Delving into the Latest Updates on Plixorafenib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

selective rapidly accelerated fibrosarcoma (RAF) murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor, FORE-8394, FORE8394

+ [4]

Target

BRAF

Mechanism

BRAF inhibitors(Serine/threonine-protein kinase B-raf inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesNervous System Diseases

Active Indication

BRAF mutation Solid TumorsLeukemiaGlioma+ [2]

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmBile Duct Neoplasms+ [6]

Originator Organization

Daiichi Sankyo Co., Ltd.

Active Organization

Fore Biotherapeutics, Inc.

Plexxikon, Inc.

Daiichi Sankyo Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationFast Track (US), Orphan Drug (US)

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Structure

Molecular FormulaC25H21F3N6O3S

InChIKeyYYACLQUDUDXAPA-MRXNPFEDSA-N

CAS Registry1393466-87-9

Evaluating the sensitivity and feasibility of using ctDNA assays optimized for detecting very low ctDNA counts from cerebrospinal fluid (CSF) and plasma. The investigators will evaluate the sensitivity of ctDNA from plasma and CSF at baseline (defined as Cycle1 Day1 (C1D1) pre-treatment) and over time in response to treatment with plixorafenib co-administered with cobicistat in BRAF-V600E mutant glioma refractory to prior therapies.

Start Date02 Jan 2025

Sponsor / Collaborator

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT06385119 / RecruitingPhase 1

A Phase 1, Open-Label, 2-Part, Single Dose, Crossover Study to Examine the Effect of Food and Cobicistat Administration on the Pharmacokinetics and Safety of Plixorafenib in Healthy Participants.

The primary goal of this phase 1 study is to evaluate the effect of food and cobicistat on the pharmacokinetics of plixerafenib in healthy volunteers. Healthy male and female participants between the ages of 18 and 55 will be enrolled into this study. This study is looking to examine the following in two parts:
Part A
* The effect of food on the single dose PK of plixorafenib administered with cobicistat.
* The effect of cobicistat administration on the single dose PK of plixorafenib.
* The safety of plixorafenib administered alone and with cobicistat in a single dose regimen in healthy participants.
Part B
* To examine the effect of a high-fat and a low-fat meal versus fasted state on the single dose PK of plixorafenib administered alone.
* To examine the effect of a low-fat meal versus fasted state on the single dose PK of plixorafenib administered with cobicistat.
* To determine the safety of plixorafenib administered alone or with cobicistat (low-fat meal only) in a single dose regimen.

Start Date24 Apr 2024

Sponsor / Collaborator

Fore Biotherapeutics, Inc.

CTIS2024-513578-23-00 / Recruiting

A Phase 2 Master Protocol to assess the efficacy and safety of FORE8394,an inhibitor of BRAF class 1 and class 2 alterations, in participants withcancer harboring BRAF alterations - F8394-201

Start Date11 Jul 2023

Sponsor / Collaborator

Fore Biotherapeutics, Inc.

100 Clinical Results associated with Plixorafenib

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100 Translational Medicine associated with Plixorafenib

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100 Patents (Medical) associated with Plixorafenib

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43

Literatures (Medical) associated with Plixorafenib

01 Aug 2024·Life Science Alliance

Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function

Article

Author: Zila, Nina ; Bromberger, Sophie ; Nawrocki, Arkadiusz ; Springer, Alexander ; Ressler, Julia Maria ; Zadorozhna, Yuliia ; Holzner, Silvio ; Røssel Larsen, Martin ; Schossleitner, Klaudia

Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected by resistance and adverse events (AEs). Approved BRAF inhibitors (BRAFi) show high levels of target promiscuity, which can contribute to these effects. The blood vessel lining is in direct contact with high plasma concentrations of BRAFi, but effects of the inhibitors in this cell type are unknown. Hence, we aimed to characterize responses to approved BRAFi for melanoma in the vascular endothelium. We showed that clinically approved BRAFi induced a paradoxical activation of endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets of off-targets per inhibitor. Endothelial barrier function and junction integrity were impaired upon treatment with vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with dabrafenib or encorafenib. Together, these findings provide insights into the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma.

01 Aug 2024·PATHOLOGY RESEARCH AND PRACTICE

Exosomal miR-19a derived from melanoma cell promotes the vemurafenib resistance of malignant melanoma through directly targeting LRIG1 to reactivate AKT and MAPK pathway

Article

Author: Luan, Wenkang ; Peng, Huiyong ; Lu, Xu ; Rao, Min ; Shen, Xuanlin ; Ruan, Hongru

Exosomes derived from neighboring v-raf murine sarcoma viral oncogene homolog B1 inhibitor (BRAFi)-resistant melanoma cells mediate the formation of resistance in melanoma cells sensitive to BRAFi. The function and molecular mechanisms of exosomal miRNA in BRAFi resistance of melanoma have not been studied. We found that the expression of miR-19a in BRAFi resistant melanoma cells was significantly higher than that in sensitive cells, and miR-19a contributes to the resistance of melanoma cells to BRAFi by targeting immunoglobulin-like domains protein 1 (LRIG1). miR-19a was highly enriched in exosomes secreted from BRAFi resistant melanoma cells, and these exosomal miR-19a promote the spread of BRAFi resistant. The reactivation of Protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways is the main reason for the BRAFi resistant of melanoma cells. We demonstrated that exosomal miR-19a derived from melanoma cell promotes the formation and spread of BRAFi resistant in melanoma through targeting LRIG1 to reactivate AKT and MAPK pathway. Therefore, miR-19a may serve as a potential therapeutic target in melanoma patients with acquired drug resistance.

01 Dec 2023·Oncogene

Inhibition of TGF-β signaling, invasion, and growth of cutaneous squamous cell carcinoma by PLX8394

Article

Author: Heino, Jyrki ; Nissinen, Liisa ; Riihilä, Pilvi ; Siljamäki, Elina ; Suwal, Ujjwal ; Rappu, Pekka ; Kallajoki, Markku ; Kähäri, Veli-Matti

Abstract:

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The prognosis of patients with metastatic cSCC is poor emphasizing the need for new therapies. We have previously reported that the activation of Ras/MEK/ERK1/2 and transforming growth factor β (TGF-β)/Smad2 signaling in transformed keratinocytes and cSCC cells leads to increased accumulation of laminin-332 and accelerated invasion. Here, we show that the next-generation B-Raf inhibitor PLX8394 blocks TGF-β signaling in ras-transformed metastatic epidermal keratinocytes (RT3 cells) harboring wild-type B-Raf and hyperactive Ras. PLX8394 decreased phosphorylation of TGF-β receptor II and Smad2, as well as p38 activity, MMP-1 and MMP-13 synthesis, and laminin-332 accumulation. PLX8394 significantly inhibited the growth of human cSCC tumors and in vivo collagen degradation in xenograft model. In conclusion, our data indicate that PLX8394 inhibits several serine-threonine kinases in malignantly transformed human keratinocytes and cSCC cells and inhibits cSCC invasion and tumor growth in vitro and in vivo. We identify PLX8394 as a potential therapeutic compound for advanced human cSCC.

29

News (Medical) associated with Plixorafenib

19 Dec 2024

·www.businesswire.com

FORE Biotherapeutics to Present at the 43rd Annual J.P. Morgan Healthcare Conference

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, today announced that William Hinshaw, Chief Executive Officer of Fore Biotherapeutics, will present at the 43 rd Annual J.P. Morgan Healthcare Conference. The presentation will take place on Tuesday, January 14, 2025, at 5:30 p.m. PT at the Westin St. Francis Hotel in San Francisco. Mr. Hinshaw will detail progress and anticipated milestones for Fore’s lead asset, plixorafenib, a novel, small-molecule, next generation, orally available selective inhibitor of mutated BRAF. Plixorafenib is currently being evaluated in a clinical trial with registrational intent in three distinct indications. Please contact Argot Partners to schedule one-on-one meetings with the management team. About FORE Biotherapeutics Fore is a registration stage targeted oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor rationally designed with a first-in-class mechanism to address treatment gaps from 1 st and 2 nd generation BRAF inhibitors. Plixorafenib has demonstrated single-agent efficacy signals across a variety of tumor types with a manageable safety profile in a Phase 1/2a clinical trial of over 100 patients and is currently enrolling patients in a clinical trial with registrational intent in three distinct indications. For more information, please visit www.fore.bio or follow us on X and LinkedIn .

Phase 1

05 Dec 2024

·www.businesswire.com

FORE Biotherapeutics to Participate in the Wells Fargo Virtual Private Biotech Symposium

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics today announced that the Company will participate in the Wells Fargo Virtual Private Biotech Symposium on Thursday, December 12. William Hinshaw, Chief Executive Officer and Michael Byrnes, Chief Financial Officer, will host and participate in one-on-one meetings. Please contact Argot Partners to schedule one-on-one meetings with the management team. About FORE Biotherapeutics Fore is a registration stage targeted oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor rationally designed with a first-in-class mechanism to address treatment gaps from 1 st and 2 nd generation BRAF inhibitors. Plixorafenib has demonstrated single-agent efficacy signals across a variety of tumor types with a manageable safety profile in a Phase 1/2a clinical trial of over 100 patients and is currently enrolling patients in a clinical trial with registrational intent in three distinct indications. For more information, please visit www.fore.bio or follow us on X and LinkedIn .

Phase 1

07 Nov 2024

·www.businesswire.com

FORE Biotherapeutics to Participate in Upcoming November Conferences

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics today announced that the Company will participate at the following investor conferences: Stifel 2024 Healthcare Conference. The Company will attend on Monday, November 18, and will provide a corporate presentation at 2:25 p.m. – 2:55 p.m. ET. Jefferies London Healthcare Conference. The Company will attend and participate in one-on-one meetings on Wednesday, November 20, and Thursday, November 21. Management will host and participate in one-on-one meetings. Please contact Argot Partners to schedule one-on-one meetings with the management team. About FORE Biotherapeutics Fore is a registration stage targeted oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor rationally designed with a first-in-class mechanism to address treatment gaps from 1 st and 2 nd generation BRAF inhibitors. Plixorafenib has demonstrated single-agent efficacy signals across a variety of tumor types with a manageable safety profile in a Phase 1/2a clinical trial of over 100 patients and is currently enrolling patients in a clinical trial with registrational intent in three distinct indications. For more information, please visit www.fore.bio or follow us on X and LinkedIn .

100 Deals associated with Plixorafenib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16038

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
BRAF mutation Solid Tumors	Phase 2	US	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	CA	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	FR	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	DE	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	IT	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	KR	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	ES	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	SE	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	GB	Fore Biotherapeutics, Inc.	21 Feb 2023
Glioma	Phase 2	US	Fore Biotherapeutics, Inc.	01 Apr 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02428712 (CTNI-76, SNO2023)	Phase 1/2	Central Nervous System Neoplasms BRAF-altered \| BRAFV600+	113	Plixorafenib 900-3600 mg/day	aqdfpruudd(ntigkcgnfv) = zpzpmielur bafxmlalbc (ohbeponpub )	Positive	10 Nov 2023
NCT02428712 (ASCO 12023 \| ASCO 22023) Manual	Phase 2	BRAF-mutation brain cancer \| HR-positive/HER2-low Solid Tumors BRAF	110	Plixorafenib±cobicistat	dtmpgpuudr(mwwhoyaavu) = Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). cbgcyqjpsp (jkssysfrbi )	Positive	31 May 2023
NCT02428712 (ASCO 12023 \| ASCO 22023) Manual	Phase 1/2	HR-positive/HER2-low Solid Tumors \| Central Nervous System Neoplasms	110	FORE8394	vjsxadzdfh(yqxefreuou) = pxhtlkqqbx mjntrxxzpe (adgykouzuk ) View more	Positive	26 May 2023
NCT02428712 (ASCO 12023 \| ASCO 22023) Manual	Phase 1/2		110	FORE8394 (pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]))	tqqtkqynhq(zlvzswcurm) = sworokjeom guuvnabidq (fymthvkake )	Positive	26 May 2023
NCT02428712 (ESMO2020)	Phase 1/2	Advanced cancer	69	PLX8394	zrxklmwwtd(zgkkhavbmh) = 4 pts tsmtgxunkm (ykzmifvofh ) View more	Positive	18 Sep 2020
NCT02428712 (ASCO 12018 \| ASCO 22018) Manual	Phase 1/2	BRAF mutation Solid Tumors BRAF Mutation	31	PLX8394+cobicistat	dtncmvlibm(ioaifdlpqm) = kvahixjnbi bewtfireqr (aldhbhgavf )	Positive	04 Jun 2018
NCT02428712 (ASCO 12018 \| ASCO 22018) Manual	Phase 1/2	BRAF mutation Solid Tumors BRAF Mutation	31	PLX8394+cobicistat	axrdbktlsd(jnehkwfuyo) = ynaflzqmme qoewvxsosk (rpyqfoxwrx ) View more	Positive	04 Jun 2018