Department of Neurological Surgery, University of California, Davis, Sacramento, CA, USA.
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
Spine J. 2024 Dec;24(12):2285-2296. doi: 10.1016/j.spinee.2024.08.006. Epub 2024 Aug 19.
SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH.
The Discovery 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH.
STUDY DESIGN/SETTING: A randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States.
Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks.
The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings.
Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery.
Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p-values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=.0223) and Week 52 (p=.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred.
Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies.
SI-6603（Condoliase）是一种化学核溶解剂，于 2018 年在日本获得批准，用于治疗与神经根性腿部疼痛相关的腰椎间盘突出症（LDH）。Condoliase 是一种具有高度糖胺聚糖（GAG）底物特异性的粘多糖酶，通过降解髓核中的 GAG 提供独特的作用机制。由于 LDH 的管理目前仅限于保守方法和手术干预，因此对于对保守治疗策略无反应的患者，Condoliase 可能提供一种比手术更具侵入性的治疗选择。
Discovery 6603 研究（NCT03607838）评估了单次注射 SI-6603（Condoliase）与假对照治疗与 LDH 相关的神经根性腿部疼痛的疗效和安全性。
研究设计/设置：在美国 41 个地点进行的一项随机、双盲、假对照、3 期研究。
352 名男性和女性参与者（年龄 30-70 岁），具有局限于后外侧的 LDH 和单侧神经根病变/神经根性腿部疼痛超过 6 周。
从基线（CFB）到 13 周时平均最差腿部疼痛评分的变化，使用 100mm 视觉模拟量表进行评估。关键次要终点：在第 52 周时 CFB 平均最差腿部疼痛评分、第 13 周时突出体积和第 13 周时 Oswestry 残疾指数（ODI）评分。安全性评估包括不良事件（AE）和影像学发现。
参与者按 1:1 随机分配接受单次椎间盘内注射 Condoliase（1.25 单位）或假注射，然后进行 52 周的观察。主要和关键次要终点使用重复测量混合模型（MMRM）分析和协议规定的多项插补（MI）敏感性分析在修改后的意向治疗（mITT）人群中进行评估。使用预设的串行门控算法进行多次比较。安全性终点包括 AE、实验室检查、生命体征、影像学（X 射线和磁共振成像[MRI]）和治疗后腰椎手术的发生。
在 352 名随机参与者中，341 名构成 mITT 人群（Condoliase n=169；Sham n=172）和安全性人群（Condoliase n=167；Sham n=174）。对于主要终点，Condoliase 组在第 13 周时的最差腿部疼痛 CFB 改善明显优于假注射组（最小二乘均值[LSM]CFB：-41.7）（-34.2；LSM 差异：-7.5；95%置信区间[CI]：-14.1，-0.9；p=.0263）基于 MMRM 分析。第 52 周时最差腿部疼痛的 CFB 有利于 Condoliase 组，但差异无统计学意义（p=.0558），这停止了串行门控测试算法，并决定在第 13 周时突出体积和 ODI 评分的 CFB 将被认为无意义，无论其 p 值如何。在所有时间点，Condoliase 组在 CFB 突出体积和 ODI 评分方面的差异均有利于 Condoliase 组。MI 敏感性分析显示，第 13 周（p=.0223）和第 52 周（p=.0433）最差腿部疼痛 CFB 偏向 Condoliase 组。治疗相关不良事件（TEAE）在 Condoliase 组更为常见（≥1TEAE：71.9%；≥1 治疗相关 TEAE：28.1%），与假治疗组（≥1TEAE：60.3%；≥1 治疗相关 TEAE：10.3%）相比。在 TEAEs 中，脊髓 MRI 异常和背痛最常见。没有治疗相关的严重不良事件发生。
Condoliase 达到了其主要终点，即显著改善与 LDH 相关的神经根性腿部疼痛，并在 LDH 患者中通常具有良好的耐受性。Condoliase 的化学核溶解具有提供比手术更具侵入性的治疗选择的潜力，对于对保守治疗策略无反应的患者。
