Myelofibrosis (MF) is a bone marrow illness that affects blood-forming tissues in the body. MF disturbs the body's normal production of blood cells, causing extensive scarring in the bone marrow. This leads to severe anemia, weakness, fatigue, and an enlarged spleen. The purpose of this study is to see how safe and tolerable ABBV-744 is, when given alone, and in combination with ruxolitinib or navitoclax, for adult participants with MF.
ABBV-744 is an investigational drug being developed for the treatment of MF. The study has 4 segments - A, B, C, and D. In Segment A, the safe dosing regimen of ABBV-744 is identified and then, given alone as monotherapy. In Segment B, C, and D, combination therapies of ABBV-744 with either ruxolitinib or navitoclax are given. Adult participants with a diagnosis of MF will be enrolled. Around 130 participants will be enrolled in 60 sites worldwide.
In Segment A, participants will receive different doses and schedules of oral ABBV-744 tablet to identify safe dosing regimen. Additional participants will be enrolled at the identified monotherapy dosign regimen. In Segment B, participants will receive oral ruxolitinib and ABBV-744 will be given as "add-on" therapy. In Segment C, participants will receive ABBV-744 and oral navitoclax. In Segment D, participants will receive ABBV-744 and ruxolitinib. Participants will receive treatment until disease progression or the participants are not able to tolerate the study drugs.
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 treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

Start Date11 Nov 2020

Sponsor / Collaborator

AbbVie, Inc.

NCT03360006 / TerminatedPhase 1

A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABBV-744 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)

This is an open-label, Phase 1, dose-escalation (Segment 1) and expansion (Segment 2) study to determine the maximum tolerated dose (MTD) and/or the recommended phase two dose (RPTD), and to assess the safety, preliminary efficacy, and pharmacokinetic (PK) profile of ABBV-744 in participants with relapsed/refractory Acute Myeloid Leukemia (AML).

Start Date16 Mar 2018

Sponsor / Collaborator

AbbVie, Inc.

100 Clinical Results associated with ABBV-744

100 Translational Medicine associated with ABBV-744

100 Patents (Medical) associated with ABBV-744

Literatures (Medical) associated with ABBV-744

02 Jan 2024·Expert Opinion on Investigational Drugs

Treatment of anemia in myelofibrosis: focusing on novel therapeutic options

Review

Author: Arslan Davulcu, Eren ; Eşkazan, Ahmet Emre ; Kılıç, Emre ; Oğuz, Merve Beyza

INTRODUCTIONMyelofibrosis is a clonal myeloproliferative neoplasm associated with the proliferation of hematopoietic stem cells, increased bone marrow fibrosis, extramedullary hematopoiesis, hepatosplenomegaly, abnormal cytokine production, and constitutional symptoms. These and many other factors contribute to the development of anemia in myelofibrosis patients.AREAS COVEREDThis review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat.EXPERT OPINIONStandard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

01 Nov 2023·Neoplasia

ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways

Article

Author: Wu, Hao ; Su, Haochen ; Lv, Ying ; Zhang, Shu ; Yu, Ranran ; Fan, Shengxian ; Tang, Jiatong ; Zhang, Yixuan ; Zou, Xiaoping ; Wang, Kun

The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

19 Sep 2023·ACS Omega

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

Article

Author: Liang, Yuanyuan ; Zou, Zhiyan ; Zhou, Yan ; Lu, Zhou ; Hu, Yan ; Shi, Mingsong ; Jing, Meng ; Zheng, Xueting ; Chen, Tingting ; Li, Xiaoan ; Lei, Dan ; Yang, Yuhan ; Yin, Yuan ; Yang, Pei

Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.

News (Medical) associated with ABBV-744

11 Jul 2023

·www.pharmaceutical-technology.com

Astellas licenses 4DMT’s AAV vector for ophthalmic targets

Astellas will make an upfront payment of $20m to 4DMT. Credit: JHVEPhoto via Shutterstock.com. Astellas Pharma has entered an agreement for licensing 4D Molecular Therapeutics’ (4DMT) R100 vector for a genetic target associated with rare monogenic ophthalmic ailments. Retinotropic R100 is an adeno-associated virus (AAV) vector intended to be administered intravitreally. Recommended Reports Reports LOA and PTSR Model - Brexucabtagene Autoleucel in Burkitt Lymphoma GlobalData Reports LOA and PTSR Model - ABBV-744 in Myelofibrosis GlobalData View all Companies Intelligence Astellas Pharma Inc Astellas B.V. View all Astellas holds options to include up to two further targets linked to rare monogenic ophthalmic ailments, contingent on the payment of further option exercise fees. R100 has the potential to cross the internal limiting membrane barrier and successfully transduce the whole retina. This approach leads to transgene expression in retinal cells. All three clinical-stage ophthalmic products of 4DMT leverage the R100 vector. Astellas will make an upfront payment of $20m to 4DMT. 4DMT is eligible to receive option fees and milestone payments totalling $942.5m. This payment includes $15m near-term development milestone fees for the first target. Astellas will also make royalty payments to 4DMT on net sales of products that are licensed under the agreement. Research, development, production and marketing will be carried out by Astellas following licensing. 4DMT co-founder and CEO David Kirn stated: “With over 70 patients dosed to date with R100-based product candidates in wet age-related macular degeneration and rare ophthalmic diseases, this collaboration also demonstrates the modularity of the therapeutic vector evolution platform resulting in the efficient design and development of new intravitreal products.” The latest development comes after the US Food and Drug Administration granted priority review for Astellas’ biologics licence application for zolbetuximab for gastric cancer.

License out/inPriority Review

100 Deals associated with ABBV-744

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Myelofibrosis	Phase 1	IL	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	IT	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	AU	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	HU	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	SE	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	TR	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	BG	AbbVie, Inc.	11 Nov 2020
Myelofibrosis	Phase 1	CL	AbbVie, Inc.	11 Nov 2020
Refractory acute myeloid leukemia	Preclinical	US	AbbVie, Inc.	16 Mar 2018
Relapsing acute myeloid leukemia	Preclinical	US	AbbVie, Inc.	16 Mar 2018

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