Bodick Neil, Williamson Toni, Strand Vibeke, Senter Becca, Kelley Scott, Boyce Rogely, Lightfoot-Dunn Ruth
Flexion Therapeutics, Inc., Burlington, MA, USA.
Division of Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.
Rheumatol Ther. 2018 Dec;5(2):475-498. doi: 10.1007/s40744-018-0125-3. Epub 2018 Sep 10.
Single intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA-ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA-ER were assessed in normal canine knees in three nonclinical studies.
Knees were evaluated for up to 6 weeks or 9 months after a single injection of TA-ER (2.1/6.25/18.75 mg TA), or TA crystalline suspension (TAcs, 18.75 mg TA), and for up to 6 months after three injections (every 1 or 3 months) of TA-ER (6.25/18.75 mg TA) or TAcs (18.75 mg). Vehicle-diluent, blank microspheres, and untreated knees were used as controls. Plasma and synovial fluid (SF) TA concentrations and standard histopathological assessment of the synovium were conducted. Articular cartilage morphology was assessed via modified Mankin scoring.
Plasma and SF concentrations indicated prolonged dose-dependent TA joint residency with TA-ER compared with TAcs. Effects in articular cartilage were dose- and time-dependent and consistent with known effects of corticosteroids in the normal knee. Loss of Safranin O staining occurred, indicative of a reduction in cartilage matrix proteoglycan, and recovered in a similar manner for TA-ER and TAcs across all studies. Structural lesions were infrequent and generally comparable in severity between TA-ER and TAcs but slightly higher in incidence for TA-ER. Focal/multifocal foreign-body responses (FBR) to PLGA were observed in the superficial layer of the synovium, peaking after 4-6 weeks, with significant recovery or complete resolution by month 6.
These findings suggest that the effects of IA injections of TA-ER on cartilage are predominantly transient, and comparable to those observed with TAcs in the normal canine knee joint. These mild effects in the normal joint differ from the beneficial effects observed with TA-ER and other corticosteroids in disease models. The synovial FBR to PLGA microspheres was focal and transient.
Flexion Therapeutics, Inc. Plain language summary available for this article.
关节腔内单次注射聚乳酸-乙醇酸共聚物（PLGA）微球载体制的曲安奈德缓释剂（TA-ER，原称FX006）在膝骨关节炎患者中显示出持续的、具有临床意义的益处。在三项非临床研究中评估了TA-ER在正常犬膝关节中的局部效应。
单次注射TA-ER（2.1/6.25/18.75mg曲安奈德）或曲安奈德结晶悬液（TAcs，18.75mg曲安奈德）后，对膝关节进行长达6周或9个月的评估；在三次注射（每1或3个月一次）TA-ER（6.25/18.75mg曲安奈德）或TAcs（18.75mg）后，对膝关节进行长达6个月的评估。使用溶媒稀释剂、空白微球和未治疗的膝关节作为对照。检测血浆和滑液（SF）中的曲安奈德浓度，并对滑膜进行标准组织病理学评估。通过改良的曼金评分评估关节软骨形态。
与TAcs相比，血浆和SF浓度表明TA-ER使曲安奈德在关节内的驻留时间延长且呈剂量依赖性。对关节软骨的影响具有剂量和时间依赖性，且与皮质类固醇在正常膝关节中的已知作用一致。番红O染色消失，表明软骨基质蛋白聚糖减少，在所有研究中，TA-ER和TAcs的恢复方式相似。结构损伤很少见，TA-ER和TAcs之间的严重程度一般相当，但TA-ER的发生率略高。在滑膜表层观察到对PLGA的局灶性/多灶性异物反应（FBR），在4-6周后达到峰值，到第6个月时显著恢复或完全消退。
这些发现表明，关节腔内注射TA-ER对软骨的影响主要是短暂的，与在正常犬膝关节中观察到的TAcs的影响相当。在正常关节中的这些轻微影响与在疾病模型中观察到的TA-ER和其他皮质类固醇的有益作用不同。滑膜对PLGA微球的FBR是局灶性和短暂的。
Flexion Therapeutics公司。本文提供通俗易懂的总结。
