A Phase 2B, Double-blind, Randomized, Placebo-controlled, Proof-of-concept Study of an Oral Vitamin D Compound (DP001) in Secondary Hyperparathyroidism in Patients on Hemodialysis

The goal of this study is to test a new vitamin D compound for its ability to reduce parathyroid hormone levels in patients who are on hemodialysis.

开始日期2013-09-01

申办/合作机构

Deltanoid Pharmaceuticals, Inc.

NCT01653379

/ Completed临床2期

A Phase 2A, Open-label, Dose-ranging and Pharmacokinetic Study of an Oral Vitamin D Compound (DP001) in Secondary Hyperparathyroidism in Patients on Hemodialysis

This is an open-label, dose-ranging study of the vitamin D analog DP001 in patients with end-stage renal disease (ESRD). The primary goals of this 4-week Phase 2A study are to identify an appropriate starting dose of DP001 to be used in subsequent studies in this population and for evaluation of pharmacokinetics of DP001 in ESRD patients.

开始日期2012-08-01

申办/合作机构

Deltanoid Pharmaceuticals, Inc.

NCT00715676

/ Completed临床2期

A Phase 2, Double-blind, Randomized, Placebo-Controlled, Daily-dose, Proof-of-concept Study of a Vitamin D Compound in Postmenopausal Women With Osteopenia

This study will evaluate the effect of a 1-year administration of the vitamin D analog 2-methylene-19-nor-(20S)-1alpha, 25-dihydroxyvitamin D3 (DP001) on bone mineral density (BMD), safety, and tolerability.

开始日期2007-03-01

申办/合作机构

Deltanoid Pharmaceuticals, Inc.

100 项与 DP-001 相关的临床结果

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100 项与 DP-001 相关的转化医学

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100 项与 DP-001 相关的专利（医药）

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项与 DP-001 相关的文献（医药）

2020-12-01·Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research1区 · 医学

A New 1,25 Dihydroxy Vitamin D Analog with Strong Bone Anabolic Activity in OVX Rats with Little or no Bone Resorptive Activity

1区 · 医学

Article

作者: Zella, Julia ; DeLuca, Hector F ; Clagett-Dame, Margaret ; Plum, Lori A

ABSTRACT:

A new 1α,25-dihydroxy vitamin D3 analog (2-methylene-22(E)-(24R)-22-dehydro-1α,24,25-trihydroxy-19-norvitamin D3 or WT-51) has been tested as a possible therapeutic for osteoporosis. It is 1/10th as active as 1,25(OH)2D3 in binding affinity for the vitamin D receptor but is at least 200 times more active than 1,25(OH)2D3 and equal to that of 2MD (2-methylene-19-nor-(20S)-1α,25(OH)2D3, an analog previously tested in postmenopausal women), in supporting bone formation by isolated osteoblasts in culture. However, in contrast to 2MD, it is virtually inactive on bone resorption in vivo. WT-51 markedly increased bone mass (lumbar and femur) in ovariectomized (OVX) female rats. Further, bone strength tested by the three-point bending system is significantly increased by WT-51. Thus, WT-51 is an attractive candidate for the treatment of postmenopausal osteoporosis. © 2019 American Society for Bone and Mineral Research.

2020-07-09·Journal of medicinal chemistry1区 · 医学

Synthesis and Biological Activity of 2,22-Dimethylene Analogues of 19-Norcalcitriol and Related Compounds

1区 · 医学

Article

作者: Sibilska-Kaminski, Izabela K. ; Plum, Lori A. ; Sicinski, Rafal R. ; DeLuca, Hector F.

Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D₃ analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig-Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D₂.

2017-12-01·Drugs in R&D4区 · 医学

Pharmacokinetics of a New Oral Vitamin D Receptor Activator (2-Methylene-19-Nor-(20S)-1α,25-Dihydroxyvitamin D3) in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism on Hemodialysis

4区 · 医学

ArticleOA

作者: Plum, Lori A ; DeLuca, Hector F ; Zella, Julia B ; Coyne, Daniel W ; Bedale, Wendy ; Blaser, William J ; Zhu, Jinge G ; Pandey, Richa ; Clagett-Dame, Margaret

BACKGROUND:

2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (DP001 or 2MD) is a novel, potent 1α-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid hormone synthesis and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis.

METHODS:

DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose.

RESULTS:

After the first and final dose, the half-life of DP001 was similar (55.8 ± 13.0 and 50.8 ± 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 ± 0.8 h, with a concentration maximum of 3.4 ± 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 ± 23.9 pg h/mL, and apparent volume of distribution was 2.03 ± 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 ± 52 vs 462 ± 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus.

CONCLUSIONS:

In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2-3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism.

项与 DP-001 相关的新闻（医药）

2024-09-15

·今日头条

复旦大学附属肿瘤医院胡夕春团队：HER2阳性实体瘤患者靶向抗体-药物DP303c的首次人体研究结果

【导读】 DP303c是一种靶向HER2的ADC，具有可切割的接头-MMAE有效载荷。先前的体外研究表明，DP303c在异种移植模型中，显示出与T-DM1相似或更好的抗肿瘤活性。这是一项在中国进行的多中心、剂量递增和剂量扩展1期研究。 2024年9月12日，复旦大学附属肿瘤医院胡夕春团队在期刊《npj Precision Oncology》上发表了题为“First-in-human study of DP303c, a HER2-targeted antibody-drug conjugate in patients with HER2 positive solid tumors”的研究论文。研究结果表明，DP303c在既往治疗的晚期HER2阳性实体瘤患者中，表现出有希望的抗肿瘤活性和可接受的安全性，尤其是在乳腺癌中。 https://www.nature.com/articles/s41698-024-00687-7 研究背景 01 人表皮生长因子受体2（HER2）在20%-25%的乳腺癌、20%-30%的卵巢癌和15-20%的胃癌中过表达，并与攻击性行为、高复发风险和不良预后有关。几项研究表明，HER2靶向治疗，已被证明可以改善HER2阳性肿瘤的生存预后。到目前为止，中国有几种HER2靶向疗法可用，包括曲妥珠单抗、帕妥珠单抗、抗HER2酪氨酸激酶抑制剂（lapatinib、pyrotinib、niratinib）、抗体偶联药物（ADC、曲妥珠单抗emtansine、曲妥珠单抗 deruxtecan和disitamab vedotin）。尽管目前有可用的药物，但很大一部分晚期实体瘤患者在接受HER2靶向治疗后，出现进展性疾病。 ADC已成为一种快速增长的抗癌疗法，它被设计为一种高效的药物递送系统，使强效细胞毒素能够进入癌细胞，同时保留非恶性细胞，从而限制脱靶不良反应的风险。影响ADC活性的5个关键因素，是靶抗原、抗体、接头、细胞毒性有效载荷和偶联方法。到目前为止，ADC药物的开发，可以细分为三代，在鉴定新抗原、全人源化抗体、具有最佳毒性和旁观者效应的新有效载荷，以及设计新的连接子，以平衡稳定性和有效载荷释放方面，取得了更大的进展。作为第二代HER2靶向ADC，DP303c由人免疫球蛋白G1（IgG1）抗HER2抗体（DP001）、一种基于酶的可切割肽接头和两种微管蛋白聚合抑制剂（MMAE）组成。DP001使用稳定的中国仓鼠卵巢（CHO）细胞系生产，与曲妥珠单抗具有相同的氨基酸序列。在这项研究中，团队报告了一项首次人体、1期、多中心、开放标签、剂量递增和剂量扩展研究，以评估DP303c在HER2阳性晚期实体瘤（NCT04146610）患者中的安全性和耐受性、药代动力学、免疫原性和疗效。研究进展 02 疗效截至2023年2月28日，中位随访时间为12.0（范围1.7-35.2）个月。在91例可评估疗效的患者中，39例患者达到客观反应（42.9%，95%置信区间[CI] 32.5-53.7），包括32例确诊反应和7例未确认反应。1例反应（1/3，33.3%）发生在1.0mg/kg Q3W时，2例反应（2/6，33.3%）发生在2.0mg/kg Q3W时，32例反应（32/75，42.7%），4例反应（4/6，66.7%）发生在4.0mg/kg Q3W时。在62例患者中，观察到疾病控制（68.1%，95%CI 57.5-77.5）。在39名达到完全缓解和部分缓解（PR）的患者中，中位缓解持续时间（DoR）为11.0[95%CI 4.0未达到（NR）] 个月，缓解时间（TTR）为1.7（范围1.2-8.4）个月。总体而言，64例患者（68.1%）存在无进展生存期（PFS）事件，所有患者的中位PFS为 4.4（95%CI 3.4-6.4）个月。在66例疗效可评估的乳腺癌患者中，34例患者（51.5%）达到客观反应，51例患者（77.3%，95%CI 65.3-86.7）得到控制。所有乳腺癌患者的中位PFS，为 6.4（95%CI 4.1-8.5）个月。52例患者（78.8%）有一定程度的肿瘤缩小，其中，36例患者目标病灶直径总和减少≥30%。乳腺癌患者的预先指定亚组分析显示，几个预后亚组的反应一致，除了接受抗HER2 ADC预处理的患者的客观缓解率（ORR）和疾病控制率（DCR）（ORR：40.9% [9/22，95%CI 20.7-63.6]，DCR：63.6% [14/22，95%CI 40.7-82.8]）略低于接受曲妥珠单抗预处理的患者（ORR：53.1% [34/64，95%CI 40.2–65.7]， DCR：79.7% [51/64，95%CI 67.8–88.7]）、帕妥珠单抗（ORR：53.6% [15/28，95%CI 33.9–72.5]， DCR：78.6% [22/28，95%CI 59.0–91.7]）和抗HER2酪氨酸激酶抑制剂（ORR：49.2%（29/59，95%CI 35.9–62.5），DCR：76.3% [45/59，95%CI 63.4–86.4]）。脑转移患者（64.3%，95%CI 35.1-87.2）与肺转移（58.1%，95%CI 39.1-75.5）、骨转移（54.8%， 95%CI 36.0-72.7）、肝转移（48.1%，95%CI 28.7-68.1）和其他转移（52.9%，95%CI 38.5-67.1）患者的ORR相似。在结直肠癌和胃癌亚组的分析中，ORR分别为10.0%（1/10， 95%CI 0.3–44.5）、25.0%（2/8， 95%CI 3.2–65.1），DCR分别为30.0%（3/10， 95%CI 6.7–65.2）、50.0%（4/8，95%CI 15.7–84.3）。此外，在唾液腺癌患者（n = 1）和小肠癌患者（n = 1）中，也观察到PR。乳腺癌患者的肿瘤反应。药代动力学和免疫原性分析在首次以1.0至4.0mg/kg的剂量施用DP303c后，DP303c和总抗体在药代动力学特征上表现出相似性，其特征是相似的暴露水平、较长的半衰期和低清除率。在3.0mg/kg的剂量水平下，t1/2DP303c和总抗体，分别为DP303c首次给药后2.98天和2.81天。 89例患者在1.0至4.0mg/kg的DP303c治疗后，获得免疫原性数据，仅在3.0mg/kg组中，观察到抗DP303c抗体（ADA）阳性，治疗后ADAs发生率为11.0%（8/73）。ADA阳性样本患者和ADA阴性样本患者，DP303c暴露无显著差异。 DP303c在剂量递增阶段的药代动力学特征。研究结论 03 DP303c在既往治疗的HER2阳性晚期实体瘤患者中，显示出有希望的抗肿瘤活性和可接受的安全性，尤其是在HER2阳性乳腺癌中。结合DP303c的安全性、有效性和PK曲线，这项研究扩大到了3.0mg/kg Q3W，结果支持3.0mg/kg Q3W被确定为推荐的2期剂量（RP2D）。参考资料： 1.Costa, R. L. B., Brian, J. & Czerniecki, B. J. Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond. NPJ Breast Cancer 6, 10 (2020). 2.Ahn, S., Woo, J. W., Lee, K. & Park, S. Y. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J. Pathol. Transl. Med. 54, 34–44 (2020). 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会点击对应文字查看详情

抗体药物偶联物临床结果临床1期

100 项与 DP-001 相关的药物交易

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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
终末期肾脏病	临床2期	美国	Deltanoid Pharmaceuticals, Inc.	2013-09-01
继发性甲状旁腺功能亢进症	临床2期	美国	Deltanoid Pharmaceuticals, Inc.	2012-08-01
骨质疏松症	临床2期	美国	Deltanoid Pharmaceuticals, Inc.	2007-03-01
绝经期后骨质疏松	临床2期	-	Pfizer Inc.	-
绝经期后骨质疏松	临床2期	-	University of Wisconsin-Madison	-

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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


NCT01922843 (2MD-7H-2B, Pubmed \| Am J Nephrol) 人工标引	临床2期	继发性甲状旁腺功能亢进症	62	2MD	製憲憲繭網襯積獵構範(願網範窪鑰製選齋淵鹽) = 積齋鑰窪範衊衊選獵淵廠積鹹願遞構獵網構簾 (觸鬱膚膚鬱積膚鏇鬱顧 ) 更多	积极	2017-01-01
				Placebo	製憲憲繭網襯積獵構範(願網範窪鑰製選齋淵鹽) = 選膚築範餘獵齋醖壓鑰廠積鹹願遞構獵網構簾 (觸鬱膚膚鬱積膚鏇鬱顧 ) 更多
NCT00715676 (2MD-3H-2B, CTgov)	临床2期	骨质疏松症	157	Placebo (Placebo)	衊夢網鑰糧糧選選醖憲(簾構顧積積觸積蓋觸繭) = 顧餘醖鑰選鏇鹹製選淵憲獵鬱衊夢蓋衊鑰淵繭 (餘構廠願鑰憲顧鬱繭鬱, 2.545) 更多	-	2010-01-11
				DP001 (220 ng DP001)	衊夢網鑰糧糧選選醖憲(簾構顧積積觸積蓋觸繭) = 餘鬱鏇積繭製選鑰衊選憲獵鬱衊夢蓋衊鑰淵繭 (餘構廠願鑰憲顧鬱繭鬱, 2.820) 更多