This Phase 1b trial is a double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety and tolerability of oral ORIN1001 at 25 mg, 50 mg or 100 mg administered daily for up to 28 days in adult subjects with idiopathic pulmonary fibrosis (IPF) alone or in conjunction with local Standard of Care for IPF (pirfenidone or nintedanib).
A maximum of 24 evaluable subjects will be required to complete the study. The study will consist of 3 dose cohorts each enrolling a maximum of 8 subjects randomized either to the active (5 subjects) group or placebo (3 subjects) group. Each subject will receive daily oral doses of ORIN1001 or placebo for 28 days.
The safety and pharmacokinetic profile will be evaluated in this study and will include cardiovascular and pulmonary endpoints.

Start Date09 Feb 2021

Sponsor / Collaborator

Fosun Orinove Pharmatech Inc

[+1]

CTR20200281 / TerminatedPhase 1

一项多中心、开放、I 期临床研究：评价 ORIN1001 在晚期恶性实体瘤患者中的单药和联合治疗的剂量探索及剂量扩展研究

[Translation] A multicenter, open-label, phase I clinical study: a dose-finding and dose-expansion study evaluating ORIN1001 as a monotherapy and in combination therapy in patients with advanced malignant solid tumors

1.观察单药和联合用药 ORIN1001 在晚期恶性实体瘤患者中的安全性和耐受性。 2.确定单药 ORIN1001和联合用药在晚期实体瘤中的 II 期临床研究推荐剂量。 3.观察单药 ORIN1001 和联合用药在各个不同实体瘤适应症中的抗肿瘤活性，安全性和耐受性。 4.评价ORIN1001单药和联合用药的药代动力学特征。 5.探索肿瘤生物标志物的变化情况，并初步评估和疗效之间的相关性。

[Translation]

1. Observe the safety and tolerability of ORIN1001 as a single agent and in combination in patients with advanced malignant solid tumors. 2. Determine the recommended dose for Phase II clinical studies of ORIN1001 as a single agent and in combination in advanced solid tumors. 3. Observe the anti-tumor activity, safety and tolerability of ORIN1001 as a single agent and in combination in various solid tumor indications. 4. Evaluate the pharmacokinetic characteristics of ORIN1001 as a single agent and in combination. 5. Explore the changes in tumor biomarkers and preliminarily evaluate the correlation with efficacy.

Start Date23 Nov 2020

Sponsor / Collaborator

Fosun Orinove Pharmatech Inc

NCT05154201 / Active, not recruitingPhase 1/2

A Multicenter, Open-label, Phase I Clinical Study: A Dose-finding and Dose Expansion Study to Evaluate ORIN1001 Monotherapy and Its Combination in Patients With Advanced Solid Malignant Tumors

Dose escalation of ORIN1001 in patients with advanced solid tumors.
Dose escalation of ORIN1001 in combination with standard of care in patients with esophageal carcinoma, metastatic breast cancer, hepatocellular carcinoma, metastatic prostate cancer, pancreatic cancer, ovarian cancer and non-small cell lung cancer.
Dose expansion of ORIN1001 as a single agent or in combination with standard of care in patients with advanced solid tumors.

Start Date01 Jul 2020

Sponsor / Collaborator

Fosun Orinove Pharmatech Inc

[+1]

100 Clinical Results associated with Fosun Orinove Pharmatech Inc

0 Patents (Medical) associated with Fosun Orinove Pharmatech Inc

Literatures (Medical) associated with Fosun Orinove Pharmatech Inc

22 Apr 2024·Oncogene

Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling

Article

Author: Zhong, Rong ; Jin, Yang ; Zhao, Faming ; Shi, Ji-Hua ; Zhang, Tingting ; Cui, Fengzhen ; Xu, Chuanrui ; Ma, Weixiang ; Wang, Kai ; Li, Ningning ; Sheng, Xia ; Liu, Yong ; Zeng, Qingping ; Zhang, Yi

Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of β-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.

01 Jun 2023·Journal of Clinical Oncology

Early efficacy evaluation of ORIN1001, a first in class IRE1 alpha inhibitor, in advanced solid tumors.

Author: Gabrail, Nashat Y. ; Patterson, John ; Elias, Anthony D. ; Hamilton, Erika P. ; Pluard, Timothy J. ; Zeng, Qingping ; Rimawi, Mothaffar F. ; Marks, Douglas Kanter ; Hurvitz, Sara A. ; Greene, Stephanie

1092 Background: ORIN1001 is a first-in-class small molecule targeting a novel enzyme with a unique mode of inhibition that selectively blocks the Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum. ORIN1001 is now undergoing Phase 1/2 clinical testing in advanced solid tumors. Methods: In a Phase 1 dose escalation trial (3+3 design), ORIN1001 was administered PO daily as a single agent in patients (pts) with advanced solid tumors and in combination with Abraxane in pts with relapsed, refractory breast cancer. Safety, tolerability, pharmacokinetics, and preliminary efficacy of ORIN1001 was evaluated and a RP2D determined. Results: As of Jan, 2023, 30 patients with advanced cancer have received ORIN1001 as a single agent at doses up to 650 mg per day in 21-day continuous cycles and 13 patients with breast cancer have received ORIN1001 at doses up to 400 mg in combination with Abraxane in 28-day continuous cycles. For single agent, DLTs consisting of thrombocytopenia were observed at 200 mg (2 pts) and 650 mg (2 pts) and, rash was observed at 200 mg (1 pt) and 500 mg (1 pt). For combination treatment, DLTs consisting of thrombocytopenia were observed at 300 mg (1 pt), fatigue/ rash at 400 mg (1 pt), febrile neutropenia/low WBC at 400/500 mg (1 pt at each dose). Common ( > 15%) adverse events were predominantly nausea and/or vomiting (Grade 1-2 in severity). ORIN1001 exposure increased in a dose proportional manner with a mean T1/2 at steady state of approximately 20 hours. For single agent, best response per RECIST 1.1 was partial response (PR) in 2 of 30 pts. These PRs included a stage IV colon cancer pt exceeding 44 months on treatment at 100 mg, and stage IV ER-/PR-/HER2+ breast cancer pt with 5 months on treatment at 500 mg. Stable disease (SD) was observed in a total of 16 of 30 pts with breast, colorectal, mesothelioma, liver, prostate, kidney or ovarian cancer. For combination therapy with Abraxane, a PR was observed in one ER+/PR-/HER2- breast cancer pt at 300 mg ORIN1001 and SD was observed in 5 of 13 pts. SD included both triple negative and ER+/HER2- breast cancer pts at 300 or 400 mg with ongoing treatment exceeding 5 months. Of note, in a separate Phase 1 oncology basket trial in China, there were 2 PRs; 1 pt with stage IV NSCLC at 300 mg and 1 pt with metastatic castrate resistant prostate cancer at 100 mg exceeding 9 and 5 months of treatment with ORIN1001 in combination with Abraxane, respectively. Conclusions: Phase 1 clinical evaluation of ORIN1001 has demonstrated tolerability and dose proportional PK. The proposed RP2D is estimated to be 500 mg and 300 mg ORIN1001 for single agent and in combination with Abraxane, respectively. Early efficacy data with ORIN1001 demonstrate clinical responses (SD and PR) in multiple pts with heavily-pretreated advanced solid tumors as a single agent or in combination with Abraxane in breast cancer patients. Clinical trial information: NCT03950570 .

20 May 2021·Journal of Clinical Oncology

A phase 1/2 trial of ORIN1001, a first-in-class IRE1 inhibitor, in patients with advanced solid tumors.

Author: Hui, Ai-Min ; Li, Chao ; Feng, Ying ; Greene, Stephanie ; Hamilton, Erika P. ; Rimawi, Mothaffar F. ; Gabrail, Nashat Y. ; Li, Wei ; Elias, Anthony D. ; Wei, Jiao ; Patterson, John ; Zeng, Qingping ; Corvez, Maria Margarita

3080 Background: ORIN1001 is a first-in-class small molecule with a novel, unique enzyme and mode of inhibition that selectively inhibits Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum (ER). IRE1α/XBP1 has been implicated in a host of pathologies, and molecules that modulate it are under intense investigation for the treatment of oncologic, metabolic, neurodegenerative and other diseases. ORIN1001 has demonstrated preclinical anti-tumor activity alone and in combination with standard of care across multiple animal models including breast, prostate, lung, liver, pancreatic, brain, colon, ovarian, esophageal, and hematologic cancers and is now undergoing first-in-human testing. Methods: A phase 1, open label, 3+3 dose escalation trial is testing ORIN1001 administered PO daily to patients (pts) with advanced solid tumors (single agent) or relapsed refractory breast cancer (in combination with Abraxane). The phase 1 dose escalation part of the trial evaluates the safety, tolerability, pharmacokinetics and preliminary efficacy of ORIN1001. After identification of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) for the single agent, the dose expansion part of the trial will test ORIN1001 in combination with Abraxane. Results: As of Jan 25, 2021, 22 patients with advanced cancer have received ORIN1001 dosed at 100mg, 200mg or 300mg per day in 21-day continuous cycles with a median age of 61 (range 42-77). The pts had received a median of 4 prior line of treatments. Two DLTs were observed at 200 mg with thrombocytopenia and rash. MTD has not been reached. Common (>15%) treatment-emergent adverse events (TEAEs) included nausea, vomiting, rash, fatigue, and hypokalaemia. The vast majority of these events were Grade 1-2 in severity. Seven (32%) pts had at least 1 TRAE grade≥ 3, the most frequent of which were thrombocytopenia (N=3) and rash (N=3). Preliminary pharmacokinetic analysis showed ORIN1001 exposure to increase in a dose proportional manner. Mean t1/2 at steady state was 18 hrs. Thirteen pts were evaluated for preliminary efficacy. Best response, per RECIST 1.1, was stable disease (SD) in 8 pts while 5 pts had progressive disease (PD). For 2 ongoing patients with advanced liver or colorectal cancer, duration of treatment has exceeded 300 days and 570 days, respectively. Conclusions: To date, the phase 1 part of the first-in-human trial has demonstrated a reasonable safety and pharmacokinetic profile for ORIN1001 at 100mg and 200mg dose levels. While efficacy data have yet to mature, chronic dosing achieved in pts with heavily treated advanced solid tumors, suggests clinical potential for in the setting of advanced solid cancers. The phase 2 part of the trial testing ORIN1001 in combination with Abraxane is currently enrolling pts with advanced breast cancer. Clinical trial information: NCT03950570.

100 Deals associated with Fosun Orinove Pharmatech Inc

100 Translational Medicine associated with Fosun Orinove Pharmatech Inc

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Drug(Targets)	Indications	Global Highest Phase

ORIN-103	Idiopathic Pulmonary Fibrosis More	Phase 2
orin10N	-	IND Application
ORIN-1001 ( IRE1 )	Advanced Malignant Solid Neoplasm More	Discontinued

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