A Phase 2, Randomized, Open-Label Study to Assess the Safety and Efficacy of GPC 100 and Propranolol With and Without G-CSF for the Mobilization of Stem Cells in Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant

This is a randomized, open-label study. Patients will be screened within 28 days prior to the study drug administration. Patients will be randomly assigned to 1 of 2 treatment arms prior to study drug administration.
Approximately 40 patients will be randomized in a 1:1 ratio to the following treatment arms:
* GPC-100 in combination with propranolol; or
* GPC-100 in combination with propranolol and G-CSF. To characterize the safety and clinical activity of GPC-100, the study will employ a Bayesian Optimal Phase II (BOP2) design to enroll patients for each arm.
All patients will receive via IV 3.14 mg/kg GPC-100 (Burixafor) at least 2 hours prior to leukapheresis sessions from Days 7-8 (Days 9-11 optional) and 30 mg propranolol (3 x 10 mg tablets) twice daily at 8:30 AM (+/- 1 hr) and 4:00 PM (+/- 1 hr) local time from Days 1 to 8 (and on Days 9-11, if applicable). Patients will administer the first dose of propranolol onsite on Day 1. Patients will be provided with doses of propranolol for self-administration at time points when they are not otherwise required to be onsite. Sites should contact patients via telephone to confirm propranolol administration for doses administered outside of clinic.

开始日期2023-02-13

申办/合作机构

GPCR Therapeutics, Inc.

CTR20130291 / Completed临床1期

评估布利沙福并用阿糖胞苷及氟达拉滨治疗复发或难治性急性髓系白血病成人患者安全性及有效性的I期临床研究

1.确定本品并用阿糖胞苷及氟达拉滨来治疗复发或难治性急性髓系白血病成人患者的最高耐受剂量。评估患者的安全性及耐受性；完全缓解率（包括CR和CRi）;无病生存期、总生存期和造血恢复时间。 2.评估布利沙福对急性髓系白血病细胞的动员特征。 3.评估布利沙福的药代动力学特征。

开始日期2015-07-28

申办/合作机构

太景医药研发（北京）有限公司

NCT02104427 / Completed临床2期

A Phase II, Open-Label Study to Evaluate the Hematopoietic Stem Cell Mobilization of TG-0054 Combined With G-CSF in Patients With Multiple Myeloma, Non-Hodgkin Lymphoma or Hodgkin Disease

This is a phase II study to evaluate the efficacy and safety of TG-0054 combined with G-CSF in mobilizing hematopoietic stem cells in patients with multiple myeloma, non-Hodgkin lymphoma or Hodgkin disease.

开始日期2015-02-01

申办/合作机构

GPCR Therapeutics, Inc.

100 项与氢溴酸布利沙福相关的临床结果

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100 项与氢溴酸布利沙福相关的转化医学

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100 项与氢溴酸布利沙福相关的专利（医药）

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项与氢溴酸布利沙福相关的文献（医药）

2023-11-01·Clinical pharmacology in drug development

Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC‐100), a Novel C‐X‐C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects

Article

作者: Caculitan, Niña G ; Sukhtankar, Devki D ; Chang, Li-Wen ; Cardarelli, Pina M ; Tsai, Cheng-Yuan

Abstract:

Adequate mobilization of hematopoietic stem cells (HSCs), especially CD34+ cells, is necessary for stem cell transplantation in patients with hematological malignancies or autoimmune diseases. Burixafor is an inhibitor of the C‐X‐C Chemokine Receptor 4 that disrupts the C‐X‐C motif chemokine 12 (CXCL12)/CXCR4 axis in the bone marrow, releasing HSCs into circulation. In mice, a single intravenous dose of burixafor was rapidly absorbed (time to maximum concentration, 5 minutes) and increased peripheral white blood cell counts within 30 minutes. Additionally, burixafor was administered to 64 healthy subjects in a randomized, double‐blind, placebo‐controlled, single‐ascending‐dose study to evaluate safety, pharmacokinetics, and pharmacodynamics. Subjects received burixafor intravenous doses ranging from 0.10 to 4.40 mg/kg in 8 cohorts. Single doses were generally safe and well tolerated. Gastrointestinal events were reported at doses of 2.24 mg/kg or greater. Exposure (maximum concentration and area under the concentration–time curve) increased in an approximately dose‐proportional manner. Time to maximum concentration occurred with a median of 0.26–0.30 hours that was not dose proportional. As expected, white blood cell, CD133+ cell, and CD34+ cell concentrations generally increased with the increases in burixafor dose from 0.10 to 3.14 mg/kg. At maximal levels, the CD34+ cell counts increased 3‐ to 14‐fold from baseline levels. These results provide support for continued clinical development of burixafor.

2020-11-01·Journal of molecular graphics & modelling4区 · 生物学

Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment

4区 · 生物学

Article

作者: Teralı, Kerem ; Baddal, Buket ; Gülcan, Hayrettin Ozan

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.

2018-12-01·Transplantation2区 · 医学

CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-based Immunosuppressive Regimen

2区 · 医学

Article

作者: Wu, Kenneth Kun-Yu ; Tseng, Ya-Hsuan ; Lin, Cheng-Hsin ; Hsu, Ming-Chu ; Lee, Chii-Ming ; Shun, Chia-Tung ; Hsu, Wan-Tseng ; Jui, Hsiang-Yiang

Background:

CXC motif chemokine receptor 4 (CXCR4) blockade is pursued as an alternative to mesenchymal stem cell treatment in transplantation based on our previous report that burixafor, through CXCR4 antagonism, mobilizes immunomodulatory mesenchymal stem cells. Here, we explored the efficacy of combining mycophenolate mofetil (MMF)-based immunosuppressants with repetitive burixafor administration.

Methods:

Swine heterotopic cardiac allograft recipients received MMF and corticosteroids (control, n = 10) combined with burixafor as a 2-dose (burixafor2D, n = 7) or 2-dose plus booster injections (burixafor2D + B, n = 5) regimen. The efficacy endpoints were graft survival, freedom from first acute rejection, and the severity of intimal hyperplasia. Each specimen was sacrificed either at its first graft arrest or after 150 days.

Results:

After 150 days, all specimens in the control group had died, but 28.5% of the burixafor2D group survived, and 60% of the burixafor2D + B group survived (P = 0.0088). Although the control group demonstrated acute rejection at a median of 33.5 days, the burixafor2D + B group survived without acute rejection for a median of 136 days (P = 0.0209). Burixafor administration significantly attenuated the incidence rate of acute rejection (P = 0.002) and the severity of intimal hyperplasia (P = 0.0097) at end point relative to the controls. These findings were associated with reduced cell infiltrates in the allografts, and modulation of C-reactive protein profiles in the circulation.

Conclusions:

The augmentation of conventional MMF plus corticosteroids with a CXCR4 antagonist is potentially effective in improving outcomes after heart transplantation in minipigs. Future studies are warranted into optimizing the therapeutic regimens for humans.

项与氢溴酸布利沙福相关的新闻（医药）

2024-04-01

·BioSpace

GPCR Therapeutics Announces Publication in PNAS Using Cutting Edge Spectroscopy to Detect GPCR Heteromers on Live Cancer Cells

- Further validates company’s dual GPCR targeting approach SEOUL, South Korea & REDWOOD CITY, Calif.--(BUSINESS WIRE)-- GPCR Therapeutics, Inc., a clinical-stage, international biopharmaceutical company, is pleased to announce the publication in the esteemed scientific journal, Proceedings of the National Academy of Sciences (PNAS) that was spearheaded by Dr. Niña Caculitan, Director of Clinical Development. This research underscores the company’s commitment to targeting diseases with cutting-edge approaches against GPCRs and discovering novel therapeutics. Detection of multimeric complexes by CXCR4 with other GPCRs in a live-cell environment validates the dual GPCR targeting hypothesis. The paper, authored in collaboration with Prof. Adam Smith, Associate Professor at Texas Tech University, is titled “The β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells.” Both CXCR4 and β2AR receptors play active roles in oncogenesis. The work uses time-resolved fluorescence spectroscopy to quantify CXCR4 and β2AR interactions as they form complexes in live cells under physiological conditions. Differential propensities of GPCRs to cluster in non-cancer versus cancer cell lines was observed, suggesting that GPCR multimerization is significantly affected by the plasma membrane environment. Furthermore, the ligand for β2AR, epinephrine, increases the CXCR4-β2AR heteromerization. Thus, antagonizing its binding could decrease heteromerization and may have therapeutic benefits that can be missed by targeting only CXCR4. This supports the development of new drugs to treat CXCR4-positive cancers using combination therapies. Dr. Dong Seung Seen, Founder and CEO of GPCR Therapeutics based in Seoul, spoke about Dr. Caculitan’s accomplishments. “Dr. Caculitan represents the highest ideals that our entire team strive for. It is this level of understanding complex science that will lead us to success with the unique approach upon which our company was founded.” References: (2024). The β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells. Proceedings of the National Academy of Sciences, 121(14), e2304897121. About GPCR Therapeutics GPCR Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing therapeutics built on its proprietary GPCR data. GPCR Therapeutics has its HQ in Seoul and a subsidiary in the San Francisco Bay Area, USA. The company’s lead asset, GPC-100/Burixafor, targets CXCR4. GPCR has a US phase 2 trial of GPC-100, G-CSF and Propranolol, a beta blocker, for stem cell mobilization in multiple myeloma patients (NCT05561751). For more information, please visit gpcr.co.kr and follow us on LinkedIn.

临床2期AACR会议

2023-12-14

·BioSpace

GPCR Therapeutics Announces Out-Licensing Agreement with Bridge Biotherapeutics in Idiopathic Pulmonary Fibrosis

SEOUL, Korea and REDWOOD CITY, Calif., Dec. 14, 2023 (GLOBE NEWSWIRE) -- GPCR Therapeutics, Inc., a clinical-stage international biopharmaceutical company, announces it enters into an out-licensing agreement with Bridge Biotherapeutics (KQ288330) for the CXCR4-LPA1 inhibitor combination method of treatment. GPCR receives an upfront payment of KRW 2 billion (approx. USD 1.5 million), and a 50:50 profit-share on future commercialization, including sub-licenses. In collaboration with Bridge Biotherapeutics, GPCR will pursue joint development and commercialization of the combination therapy. Conducting a multinational phase 2a clinical trial of BBT-877, an autotaxin inhibitor for the treatment of IPF, Bridge Biotherapeutics has been accelerating development of its proprietary IPF pipeline. Last September, GPCR published the paper on the direct interaction between two different GPCRs, CXCR4 and LPA1, in the peer-reviewed academic journal ‘Cell Communication and Signaling’(1). The target GPCRs are known to promote fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Through various in vitro experiments, the company found that the efficacy of LPA1 inhibition can be further maximized by inhibition of CXCR4, thereby securing a scientific basis that the CXCR4- LPA1 inhibitor combination may be necessary for full anti-fibrotic activity. Based on this finding, GPCR filed a provisional patent application on the CXCR4-LPA1 inhibitor combination method of treatment. Dr. Dong Seung Seen, founder and CEO of GPCR Therapeutics, commented, “Since the publication of our paper, various global companies have expressed interest in the relationship between LPA1 and CXCR4 and its inhibitory effect. Due to the versatility of our patent, we look forward to collaborating with many IPF-targeting companies, starting with Bridge Biotherapeutics.” James Lee, founder and CEO of Bridge Biotherapeutics, said, “We are encouraged to collaborate with GPCR Therapeutics to uncover new possibilities of IPF treatment. Our collaboration will help us move forward to identifying and bringing novel treatment of IPF, such as a combination therapy of LPA1 and CXCR4 inhibitor, based on GPCR’s latest research.” IPF is a progressive chronic lung condition that causes scarring (fibrosis) of a patients’ lungs which makes breathing increasingly difficult as the lungs become stiffer and lose their elasticity. The lungs become less efficient at transferring oxygen so that when someone with IPF breathes in, the transfer of oxygen through air sacs in their lungs and into their blood stream is impaired. Lung damage from IPF is irreversible, and there is currently no treatment that stops or reverses the scarring. In the US there are around 495 cases per 100,000 people, with median survival estimated at 2–5 years from the time of diagnosis. (2) (3) References (1) Cell Communication and Signaling paper, “LPA1-mediated inhibition of CXCR4 attenuates CXCL12-induced signaling and cell migration”: (2) American Lung Association data on IPF: (3) PubMed paper on incidence and prevalence of IPF: About GPCR Therapeutics GPCR Therapeutics, Inc. is a clinical-stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has an ongoing US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and propranolol in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life-changing treatments for cancer and other diseases. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn. For more information, please contact: GPCR Therapeutics (in Seoul) DaYoon Kim - Business Development Manager Tel: +82-2-878-2848 dayoon.kim@gpcr.co.kr Scius Communications (in London): Katja Stout - Founder & Managing Partner +44 778 943 5990 katja@sciuscommunications.com Daniel Gooch - Partner +44 774 787 5479 daniel@sciuscommunications.com About Bridge Biotherapeutics, Inc. Bridge Biotherapeutics Inc., based in the Republic of Korea and the U.S., is a publicly traded, clinical-stage biotech company founded in 2015. Bridge Biotherapeutics is engaged in the discovery and development of novel therapeutics, focusing on therapeutic areas with high unmet needs, including fibrotic diseases and cancers. The company is developing BBT-877, a novel autotaxin inhibitor for the treatment of fibrotic diseases including idiopathic pulmonary fibrosis (IPF), and BBT-207, a potent targeted cancer therapy for non-small cell lung cancer (NSCLC) with EGFR C797S mutations. Learn more at

引进/卖出临床2期

2023-10-26

·GlobeNewswire-Health Care

GPCR Therapeutics Announces Publication on Improving Hematopoietic Stem Cell Mobilization Using Propranolol with GPC-100

Paper in PLOS ONE Reinforces Potential for Combination Therapy in Hematological MalignanciesSEOUL, Korea and REDWOOD CITY, Calif., Oct. 26, 2023 (GLOBE NEWSWIRE) -- GPCR Therapeutics, Inc., a clinical stage international biopharmaceutical company with an innovative approach to developing cancer therapeutics based on targeting G Protein Coupled Receptors (GPCR) pairs, announces publication of a research paper in PLOS ONE. The paper shows that the company’s lead small molecule asset, GPC-100, a novel CXCR4 antagonist and a potent hematopoietic stem cell (HSC) mobilizer, when combined with the beta-adrenergic receptor blocker propranolol, results in a significant increase in circulating HSCs in mice. These findings strongly support the use of this combination for peripheral blood HSC harvest in autologous stem cell transplant treatment in hematological cancers. The paper, authored in collaboration with Seoul National University’s School of Biological Sciences and Institute of Microbiology, is entitled, “GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol” (1). The authors highlight that GPC-100 alone shows greater mobilization efficacy than a drug already approved for stem cell mobilization. Importantly, when combined with propranolol, GPC-100-induced HSC mobilization increases by another 2-fold. The mobilization efficiency by GPC-100 plus propranolol is similar to that of the standard of care treatment with granulocyte-colony stimulating factor (G-CSF). Together, this study suggests a strategy with a potential to mobilize sufficient HSC without the use of G-CSF, and thereby reduce the risk of G-CSF associated moderate to severe side effects such as severe bone pain. This also provides a better stem cell transplant treatment option for cancer patients with autoimmune diseases which may be exacerbated by G-CSF or sickle cell disease, where it is contraindicated. Finally, the paper supports that the triple combination of GPC-100 plus propranolol and G-CSF mobilizes a greater number of HSCs compared to the standards of care and is predicted to be a best-in-class mobilizer. Dr. Dong Seung Seen, GPCR Therapeutics’ founder and CEO, commented, “This latest high-quality paper, produced in close collaboration between our Korean and US sites, together with Seoul National University, shines a spotlight on the potential for our lead asset, GPC-100, to be used with propranolol as a combination therapy for hematological malignancies, including multiple myeloma. Our discovery of this powerful functional relationship provides new hope in this notoriously hard to treat cancer.” Hematological malignancies, such as multiple myeloma, are hard to treat. Increasingly, clinicians are using Autologous Stem Cell Transplant (ASCT) to treat patients, which has improved the anti-cancer response and survival compared to conventional chemotherapy. However, for ASCT to work well, hematopoietic stem cells, especially CD34+ cells, need to be successfully mobilized out of the patient’s bone marrow and into their peripheral blood, where the cells are more easily collected, and can then be stored for later transplantation. A key limiting factor is that mobilization is often inadequate, and insufficient cells are harvested for use in the patient’s treatment. This paper reports on how this common treatment limitation could be overcome through use of a combination of GPC-100 and propranolol. As announced on 17 January 2023, the company has initiated a phase 2 trial in the US for GPC-100, which targets CXCR4, one of the most prevalent chemokine GPCRs over-expressed in more than 23 cancers. This randomized, open-label phase 2 study assesses the efficacy of GPC-100 and propranolol, with and without G-CSF, for the mobilization of stem cells in patients with multiple myeloma undergoing ASCT. The paper announced today supports this clinical trial. References (1) https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0287863 ※ More than 35% of FDA approved drugs are GPCRs. Still, GPCRs’ complex pharmacology arising from their interactions with other GPCRs presents unique opportunities for drug development. About GPCR Therapeutics GPCR Therapeutics, Inc. is a clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has recently initiated a US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and propranolol in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn. For more information, please contact: GPCR Therapeutics (in Seoul)DaYoon Kim - Business Development ManagerTel: +82-2-878-2848dayoon.kim@gpcr.co.kr

临床2期细胞疗法

100 项与氢溴酸布利沙福相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11970

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
霍奇金淋巴瘤	临床2期	中国台湾	GPCR Therapeutics, Inc.	2010-02-01
多发性骨髓瘤	临床2期	中国台湾	GPCR Therapeutics, Inc.	2010-02-01
急性髓性白血病	临床1期	中国	太景医药研发（北京）有限公司	2015-07-28

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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


NCT05561751 (ASH2024) 人工标引	临床2期	多发性骨髓瘤 CD34+	20	Propranolol+G-CSF+ Burixafor	廠蓋選鹽醖餘膚餘網鬱(壓簾艱鏇鬱積齋窪鹽夢) = 鑰積選壓選窪鑰壓鹹製繭製蓋範築醖糧範憲膚 (鹽糧壓鏇壓選積鹹積夢 )	积极	2024-12-09
ASH2024	N/A	急性髓性白血病	-	CXCR4 inhibitor GPC-100 (burixafor)	簾淵蓋獵糧鹽夢壓廠襯(觸獵鏇鹽製膚鬱醖糧網) = 觸蓋積淵艱糧鬱膚廠鑰窪觸餘鏇鹹蓋糧鹹願艱 (餘齋範遞簾夢鏇鬱壓觸 )	-	2024-12-08
ASH2024	N/A	急性髓性白血病	-	Beta 2 adrenergic receptor blocker (propranolol)	製餘鏇繭齋鏇壓觸簾獵(願構壓構憲憲鏇艱齋襯) = 鑰艱鑰製廠餘觸鏇齋齋壓築願鏇壓鏇鹹艱範遞 (餘壓選襯積構憲遞衊餘, 0.4 ~ 20.1)	-	2024-12-08
NCT01458288 (CTgov)	临床2期	霍奇金淋巴瘤 \| 多发性骨髓瘤	12	TG-0054	繭鬱窪壓餘鹹構鹹壓選(顧顧蓋艱糧顧選蓋壓選) = 艱齋衊鬱觸齋艱製獵築選夢鬱製鑰淵願簾顧壓 (齋廠範鹽憲齋鹽築鹹鏇, 廠壓艱願衊簾襯齋窪鏇 ~ 鏇選膚積顧夢構鹹網淵) 更多	-	2015-01-08