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

+ [3]

Target

IAP x XIAP x cIAP1 x cIAP1/cIAP2

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+ [7]

Active Indication

Head and Neck NeoplasmsSquamous Cell Carcinoma of Head and NeckCutaneous Squamous Cell Carcinoma of the Head and Neck+ [9]

Inactive Indication

Acute Myeloid LeukemiaAdvanced Malignant Solid NeoplasmColorectal Cancer+ [5]

Originator Organization

ASCENTA

Active Organization

Merck KGaAEMD Serono Research & Development Institute, Inc.

Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.

+ [7]

Inactive Organization

Farmea

Ascentage Pharma Group International Co., Ltd.

Ascenta Therapeutics, Inc.

+ [1]

Drug Highest PhasePhase 3

First Approval Date-

RegulationBreakthrough Therapy (US)

Structure

Molecular FormulaC32H44ClN5O4

InChIKeyDBXTZCYPHKJCHF-ZZPLZQMBSA-N

CAS Registry1071992-57-8

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 Date01 Jan 2025

Sponsor / Collaborator

The University of Chicago

[+1]

NCT06084845 / Not yet recruitingPhase 2

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]

NCT06056310 / RecruitingPhase 1

A Single Arm, Open Label, Phase 1b Study of Xevinapant in Combination With Weekly Cisplatin and Intensity-modulated Radiotherapy to Assess Safety and Tolerability in Participants With LA SCCHN, Suitable for Definitive Chemoradiotherapy (HyperlynX)

The purpose of this study is to evaluate the tolerability and safety of Xevinapant when added to weekly cisplatin-based concurrent chemoradiotherapy (CRT) in the treatment of participants with unresectable locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy.

Start Date18 Jan 2024

Sponsor / Collaborator

EMD Serono Research & Development Institute, Inc.

[+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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387

Literatures (Medical) associated with Xevinapant

05 Jul 2106·Oncotarget

Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib

Article

Author: Heinrich, Michael ; Corless, Christopher ; Bauer, Sebastian ; Marino-Enriquez, Adrian ; Reis, Anna-Carina ; Podleska, Lars Erik ; Mühlenberg, Thomas ; Fletcher, Jonathan Alfred ; Treckmann, Jürgen ; Grunewald, Susanne ; Falkenhorst, Johanna ; Schuler, Martin

Gastrointestinal stromal tumors (GIST) exhibit a strong oncogenic dependency on KIT and KIT inhibitors confer long lasting disease stabilization in the majority of patients. Nonetheless, KIT inhibition alone does not cure GIST as a subset of GIST cells evade apoptosis and eventually develop resistance. Inhibitors of Apoptosis Proteins (IAPs) may confer resistance to drug-induced apoptosis. We observed that the mRNA and protein of IAPs XIAP (BIRC4) and survivin (BIRC5) were highly expressed in primary GIST tumors and cell line models. Amplification of the respective gene loci (BIRC2, BIRC3, BIRC4, BIRC5) was detected in 47% of GIST studied by SNP arrays. Whole exome analyses revealed a mutation of SMAC(DIABLO) in a heavily pretreated patient. Both, survivin (rank 62-92/11.194 tested proteins) and XIAP (rank 106-557/11.194) were found to be essential proteins for survival in a synthetic lethality screen. Expression of XIAP and survivin decreased upon KIT inhibition and may play a role in KIT-regulated pro-survival signaling. SMAC-mimetic treatment with LCL161 and TL32711 reduced cIAP1 and XIAP expression. Survivin inhibitor YM155 lead to transcriptional repression of BIRC5/survivin (YM155) and induced apoptosis. Combinational treatment with KIT inhibitors (imatinib, regorafenib) enhanced the proapoptotic effect. These findings support the combination of KIT inhibition with IAP antagonists in GIST.

01 Feb 2024·Molecular Metabolism

Sestrin2 maintains hepatic immune homeostasis and redox balance partially via inhibiting RIPK3-mediated necroptosis in metabolic dysfunction-associated steatohepatitis

Article

Author: Lin, Shuang-Zhe ; Zhang, Qian-Ren ; Fan, Jian-Gao ; Jin, Qian ; Zhang, Jian-Bin ; Yang, Jing

BACKGROUND & AIMS:

Necroptosis, a novel type of programmed cell death, is intricately associated with inflammatory response. Currently, most studies focus on the activation of necroptosis, while the mechanisms underlying the negative regulation of necroptosis remain poorly understood.

METHODS:

The effects of sestrin2 (SESN2) overexpression or knockdown on the regulation of necroptosis were assessed in the TNFα/Smac-mimetic/Z-VAD-FMK (T/S/Z)-induced necroptosis model and palmitic acid (PA)-induced lipotoxicity model. Western-blot, co-Immunoprecipitation, Glutathione S-transferase pull-down, and confocal assays were employed to explore the regulatory mechanisms including protein-protein interactions and post-translational modification. Furthermore, we used GSK'872, a specific inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK) 3, to evaluate the relationship between SESN2-related alterations and RIPK3-mediated necroptosis in T/S/Z-induced necroptosis model, PA-induced lipotoxicity model, and high-fat high-cholesterol diet (HFHCD)-induced non-alcoholic steatohepatitis model.

RESULTS:

Our findings revealed that SESN2 was upregulated under conditions that induce necroptosis and functioned as a negative regulator of necroptosis. High levels of SESN2 could equipped hepatocytes with the ability to defend against necroptotic inflammation and oxidative stress. Mechanistically, SESN2 interacted with RIPK3 and tuned down necroptosis by inhibiting the phosphorylation of RIPK3, promoting the ubiquitination of RIPK3, and preventing the formation of the RIPK1/RIPK3 necrosome. The depletion of SESN2 resulted in excessive necroptosis, accompanied by increased fat accumulation, inflammation, and oxidative stress in the experimental steatohepatitis model. Blocking necroptosis by GSK'872 reduced the liberation of pro-inflammatory cytokines and reactive oxygen species generation, but not hepatocyte fat deposition, in both PA-treated SESN2 knockout cells and HFHCD-fed SESN2 knockout mice, suggesting that the activation of RIPK3-mediated necroptosis may partially account for the hyperinflammation and excessive oxidative stress induced by SESN2 deficiency.

CONCLUSION:

Our results suggested that SESN2 inhibited RIPK3-mediated necroptosis; this regulation is an important for the immune homeostasis and the redox balance in the liver.

01 Aug 2024·Mini-Reviews in Medicinal Chemistry

SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects

Article

Author: Bisht, Priya ; Ravichandiran, V ; Murti, Krishna ; Kumar, Nitesh ; Wal, Pranay ; Pandey, Ruchi

Background::

Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades.

Objective::

This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer.

Method::

Articles were analysed using search engines and databases namely Pubmed and Scopus.

Result::

Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation.

Conclusion::

SMAC mimetics acts in a restorative way in the prevention of lung cancer.

63

News (Medical) associated with Xevinapant

06 Dec 2023

·www.prnewswire.com

Medivir to present at the Carlsquare Equity Research Investor Day

STOCKHOLM, Dec. 6, 2023 /PRNewswire/ -- Medivir AB (Nasdaq Stockholm: MVIR), a pharmaceutical company focused on developing innovative treatments for cancer in areas of high unmet medical need, announces that the company will present at the Carlsquare Equity Research Investor Day, today December 6, 2023. CEO Jens Lindberg will present at 14.30 CET, with focus on the latest developments and the company's future plans. This will include, among other things, the company's rights issue and how it aims to ensure the highest possible speed and momentum in the development program for fostrox with the aim of starting a pivotal phase 2b study in 2024. The presentation is live broadcasted and can be followed at the event page; Carlsquare | Investor Day - Life Science - YouTube For additional information, please contact Magnus Christensen, CFO, Medivir AB Telephone: +46 8 5468 3100 E-mail: [email protected] Medivir in brief Medivir develops innovative drugs with a focus on cancer where the unmet medical needs are high. The drug candidates are directed toward indication areas where available therapies are limited or missing and there are great opportunities to offer significant improvements to patients. Medivir is focusing on the development of fostroxacitabine bralpamide (fostrox), a pro-drug designed to selectively treat liver cancer cells and to minimize side effects. Collaborations and partnerships are important parts of Medivir's business model, and the drug development is conducted either by Medivir or in partnership. Birinapant, a SMAC mimetic, is exclusively outlicensed to IGM Biosciences (Nasdaq: IGMS) to be developed in combination with IGM-antibodies for the treatment of solid tumors. Medivir's share (ticker: MVIR) is listed on Nasdaq Stockholm's Small Cap list. . The following files are available for download: SOURCE Medivir

Phase 2

06 Dec 2023

·www.biospace.com

Medivir to present at the Carlsquare Equity Research Investor Day - December 06, 2023

STOCKHOLM, Dec. 6, 2023 /PRNewswire/ -- Medivir AB (Nasdaq Stockholm: MVIR), a pharmaceutical company focused on developing innovative treatments for cancer in areas of high unmet medical need, announces that the company will present at the Carlsquare Equity Research Investor Day, today December 6, 2023. CEO Jens Lindberg will present at 14.30 CET, with focus on the latest developments and the company's future plans. This will include, among other things, the company's rights issue and how it aims to ensure the highest possible speed and momentum in the development program for fostrox with the aim of starting a pivotal phase 2b study in 2024. The presentation is live broadcasted and can be followed at the event page; Carlsquare | Investor Day - Life Science - YouTube For additional information, please contact Magnus Christensen, CFO, Medivir AB Telephone: +46 8 5468 3100 E-mail: magnus.christensen@medivir.com Medivir in brief Medivir develops innovative drugs with a focus on cancer where the unmet medical needs are high. The drug candidates are directed toward indication areas where available therapies are limited or missing and there are great opportunities to offer significant improvements to patients. Medivir is focusing on the development of fostroxacitabine bralpamide (fostrox), a pro-drug designed to selectively treat liver cancer cells and to minimize side effects. Collaborations and partnerships are important parts of Medivir's business model, and the drug development is conducted either by Medivir or in partnership. Birinapant, a SMAC mimetic, is exclusively outlicensed to IGM Biosciences (Nasdaq: IGMS) to be developed in combination with IGM-antibodies for the treatment of solid tumors. Medivir's share (ticker: MVIR) is listed on Nasdaq Stockholm's Small Cap list. . The following files are available for download: View original content: SOURCE Medivir Company Codes: Bloomberg:MVIR@SS, ISIN:SE0020181014, RICS:MVIR.ST, Stockholm:MVIR

Phase 2

01 Dec 2023

·www.prnewswire.com

Bulletin from Extraordinary General Meeting in Medivir AB (publ)

STOCKHOLM, Dec. 1, 2023 /PRNewswire/ -- Today on 1 December 2023, Medivir AB (publ) (the "Company") held an extraordinary general meeting in Stockholm, whereby the resolution below was adopted. The general meeting was held at Helio GT30 on Grev Turegatan 30 in Stockholm. For more detailed information on the content of the resolution, please see the complete notice of the extraordinary general meeting that is available on the Company's website, . Minutes from the extraordinary general meeting will be provided on the said website within two weeks from the day of the meeting. The general meeting's subsequent approval of the board of directors' resolution on 7 November 2023 on issue of new common shares with preferential rights for existing shareholders The general meeting resolved to approve the board of directors' resolution on a rights issue which was resolved on by the board of directors on 7 November 2023. The rights issue includes an issue of new shares of not more than 55,841,401 new common shares which entails an increase of the Company's share capital with not more than SEK 27,920,700.50. The right to subscribe for new common shares shall belong to those persons who on the record date for the new issue of shares are recorded as shareholders of the Company, where one (1) existing share shall entitle to one (1) new common share, corresponding to a subscription ratio of 1:1.1 Should all new shares not be subscribed based on subscription rights, the board of directors shall resolve on the allocation of new shares without subscription rights according to certain principles described in the notice to the general meeting, where allocation may ultimately be made to those who have entered into guarantee commitments. The new shares are issued at a subscription price of SEK 2.65 per share. The record date for participation in the new issue is on 5 December 2023. The resolution by the general meeting was adopted with the required majority. Preliminary time table of the rights issue: 1 Shares held by the Company do not entitle to participation in the rights issue. For additional information, please contact; Magnus Christensen, CFO Telephone: +46 8 5468 3100 E-mail: [email protected] Medivir in brief Medivir develops innovative drugs with a focus on cancer where the unmet medical needs are high. The drug candidates are directed toward indication areas where available therapies are limited or missing and there are great opportunities to offer significant improvements to patients. Medivir is focusing on the development of fostroxacitabine bralpamide (fostrox), a pro-drug designed to selectively treat liver cancer cells and to minimize side effects. Collaborations and partnerships are important parts of Medivir's business model, and the drug development is conducted either by Medivir or in partnership. Birinapant, a SMAC mimetic, is exclusively outlicensed to IGM Biosciences (Nasdaq: IGMS) to be developed in combination with IGM-antibodies for the treatment of solid tumors. Medivir's share (ticker: MVIR) is listed on Nasdaq Stockholm's Small Cap list. . The following files are available for download: SOURCE Medivir

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
Head and Neck Neoplasms	Phase 3	US	Debiopharm International SA	30 Jan 2022
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	CN	Farmea	02 Dec 2021
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	CN	Debiopharm International SA	02 Dec 2021
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 3	CN	Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.	02 Dec 2021
Squamous Cell Carcinoma of Head and Neck	Phase 3	US	EMD Serono Research & Development Institute, Inc.	07 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 3	CN	EMD Serono Research & Development Institute, Inc.	07 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 3	JP	EMD Serono Research & Development Institute, Inc.	07 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 3	AR	EMD Serono Research & Development Institute, Inc.	07 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 3	AU	EMD Serono Research & Development Institute, Inc.	07 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 3	AT	EMD Serono Research & Development Institute, Inc.	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


NCT04122625 (CTgov)	Phase 1/2	Solid tumor	46	nivolumab+Debio 1143 (Part A - Debio 1143 150 mg + Nivolumab)	wrvyiancwd(ydpofwtotp) = dyvzhrepok hvbnhajmwy (jsrpyvdkim, bdfpwktqpc - bzgdjgdnic) View more	-	12 Jun 2023
				nivolumab+Debio 1143 (Part A - Debio 1143 200 mg + Nivolumab)	wrvyiancwd(ydpofwtotp) = nxzbmcgnob hvbnhajmwy (jsrpyvdkim, dktbjaprsm - duukfsjsjn) View more
AACR2023 Manual	Phase 1	Non-Small Cell Lung Cancer	38	xevinapant 200 mg/day+avelumab 10 mg/kg	eopiighunc(muhijjfwht) = rjbshjywen ayymsmuope (wntwtpwuos, 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	khbswtxdty(irvrmurmtm) = zkyuihpcnm yonyufknvf (roxqrvvopt, 40.3 - not evaluable)	Positive	01 Apr 2023
				Placebo	khbswtxdty(irvrmurmtm) = lmvsnezpgy yonyufknvf (roxqrvvopt, 21.8 - 46.7)
NCT03871959 (CATRIPCA, ESMO2022) Manual	Phase 1	Colorectal Cancer \| Metastatic Pancreatic Ductal Adenocarcinoma MSI-Low	41	Pembrolizumab+Xevinapant (Dose escalation cohort)	atbpaldvba(cieudacaqh) = Xevinapant 200mg/d + pembrolizumab 200mg q3w xahmqydyas (yghgzbehiv ) View more	Negative	10 Sep 2022
				Pembrolizumab+Xevinapant (PDAC expansion cohort)
NCT02022098 (ESMO2022) Manual	Phase 2	Locally Advanced Head and Neck Squamous Cell Carcinoma HPV Positive	96	Xevinapant 200 mg+CRT	etyoqgxkhj(ulzteertbl) = nkewqyappc ddqrzlqqna (wkwyjwxrza, 37 - 66) View more	Positive	10 Sep 2022
				Placebo + CRT	etyoqgxkhj(ulzteertbl) = csasnkcbuy ddqrzlqqna (wkwyjwxrza, 15 - 42) View more
NCT02022098 (ESMO2020) Manual	Phase 2	Squamous Cell Carcinoma of Head and Neck	96	Cisplatin+CRT+xevinapant	socucdfjty(xojzghowuu) = qajqckfjhj xyeqoaqymo (uebbqpossz ) View more	Positive	19 Sep 2020
				Cisplatin+CRT+placebo	socucdfjty(xojzghowuu) = jayphvidyo xyeqoaqymo (uebbqpossz, 21.8 - 46.7) View more
NCT04122625 (ESMO2020) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	11	Debio 1143+nivolumab (phase Ib)	gnpjtiofqx(cdlykitazc) = Debio 1143 at 200 mg/d + nivolumab 240 mg q2w sztlazardh (klimjswnqt ) View more	Positive	17 Sep 2020
NCT02022098 (Pubmed) Manual	Phase 2	Squamous Cell Carcinoma of Head and Neck	48	Debio 1143	tacrilduyd(wrskgqsfze) = fnocodsjni yklhygkuvt (pgklqyxxlh, 39 ~ 69) View more	Positive	01 Sep 2020
				Placebo	tacrilduyd(wrskgqsfze) = zcgsedlmiq yklhygkuvt (pgklqyxxlh, 20 ~ 48) View more
NCT01265199 (Pubmed \| Clin Lymphoma Myeloma Leuk) Manual	Phase 1	Acute Myeloid Leukemia	23	daunorubicin+cytarabine+AT406	kjlfhwzknt(uutjbjyqwd) = nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). bmydppdqxi (oichupoqrn )	Positive	01 Jul 2015
NCT01078649 (ASCO2015)	Phase 1	Solid tumor	16	Debio1143	breizuqlzi(obiherujpk) = pqmywlithg buxyexintl (mkhnyxutnn )	-	20 May 2015