Delving into the Latest Updates on Zenocutuzumab with Synapse

Overview

Basic Info

Drug Type

Bispecific antibody

Synonyms

HER3 x HER2 Biclonics, Immunoglobulin g1, bispecific, anti-(human epidermal growth factor receptors, her2 and her3) (humanized clone mcla-128 .gamma.1-chain), disulfide with humanized clone mcla-128 light chain, dimer, Mcla-128 (igg1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (adcc) activity targeting her2 and her3 receptors.)

+ [5]

Target

HER2 x HER3

Mechanism

HER2 antagonists(Receptor protein-tyrosine kinase erbB-2 antagonists), HER3 antagonists(Receptor tyrosine-protein kinase erbB-3 antagonists)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [3]

Active Indication

NRG1 Fusion Positive non-small cell lung cancerNRG1 Fusion Positive Pancreatic CancerMetastatic castration-resistant prostate cancer+ [4]

Inactive Indication

Esophageal Carcinoma

Originator Organization

Merus NV

Active Organization

Merus NV

Inactive Organization-

Drug Highest PhaseNDA/BLA

First Approval Date-

RegulationBreakthrough Therapy (US), Orphan Drug (US), Priority Review (US)

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Gene Sequence

Sequence Code 43197L

Source: *****

Sequence Code 26101535H

Source: *****

Sequence Code 315583329H

Source: *****

A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2.
MCLA-128 (zenocutuzumab) is given in combinations in two metastatic breast cancer (MBC) populations, Human Epidermal Growth Factor Receptor (HER) 2-positive/amplified (Cohort 1) and Estrogen Receptor-positive/low HER2 expression (Cohort2).
Two combinations treatments will be evaluated in Cohort 1, the doublet and triplet. Initially zenocutuzumab is given in combination with trastuzumab in the doublet. After the safety of the doublet has been assessed in 4-6 patients, MCLA-128 is given in combination with trastuzumab and vinorelbine in the triplet, in parallel to the efficacy expansion of the doublet.
The doublet and triplet combinations are both evaluated in two steps with an initial safety run-in followed by a cohort efficacy expansion. In total up to 40 patients evaluable for efficacy are included in both the doublet and triplet.
In Cohort 2 zenocutuzumab is administered in combination with the same previous endocrine therapy on which progressive disease is radiologically documented. A total of up to 40 patients evaluable for efficacy are included in the Cohort 2.

Start Date15 Jan 2018

Sponsor / Collaborator

Merus NV

NCT02912949 / RecruitingPhase 2

A Phase I/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients With Solid Tumors (eNRGy)

This is a Phase I/II, open-label, multi-center, multi-national, dose escalation, single agent study to assess the safety, tolerability, PK, PD, immunogenicity and anti-tumor activity of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy)

Start Date01 Jan 2015

Sponsor / Collaborator

Merus NV

100 Clinical Results associated with Zenocutuzumab

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100 Translational Medicine associated with Zenocutuzumab

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100 Patents (Medical) associated with Zenocutuzumab

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22

Literatures (Medical) associated with Zenocutuzumab

31 Dec 2024·mAbs

Antibodies to watch in 2024

Article

Author: Kaplon, Hélène ; Reichert, Janice M. ; Crescioli, Silvia ; Chenoweth, Alicia ; Visweswaraiah, Jyothsna ; Wang, Lin

The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.

06 Jun 2024·Future Oncology

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions

Article

Author: Neuzillet, Cindy ; Ford, Jim ; Wesseler, Claas ; Nishino, Kazumi ; Goto, Koichi ; Springfeld, Christoph ; Macarulla, Teresa ; Joe, Andrew ; Liu, Stephen V ; Al Hallak, Mohammed Najeeb ; Umemoto, Kumiko ; Cleary, James M ; Hollebecque, Antoine ; Duruisseaux, Michaël ; Jauhari, Shekeab ; Rha, Sun Young ; Schram, Alison M ; Kim, Dong-Wan

Neuregulin 1 ( NRG1) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a ‘Dock & Block®’ mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

17 Aug 2023·The journal of physical chemistry letters

Zeno and Anti-Zeno Effects in Nonadiabatic Molecular Dynamics.

Article

Author: Gumber, Shriya ; Prezhdo, Oleg V

Decoherence plays an important role in nonadiabatic (NA) molecular dynamics (MD) simulations because it provides a physical mechanism for trajectory hopping and can alter transition rates by orders of magnitude. Generally, decoherence effects slow quantum transitions, as exemplified by the quantum Zeno effect: in the limit of infinitely fast decoherence, the transitions stop. If the measurements are not sufficiently frequent, an opposite quantum anti-Zeno effect occurs, in which the transitions are accelerated with faster decoherence. Using two common NA-MD approaches, fewest switches surface hopping and decoherence-induced surface hopping, combined with analytic examination, we demonstrate that including decoherence into NA-MD slows down NA transitions; however, many realistic systems operate in the anti-Zeno regime. Therefore, it is important that NA-MD methods describe both Zeno and anti-Zeno effects. Numerical simulations of charge trapping and relaxation in graphitic carbon nitride suggest that time-dependent NA Hamiltonians encountered in realistic systems produce robust results with respect to errors in the decoherence time, a favorable feature for NA-MD simulations.

60

News (Medical) associated with Zenocutuzumab

05 Nov 2024

·endpts.com

Syndax inks a $350M royalty deal; FDA pushes back decision on Organon’s eczema drug

Plus, news about Merus, Supernus and Verrica: Syndax Pharmaceuticals’ $350M deal with Royalty Pharma: The agreement is based on US sales of Niktimvo, Syndax’s graft-versus-host disease treatment. Syndax got the upfront payment in exchange for a 13.8% royalty on US sales of the drug. Syndax CEO Michael Metzger said the agreement will “fund us through profitability, while ensuring that we continue to participate in the profits from Niktimvo and retain the upside of its future growth.” — Katherine Lewin FDA delays decision on Organon’s eczema drug: The agency extended its decision on Organon’s Vtama cream by three months after receiving the final datasets it had requested. The company said the FDA has not raised any concerns about the drug’s safety or efficacy and is now due to make a decision by March 12. Its shares $OGN fell about 4% on Tuesday morning. — Ayisha Sharma Merus also announces FDA delay: The FDA has pushed back the company’s PDUFA date for zenocutuzumab to Feb. 4. The drug is being studied in non-small cell lung and pancreatic cancer, and Merus presented data at ESMO last year. — Max Gelman Supernus resubmits Parkinson’s drug: The company said the FDA accepted the resubmission back in August and has set a new PDUFA date of Feb. 1. The program, called SPN-830, was rejected for a second time this past April. — Max Gelman Verrica shuffles exec team, mulls options: The West Chester, PA-based biotech is “exploring strategies” to help strengthen its balance sheet after restructuring its sales and operating teams last month in an effort to cut costs. Jayson Rieger joined the company as CEO while John Kirby is stepping in as interim CFO. Its stock $VRCA was down about 39% on Tuesday morning. — Ayisha Sharma

Executive Change

05 Nov 2024

·firstwordpharma.com

Merus must wait for maiden FDA approval as decision on lung, pancreatic cancer drug delayed

Merus is facing a delay in securing approval of its first Biclonic product after the FDA extended its review of zenocutuzumab to Feb. 4, 2025. The company said Tuesday that the extension will give the agency more time to assess recently submitted information in response to a request around the chemistry, manufacturing and controls (CMC) component of the application.The filing is seeking approval of zenocutuzumab — a bispecific antibody designed to inhibit the neuregulin/HER3 tumour-signalling pathway — in patients with neuregulin 1 fusion (NRG1)-positive non–small-cell lung (NSCLC) and pancreatic cancer. The FDA accepted the submission earlier this year, granting it priority review.Merus indicated on Tuesday that the FDA has not asked for additional clinical data on zenocutuzumab. The submission is based on data from the Phase I/II eNRGy trial, with interim results announced last year demonstrating overall response rates of 37% in NSCLC patients and 42% in those with pancreatic cancer.Awaiting partnerDespite likely being Merus' first product to gain approval, the pharma is hoping to secure a commercialisation partner for zenocutuzumab so it can concentrate on its next-most advanced Biclonic, petosemtamab — a bispecific antibody that targets EGFR and leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5).As recently noted by analysts at BMO Capital Markets, "the commercial opportunity [for zenocutuzumab] is modest and the money needed to build out a commercial infrastructure is better allocated to [petosemtamab] development."

Priority ReviewAccelerated ApprovalDrug Approval

05 Nov 2024

·www.pharmamanufacturing.com

FDA extends review deadline for Merus’ cancer treatment

The FDA has extended the Prescription Drug User Fee Act (PDUFA) goal date for Merus N.V.’s zenocutuzumab (Zeno) Biologics License Application (BLA), pushing the decision to February 4, 2025. The delay will allow the FDA additional time to assess recent information submitted by Merus regarding chemistry, manufacturing, and controls (CMC) for Zeno, a treatment under priority review targeting NRG1+ cancers. The FDA did not request any additional clinical data concerning this extension. Merus, headquartered in Utrecht, Netherlands, and Cambridge, Massachusetts, specializes in developing bispecific and trispecific antibody therapeutics, known as Multiclonics. These therapies, engineered to perform like traditional human monoclonal antibodies, have shown promise for durable therapeutic effects with minimal immunogenicity.

Priority Review

100 Deals associated with Zenocutuzumab

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External Link

KEGG	Wiki	ATC	Drug Bank
D11991	-	-	DB15559

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
NRG1 Fusion Positive non-small cell lung cancer	NDA/BLA	US	Merus NV	06 May 2024
NRG1 Fusion Positive Pancreatic Cancer	NDA/BLA	US	Merus NV	06 May 2024
NRG1 Fusion Positive Solid Tumors	Phase 2	CA	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	ES	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	FR	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	NO	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	IL	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	SG	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	IT	Merus NV	01 Jan 2015
NRG1 Fusion Positive Solid Tumors	Phase 2	US	Merus NV	01 Jan 2015

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Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03321981 (CTgov)	Phase 2	HER2 Positive Breast Cancer \| Metastatic breast cancer \| ER Positive/HER2 Low Breast Cancer	105	Zenocutuzumab+Trastuzumab (Cohort 1 Doublet)	rwljjzzaza(uncafgofmz) = dzfyyenbdj mmsfipfbco (pqrsiaktlw, iorqhkfwce - ooddtqztit) View more	-	07 Mar 2024
NCT03321981 (CTgov)	Phase 2		105	Zenocutuzumab+Trastuzumab+Vinorelbine (Cohort 1 Triplet)	rwljjzzaza(uncafgofmz) = gpktkezabv mmsfipfbco (pqrsiaktlw, zqdammafpt - czyditkrid) View more	-	07 Mar 2024
NCT02912949 (ESMO_ASIA2023) Manual	Phase 2	NRG1 Fusion Positive non-small cell lung cancer	85	Zenocutuzumab	(fddeszfuap) = pmtedyyope hknmqrxnyx (fyuiwhhcig, 23 - 47) View more	Positive	02 Dec 2023
NCT02912949 (eNRGy, ESMO2023) Manual	Phase 2	NRG1 Fusion Positive Pancreatic Cancer NRG1 fusion positive	38	Zenocutuzumab	(mdvnptgzuq) = wticcakkkk acqtmvszfl (eexopysgnp, 26 - 65) View more	Positive	23 Oct 2023
NCT02912949 (eNRGy, ASCO2022)	Phase 2	NRG1 Fusion Positive Solid Tumors	99	Zenocutuzumab (MCLA-128)	(iietwatnil) = klhltmfbjj jqfinwctgg (ipcralnalk, 25 - 44) View more	Positive	02 Jun 2022
ASCO2022	Phase 3	Advanced breast cancer	-	Margetuximab	(uvbyekcefb) = these therapies are generally well tolerated with manageable side effects as listed in the table. helkkpbehc (wcupyyrjtr ) View more	Positive	02 Jun 2022
ASCO2022	Phase 3	Advanced breast cancer	-	Trastuzumab		Positive	02 Jun 2022
NCT03321981 (Corporate Publications) Manual	Phase 2	Metastatic human epidermal growth factor 2 positive carcinoma of breast HER2 Positive \| HER2 Amplification	39	trastuzumab+vinorelbine+MCLA-128	(icvclsacgy) = wtlwaibcct htgjoblisk (adkblkjwui, 34 - 63) View more	Positive	10 Dec 2021
NCT02912949 (ASCO2021) Manual	Phase 2	Solid tumor \| Pancreatic Cancer NRG1 Positive	51	zenocutuzumab 750 mg	(zbhlvraxjv) = dvzpfybzhf dmeamfzank (jpeionvlst, 15 - 70) View more	Positive	20 May 2021
NCT03321981 (ASCO2020) Manual	Phase 2	Metastatic breast cancer ER positive \| HER2 Low Expression	48	endocrine therapy+zenocutuzumab	(qpknupvjlw) = opjdbdgmix qzmbxeqnnn (ilbutfpdgg, 32 - 59)	Positive	29 May 2020
NCT03321981 (ASCO2020)	Phase 2	Metastatic breast cancer	28	MCLA-128 (750 mg, 2h IV) + trastuzumab (8 mg/kg loading, then 6 mg/kg) + vinorelbine (25 mg/m², D1 and 8), q3w	(rijbeegwhu) = No clinically significant LVEF decline was seen wcqpqtdrqk (xdkgsgptmp ) View more	Positive	25 May 2020
NCT02912949 (ASCO2017)	Phase 1/2	Metastatic human epidermal growth factor 2 positive carcinoma of breast	28	MCLA-128	(jwkjvnqhhm) = G1-2 diarrhea in 2 pts each (13%) ahhjfzitux (qqzcjowfsu ) View more	Positive	30 May 2017