Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis.
Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis.
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DOI：
10.1002/art.40527
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Bay-Jensen AC
中科院分区：
文献类型：
--
作者：
Kjelgaard-Petersen CF;Platt A;Braddock M;Jenkins MA;Musa K;Graham E;Gantzel T;Slynn G;Weinblatt ME;Karsdal MA;Thudium CS;Bay-Jensen AC
风湿性关节炎（RA）是一种慢性退行性自身免疫性关节疾病，可导致残疾、生活质量降低和死亡率增加。虽然有几种合成和生物疾病缓解抗风湿药物可用，但仍然需要控制疾病进展的新药。由于只有10%的进入I期试验的治疗RA的实验性候选药物最终被美国食品和药物管理局注册，因此迫切需要翻译工具来促进药物开发的早期决策。在这项研究中，我们的目的是确定是否可以在开发过程的早期预测到fostamatinib（一种Syk的小分子抑制剂）在先前临床研究的III期中无法证明足够的疗效。在基线和随访时，在风湿性关节炎口服Syk抑制1研究（OSKIRA-1，一项评估fostamatinib治疗RA疗效的III期临床研究）的450份血清样本中测量了骨、软骨和间质基质转换的生物标志物（I型胶原C端肽[CTX-I]，基质金属蛋白酶衍生的I、II和III型胶原新表位[C1 M、C2 M和C3 M]）。此外，随后在用福他替尼的活性代谢产物R406培养的破骨细胞、软骨和滑膜的条件培养基中测量相同的生物标志物，以评估药物诱导的抑制水平。在OSKIRA-1血清样本以及破骨细胞和软骨培养物中，fostamatinib抑制了CTX-I和C2M的水平。在OSKIRA-1血清样本和滑膜培养物中，fostamatinib对C1 M或C3 M没有介导任何临床或临床前效应，这些效应之前与疾病缓解和疗效相关。这些数据表明，翻译生物标志物是早期评估和制定RA治疗药物开发决策的潜在工具。
Rheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease‐modifying antirheumatic drugs are available, there is still a medical need for novel drugs that control disease progression. As only 10% of experimental drug candidates for treatment of RA that enter phase I trials are eventually registered by the Food and Drug Administration, there is an immediate need for translational tools to facilitate early decision‐making in drug development. In this study, we aimed to determine if the inability of fostamatinib (a small molecule inhibitor of Syk) to demonstrate sufficient efficacy in phase III of a previous clinical study could have been predicted earlier in the development process. Biomarkers of bone, cartilage, and interstitial matrix turnover (C‐telopeptide of type I collagen [CTX‐I], matrix metalloproteinase–derived types I, II, and III collagen neoepitopes [C1M, C2M, and C3M]) were measured in 450 serum samples from the Oral Syk Inhibition in Rheumatoid Arthritis 1 study (OSKIRA‐1, a phase III clinical study of the efficacy of fostamatinib in RA) at baseline and follow‐up. Additionally, the same biomarkers were subsequently measured in conditioned media from osteoclast, cartilage, and synovial membrane cultured with the active metabolite of fostamatinib, R406, to assess the level of suppression induced by the drug. In OSKIRA‐1 serum samples and osteoclast and cartilage cultures, fostamatinib suppressed the levels of CTX‐I and C2M. In OSKIRA‐1 serum samples and synovial membrane cultures, fostamatinib did not mediate any clinical or preclinical effect on either C1M or C3M, which have previously been associated with disease response and efficacy. These data demonstrate that translational biomarkers are a potential tool for early assessment and decision‐making in drug development for RA treatment.
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影响因子：
4.9
作者：
Aschenberg S;Finzel S;Schmidt S;Kraus S;Engelke K;Englbrecht M;Rech J;Schett G
通讯作者：
Schett G
DOI：
10.3109/1354750x.2015.1105497
发表时间：
2015
期刊：
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals
影响因子：
--
作者：
Kjelgaard-Petersen C;Siebuhr AS;Christiansen T;Ladel C;Karsdal M;Bay-Jensen AC
通讯作者：
Bay-Jensen AC
影响因子：
2.8
作者：
Bay-Jensen, Anne-Christine;Liu, Qi;Karsdal, Morten A.
通讯作者：
Karsdal, Morten A.
影响因子：
82.9
作者：
Faccio, R;Teitelbaum, SL;Swat, W
通讯作者：
Swat, W
影响因子：
3.7
作者：
Bay-Jensen, Anne C.;Wichuk, Stephanie;Maksymowych, Walter P.
通讯作者：
Maksymowych, Walter P.