Delving into the Latest Updates on Fovinaciclib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CDK4 x CDK6

Mechanism

CDK4 inhibitors(Cyclin-dependent kinase 4 inhibitors), CDK6 inhibitors(Cyclin-dependent kinase 6 inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesDigestive System Disorders

Active Indication

Metastatic Solid TumorHormone receptor positive HER2 negative breast cancerBreast Cancer+ [3]

Inactive Indication

Advanced Malignant Solid Neoplasm

Originator Organization

Fochon Pharmaceuticals Ltd.

Active Organization

Fochon Pharmaceuticals Ltd.

Jinzhou Ahon Pharmaceutical Co., Ltd.

Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.

Inactive Organization-

Drug Highest PhaseNDA/BLA

First Approval Date-

RegulationSpecial Review Project (CN)

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Structure/Sequence

Molecular FormulaC29H40N8OS

InChIKeyPGGPKYATZSPYKB-UHFFFAOYSA-N

CAS Registry2146171-49-3

主要研究目的：评价并比较 FCN-437c 在轻度、中度肝功能损害受试者和健康受试者中的药代动力学特征，为肝功能损害患者的临床用药提供依据次要研究目的：评价轻度、中度肝功能损害受试者以及健康受试者服用 FCN-437c 的安全性

[Translation]

Primary study objective: To evaluate and compare the pharmacokinetic characteristics of FCN-437c in subjects with mild and moderate liver impairment and healthy subjects, and to provide a basis for clinical medication in patients with liver impairment Secondary study objective: To evaluate the safety of FCN-437c in subjects with mild and moderate liver impairment and healthy subjects

Start Date04 Sep 2023

Sponsor / Collaborator

Fochon Pharmaceuticals Ltd.

[+1]

NCT06290466

/ CompletedPhase 1

A Phase I, Single-center, Randomized, Double-blind, Placebo-controlled Design to Evaluate the Pharmacokinetics and Effects on QT Interval of a Single Oral Dose of FCN-437c Capsule in Healthy Subjects.

This is a single-center, randomized, double-blind, placebo-controlled Phase I clinical trial in healthy subjects.In healthy subjects, 300mg and 400mg FCN-437c capsules were taken orally for a single time. C-QTc effect model was used to evaluate the influence of blood concentration on QT interval, and the pharmacokinetic characteristics and safety of FCN-437c were also evaluated.Based on the C-QTc effect model, this study quantitatively analyzed the relationship between ΔΔQTcF and blood concentration, and evaluated the upper limit of 90% bilateral confidence interval of ΔΔQTcF corresponding to the geometric mean of Cmax at clinically relevant dose of FCN-437c capsule.
This study plans to set up 2 dose groups, low-dose group 300mg and high-dose group 400mg.Nine healthy subjects were planned to be enrolled in each dose group, with a 2:1 ratio of placebo control.
This study was carried out in the order of dose from low to high. After the administration of the low-dose group (300mg) and the safety assessment on the fourth day after administration, the study of the high-dose group (400mg) was decided through comprehensive evaluation.

Start Date11 Nov 2022

Sponsor / Collaborator

Jinzhou Ahon Pharmaceutical Co., Ltd.

100 Clinical Results associated with Fovinaciclib

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100 Translational Medicine associated with Fovinaciclib

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100 Patents (Medical) associated with Fovinaciclib

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3

Literatures (Medical) associated with Fovinaciclib

01 Jan 2022·Annals of Translational Medicine

Chemotherapy modulates CDK4/6 inhibitors resistance in metastatic breast cancer by Rb1 mutations: a case report and literature review

Author: Liu, Yiyuan ; Shao, Xiying ; Wang, Xiaojia ; Gao, Lu ; Wu, Jiayi ; Shen, Xiabo ; He, Libin

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) plays a major role in breast cancer therapeutics acting through preventing the cell cycle from G1 to the S phase. Recently, Endocrine therapy combined with CDK4/6i represented a major milestone in hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer treatment. However, the resistance of CDK4/6i is clinically common, and the mechanism remains to be clarified. Retinoblastoma (Rb) is a negative regulator of cell cycle. It inhibits cell cycle transition by binding to E2F transcription factors, and prevent cells division in this way. Rb is regulated by phosphorylation. The CDK4/6i have been shown to affect cancer by blocking phosphorylation of Rb. In addition, decreasing estrogen signal has been confirmed to reduce cyclin D-CDK4/6 complexing. Currently, FCN-437c is a new CDK4/6i that is in clinical trials. Here, we present the case of an HR-positive and HER2-negative patient whose disease continued to rapidly progress after receiving FCN-437c. To determine why, we did a series of examinations and found that her Rb1 had mutated after using CDK4/6i. To our surprise, the Rb1 mutations recovered after treatment with eribulin, and CDK4/6i was shown to exert a renewed effect. In this way, a hypothesis was made that eribulin may influence the pathway of cyclin D- CDK4/6- Rb- E2F by effecting in Rb. This case provides new insights into strategies for CDK4/6i therapy resistance options and shows the significance of next-generation sequencing in the clinic.

01 Dec 2021·Investigational New DrugsQ3 · MEDICINE

Phase 1a study of the CDK4/6 inhibitor, FCN-437c, in Chinese patients with HR + /HER2- advanced breast cancer

Q3 · MEDICINE

Article

Author: Zhang, Jian ; Zhang, Wenjing ; Hu, Xichun ; Tian, Ling ; Hui, Aimin ; Wu, Zhuli ; Wang, Xian ; Xu, Changjiang ; Wang, Xiaojia ; Yang, Yuchen

Summary Purpose This phase 1a, first-in-human study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and antitumor activity of FCN-437c, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Methods The study enrolled female patients with HR + /HER2- advanced breast cancer (BC) who failed standard of care therapy. A 3 + 3 dose-escalation design was utilized with a starting dose of 50 mg daily for 3 weeks on and 1 week off treatment in 28-day cycles. Patients received escalating doses of FCN-437c monotherapy (50, 100, 200, 300, and 450 mg). Results Seventeen patients received FCN-437c 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 6), and 450 mg (n = 2). Two patients who received the 450-mg dose experienced dose-limiting toxicities (DLTs; grade 4 thrombocytopenia and neutropenia); no DLT was observed at any other dose level. Frequently reported treatment-emergent adverse events (TEAEs) of any grade were hematological: leukopenia (94.1%), neutropenia (88.2%), anemia (64.7%), and thrombocytopenia (47.1%). Grade 3–4 TEAEs included neutropenia (64.7%) and leukopenia (47.1%). Exposure of FCN-437c increased almost proportionally to doses ranging from 50 to 200 mg. At doses from 200 to 450 mg, there appeared to be a trend of saturation. The MTD was determined to be 300 mg. Of 15 patients with measurable disease, nine (60.0%) patients experienced stable disease; no complete or partial responses were observed. Conclusions These results established an acceptable safety profile for FCN-437c in patients with advanced BC, and there were no unexpected signals relative to other CDK4/6 inhibitors. (NCT04488107; July 13, 2020)

Cancers

A Phase I Dose-Escalation and Dose-Expansion Study of FCN-437c, a Novel CDK4/6 Inhibitor, in Patients with Advanced Solid Tumors

Article

Author: Patnaik, Amita ; Lee, Ya-Li ; Hamilton, Erika ; Smith, Lon ; Fang, Steven ; Hui, Ai-Min ; Rasco, Drew W. ; Wei, Jiao ; Xing, Yan

A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRASmut) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRASmut NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRASmut NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted.

2

News (Medical) associated with Fovinaciclib

26 Jun 2019

·fochonpharma.com

Fochon Pharmaceuticals Doses First Patient in the US in Phase I Clinical Study of FCN-437, a CDK4/6 Inhibitor for Advanced Solid Tumors

Fochon Pharmaceuticals, Ltd. (Fochon), a pharmaceutical company based in the San Francisco Bay Area, Chongqing and Shanghai focusing on R&D of small-molecule drugs, announced June 25, 2019 dosing of the first patient in the US in the recently initiated Phase I clinical trials of FCN-437 in patients with advanced solid tumors. “This is a truly remarkable moment for both Fochon and oncology patients around the world”, said Dr. Weibo Wang, Co-Founder and CEO of Fochon. “We are tremendously excited to advance our novel and potent CDK4/6 inhibitor —— FCN-437 into the US trial for advanced solid tumors and see if it will deliver the expected benefits to patients. Congratulations to the team for this very significant step forward in the program.” About FCN-437 FCN-437 is a novel, proprietary and orally active inhibitor of Cyclin Dependent Kinase 4 and 6 (CDK4/6) developed by Fochon to treat solid tumors. FCN-437 demonstrated much higher in vitro and in vivo potency and selectively inhibitory activities against CDK4/6 compared to approved CDK4/6 inhibitors. FCN-437 exhibited broad anti-tumor activity in preclinical pharmacology models, favorable physical and pharmacokinetic properties, and improved toxicity profile in non-clinical studies. In particular, FCN-437 can distribute to the brain and provide an opportunity to treat tumors that have metastasized to the brain. Preclinical data of FCN-437 was presented by Fochon at 2019 AACR Annual meeting at Atlanta, USA. Phase I clinical trials of FCN-437 is on-going in China in parallel with the US trial as Fochon also received the approval from China NMPA for the IND application of FCN-437 to treat patients with solid tumors. CDK4/6 and solid tumors CDK4/6 can form complex with Cyclin D to phosphorylate Retinoblastoma protein (Rb), which enables cell cycle progression. Phosphorylation of Rb leads to dissociation of Rb from the E2F family of transcription factors and allows transcription of E2F target genes progression that drives cell cycle transition from G1 to the S phase. Loss of cell cycle control caused by aberrations in the CDK/Rb signaling pathway are common in a variety of solid tumors. Inhibiting CDK4/6 blocks CDK/Rb signaling pathway, which prevents cell cycle progression through the G1 restriction point, thus arresting tumor cell growth. About Fochon Fochon Pharmaceuticals, Ltd. is a pharmaceutical company focusing on research and development (R&D) of small-molecule drugs for advancing best-in-class therapies to improve human lives. We are based in the San Francisco Bay Area, Chongqing and Shanghai, with strong financial backing by Shanghai Fosun Pharmaceutical (Group) Co., Ltd. Fochon has a proven track record of accelerating the discovery of best-in-class potential small-molecule therapeutics to clinical development for cancer and metabolic diseases. Since its foundation, Fochon has built a significant R&D pipeline consist of drug candidates targeting ALK/ROS1, BCL-2, BTK, pan-TRK (1st & 2nd generation), CDK4/6, MEK, pan-HER, PI3Kdelta, URAT, DPP-4 and etc., of which FCN-005 (Fotagliptin, DPP-4 inhibitor) in Phase II/III is the most advanced.

Phase 1INDAACR

26 Apr 2018

·fochonpharma.com

Fochon Pharmaceuticals Receives CFDA Approval for Clinical Trials of Innovative Medicine to Treat Solid Tumors

Fochon Pharmaceuticals receives CFDA approval for clinical trials of the innovative drug FCN-437 capsule, which is intended to treat solid tumors. Until December 2017, Fochon receives the investment with approximately RMB 28 million on R&D for FCN-437. Until January 23th, 2018, there is no medicine with independent intellectual property right launched in China (excluding Hong Kong, Macau and Taiwan) with the same targeted therapy as FCN-437. In 2016, the global sales of similar medicine amounted to about $2.1 billion.

INDNDA

100 Deals associated with Fovinaciclib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Solid Tumor	NDA/BLA	CN	Jinzhou Ahon Pharmaceutical Co., Ltd.	09 Jan 2025
Hormone receptor positive HER2 negative breast cancer	NDA/BLA	CN	Jinzhou Ahon Pharmaceutical Co., Ltd.	21 Nov 2023
Breast Cancer	Phase 3	CN	Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd.	30 Jan 2023
Advanced breast cancer	Phase 3	CN	Jinzhou Ahon Pharmaceutical Co., Ltd.	18 Jan 2022
ER-positive/HER2-negative Breast Cancer	Phase 2	CN	Fochon Pharmaceuticals Ltd.	21 Aug 2020
Liver Injury	Phase 1	CN	Jinzhou Ahon Pharmaceutical Co., Ltd.	04 Sep 2023
Advanced Malignant Solid Neoplasm	Discovery	US	Fochon Pharmaceuticals Ltd.	25 Jun 2019

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05004142 (Phase 2 Study of the CDK4/6 Inhibitor FCN-437c, SABCS2023)	Phase 2	Advanced breast cancer	67	FCN-437c + Fulvestrant	(riwffqelxw) = enpgxwglod yxdfzzwqcp (wgahktnduw, 29.0 - 53.7) View more	Positive	01 Mar 2023
				FCN-437c + Letrozole + Goserelin	(riwffqelxw) = nuhdcflncj yxdfzzwqcp (wgahktnduw, 33.1 - 69.9) View more
NCT04488107 (ASCO2022) Manual	Phase 1	Hormone receptor positive HER2 negative breast cancer First line HR Positive \| HER2 Negative	29	FCN-437c 200 mg+letrozole 2.5 mg	(osrzmyrgla) = hugvlumfts omlecqzocv (bfmxbjklgo ) View more	Positive	02 Jun 2022
				FCN-437c 300 mg+Letrozole 2.5 mg	(jgxzqbiakk) = qgifjrhzue qjychhpbkq (mkepyzwdpq, 47.82 - 100) View more
AACR2021	Phase 1	Advanced breast cancer	17	FCN-437c	(ggvyuwblgk) = clddpznuuf syrngxkfgh (pxswsitroj ) View more	-	01 Jul 2021
NCT04488107 (Pubmed \| Invest New Drugs)	Phase 1	Advanced breast cancer	-	FCN-437c 50 mg	(xvydxxhrtk) = youdjittiu bupjpabked (jsffnqumuw ) View more	-	09 Jun 2021
				FCN-437c 100 mg	(xvydxxhrtk) = flxaxwyrcf bupjpabked (jsffnqumuw ) View more