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Click the poster for more detailsAugust 22, 2024
eMedClub News
On August 20 US time, Regeneron announced that it had received communication from the FDA regarding its BCMA/CD3 bispecific antibody Linvoseltamab.Biologics License Application (BLA)Complete Response Letter (CRL) issued,The marketing application for the drug was not approved due to Chemistry, Manufacturing, and Controls (CMC) issues.Regeneron stated that the reason for the rejection of this application was due to the pre-approval inspection failure of another company's market candidate product manufactured by a third-party filling and sealing manufacturer, which had a knock-on effect. However, the third-party manufacturer has informed Regeneron,They believe that the relevant issues have been resolved.Its facilities are currently awaiting reinspection by the FDA, which is expected to occur in the coming months.
▲ Image Source: Regeneron Official Website
Linvoseltamab is indicated for the treatment of relapsed or refractory (R/R) multiple myeloma (MM) in patients who have received at least three prior lines of therapy. If approved this time,Linvoseltamab will becomeThe Third in the WorldApproved for MarketingBCMA/CD3 Bispecific Antibody, the first two are respectivelyJohnson & Johnson's Tecvayli and Pfizer's Elrexfio.
This is Regeneron's second bispecific antibody to be rejected for marketing this year. In March, the BLA for Regeneron’s CD20/CD3 bispecific antibody Odronextamab was rejected by the FDA due to issues with the clinical trial enrollment status.According to incomplete statistics, in the first half of 2024, the FDA rejected 16 new drugs.Among them, the rejection reasons for eight products are related to issues with third-party suppliers/manufacturers or CMC problems.In 2023, 50% (18/36) of drugs received CRLs due to Chemistry, Manufacturing, and Controls (CMC) issues.Compared with small-molecule drugs, biologics have a higher probability of receiving a CRL due to CMC issues (4 vs. 14).Become a "severely affected area" for receiving CRLs.This reminds us that even if product production is outsourced, the supervision and verification of third parties need to be given high attention.CMC issues encountered during the marketing application process can sometimes be traced back to the IND (Investigational New Drug) application stage. This means that if quality can be strictly controlled at the IND application stage, many unnecessary troubles can be avoided in the subsequent marketing application process.Thursday, August 22, 2024, 19:30-20:30, EMedClub will join hands with Hengyu Bio, to"Key Points and Considerations for Biosafety Evaluation in Oncolytic Virus IND Submission"To conduct an in-depth discussion on the topicAt that time, everyone is welcome to communicate and learn online!
An Overview of Biologic Innovations Expected to Gain Global Approval in 2024
Bispecific Antibody Drugs
Target: HER2/HER3 Bispecific Antibody (World's First)Indications: NRG1+ Non-Small Cell Lung Cancer (NSCLC) and pancreatic cancerCountry of application for listing: United StatesPDUFA Date (Target Action Date): December 2024Zeno is a bispecific antibody targeting HER2 and HER3 proteins, which can block the interaction between HER3 and NRG1 by binding to HER2.If approved, Zeno will become the first targeted therapy for NRG1+ cancers.
This BLA application is based on data from the Phase Ⅰ/Ⅱ clinical trial eNRGy: In patients with advanced NRG1+ non-small cell lung cancer, Zeno's overall response rate (ORR) was37.2%(29/78; 95% CI, 26.5-48.9), median duration of response (DOR) was14.9 months。In advanced NRG1+ pancreatic ductal adenocarcinoma, Zeno's ORR is42.4%(95% CI, 25.5-60.8); 1 patient (3%) achieved complete remission, and 13 patients (39%) achieved partial remission,82%The tumors of the patients shrank. The median DOR was 9.1 months (95% CI, 5.5-12.0).1. Lukang Satuzumab (SKB264)
Company: Kelun-Biotech/MSD
Target:Surface glycoprotein antigen 2 (TROP2）
Indications: Locally advanced or metastatic triple-negative breast cancer that has previously received at least 2 systemic treatments (at least 1 of which was for advanced or metastatic stage).
Country of application for listing: China
On December 8, 2023, Kelun Biotech announced that Lukansatuzumab (SKB264) targets locally advanced or metastatic triple-negative breast cancer.New Drug Application（NDA) accepted by the CDE.As early as 2022,Kelun-Biotech and MerckCollaboration on the development, manufacturing, and commercialization of Lurocansatuzumab (SKB264) in all regions outside Greater China,Total transaction amount up to 1.41 billion US dollars。Latest Phase III clinical data for Lukansatuzumab shows: Compared with chemotherapy, SKB-264 reduced the risk of disease progression or death (PFS) in patients.69%. In addition, the overall risk of death (OS) for patients was reduced47%。In this study, the median PFS was 5.7 months in the treatment group and 2.3 months in the chemotherapy group. The median OS was not reached in the treatment group and was 9.4 months in the chemotherapy group. Additionally, the objective response rate (ORR) was 43.8% in the treatment group and 12.8% in the chemotherapy group.In terms of safety, the most common ≥3 grade treatment-related adverse events (TRAEs) were decreased neutrophil count (32.3%), anemia (27.7%), and decreased white blood cell count (25.4%).August 20,The Second Indication Application for Lukansatuzumab (SKB264) Approved for MarketingCDEAcceptance, for the treatment of patients with locally advanced or metastatic EGFR-mutant non-small cell lung cancer (NSCLC) who have failed treatment with EGFR-TKI and platinum-based chemotherapy. The application was granted priority review by the CDE on August 14.
2. Shutai (A166 for Injection)
Target: Human Epidermal Growth Factor Receptor 2 (HER2)Indications: HER2-positive locally advanced, recurrent, or metastatic breast cancer that is unresectable and has failed prior second-line or higher anti-HER2 therapy.Country of application for listing: China
On May 11, 2023, Kelun-Biotech HER2-ADCStelara (A166 for Injection)The submitted Class 1 new drug marketing application has been accepted by the CDE. The indication is for HER2-positive unresectable patients who have failed previous second-line or higher anti-HER2 treatments.Locally advanced, recurrent, or metastatic breast cancer.At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, updated data from the Phase 1 dose-expansion study of A166 in HER2-positive breast cancer patients who had undergone multiple lines of treatment were presented: the objective response rate (ORR) in the 4.8mg/kg group reached 73.9%, with a median progression-free survival (PFS) of 12.3 months.Company: Daiichi Sankyo / AstraZenecaIndications: Adult patients with locally advanced or metastatic non-squamous NSCLC who have previously received systemic therapyCountry of application for listing: United StatesPDUFA Date (Target Action Date): December 20
Dato-Dxd is an ADC targeting TROP2. Daiichi Sankyo stated that, if approved,Dedabotu monoclonal antibody will become the first TROP2-targeted antibody-drug conjugate for the treatment of lung cancer patients.Phase Ⅲ clinical trial TROPION-PanTumor02 results showed: the confirmed ORR reached 45.0% (all partial responses),The ORR in the non-squamous cell carcinoma subgroup was as high as 56.5%.The median PFS for Dato-DXd treatment was 7.4 months.The non-squamous cell carcinoma subgroup demonstrated a longer median PFS (9.6 months).In terms of safety, the drug is generally controllable and tolerable in clinical use.In addition, Degarelix was also approved in March and April this year.In China and the United StatesAs forPreviously treated with systemic therapy at the stage of unresectable or metastatic disease, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-).Marketing application submitted for breast cancer indication. Among them, the marketing application in China has been included in the priority review.1. Obecabtagene autoleucel（obe-cel）
Company: Autolus Therapeutics
Target:CD19 CAR-T
Indications: Relapsed/Refractory (r/r) Adult B-cell Acute Lymphoblastic Leukemia (B-ALL)
Country of application for listing: United States
PDUFA Date (Target Action Date): November 6, 2024
Obe-cel is an autologous CAR-T cell therapy targeting CD19.Its uniqueness lies in the design of the chimeric antigen receptor, which has a faster dissociation rate after binding to CD19.Thereby minimizing the overactivation of T cells, reducing toxic side effects while avoiding T cell exhaustion.Enhance the persistence of CAR-T therapy.This BLA application is based on the data from the pivotal Phase 2 clinical trial FELIX of obe-cel. The trial results showed that, among the 94 patients treated,76% of patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi).。In patients who achieved remission,97%No minimal residual disease (MRD) was detected in the patients. Additionally, at a median follow-up of 9.5 months, 61% of the patients who achieved remission remained in remission without receiving new anti-cancer therapy.2. Runda Kiorun Cell Injection
Company: Hengrui Dason Biotech
Target: CD19 CAR-T
Indications: Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (r/r B-NHL)
Country of application for listing: China
On December 14, 2023, Hengrun Dason's Run Dakin Oreluce Injection (tentative) was accepted by the CDE for marketing application. The drug targets CD19 and is indicated for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). Previously, the drug had been granted priority review.
Company: Bosheng Excellence Bio
Target: Stem Cells
Indications: Acute graft-versus-host disease (aGVHD) failing to respond to steroid treatment
Country of application for listing: China
On June 27, 2024, the "Amymetrix Injection" independently developed by Biospring Excellence Biotechnology,Becoming the first stem cell new drug in China to receive formal NDA acceptance and be included in the priority review category.Eylea InjectionClinical indication is acute graft-versus-host disease failing to respond to steroids.Acute Graft-versus-Host Disease is one of the important complications of allogeneic hematopoietic stem cell transplantation and also a significant event affecting the quality of immune reconstitution after transplantation.Severe aGVHD is often accompanied by hematopoietic failure, significantly impacting patient survival.
The immunomodulatory properties of mesenchymal stem cells make them promising for clinical treatmentaGVHD provides possibilities. Relevant studies in recent years have shown that MSCs can exert immunomodulatory effects through various pathways, such as inhibiting lymphocyte proliferation, suppressing the differentiation, maturation, and function of antigen-presenting cells, inhibiting CTL formation, and increasing the proportion of regulatory T cells.
Company: Ionis Pharmaceuticals
Target: Apolipoprotein C-III (APOC3) mRNA
Indications: Familial Chylomicronemia Syndrome (FCS)
Country of application for listing: United States
PDUFA Date (Target Action Date): December 19
Olezarsen (IONIS-APOCIII-LRx) is a novel N-acetylgalactosamine (GalNAc)-conjugatedAntisense Oligonucleotide, targeting liver APOC III mRNA,Can selectively inhibit the synthesis of APOC III.Inhibition of APOC III synthesis may be an effective way to reduce triglyceride levels. Familial chylomicronemia syndrome is a rare genetic disorder caused by impaired lipoprotein lipase (LPL) function, characterized by extremely high triglyceride levels.This NDA is primarily based on the Phase III Balance study data: The results showed that in the 80mg dose group, Olezarsen achieved the primary endpoint, with patients' triglyceride levels decreasing from baseline by a placebo-adjusted amount at 6 months.44%(p<0.001); from 6 months to 12 months, the patients' triglyceride levels were reduced after placebo adjustment59%; apoC-III levels, adjusted for placebo, decreased by 74% and 81% from baseline at 6 months and 12 months, respectively.AndOlezarsen demonstrates good safety and tolerability.
Despite Challenges, the Enthusiasm for R&D in Biologic Innovation Drugs Remains Unabated. From several biologic innovation drugs expected to gain approval in 2024, whether bispecific antibodies, ADC drugs, cell therapies, or small nucleic acid drugs, all have demonstrated tremendous potential and hope. It is hoped that these drugs will be successfully approved in Q4 2024, bringing new treatment options to patients.
References:
1.https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application-0
2. Public Information on the Internet
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