全球关键 3 期研究显示匹米替尼显著提升腱鞘巨细胞瘤患者的临床疗效

和誉医药今天宣布，根据独立盲审委员会（BIRC）的RECIST v1.1标准，评估匹米替尼治疗腱鞘巨细胞瘤（TGCT）的3期MANEUVER研究在第25周客观缓解率（ORR）方面取得了统计学意义上的显著改善，达到54.0%，而安慰剂为3.2%。

值得注意的是，该研究还表明，匹米替尼治疗对与TGCT重要患者临床结果相关的次要终点有统计学意义和临床意义的显著改善，这些次要终点包括按数字评定量表测定僵硬程度（NRS；与基线相比，平均变化为-3.00%，安慰剂组为- 0.57%，p<0.0001），和按简明疼痛量表测定疼痛程度（BPI；-2.32%对0.23%的基线平均变化，p<0.0001）。MANEUEVER研究第1部分的详细疗效和安全性数据将在即将召开的医学会议上公布。

在 MANEUVER 研究中，匹米替尼展现出良好的的耐受性，安全性数据与先前报告的数据一致，未观察到胆汁淤积性肝毒性发生。治疗中匹米替尼组出现的不良事件 （TEAE）导致治疗终止和剂量下调的患者分别是1.6%（1名）和7.9%（5名）。

“腱鞘巨细胞瘤往往多发于年轻人。这种罕见的良性肿瘤生长在关节内部和周围，主要影响处于工作年龄的年轻人和中年人。腱鞘巨细胞瘤主要表现为关节肿胀、疼痛、僵硬和活动受限，会严重影响日常活动能力，限制患者的工作和社交生活。其一般需要通过手术进行治疗，但是术后的高复发率以及反复手术可能带来的并发症给患者带来了巨大挑战，因此迫切需要能够控制肿瘤生长的系统性疗法。” 北京积水潭医院骨与软组织肿瘤诊疗中心主任牛晓辉教授表示，“基于MANEUVER研究的最新数据以及匹米替尼对CSF-1R的高选择性和有效抑制作用，加上每日一次的口服给药方式还有助于提高患者的长期依从性，匹米替尼有可能为腱鞘巨细胞瘤患者建立一种新的治疗模式。

和誉医药董事长兼CEO徐耀昌博士表示：“MANEUVER 是一项具有里程碑意义的全球性研究。它是首个在多个地区以均衡比例招募亚洲和西方腱鞘巨细胞瘤患者的全球性试验。这样就可以进行详细的结果比较，有助于更深入地了解不同人群的疾病特征和潜在的反应差异。匹米替尼代表了新兴CSF-1R抑制剂类别的关键进展，有望为全球的腱鞘巨细胞瘤患者提供新型口服小分子药物治疗方案。我们期待和默克团队紧密合作，共同推动匹米替尼的注册申报，让匹米替尼成为系统性治疗腱鞘巨细胞瘤的首选方案！” 

“对于主要由CSF-1过表达引起的TGCT，临床上迫切需要有效且耐受性良好的系统性治疗，该疾病会导致关节组织增厚和过度生长，严重影响患者的生活。MANEUVER的III期数据证实了和誉医药I期研究的结果，表明pimicotinib靶向CSF-1有望为患者提供新的治疗选择。我们将与和誉医药合作并审阅该研究数据，准备和中国的监管机构分享研究结果，我们的共同目标是尽快将pimicotinib带给有需要的患者。”默克医药健康全球研发负责人兼首席医学官Danny Bar-Zohar表示。

关于MANEUVER

MANEUVER 关键研究是一项由三部分组成的、随机、双盲、安慰剂对照临床3 期研究，旨在评估匹米替尼对符合接受系统性治疗条件且既往未接受过抗 CSF1/CSF1R 治疗的 TGCT 患者中的疗效和安全性。该研究正在中国（45 例患者）、欧洲（28 例）、美国和加拿大（21 例）开展。

在第1部分双盲研究阶段，94名患者 以 2：1 的比例随机接受 50 mg QD 的 匹米替尼（n=63）或安慰剂 （n=31）治疗24 周。其主要终点是在意向治疗人群中第 25 周时的客观缓解率 （ORR），由独立盲审委员会基于实体瘤反应评估标准 （RECIST）1.1 版进行评估。次要终点包括基于肿瘤体积的评分、主动关节活动度、数字评定量表（NRS）测定的僵硬程度、简要疼痛量表（BPI）测定的疼痛程度和 PROMIS 身体功能评估。

在第 1 部分双盲研究完成后，符合条件的患者可以继续接受开放标签的第 2 部分，完成最长 24 周的治疗。完成第 2 部分的患者可以进入开放标签延长期（第 3 部分）以进行延长治疗和安全随访。

匹米替尼治疗腱鞘巨细胞瘤 1b期研究的最新长期随访结果

和誉医药还公布了评估匹米替尼对TGCT患者安全性和有效性的1期开放标签多中心研究的最新结果。题为“匹米替尼（ABSK021）在腱鞘巨细胞瘤（TGCT）中的长期疗效和安全性概况：1b期研究更新报告”的壁报将在2024年11月13日至16日于美国圣地亚哥举行的结缔组织肿瘤学会（CTOS）年会上展示。

截至2024年6月30日，此前报告的42名50 mg剂量组患者的数据更新如下：

- 根据独立审查委员会（IRC）的RECIST v1.1评估，最佳ORR为85.0%。中位治疗持续时间为20.67个月（0.5, 30.1），54.8%的患者持续治疗时间≥18个月，38.1%的患者持续治疗时间≥24个月。基于Kaplan-Meier评估，中位缓解持续时间尚未达到（NR），69.0%的患者仍在接受治疗。在长期治疗过程中，观察到肿瘤持续缩小、疼痛程度和僵硬缓解程度以及关节活动能力的逐步改善。

- 总体安全性状况与既往报道保持一致，长期随访未发现特殊的不良事件。  

- 未观察到胆汁淤积性肝毒性发生。  

Pimicotinib Significantly Improved Outcomes for Patients with Tenosynovial Giant Cell Tumor in a Global Phase III Trial 

– The MANEUVER study met the primary endpoint with an objective response rate (ORR) at week 25 of 54.0% compared with 3.2%  for placebo (p< 0.0001 ) –

– Statistically significant and clinically meaningful improvements also seen in all key secondary endpoints, including pain and stiffness - 

– Treatment with oral, once-daily pimicotinib was well-tolerated, with very low rates of discontinuation due to treatment-related adverse events  – 

–  Updated results from Phase 1b study of pimicotinib demonstrated best ORR of 85% with median treatment duration of 20 months –

Abbisko today announced that the Phase 3 MANEUVER study evaluating pimicotinib in the treatment of tenosynovial giant cell tumor (TGCT) achieved statistically significant improvements in objective response rate (ORR) at Week 25 of 54.0%, compared with 3.2% for placebo (p< 0.0001) based on RECIST v1.1 per Blinded Independent Review Committee（BIRC）.  

Notably, the study also showed that treatment with pimicotinib provided statistically significant and clinically meaningful improvements in secondary endpoints associated with important patient outcomes in TGCT, including stiffness by Numeric Rating Scale (NRS; -3.00% mean change from baseline vs. -0.57 %  for placebo, p<0.0001) and pain by Brief Pain Inventory (BPI; -2.32% vs. 0.23% mean change from baseline, p<0.0001). Further efficacy and safety data from Part 1 of the MANEUEVER study will be presented at an upcoming medical conference. 

In MANEUVER, pimicotinib was well-tolerated, and the safety profile was consistent with prior reported data, with no evidence of cholestatic hepatotoxicity. Treatment-emergent adverse events (TEAEs) leading to treatment discontinuation occurred in 1.6% (n=1) of patients treated with pimicotinib; TEAEs leading to dose reduction occurred in 7.9% (n=5) of pimicotinib-treated patients.

“TGCT tends to be a disease of the young. This rare, benign tumor that grows in and around the joints primarily affects young and middle-aged adults in their working years. The swelling, pain, stiffness and limited mobility caused by the disease can have a significant impact on the ability to perform daily activities, limiting patients’ work and social lives. Treatment often involves surgery, yet the high recurrence rate and potential complications from repeated surgical interventions can be very challenging for patients to deal with, creating an urgent need for systemic therapy that could control tumor growth,” said Professor Niu Xiaohui, Director of the Bone and Soft Tissue Tumour Diagnosis and Research Centre at Beijing Jishuitan Hospital. “Based on these new data from the MANEUVER study, together with once-daily oral administration that may promote long-term adherence and pimicotinib’s  selective  inhibition of CSF-1R, this investigational medicine has the potential to establish a new treatment paradigm for patients with TGCT .”

Yaochang Xu, Chairman and CEO of Abbisko Therapeutics, said, “As the first global trial to enroll both Asian and Western patients with TGCT in balanced proportions across multiple regions, MANEUVER is a landmark global study that allows for detailed outcome comparisons. This can facilitate a deeper understanding of disease characteristics and potential similar response across different populations. This unique study shows that pimicotinib has the potential to provide a novel oral small molecule therapy option for TGCT patients, representing a key advancement within the emerging class of CSF-1R inhibitors. We look forward to collaborating with Merck as we pursue registration of pimicotinib as the first therapy option indicated for the systemic treatment of TGCT in China.”

In December 2023, Abbisko Therapeutics entered into a licensing agreement granting Merck, a leading science and technology company headquartered in Darmstadt, Germany, an exclusive license to commercialize pimicotinib in Chinese mainland, Hong Kong, Macau, and Taiwan, as well as an exclusive option for global commercial rights of pimicotinib.

“There is a tremendous unmet need for effective, well-tolerated systemic treatment for TGCT, a disease primarily caused by CSF-1 overexpression that leads to joint tissue thickening and overgrowth, severely impacting patients’ lives. These Phase III data from MANEUVER confirm results of Abbisko’s Phase I study, indicating that targeting CSF-1R with pimicotinib has the potential to offer a new treatment option for patients. As we work with Abbisko to review the data from this study and prepare to share it with regulators in China, we are focused on our shared goal of bringing pimicotinib to patients in need,” said Danny Bar-Zohar, Global Head of Research & Development and Chief Medical Officer for the Healthcare business sector of Merck.

About MANEUVER

The pivotal Phase 3 MANEUVER study is a three-part, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of pimicotinib in patients with TGCT who are eligible for systemic therapy and who have not received prior anti-CSF1/CSF1R therapy. The study is being conducted in China (n=45), Europe (n=28), and the US and Canada (n=21). 

In the double-blind Part 1, 94 patients were randomized 2:1 to receive either 50 mg QD of pimicotinib (n=63) or placebo (n=31) for 24 weeks. The primary endpoint is objective response rate (ORR) at Week 25 as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by BIRC in the intent-to-treat (ITT) population. Secondary endpoints include tumor volume score, active range of motion, stiffness by Numeric Rating Scale (NRS), pain by Brief Pain Inventory (BPI), and physical function measured by PROMIS. 

After the double-blind Part 1, eligible patients may continue to the open-label Part 2 for up to 24 weeks of dosing. Patients who complete Part 2 may then enter the open-label extension phase (Part 3) for extended treatment and safety follow-up.   

Updated long-term follow-up results from the phase 1b study of pimicotinib in TGCT

Abbisko also announced the updated results from the Phase 1 open-label, multicenter study evaluating the safety and efficacy of pimicotinib in patients with TGCT. The poster, titled, “Long-term efficacy and safety profile of Pimicotinib (ABSK021) in tenosynovial giant cell tumor: Phase 1b update,” will be presented at the Connective Tissue Oncology Society 2024 Annual Meeting in San Diego, United States on November 13-16, 2024.

As of June 30, 2024, data from 42 patients who received the 50 mg dose of pimicotinib showed:

- The best ORR was 85.0% by RECIST v1.1 per IRC. With a median treatment duration of 20.67 months (0.5, 30.1), 54.8% and 38.1% patients had an exposure of ≥ 18 months and ≥ 24 months, respectively. The median duration of response was not reached (NR) by Kaplan-Meier estimates, and 69.0% patients remained on treatment. Continuous and gradual improvement in tumor regression, pain and stiffness relief, and joint mobility were observed during long-term treatment.

- The overall safety profile remains largely consistent, with no distinct adverse events emerging upon long-term follow-up.

- No evidence of cholestatic hepatotoxicity was observed.