Delving into the Latest Updates on Xevinapant with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Iap inhibitor at-406, SMAC mimetic, AT 406

+ [5]

Target

IAP x XIAP x cIAP1 x cIAP1/cIAP2

Action

inhibitors, inducers

Mechanism

Inhibitors of apoptosis (IAP) protein family inhibitors, XIAP inhibitors(Inhibitor of apoptosis protein 3 inhibitors), cIAP1 inhibitors(Cellular inhibitor of apoptosis protein 1 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesEndocrinology and Metabolic Disease+ [2]

Active Indication

Head and Neck NeoplasmsLymphomaOvarian Epithelial Carcinoma

Inactive Indication

Acute Myeloid LeukemiaAdvanced Malignant Solid NeoplasmColonic Cancer+ [17]

Originator Organization

ASCENTA

Active Organization

Debiopharm International SAASCENTA

University of Michigan College of Engineering

Inactive Organization

Merck KGaA

Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.EMD Serono Research & Development Institute, Inc.

+ [4]

License Organization

Merck KGaA

Ascentage Pharma Group International Co., Ltd.

Debiopharm International SA

+ [1]

Drug Highest PhasePhase 3

First Approval Date-

RegulationBreakthrough Therapy (United States)

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Structure/Sequence

Molecular FormulaC32H44ClN5O4

InChIKeyDBXTZCYPHKJCHF-ZZPLZQMBSA-N

CAS Registry1071992-57-8

Researchers will investigate the ability of Xevinapant to cross the blood-brain barrier and exert anti-tumor effects on rHGG through activation of apoptosis. Researchers hypothesize that oral administration of Xevinapant has acceptable safety and tolerability in patients with recurrent HGG and demonstrate pharmacokinetic and pharmacodynamic effects in HGG tumors. To that end, Researchers will engage in a phase I "window of opportunity" translational clinical trial in patients undergoing a clinically-indicated craniotomy for resection of recurrent tumors to evaluate the impact of treatment on rHGG.

Start Date22 Jul 2024

Sponsor / Collaborator

H. Lee Moffitt Cancer Center & Research Institute, Inc.

[+1]

NCT06084845

/ WithdrawnPhase 2IIT

Phase II Trial of Xevinapant and Chemoradiotherapy in Adjuvant Treatment for Patients With Head and Neck Squamous Cell Carcinoma With High Risk Pathologic Features

This phase II trial compares the effect of usual radiation therapy with cisplatin/carboplatin (chemoradiation) to the addition of xevinapant with chemoradiation in patients with head and neck cancer. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Xevinapant is a first-in-class antagonist of inhibitor of apoptosis (programmed cell death) proteins (IAPs), which leads to tumor cell death and enhances tumor cell sensitivity to chemotherapy and radiotherapy. Giving xevinapant with chemoradiation may be more effective in preventing head and neck cancer from growing or spreading than chemoradiation alone.

Start Date12 Apr 2024

Sponsor / Collaborator

ECOG-ACRIN Medical Research Foundation, Inc.

[+1]

NCT06110195

/ Active, not recruitingPhase 1IIT

A Phase I Study of Xevinapant With Radiation and Concurrent Carboplatin and Paclitaxel in Patients Ineligible for Cisplatin With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck

The goal of this clinical trial is to determine the best safe dose of xevinapant that can be given in combination with chemotherapy and radiation in patients with head and neck cancer. Up to 4 doses of xevinapant will be tested in the dose escalation portion of the study. After the best safe dose is found during escalation, an additional group of participants will be enrolled at that dose to learn more about the treatment combination (dose expansion).
The main question[s] it aims to answer are:
* what is the maximum safe dose that can be given
* what dose should be used in subsequent (phase 2) trials
Participants will receive xevinapant in combination with paclitaxel and carboplatin chemotherapy and radiation. Treatment will be given in 3-week cycles for 3 cycles.

Start Date24 Jan 2024

Sponsor / Collaborator

The University of Chicago

[+1]

100 Clinical Results associated with Xevinapant

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100 Translational Medicine associated with Xevinapant

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100 Patents (Medical) associated with Xevinapant

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258

Literatures (Medical) associated with Xevinapant

01 Nov 2025·EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

IFN-γ enhances Poly(I:C)-induced necroptosis and immunogenic cell death via TLR3 upregulation in cholangiocarcinoma cells

Article

Author: Sae-Fung, Apiwit ; Jitkaew, Siriporn ; Lomphithak, Thanpisit ; Duangthim, Nattaya

Cholangiocarcinoma (CCA), a heterogeneous tumor arising in the bile ducts, is associated with unfavorable prognosis and high mortality rates due to limited effective treatment options. Though promising, immunotherapy is hindered by CCA's desmoplastic tumor microenvironment, known for its inflammatory and immunosuppressive characteristics, often termed a "cold tumor". Previously, we reported that Poly(I:C), a TLR3 agonist, synergizes with a Smac mimetic, an IAP antagonist, to trigger necroptosis when caspase activity is blocked. In this study, we aimed to evaluate rational combination strategies to advance Poly(I:C)-based necroptosis immunotherapy in preclinical models. Transcriptomic analysis of public CCA patient datasets revealed that low expression of TLR3, accompanied by low IFNG or IRF1 expression, is significantly associated with poorer prognosis. These findings highlight the clinical relevance of the IFN-γ/IRF1/TLR3 axis and support the development of therapies targeting this pathway. We further found that IFN-γ treatment increases TLR3 expression. Importantly, we demonstrated that IFN-γ could enhance Poly(I:C)-induced necroptosis and immunogenic cell death (ICD) when IAPs and caspases are inhibited by Smac mimetic and the pan-caspase inhibitor Z-VAD-FMK in human CCA cell lines. CU-CPT 4a, a highly selective TLR3 inhibitor, partially reduced this cell death. This indicates that the effect is mediated in part through TLR3. The combined effects were shown to depend on RIPK1/RIPK3/MLKL-induced necroptosis. Additionally, the dying cells released HMGB1, a marker of ICD, and their conditioned medium promoted dendritic cell maturation (CD80, CD86, HLA-DR), which is critical for antigen presentation and T-cell priming. From a personalized medicine perspective, TLR3, IFNG, and IRF1 expression levels may serve as predictive biomarkers to guide patient selection for TLR3 agonist-based therapies. These findings could advance TLR3 ligand, Poly(I:C)-based necroptosis cancer immunotherapy, alone or with immune checkpoint inhibitors, for CCA and possibly other cancers.

26 Sep 2025·JOURNAL OF ORGANIC CHEMISTRY

Synthesis of the 1,5-Diazabicyclo[6.3.0]dodecane Core Structure of Xevinapant

Article

Author: Ren, Yingzhi ; Yu, Shouyun ; Zeng, Guixiang ; Wang, Bohao ; Zhou, Bugao ; Zhai, Shen ; Li, Chen

Inhibitors of apoptosis proteins (IAPs) are key targets in cancer therapy due to their role in promoting cancer cell survival. The second mitochondria-derived activator of caspases (SMAC) mimetics, which antagonize IAPs, have shown therapeutic potential for cancers. 1,5-Diazabicyclo[6.3.0]dodecanone amino acid scaffold serves as an important scaffold for developing SMAC mimetics, including clinical candidates like Xevinapant and Dasminapant. Herein, we report a novel, efficient, and potentially scalable synthesis of the core structure of Xevinapant achieved in 7 steps from a pyroglutamic acid derivative, with an overall yield of 8.4%, facilitating further development of IAP inhibitors.

01 Aug 2025·INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

BRD4 inhibition ameliorates aberrant mechanical stress-induced temporomandibular joint osteoarthritis through modulating MLKL and necroptosis

Article

Author: Huang, Ziwei ; Han, Miaomiao ; Zhang, Jinglun ; Li, Huang ; Zhu, Mengjiao ; Zhang, Caixia ; Ren, Yang ; Ren, Jiangyan

This study aimed to investigate the role and underlying mechanisms of BRD4 in temporomandibular joint osteoarthritis (TMJOA) and to evaluate the therapeutic potential of its inhibitor, JQ1. A rat model of TMJOA was established through mechanical stress induction, and the protective effects of BRD4 inhibition were assessed via intra-articular injection of JQ1. In vitro, a chondrocyte necroptosis model was induced using TNF-α, Smac mimetic, and z-VAD-FMK (TSZ). Cell viability and necroptosis were evaluated using CCK-8, LDH release assays, flow cytometry, and immunofluorescence staining. BRD4 expression was notably upregulated in TMJ tissues subjected to aberrant mechanical stress. Inhibition of BRD4 by JQ1 exerted a protective effect and attenuated TMJOA progression. Mechanistically, BRD4 was found to regulate chondrocyte necroptosis and showed a positive correlation with the expression of RIP3 and MLKL. Chromatin immunoprecipitation revealed BRD4 enrichment at the MLKL promoter region. Both BRD4 knockdown and JQ1 treatment markedly reduced chondrocyte death and downregulated the expression of TNF-α, RIP3, MLKL, and p-MLKL. In summary, BRD4 overexpression contributes to the pathogenesis of TMJOA. Inhibition of BRD4 suppresses MLKL expression, thereby reducing chondrocyte necroptosis and alleviating TMJOA-associated pathological changes. These findings suggest that JQ1 and other BRD4-targeting strategies may represent promising therapeutic approaches for TMJOA.

96

News (Medical) associated with Xevinapant

28 Apr 2025

·pharma.economictimes.indiatimes.com

Germany's Merck KGaA in $3.9 billion deal to buy US biotech firm SpringWorks

Frankfurt: Merck KGaA has struck a deal to buy U.S. biotech company SpringWorks Therapeutics for an equity value of $3.9 billion, as the German company seeks to acquire treatments for rare tumours to boost its cancer drugs business. The family-controlled company said in a statement on Monday the purchase price of $47 per share in cash represents an equity value of about $3.9 billion, equivalent to an enterprise value of $3.4 billion (3.0 billion euros), when SpringWorks' cash holdings are deducted. The deal is one of the largest in years for Merck, but its price tag was 22 per cent lower than the about $60 per share analysts had expected after a Reuters report on February 10 that the companies were in advanced talks. Merck on April 24 lowered price expectations, saying the two companies were in late-stage discussions over a bid of around $47 per SpringWorks share. Merck's shares were down 0.4 per cent in early trade, underperforming the broader German stock market. The deal will be funded with available cash and new debt. It is expected to be accretive to Merck's earnings per share, adjusted for special items, in 2027, said a statement from the German group, based in Darmstadt, near Frankfurt. It added it would still be able to pursue larger transactions. Stamford, Connecticut-based SpringWorks, which listed its shares in New York in 2019, develops drugs to treat cancer and rare types of tumour. It has two products on the market: Ogsiveo with 2024 sales of $172 million to treat desmoid tumours, an aggressive disease affecting soft tissue, as well as Gomekli, which was approved in February to treat NF1-PN, characterised by nerve sheath tumours. "We have the unique opportunity with SpringWorks to establish a leadership position in rare tumours and build a strong foundation for further investments in this area," Peter Guenter, head of healthcare at Merck, said. The transaction will likely close during the second half of 2025, subject to approval of SpringWorks' shareholders and regulatory clearance, Merck added. TRUMP DISRUPTION JP Morgan analyst Anupam Rama previously said the lack of other serious bidders and the challenging macroeconomic environment had probably lowered the valuation. This year had been expected to be stellar for mergers and acqusitions in the sector until the disruption caused by U.S. President Donald Trump's policies, including massive layoffs at the U.S. Food and Drug Administration. That has brought uncertainty to the drug approval process, hampering projected drug sales and affecting valuations. Merck is particularly keen to strengthen its drug development pipeline after high-profile setbacks in late-stage drug trials, including a decision last year to halt development of head and neck cancer drug Xevinapant. A major trial testing multiple sclerosis drug Evobrutinib failed in December 2023. In 2015, the company agreed to buy U.S. lab equipment supplier Sigma-Aldrich for $17 billion, its biggest deal to date. In 2019, Merck acquired U.S. electronics materials manufacturer Versum for around $6.5 billion. (Reporting by Ludwig Burger, Emma-Victoria Farr in Frankfurt and Sabrina Valle in New York; Editing by Kirsten Donovan and Barbara Lewis)

AcquisitionDrug Approval

28 Apr 2025

·pharma.economictimes.indiatimes.com

Germany's Merck KGaA in $3.9 billion deal to buy US biotech firm SpringWorks

Frankfurt: Merck KGaA has struck a deal to buy U.S. biotech company SpringWorks Therapeutics for an equity value of $3.9 billion, as the German company seeks to acquire treatments for rare tumours to boost its cancer drugs business. The family-controlled company said in a statement on Monday the purchase price of $47 per share in cash represents an equity value of about $3.9 billion, equivalent to an enterprise value of $3.4 billion (3.0 billion euros), when SpringWorks' cash holdings are deducted. The deal is one of the largest in years for Merck, but its price tag was 22 per cent lower than the about $60 per share analysts had expected after a Reuters report on February 10 that the companies were in advanced talks. Merck on April 24 lowered price expectations, saying the two companies were in late-stage discussions over a bid of around $47 per SpringWorks share. Merck's shares were down 0.4 per cent in early trade, underperforming the broader German stock market. The deal will be funded with available cash and new debt. It is expected to be accretive to Merck's earnings per share, adjusted for special items, in 2027, said a statement from the German group, based in Darmstadt, near Frankfurt. It added it would still be able to pursue larger transactions. Stamford, Connecticut-based SpringWorks, which listed its shares in New York in 2019, develops drugs to treat cancer and rare types of tumour. It has two products on the market: Ogsiveo with 2024 sales of $172 million to treat desmoid tumours, an aggressive disease affecting soft tissue, as well as Gomekli, which was approved in February to treat NF1-PN, characterised by nerve sheath tumours. "We have the unique opportunity with SpringWorks to establish a leadership position in rare tumours and build a strong foundation for further investments in this area," Peter Guenter, head of healthcare at Merck, said. The transaction will likely close during the second half of 2025, subject to approval of SpringWorks' shareholders and regulatory clearance, Merck added. TRUMP DISRUPTION JP Morgan analyst Anupam Rama previously said the lack of other serious bidders and the challenging macroeconomic environment had probably lowered the valuation. This year had been expected to be stellar for mergers and acqusitions in the sector until the disruption caused by U.S. President Donald Trump's policies, including massive layoffs at the U.S. Food and Drug Administration. That has brought uncertainty to the drug approval process, hampering projected drug sales and affecting valuations. Merck is particularly keen to strengthen its drug development pipeline after high-profile setbacks in late-stage drug trials, including a decision last year to halt development of head and neck cancer drug Xevinapant. A major trial testing multiple sclerosis drug Evobrutinib failed in December 2023. In 2015, the company agreed to buy U.S. lab equipment supplier Sigma-Aldrich for $17 billion, its biggest deal to date. In 2019, Merck acquired U.S. electronics materials manufacturer Versum for around $6.5 billion. (Reporting by Ludwig Burger, Emma-Victoria Farr in Frankfurt and Sabrina Valle in New York; Editing by Kirsten Donovan and Barbara Lewis)

AcquisitionDrug Approval

25 Apr 2025

·pharma.economictimes.indiatimes.com

Germany's Merck says in late-stage discussions to buy SpringWorks for $3.5 billion

Bengaluru: Germany's Merck KGaA said on Thursday it is in late-stage talks to acquire U.S.-based SpringWorks Therapeutics for about $3.5 billion, a deal that could give it access to a recently approved rare disease drug and expand its portfolio of experimental cancer treatments . Merck said that the companies are in discussions on the basis of a price of around $47 per share, which gives a valuation of roughly $3.5 billion, according to Reuters calculations. No final decision has been taken and no legally binding agreement has been entered into, Merck said in a statement. The SpringWorks acquisition would rank as one of the biggest pharma deals for the German healthcare and technology group in recent years, boosting its ongoing efforts to build out its cancer treatment pipeline. In 2015, Merck agreed to buy U.S. lab equipment supplier Sigma-Aldrich for $17 billion. Reuters reported in February that the companies were in advanced talks, which Merck subsequently confirmed. SpringWorks' shares have fallen 17% since then. Shares of SpringWorks settled 9 per cent higher at close, after the Wall Street Journal first reported that Merck is nearing a deal, which could be completed as soon as Monday. The stock was trading closer to $60 in February. SpringWorks, which has a market value of more than $3 billion, did not respond to a Reuters request for comment. The deal could accelerate growth in Merck, particularly as sales of its cancer drug Bavencio slow and multiple sclerosis treatment Mavenclad faces loss of exclusivity, said Barclays analyst Emily Field. The Connecticut-based drugmaker, which went public in 2019, focuses on developing drugs to treat several rare cancers and genetic disorders. Its monotherapy, Ogsiveo , has been approved in the U.S. to treat desmoid tumours - abnormal growth that occurs in connective tissues. In February, the U.S. health regulator approved SpringWorks' genetic disorder drug Gomekli . Merck has recently suffered high-profile setbacks in late-stage drug trials, prompting it to halt development of its head and neck cancer drug xevinapant. A major trial testing multiple sclerosis drug evobrutinib failed in December 2023. (Reporting by Sriparna Roy and Christy Santhosh in Bengaluru, and Sabrina Valle in New York; Editing by Alan Barona)

AcquisitionDrug Approval

100 Deals associated with Xevinapant

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16305

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Squamous Cell Carcinoma of Head and Neck	Phase 3	China	Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.	06 Oct 2022
Squamous Cell Carcinoma of Head and Neck	Phase 3	Taiwan Province	Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.	06 Oct 2022
Head and Neck Neoplasms	Phase 3	United States	Debiopharm International SA	30 Jan 2022
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	United States	Merck KGaA	07 Aug 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	China	Merck KGaA	07 Aug 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	Japan	Merck KGaA	07 Aug 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	Argentina	Merck KGaA	07 Aug 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	Australia	Merck KGaA	07 Aug 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	Austria	Merck KGaA	07 Aug 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	Belgium	Merck KGaA	07 Aug 2020

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT06056310 (CTgov)	Phase 1	Oropharyngeal Neoplasms \| Locally Advanced Head and Neck Squamous Cell Carcinoma \| Head and Neck Neoplasms	18	Cisplatin+Xevinapant	xtuvvdukgb = pbksfkdmgu ihejzxmspz (khebrmurbe, mqcvbldmmn - ruauqbptsh) View more	-	29 Sep 2025
NCT05519540 (CTgov)	Phase 1	-	24	Xevinapant (Debio 1143) (Group 1: Japanese Participants: Xevinapant (Debio 1143))	nejqauivnx(ebudjresyr) = muwmnpcsbo xqxmkgfszd (gdrcqyiypc, 34.6) View more	-	20 Aug 2025
				Xevinapant (Debio 1143) (Group 2: Non-Japanese East Asian Participants: Xevinapant (Debio 1143))	nejqauivnx(ebudjresyr) = uyircqopne xqxmkgfszd (gdrcqyiypc, 21.4) View more
NCT03270176 (Phase Ib study, Pubmed \| Ther Adv Med Oncol)	Phase 1	Advanced Lung Non-Small Cell Carcinoma plasma IL-10 \| IL-1β \| IL-13 ... View more	-	Xevinapant RP2D + Avelumab	iwyutyshxn(agcwrcmmyf) = n = 13 (34.2%) llzxltmbej (nbnalecsas ) View more	Negative	01 May 2025
NCT04459715 (TrilynX, BusinessWire) Manual	Phase 3	Locally Advanced Head and Neck Squamous Cell Carcinoma	-	xevinapant + CRT	njfcwqadqg(vsziaurloa) = the trial would be unlikely to meet its primary objective of prolonging event-free survival. ejxirvbnpf (rvurqfdihk ) Not Met	Negative	24 Jun 2024
NCT02022098 (ASCO2024) Manual	Phase 2	Squamous Cell Carcinoma of Head and Neck	96	Xevinapant + CRT	tekucmdnaf(rbcfmqgpca) = xzmcffjdap gbqplrnirr (buolybficx ) View more	Positive	24 May 2024
				Placebo + CRT	tekucmdnaf(rbcfmqgpca) = ydugdijqci gbqplrnirr (buolybficx ) View more
NCT04122625 (SMARTPLUS-106, CTgov)	Phase 1/2	Female Genital Neoplasms \| Primary peritoneal carcinoma \| Solid tumor ... View more	46	Nivolumab+Debio 1143 (Part A - Debio 1143 150 mg + Nivolumab)	riwqqttpht = obcuzsvsot chfkmrcoed (nokhqmiula, jpzgciesnt - knwpppqsox) View more	-	12 Jun 2023
				Nivolumab+Debio 1143 (Part A - Debio 1143 200 mg + Nivolumab)	riwqqttpht = aczktpoxro chfkmrcoed (nokhqmiula, daoqolvuff - dffdehhwgj) View more
AACR2023 Manual	Phase 1	Non-Small Cell Lung Cancer	38	xevinapant 200 mg/day+avelumab 10 mg/kg	mxoblqrumc(nppumcgitp) = xjsavmenxr mbglgzvmos (rumcldnsom, 2.9 - 24.8) View more	Negative	14 Apr 2023
NCT02022098 (Pubmed)	Phase 2	Locally Advanced Head and Neck Squamous Cell Carcinoma	96	Xevinapant 200 mg/day	fyahaaehgy(envuacdfxd) = tdieqnnobx bbemuspnkv (nvbqskueee, 40.3 - not evaluable)	Positive	01 Apr 2023
				Placebo	fyahaaehgy(envuacdfxd) = wvdjwfnmio bbemuspnkv (nvbqskueee, 21.8 - 46.7)
NCT02022098 (Trilynx, ESMO2022) Manual	Phase 2	Locally Advanced Head and Neck Squamous Cell Carcinoma HPV Positive	96	Xevinapant 200 mg+CRT	rvgeeqsasx(gfexfhjqvs) = sepiyimemq vxfsifxcjo (vxxpalowln, 37 - 66) View more	Positive	10 Sep 2022
				Placebo + CRT	rvgeeqsasx(gfexfhjqvs) = cmyivdyond vxfsifxcjo (vxxpalowln, 15 - 42) View more
NCT03871959 (CATRIPCA, ESMO2022) Manual	Phase 1	Colorectal Cancer \| Metastatic Pancreatic Ductal Adenocarcinoma MSI-Low	13	Pembrolizumab+Xevinapant (Dose escalation cohort)	oxzbkcqecw(nhezlbxjom) = Xevinapant 200mg/d + pembrolizumab 200mg q3w pbjfshvfca (rwoqdxsyai ) View more	Negative	10 Sep 2022
				Pembrolizumab+Xevinapant (PDAC expansion cohort)