. The EC’s decision was based on the results of the Phase 2 PHAROS clinical trial. In the primary analysis (data cutoff date: September 22, 2022), the trial met its primary endpoint of overall response rate (ORR). Among treatment-naive patients (n=59), the ORR was 75% (95% CI: 62, 85), and for previously treated patients (n=39), the IRR-determined ORR was 46% (95% CI: 30, 63).

Braftovi is an oral small-molecule BRAF kinase inhibitor, and Mektovi is an oral small-molecule MEK inhibitor, both targeting key proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Last October, Pfizer, the collaboration partner of Pierre Fabre Laboratories, announced that this combination therapy had received FDA approval.

3.Sanofi's BTK Inhibitor Reports Progress in Three Phase 3 Multiple Sclerosis Trials

On September 2, Sanofi announced the latest progress of three Phase 3 clinical trials for the BTK inhibitor Tolebrutinib in the treatment of multiple sclerosis (MS). The GEMINI 1 and GEMINI 2 trials, targeting relapsing forms of MS (RMS), did not meet the primary endpoint of annualized relapse rate (ARR). However, the HERCULES trial for non-relapsing secondary progressive multiple sclerosis (nrSPMS) achieved its primary endpoint, making Tolebrutinib the first and only drug to demonstrate a delay in disability accumulation in nrSPMS patients. Tolebrutinib is undergoing four Phase 3 clinical trials for MS, including GEMINI 1 and GEMINI 2 for RMS, HERCULES for nrSPMS, and PRESEUS for primary progressive multiple sclerosis (PPMS). RMS covers a patient population of 910,000, while nrSPMS covers 170,000 patients. Although it missed the largest RMS patient population, the achievement of the primary endpoint in the Phase 3 trial for nrSPMS remains a significant breakthrough for Tolebrutinib.

4.Lilly's Long-Acting RXFP1 Agonist Approved for Clinical Trials in China

On August 30, the CDE website revealed that Eli Lilly's new long-acting relaxin analog, Volenrelaxin, received its first clinical trial approval in China for the treatment of chronic kidney disease (CKD). Volenrelaxin, with the research code LY3540378, is a novel long-acting relaxin analog that combines a single-chain relaxin-like peptide 2 with an anti-albumin single-domain antibody to extend its half-life. In a Phase 1 clinical trial with healthy subjects (NCT04768855), LY3540378 was administered in single ascending doses (SAD) and multiple ascending doses (MAD) to assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured in selected SAD and MAD cohorts. Preliminary results showed that subcutaneous administration of LY3540378 led to an increase in ERPF during the acute phase (1.32 [1.17, 1.50]) and chronic phase (1.51 [1.31, 1.76]) compared to baseline (mean ratio to placebo [90% confidence interval]) while maintaining GFR (p-NS).

5.GSK's New BCMA ADC Drug to Be Considered for Breakthrough Therapy Designation

On September 2, the CDE website indicated that the injectable form of Belantamab mafodotin, registered by GlaxoSmithKline (GSK), is being considered for designation as a breakthrough therapy. The proposed indication is for its use in combination with Bortezomib and Dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Belantamab mafodotin is an antibody-drug conjugate (ADC) developed by GSK, consisting of a monoclonal antibody targeting B-cell maturation antigen (BCMA) linked to the toxic payload auristatin F via a non-cleavable linker. This drug can eliminate myeloma cells through multiple mechanisms of action. In August 2020, it received approval from the U.S. FDA and the European EMA, becoming the first BCMA ADC to be approved globally. However, following the failure of the Phase 3 DREAMM-3 trial, which compared the efficacy of Blenrep monotherapy against Pomalidomide combined with low-dose Dexamethasone, GSK was required by the FDA to withdraw the drug from the market in December 2022. On November 28, 2023, GSK announced positive top-line results from an interim efficacy analysis of the Phase 3 DREAMM-7 trial, where the drug met its primary endpoint of progression-free survival (PFS) as a second-line therapy. GSK plans to share the trial data with regulatory authorities in the U.S., Japan, and the European Union in the second half of 2024, aiming for second-line approval and a return to the market.

6.AstraZeneca Initiates Two Phase 2b Clinical Trials for Small Molecule GLP-1

On August 30, AstraZeneca registered two Phase 2b clinical trials for its small molecule GLP-1 receptor agonist AZD5004 on ClinicalTrials.gov. These trials are focused on the treatment of type 2 diabetes and obesity. The obesity trial plans to enroll 285 patients, with completion expected by the end of 2025, while the type 2 diabetes trial plans to enroll 384 patients, also expected to be completed by the end of 2025. AstraZeneca's GLP-1 project originated from Chengyi Biological, which in November 2023 licensed the overseas rights to AstraZeneca. AstraZeneca agreed to pay $185 million upfront, with milestone payments of up to $1.825 billion, along with a specified percentage of sales royalties.

7.Evopoint Biosciences' EZH2 Small Molecule Inhibitor to Be Considered for Breakthrough Therapy Designation

On September 2, the CDE website indicated that the XNW5004 tablet, submitted by Evopoint Biosciences, is being considered for designation as a breakthrough therapy, with a proposed indication for the treatment of relapsed or refractory peripheral T-cell lymphoma. Public information reveals that XNW5004 is a new generation EZH2 small molecule inhibitor that has shown promising anti-tumor efficacy in indications such as hematologic malignancies and prostate cancer. It is currently in Phase 2 clinical trials. According to Phase 1 clinical trial data presented by researchers at the 2023 AACR Annual Meeting, XNW5004 demonstrated significant anti-tumor efficacy across various dosage groups and tumor types, particularly in patients with follicular lymphoma, and exhibited good safety and tolerability. Additionally, based on its mechanism of action, XNW5004 has the potential to enhance the efficacy of AR inhibitors, PARP inhibitors, and anti-PD-1 therapies. Researchers have also confirmed the synergistic effects of these combinations in multiple solid tumors. Evopoint has already entered into a clinical collaboration with Merck to explore combination therapies with Keytruda.

8.Simcere Zaiming Acquires Chinese Commercial Rights to TargetRx's ALK/ROS1 Inhibitor

On September 2, Simcere Pharmaceutical announced that its subsidiary, Simcere Zaiming, has acquired the mainland Chinese commercialization rights to TGRX-326, an ALK/ROS1 inhibitor developed by TargetRx. Simcere will pay a $20 million upfront payment, and TargetRx will cover the promotional service fees. TGRX-326, independently developed by TargetRx, is a third-generation ALK inhibitor that is a potent, highly selective dual receptor tyrosine kinase (RTK) small molecule inhibitor targeting ALK and c-ROS oncogene 1 (ROS1). It holds significant therapeutic potential for non-small cell lung cancer (NSCLC) patients with ALK/ROS1 fusion genes, including those with various ALK-resistant mutations such as G1202R. TGRX-326 has demonstrated strong anti-tumor efficacy and safety in preclinical studies and Phase 1 clinical trials. Furthermore, this molecule can efficiently penetrate the blood-brain barrier, showing excellent efficacy in NSCLC patients with brain metastases. Currently in Phase 3 clinical development, this collaboration will further expand Simcere's presence in the lung cancer field.

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