Delving into the Latest Updates on Caxmotabart entudotin with Synapse

Overview

Basic Info

Drug Type

Antibody drug conjugate (ADC)

Synonyms

重组HER2人源化单克隆抗体单甲基奥瑞他汀F偶联剂

+ [4]

Target

HER2 x Tubulin

Action

antagonists, inhibitors

Mechanism

HER2 antagonists(Receptor protein-tyrosine kinase erbB-2 antagonists), Tubulin inhibitors

Therapeutic Areas

NeoplasmsDigestive System DisordersRespiratory Diseases+ [1]

Active Indication

Metastatic human epidermal growth factor 2 positive carcinoma of breastMetastatic Colorectal CarcinomaNon-Small Cell Lung Cancer+ [10]

Inactive Indication

HER2 mutant non-small cell lung cancerRAS/BRAF Wild Type HER2 Positive Colorectal Cancer

Originator Organization

LigaChem Biosciences, Inc.

Active Organization

Iksuda Therapeutics Ltd.

Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.

Shanghai Fosun High Technology (Group) Co., Ltd.

+ [1]

Inactive Organization-

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC39H65N5O8

InChIKeyMFRNYXJJRJQHNW-DEMKXPNLSA-N

CAS Registry745017-94-1

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Sequence Code 44772H

Source: *****

Sequence Code 1147408625L

Source: *****

AimsThe dose‐escalation phase (phase Ia study) of a novel human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate (ADC) FS‐1502 included a dose range from 0.1 to 3.5 mg/kg in HER2‐expressing advanced malignant solid tumours. However, the defined maximum tolerated dose was not reached. This model‐informed approach integrated population pharmacokinetic (PopPK) modelling and exposure–response (E‐R) analysis to facilitate dose selection for phase II.MethodsThe PopPK model was constructed using PK data from 109 Chinese patients who received doses of 0.1–3.5 mg/kg FS‐1502 every 3 (Q3W) or 4 weeks during a phase I dose‐escalation and dose expansion trial. The structural model consisted of compartment models for FS‐1502 and unconjugated monomethyl auristatin F. E‐R was explored for the percentage change in tumour size, overall response rate and treatment‐related adverse events.ResultsA semi‐mechanistic 2‐analyte PopPK model was developed. The FS‐1502 PK data were best described by a 2‐compartment PK model with parallel linear and nonlinear Michaelis–Menten eliminations. The PK of unconjugated monomethyl auristatin F was described by a 2‐compartment model with first‐order elimination. E‐R analysis supported the clinically meaningful efficacy of FS‐1502 at 2.3 mg/kg and above. However, 2.3 mg/kg Q3W was considered to have a better benefit–risk balance due to a lower incidence of safety events without a significant reduction in efficacy compared to 3.0 mg/kg Q3W.ConclusionThis PopPK and E‐R analysis guided the recommended phase II dose selection of 2.3 mg/kg Q3W and supported body weight‐based dosing for an investigational HER2 ADC FS‐1502.

06 Apr 2023·Bioconjugate chemistry

One-Pot Assembly of Dual-Site-Specific Antibody-Drug Conjugates via Glycan Remodeling and Affinity-Directed Traceless Conjugation.

Article

Author: Tang, Feng ; Tang, Caihong ; Zeng, Yue ; Yao, Xu ; Zhang, Jianxin ; Huang, Wei ; Zheng, Xing ; Jiang, Zhong-Xing ; Shi, Wei

The drug-to-antibody ratio (DAR) value and dual-drug combination greatly influence the therapeutic index of antibody-drug conjugates (ADCs). The reported approaches usually require multifunctional branched linkers, a combination of complicated technologies, or protein-protein ligation, which may incorporate multihydrophobic fragments or result in low coupling efficiency. Herein, we developed a facile and efficient one-pot method to assemble dual-site-specific ADCs with defined DARs at both the N-glycosylation site and K248 site, either with the same payloads or with two types of payloads. The constructed dual-site ADCs showed acceptable homogeneity, excellent buffer stability, and enhanced in vitro and in vivo efficiency.

21 Mar 2023·Leukemia & Lymphoma

Hepatic Veno-occlusive disease (VOD) in multiple myeloma patient receiving Belantamab Mafodotin

Letter

Author: Petropoulos, Fotios ; Argyrakopoulou, Georgia ; Chandrinou, Eleni ; Rapti, Irene ; Trajce, Enkeleida ; Pessach, Ilias ; Danglis, Fotios

This is a case of a 74 yr old man with a history of IgGkappa MM from 2009.He had undergone treatment with Bortezomib-Dexamethasone at diagnosis, which was repeated 6 years afterwards followed by ASCT and Lenalidomide maintenance.Belamaf is a first-in-class humanized IgG1 ADC targeting B-cell maturation antigen (BCMA), covalently linked via a cysteine linker to the microtubule inhibitor monomethyl auristatin F (MMAF), which is released after internalization of the ADC to BCMA on tumor plasma cell, and inhibits its polymerization with the arrest of G2/M caspase dependent apoptosis.The patient received Levofloxacin 12-wk prophylaxis, acyclovir and co-trimoxazole prophylaxis, hydromellose eye drops throughout the treatment period, a coolant eye mask during every Belamaf infusion, and was ophthalmologicaly assessed before each cycle.2 Wk later, patient was urgently re-admitted with consciousness disturbances, weight gain, abdominal pain, defecation incapacity, and significant hyperbilirubinemia (total bilirubin: 6 mg/dL, direct bilirubin: 3 mg/dL, indirect bilirubin: 3 mg/dL).Our patient had never received an Allo-SCT, he had undergone an Autologous SCT many years before the VOD presentation and he had received several lines of treatment without presenting signs of hepatic toxicity.In conclusion, we described a rare case of VOD, histol. proven, in a MM patient on Belamaf-a novel ADC approved for treatment of relapsed or refractory MM.

2

News (Medical) associated with Caxmotabart entudotin

24 Oct 2023

·www.legochembio.com

Iksuda initiates HER2-ADC (LCB14/IKS014) Phase 1 trial

Iksuda Therapeutics announces first patient dosed in Phase 1 trial of IKS014 in patients with advanced solid tumours that express HER2 Study is designed to evaluate the safety and tolerability of increasing dose levels of the antibody drug conjugate, IKS014, to establish a recommended Phase 2 dose IKS014 is the first of Iksuda’s ADCs to enter clinical trials Newcastle, UK, 23 October 2023: Iksuda Therapeutics (Iksuda), the developer of class leading antibody drug conjugates (ADCs) with enhanced tumour specificity, today announces that the first patient has completed a first cycle of therapy with IKS014, a human epidermal growth factor receptor 2 (HER2) ADC targeting patients with advanced HER2+ solid tumours. This follows positive data from Phase 1 clinical trials through Fosun Pharma, which is now progressing FS-1502 (IKS014) through Phase 2 and Phase 3 trials in China. The open-label, interventional study (https://clinicaltrials.gov/study/NCT05872295) is designed to evaluate the safety and tolerability of increasing dose levels of IKS014 to establish a recommended Phase 2 dose. The second, dose-expansion, phase of the study (Phase 1b) is to further evaluate the safety, pharmacokinetics / pharmacodynamics, and efficacy of IKS014 at the recommended Phase 2 dose. The study is currently enrolling patients at five planned loca tions in Australia. The Phase 1b trial is expected to read out in 2H 2025. Dr Dave Simpson, Chief Executive Officer, Iksuda Therapeutics, said: “The dosing of the first patient in our Phase 1 trial of IKS014 marks a significant milestone for Iksuda: our transition to being a clinical-stage company. We hope that this trial of IKS014 could lead to improved treatment options for patients with HER2+ solid tumours.” ENDS About IKS014 IKS014 is a potential best-in-class antibody drug conjugate, benefiting from tumour ive activation and release of the cytotoxic agent monomethyl auristatin F (MMAF). In preclinical trials, it displayed impressive activity in high- and low-HER2 expressing tumours with significantly higher non-severely toxic dose (HNSTD) vs other HER2-directed drugs. Iksuda gained (exclusive world-wide rights (excluding Greater China and South Korea) to IKS014 from LegoChem Biosciences. (https://iksuda.com/2022/01/iksuda-deepens-clinical-pipeline/) Fosun Pharma holds the licence to the ADC in Greater China where it is designated FS-1502. Fosun is currently conducting a Phase 2 clinical trial in China in patients with a range of solid tumours and has also initiated a Phase 3 trial in patients with advanced breast cancer.

Phase 1ADCLicense out/inPhase 2Phase 3

23 Oct 2023

·www.biospace.com

Iksuda Therapeutics announces first patient dosed in Phase 1 trial of IKS014 in patients with advanced solid tumours that express HER2

Study is designed to evaluate the safety and tolerability of increasing dose levels of the antibody drug conjugate, IKS014, to establish a recommended Phase 2 dose IKS014 is the first of Iksuda’s ADCs to enter clinical trials NEWCASTLE, England--(BUSINESS WIRE)-- Iksuda Therapeutics (Iksuda), the developer of class leading antibody drug conjugates (ADCs) with enhanced tumour specificity, today announces that the first patient has completed a first cycle of therapy with IKS014, a human epidermal growth factor receptor 2 (HER2) ADC targeting patients with advanced HER2+ solid tumours. This follows positive data from Phase 1 clinical trials through Fosun Pharma, which is now progressing FS-1502 (IKS014) through Phase 2 and Phase 3 trials in China. The open-label, interventional study ( ) is designed to evaluate the safety and tolerability of increasing dose levels of IKS014 to establish a recommended Phase 2 dose. The second, dose-expansion, phase of the study (Phase 1b) is to further evaluate the safety, pharmacokinetics / pharmacodynamics, and efficacy of IKS014 at the recommended Phase 2 dose. The study is currently enrolling patients at five planned locations in Australia. The Phase 1b trial is expected to read out in 2H 2025. Dr Dave Simpson, Chief Executive Officer, Iksuda Therapeutics, said: “The dosing of the first patient in our Phase 1 trial of IKS014 marks a significant milestone for Iksuda: our transition to being a clinical-stage company. We hope that this trial of IKS014 could lead to improved treatment options for patients with HER2+ solid tumours.” About IKS014 IKS014 is a potential best-in-class antibody drug conjugate, benefiting from tumour selective activation and release of the cytotoxic agent monomethyl auristatin F (MMAF). In preclinical trials, it displayed impressive activity in high- and low-HER2 expressing tumours with significantly higher non-severely toxic dose (HNSTD) vs other HER2-directed drugs. Iksuda gained exclusive world-wide rights (excluding Greater China and South Korea) to IKS014 from LegoChem Biosciences. ( ) Fosun Pharma holds the licence to the ADC in Greater China where it is designated FS-1502. Fosun is currently conducting a Phase 2 clinical trial in China in patients with a range of solid tumours and has also initiated a Phase 3 trial in patients with advanced breast cancer. About Iksuda Therapeutics: Iksuda Therapeutics is a UK-based clinical stage biotechnology company focused on the development of class leading Antibody Drug Conjugates (ADCs) with enhanced tumour specificity, targeting difficult-to-treat cancers. Iksuda’s ADC design and pipeline is enabled by a broad armoury of payload mechanisms, tumour selective activation platforms and stable conjugation chemistries. The Company’s ADC portfolio is designed to significantly improve the therapeutic index of this important modality and improve the outcomes for patients living with cancer. View source version on businesswire.com: Contacts Iksuda Therapeutics Dave Simpson, Chief Executive Officer Tel: +44 (0) 191 6031680 Email info@iksuda.com FTI Consulting (Financial Media and IR) Simon Conway / Rob Winder Tel: +44 (0) 20 3727 1000 Iksuda@fticonsulting.com Source: Iksuda Therapeutics View this news release online at:

Phase 1ADCPhase 3Phase 2License out/in

100 Deals associated with Caxmotabart entudotin

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	28 Mar 2023
Metastatic Colorectal Carcinoma	Phase 3	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	30 Jan 2023
Non-Small Cell Lung Cancer	Phase 3	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	30 Jan 2023
Stomach Cancer	Phase 3	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	30 Jan 2023
Breast Cancer	Phase 3	China	Shanghai Fosun High Technology (Group) Co., Ltd.	-
HER2-positive gastric cancer	Phase 2	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	08 Nov 2022
HER2 Positive Solid Tumors	Phase 2	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	14 Jun 2022
RAS/BRAF Wild Type HER2 Positive Colorectal Cancer	Phase 2	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	07 Jun 2022
Gastroesophageal junction adenocarcinoma	Phase 2	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	31 May 2022
HER2 mutant non-small cell lung cancer	Phase 2	China	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	18 Mar 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03944499 (Pubmed) Manual	Phase 1	Metastatic human epidermal growth factor 2 positive carcinoma of breast	150	FS-1502 (HER2-expressing solid tumors (n = 5) and BC (n = 145))	(ypbsqzjlfq) = qwuumxzcnj aaoqgulgax (vjcqnyqavy ) View more	Positive	17 Jun 2024
NCT03944499 (Pubmed) Manual	Phase 1		150	FS-1502 (HER2-positive BC patients receiving the RP2D)	(xpvzylfrmr) = tphzuueqjn qruabtjroy (qoqoidvovs ) View more	Positive	17 Jun 2024
NCT03944499 (ASCO 12023 \| ASCO 22023) Manual	Phase 1	Advanced HER2-Positive Breast Carcinoma HER2 Positive	70	FS-1502	(kgykgzzcbx) = mvwkkwkxsh pwclwbjkyt (bglruzqbwg, 40.45 - 65.17) View more	Positive	26 May 2023

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Biosimilar

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