OBJECTIVES In January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP. PATIENTS AND METHODS This CUP was initiated in February 2017 - shortly before US Food and Drug administration approval in March 2017 - and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately. RESULTS Of 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24-73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-β and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment. CONCLUSION This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.

中文翻译：

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Ocrelizumab 治疗原发性进行性多发性硬化症：德国同情用药计划的短期安全性结果

目标 2018 年 1 月，欧盟 (EU) 批准 ocrelizumab 用于治疗复发性多发性硬化症 (RMS) 并作为第一种针对原发性进行性多发性硬化症 (PPMS) 患者的疾病缓解疗法 (DMT)，其疗效在 3审判。在欧洲监管机构批准前 11 个月，一项同情使用计划 (CUP) 使德国的 489 名 PPMS 患者可以使用 ocrelizumab，从而首次为无法参与 ocrelizumab 研究的 PPMS 患者提供治疗选择。在这里，我们报告了在本次 CUP 中使用 ocrelizumab 治疗的 PPMS 患者的真实世界患者特征和短期安全性数据。患者和方法 该 CUP 于 2017 年 2 月启动 - 在美国食品和药物管理局于 2017 年 3 月批准之前不久 - 并于 2018 年 1 月在欧盟批准 ocrelizumab 后结束。根据治疗医师的判断，具有正收益/风险比的 PPMS 成年患者（年龄≥18 岁）有资格进入德国治疗中心。主要排除标准是当前/最近用其他免疫疗法进行的治疗和未解决的/慢性/活动性感染。患者在 6 个月周期内接受静脉注射 ocrelizumab 治疗前接受甲基强的松龙和抗组胺药治疗。第一次 ocrelizumab 剂量是 300 mg 输注，然后在 2 周后进行第二次 300 mg 输注；随后的剂量以单次 600 毫克输注形式给药。立即报告了不良事件。结果 在 104 个中心收到的 580 份请求中，525 名患者符合资格标准。35 名患者因治疗医师退出而未参加，1 名患者因治疗前死亡而未参加。总共 489 名患者接受了至少一剂 600 毫克的 ocrelizumab（以两次 300 毫克输注的形式给药），51 名患者接受了第二剂。由于 CUP 在上市授权后终止，最长随访期为 12 个月。患者年龄中位数为 52 岁（范围：24-73），49% 为女性。41% 的患者以前接受过免疫调节或免疫抑制治疗，最常用的是糖皮质激素、米托蒽醌、干扰素-β 和醋酸格拉替雷。先前患有恶性肿瘤、严重疾病或感染的患者（42 名患者，9%）在 CUP 之前已从中康复。40 名患者报告了 9 起严重不良事件和 70 起非严重不良事件。不良事件类别通常与 ocrelizumab 的已知安全性特征一致；一名患者由于之前的那他珠单抗治疗而出现遗留进行性多灶性白质脑病 (PML)。结论 本次 CUP 首次提供了 ocrelizumab 在德国大型患者队列中治疗 PPMS 的真实世界观察结果，支持 ocrelizumab 在临床实践中通常具有良好的耐受性。医生应警惕 PML 的早期症状，迄今为止，全世界已报告 9 例 PML 病例均混杂在接受 ocrelizumab 治疗的患者中，其中 8 例来自先前的 DMT 遗留病例。不良事件类别通常与 ocrelizumab 的已知安全性特征一致；一名患者由于之前的那他珠单抗治疗而出现遗留进行性多灶性白质脑病 (PML)。结论 本次 CUP 首次提供了 ocrelizumab 在德国大型患者队列中治疗 PPMS 的真实世界观察结果，支持 ocrelizumab 在临床实践中通常具有良好的耐受性。医生应警惕 PML 的早期症状，迄今为止，全世界已报告 9 例 PML 病例均混杂在接受 ocrelizumab 治疗的患者中，其中 8 例来自先前的 DMT 遗留病例。不良事件类别通常与 ocrelizumab 的已知安全性特征一致；一名患者由于之前的那他珠单抗治疗而出现遗留进行性多灶性白质脑病 (PML)。结论 本次 CUP 首次提供了 ocrelizumab 在德国大型患者队列中治疗 PPMS 的真实世界观察结果，支持 ocrelizumab 在临床实践中通常具有良好的耐受性。医生应警惕 PML 的早期症状，迄今为止，全世界已报告 9 例 PML 病例均混杂在接受 ocrelizumab 治疗的患者中，其中 8 例来自先前的 DMT 遗留病例。结论 本次 CUP 首次提供了 ocrelizumab 在德国大型患者队列中治疗 PPMS 的真实世界观察结果，支持 ocrelizumab 在临床实践中通常具有良好的耐受性。医生应警惕 PML 的早期症状，迄今为止，全世界已报告 9 例 PML 病例均混杂在接受 ocrelizumab 治疗的患者中，其中 8 例来自先前的 DMT 遗留病例。结论 本次 CUP 首次提供了 ocrelizumab 在德国大型患者队列中治疗 PPMS 的真实世界观察结果，支持 ocrelizumab 在临床实践中通常具有良好的耐受性。医生应警惕 PML 的早期症状，迄今为止，全世界已报告 9 例 PML 病例均混杂在接受 ocrelizumab 治疗的患者中，其中 8 例来自既往 DMT 的遗留病例。