Efficacy and safety of a bodyweight-adjusted higher dose of ocrelizumab in relapsing (MUSETTE) and primary progressive (GAVOTTE) multiple sclerosis: two multicentre, randomised, double-blind, parallel-group phase 3b trials.

In a post-hoc analysis of phase 3 trials in RMS and PPMS using a 600 mg dose, higher exposure to ocrelizumab was associated with greater B-cell depletion and lower risk of confirmed disability progression.

在对RMS和PPMS的III期试验进行的事后分析中，使用600 mg剂量的Ocrelizumab，更高的暴露量与B细胞的更大程度的耗竭以及确认残疾进展的较低风险相关。

Here, we prospectively assessed the efficacy and safety of a high dose of ocrelizumab in patients with RMS or PPMS.

在这里，我们前瞻性地评估了高剂量的奥克珠单抗在复发性多发性硬化症（RMS）或原发性进行性多发性硬化症（PPMS）患者中的疗效和安全性。

Methods

Two multicentre, double-blind, phase 3 controlled trials were conducted to compare high-dose ocrelizumab with the approved 600 mg dose of the drug in patients with RMS (MUSETTE) and PPMS (GAVOTTE) aged 18-56 years.

进行了两项多中心、双盲、3期对照试验，比较了高剂量奥克珠单抗与批准的600 mg剂量药物在18-56岁复发性多发性硬化症（RMS）患者（MUSETTE试验）和原发性进行性多发性硬化症（PPMS）患者（GAVOTTE试验）中的效果。

MUSETTE involved 122 centres in 21 countries and GAVOTTE involved 149 centres in 22 countries.

MUSETTE涉及21个国家的122个中心，而GAVOTTE涉及22个国家的149个中心。

Participants were randomly assigned 2:1, with a permuted-block randomisation method, to high-dose ocrelizumab (1200 mg or 1800 mg for baseline body weight <75 kg or ≥75 kg, respectively) or 600 mg ocrelizumab.

参与者按2:1的比例随机分配，采用置换块随机化方法，接受高剂量的奥克珠单抗（基线体重<75公斤或≥75公斤分别给予1200毫克或1800毫克）或600毫克奥克珠单抗。

Patients, investigators, and the sponsor were blinded to treatment allocation.

患者、研究者和赞助商对治疗分配情况不知情。

Patients received ocrelizumab infusions every 24 weeks for a minimum 120 weeks and until a prespecified minimum number of confirmed disability events (MUSETTE, 205; GAVOTTE, 357) had occurred.

患者每24周接受一次奥瑞珠单抗输注，至少持续120周，直到达到预定的最小数量的确认残疾事件（MUSETTE，205；GAVOTTE，357）发生。

In both trials, the primary endpoint was time to onset of 12-week composite confirmed disability progression (cCDP), assessed by prespecified increases in Expanded Disability Status Scale, Timed 25-Foot Walk Test, or 9-Hole Peg Test scores.

在这两项试验中，主要终点是12周复合确认残疾进展（cCDP）的发生时间，通过预先设定的扩展残疾状态量表评分增加、25英尺计时步行测试或9孔钉板测试评分来评估。

Efficacy endpoints were evaluated in all randomised participants and safety endpoints were evaluated in participants who received at least one ocrelizumab infusion.

所有随机参与者均评估了疗效终点，而安全性终点则在至少接受了一次奥克珠单抗输注的参与者中进行评估。

These studies are registered with ClinicalTrials.gov: MUSETTE, NCT04544436; GAVOTTE, NCT04548999.

这些研究已在ClinicalTrials.gov注册：MUSETTE，NCT04544436；GAVOTTE，NCT04548999。

Results

Participants in MUSETTE were enrolled between Nov 26, 2020, and Aug 30, 2022; participants in GAVOTTE were enrolled between Dec 3, 2020, and May 15, 2023.

MUSETTE研究的参与者招募时间为2020年11月26日至2022年8月30日；GAVOTTE研究的参与者招募时间为2020年12月3日至2023年5月15日。

In MUSETTE, 860 patients were randomly assigned (high-dose ocrelizumab, n=577; 600 mg ocrelizumab, n=283) and had median overall treatment duration of 184·4 weeks.

在MUSETTE研究中，860名患者被随机分配（高剂量的奥克珠单抗，n=577；600毫克奥克珠单抗，n=283），中位治疗总持续时间为184.4周。

In GAVOTTE, 753 patients were randomly assigned (high-dose ocrelizumab, n=500; 600 mg ocrelizumab, n=253) and had median overall treatment duration of 174·1 weeks.

在GAVOTTE研究中，753名患者被随机分配（高剂量的奥克珠单抗，n=500；600毫克奥克珠单抗，n=253），中位治疗总持续时间为174.1周。

In MUSETTE, the percentage of patients with 12-week cCDP was 34% (198 of 577) with high-dose ocrelizumab versus 37% (104 of 283) with 600 mg ocrelizumab (hazard ratio[HR] 0·93 [95% CI 0·73-1·18]; p=0·53).

在MUSETTE研究中，使用高剂量的奥克珠单抗治疗的患者中，有12周cCDP的患者比例为34%（198/577），而使用600 mg奥克珠单抗治疗的患者中，该比例为37%（104/283）（风险比[HR] 0.93 [95% 置信区间 0.73-1.18]；p=0.53）。

In GAVOTTE, the percentage of patients with 12-week cCDP was 47% (235 of 500) with high-dose ocrelizumab versus 49% (124 of 253) with 600 mg ocrelizumab (HR 0·95 [95% CI 0·76-1·18]; p=0·64).

在GAVOTTE研究中，使用高剂量的奥克珠单抗治疗的患者中，有12周cCDP的患者比例为47%（235/500），而使用600 mg奥克珠单抗治疗的患者中，该比例为49%（124/253）（风险比[HR] 0.95 [95% 置信区间 0.76-1.18]；p=0.64）。

Safety profiles were similar for the high-dose ocrelizumab and 600 mg ocrelizumab; in MUSETTE, rates of adverse events (552 [96%] of 577 and 267 [94%] of 283), serious adverse events (77 [13%] of 577 and 34 [12%] of 283), and fatalities (four [1%] of 577 and one [<1%] of 283) were comparable, as were rates of adverse events (447 [90%] of 499 and 230 [91%] of 254), serious adverse events (61 [12%] of 499 and 29 [11%] of 254), and fatalities (two [<1%] of 499 and three [1%] of 254) in GAVOTTE.

高剂量的奥克珠单抗和600毫克奥克珠单抗的安全性概况相似；在MUSETTE研究中，不良事件的发生率（577例中的552例[96%]和283例中的267例[94%]）、严重不良事件的发生率（577例中的77例[13%]和283例中的34例[12%]）以及死亡率（577例中的4例[1%]和283例中的1例[<1%]）相当，GAVOTTE研究中不良事件的发生率（499例中的447例[90%]和254例中的230例[91%]）、严重不良事件的发生率（499例中的61例[12%]和254例中的29例[11%]）以及死亡率（499例中的2例[<1%]和254例中的3例[1%]）也相当。

interpretation

In both studies, high-dose ocrelizumab did not further improve control of disability progression in either RMS or PPMS, and no new safety concerns were identified.

在这两项研究中，高剂量的奥克珠单抗并未进一步改善复发缓解型多发性硬化症（RMS）或原发进展型多发性硬化症（PPMS）的残疾进展控制，并且没有发现新的安全问题。

funding

F Hoffmann-La Roche.

F Hoffmann-La Roche 公司