依托奈明α(Eftozanermin alfa) - 药物靶点：DR4_在研适应症：浆细胞骨髓瘤难治_专利_临床

概要

基本信息

药物类型

肿瘤坏死因子

别名

eftoza、Eftozanermin alfa (USAN/INN)、ABBV-621

+ [3]

靶点

DR4

作用机制

DR4激动剂(肿瘤坏死因子受体超家族成员10A激动剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

序列信息

Sequence Code 20117249

来源: *****

关联

2

项与依托奈明α 相关的临床试验

NCT04570631 / Active, not recruiting临床1期

A Phase 1b, Open-Label Study of Eftozanermin Alfa (ABBV-621) in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Multiple myeloma (MM) is a rare cancer caused by abnormal survival of plasma cells (blood cells). Most trial participants with MM relapse (cancer has come back) or become non- responsive to treatment and remission gets shorter after each line of treatment. This is a study to determine recommended Phase 2 dose and change in disease symptoms of eftozanermin alfa in combination with bortezomib and dexamethasone to assess how efficient the treatment is in adult participants with relapsed/refractory (R/R) MM.
Eftozanermin alfa (ABBV-621) is an investigational drug being developed for the treatment of R/R Multiple Myeloma (MM). Study doctors put the participants in 1 of the 2 groups, called treatment arms. Each group receives a different treatment. Participants in one arm will receive different doses of eftozanermin alfa in combination with bortezomib and dexamethasone to determine phase 2 dose (RP2D). Participants in the other arm will receive eftozanermin alfa at RP2D in combination with bortezomib and dexamethasone. Around 40 adult participants with relapsed/refractory multiple myeloma will be enrolled at approximately 20 sites across the world.
Participants will receive eftozanermin alfa as an infusion into the vein in combination with bortezomib as an infusion into the vein or an injection under the skin and oral dexamethasone tablets for 12 cycles. Each cycle is 21 days for cycles 1-8 and 35 days for cycles 9-12.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects.

开始日期2020-11-05

申办/合作机构

AbbVie, Inc.

NCT03082209 / Completed临床1期

An Open-Label, Phase 1, First-In-Human Study of TRAIL Receptor Agonist ABBV-621 in Subjects With Previously-Treated Solid Tumors and Hematologic Malignancies

This is an open-label, Phase I, dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase two dose (RPTD), and evaluate the safety, efficacy, and pharmacokinetic (PK) profile of ABBV-621 for participants with previously-treated solid tumors or hematologic malignancies.
Only chemotherapy combination (ABBV-621 + FOLFIRI) enrolling participants with RAS-mutant CRC who have received one prior line of therapy is open for enrollment.

开始日期2017-03-20

申办/合作机构

AbbVie, Inc.

100 项与依托奈明α 相关的临床结果

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100 项与依托奈明α 相关的转化医学

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100 项与依托奈明α 相关的专利（医药）

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7

项与依托奈明α 相关的文献（医药）

2024-04-01·Cancer chemotherapy and pharmacology

Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study

Article

作者: Doi, Toshihiko ; Menon, Rajeev M ; de Jonge, Maja ; Rasco, Drew ; Boehm, Nils ; Guan, Xiaowen ; Siddani, Satya R ; Biesdorf, Carla ; Medeiros, Bruno C ; Polepally, Akshanth R ; Hoffman, David

PURPOSE:

Eftozanermin alfa is a second-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist that enhances death receptor 4/5 clustering on tumor cells to induce apoptosis. We report the pharmacokinetics and immunogenicity of eftozanermin alfa administered intravenously to 153 adults with previously-treated solid tumors or hematologic malignancies from the first-in-human, open-label, dose-escalation and dose-optimization study.

METHODS:

Dose escalation evaluated eftozanermin alfa monotherapy 2.5-15 mg/kg on Day 1 or Days 1/8 of a 21-day cycle. Dose optimization evaluated eftozanermin alfa monotherapy or combination therapy with either oral venetoclax 400-800 mg daily (eftozanermin alfa 1.25-7.5 mg/kg Days 1/8/15 of a 21-day cycle) or chemotherapy (eftozanermin alfa 3.75 or 7.5 mg/kg Days 1/8/15/22 of a 28-day cycle and FOLFIRI regimen [leucovorin, 5-fluorouracil, and irinotecan] with/without bevacizumab on Days 1/15 of a 28-day cycle).

RESULTS:

Systemic exposures (maximum observed concentration [C_max] and area under the concentration-time curve [AUC]) of eftozanermin alfa were approximately dose-proportional across the entire dose escalation range with minimal to no accumulation in Cycle 3 versus Cycle 1 exposures. Comparable exposures and harmonic mean half-lives (35.1 h [solid tumors], 31.3 h [hematologic malignancies]) were observed between malignancy types. Exposures (dose-normalized C_max and AUC) in Japanese subjects were similar to non-Japanese subjects. Furthermore, eftozanermin alfa/venetoclax combination therapy did not have an impact on the exposures of either agent. Treatment-emergent anti-drug antibodies were observed in 9.4% (13/138) of subjects.

CONCLUSIONS:

The study results, including a pharmacokinetic profile consistent with weekly dosing and low incidence of immunogenicity, support further investigation of eftozanermin alfa.

TRIAL REGISTRATION ID:

NCT03082209.

2023-04-27·Blood

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

Article

作者: Jongen-Lavrencic, Mojca ; Motwani, Monica ; Sharon, David ; Smith, Morey ; Phillips, Darren C. ; Uziel, Tamar ; Buchanan, Fritz G. ; Medeiros, Bruno C. ; Modi, Dimple A. ; Biesdorf, Carla ; Carneiro, Benedito A. ; Shreenivas, Aditya ; Cheng, Dong ; Gort, Eelke ; Morillo, Daniel ; Tahir, Stephen K. ; Yuda, Junichiro ; Calvo, Emiliano ; Morgan-Lappe, Susan ; Ishizawa, Kenichi

Abstract:

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.

2022-08-01·Investigational new drugs

Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study

Article

作者: de Jonge, Maja J A ; Medeiros, Bruno C ; Motwani, Monica ; Ratain, Mark J ; Moreno, Victor ; Dunbar, Martin ; Petrich, Adam ; LoRusso, Patricia ; Devriese, Lot A ; Calvo, Emiliano ; Morgan-Lappe, Susan ; Carneiro, Benedito A ; Modi, Dimple ; Rasco, Drew W ; Doi, Toshihiko ; Nuthalapati, Silpa ; Glasgow, Jaimee

Abstract:

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

1

项与依托奈明α 相关的新闻（医药）

2023-02-09

·Endpoints

Updated: AbbVie leaves some oncology programs out of 2023 pipeline highlights

In an investor update Thursday morning, AbbVie left eight programs out of its pipeline highlights it shared with investors, as compared to what exists on the R&D page of its website, last refreshed in December. A Phase III study of Rinvoq in Takayasu arteritis , a rare group of disorders in which blood vessels become inflamed, was not included. The JAK inhibitor is approved for indications like rheumatoid arthritis and carries with it a black box warning. There’s also the removal of late-stage veliparib in breast and ovarian cancers after multiple failures for the PARP inhibitor were announced years ago . A company spokesperson noted the programs remain ongoing. “The updates listed in the slide from this morning highlight our key programs of interest for the investment community and is not a comprehensive snapshot of our entire pipeline,” the spokesperson wrote in an email. Further down the pipeline, AbbVie was quiet on Phase II assets ABBV-4083 in filarial diseases and its Allergan-snagged AGN-231868 in dry eye. A different Allergan asset continues in dry eye, according to the Chicago-area pharma giant’s pipeline update Thursday. Down in Phase I, AbbVie left out four oncology drug candidates. The company reneged on solid and hematologic tumor assets ABBV-155 and ABBV-621 , an IV-infused drug candidate also known as eftozanermin alfa . Small cell lung cancer asset ABBV-011 no longer shows up on the pipeline, and the same goes for ABBV-368 in solid tumors. AbbVie previously nixed a Phase Ib study of ABBV-368 in combination with Idera’s (Aceragen as of last month) tilsotolimod. In its update, AbbVie reminded investors of its four regulatory submissions: Rinvoq for Crohn’s disease; the Genmab-partnered CD3xCD20 bispecific epcoritamab for relapsed/refractory diffuse large B-cell lymphoma; ABBV-951 for advanced Parkinson’s disease and Qulipta for chronic migraine prevention . Editor’s note: This article has been updated to include comment and additional context from an AbbVie spokesperson that the programs remain ongoing.

临床1期临床3期临床2期上市批准临床终止

100 项与依托奈明α 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11746	-	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
浆细胞骨髓瘤难治	临床1期	美国	AbbVie, Inc.	2020-11-05
浆细胞骨髓瘤难治	临床1期	日本	AbbVie, Inc.	2020-11-05
浆细胞骨髓瘤难治	临床1期	法国	AbbVie, Inc.	2020-11-05
浆细胞骨髓瘤难治	临床1期	德国	AbbVie, Inc.	2020-11-05
浆细胞骨髓瘤难治	临床1期	意大利	AbbVie, Inc.	2020-11-05
浆细胞骨髓瘤难治	临床1期	西班牙	AbbVie, Inc.	2020-11-05
晚期恶性实体瘤	临床1期	美国	AbbVie, Inc.	2017-03-20
晚期恶性实体瘤	临床1期	日本	AbbVie, Inc.	2017-03-20
晚期恶性实体瘤	临床1期	荷兰	AbbVie, Inc.	2017-03-20
晚期恶性实体瘤	临床1期	西班牙	AbbVie, Inc.	2017-03-20

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03082209 (phase 1 first-in-human study, Pubmed \| Cancer Chemother Pharmacol)	临床1期	实体瘤 \| 血液肿瘤	153	Eftozanermin alfa monotherapy	觸夢遞簾憲窪範鏇襯襯(獵鹽願淵積獵鬱廠範艱) = 築鬱築製鏇選鬱夢鬱獵鹽鑰餘鹽網鹽壓築廠衊 (醖範醖鹹鑰範範衊淵繭 ) 更多	积极	2024-04-01
				Eftozanermin alfa + Venetoclax	觸夢遞簾憲窪範鏇襯襯(獵鹽願淵積獵鬱廠範艱) = 遞醖糧糧壓鹹窪齋壓遞鹽鑰餘鹽網鹽壓築廠衊 (醖範醖鹹鑰範範衊淵繭 ) 更多
NCT03082209 (EHA2020)	临床1期	复发性急性髓细胞白血病 \| 弥漫性大B细胞淋巴瘤	34	Eftozanermin alfa monotherapy	糧鹹蓋鏇憲蓋鹹醖鏇鏇(膚製襯遞蓋壓築顧糧廠) = Serious eftoza-related AEs were reported in 5 pts (AML eftoza-VEN); none occurred in >1 pt. 壓衊製壓簾夢鏇繭窪鏇 (簾選衊獵簾襯窪醖鬱遞 )	-	2020-05-14
				Eftozanermin alfa and Venetoclax combination therapy
NCT03082209 (ASCO2019) 人工标引	临床1期	实体瘤	57	ABBV-621	網願艱衊鏇窪餘選範廠(網網夢蓋襯膚繭壓繭淵) = Not reached 膚蓋鬱餘襯鹹願遞糧鹽 (衊積鹹窪艱鹽壓範願襯 ) 更多	积极	2019-06-01
AACR2017	临床1期	实体瘤	-	ABBV-621	糧繭網壓鬱衊製鏇襯鬱(鹹遞鹹廠網襯網獵襯繭) = 夢艱餘夢繭鑰壓艱窪鬱製鏇獵齋鏇膚淵遞衊網 (製鬱築選夢鏇襯觸鏇顧 )	-	2017-07-01