美国时间2025年2月11日，复星医药子公司复宏汉霖自主开发的地舒单抗生物类似药候选药物HLX14（重组抗RANKL 全人单克隆抗体注射液）国际多中心III期临床研究（NCT05352516）数据于2025年美国骨科研究学会（ORS）年会发布，并由徐州医科大学附属医院辛立教授进行口头报告。
HLX14为复宏汉霖按照中国、欧盟和美国等生物类似药相关法规自主开发的地舒单抗生物类似药。复宏汉霖已于2022年与Organon达成授权许可和供应合作，授予其对包括HLX14在内的两款候选生物类似药在除中国以外的全球区域进行独家商业化的权益，协议覆盖美国、欧盟、加拿大等市场。2024年4月，HLX14用于治疗骨折高风险的绝经后妇女的骨质疏松症的国际多中心临床III期对照研究达到主要研究终点。基于一系列的头对头比对研究，HLX14的上市申请于2024年相继获得美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）和加拿大卫生部（Health Canda）受理。
以下为此次发布的详细信息：
试验设计
本研究为一项随机、双盲、国际、平行对照的III期研究。受试者为年龄在60至90岁之间、确认已绝经且腰椎或全髋骨矿物质密度（BMD）T评分通过中心双能X线吸收法扫描为−4.0 < T评分 ≤ −2.5的女性。合格的受试者按1:1分配分别接受两剂HLX14或欧盟市售原研地舒单抗（PROLIA）。在第52周，接受PROLIA的受试者再次按1:1随机分配接受第三剂HLX14或PROLIA。本研究的共同主要终点为第52周腰椎BMD（LS-BMD）从基线变化的百分比（由中心影像评估）及基线至第26周的血清胶原蛋白C端肽（s-CTX）较基线改变百分比-时间曲线下面积 （AUEC0-26W）。次要终点包括腰椎BMD基线变化百分比（由研究者评估），股骨颈及全髋部BMD的百分比变化（由中心影像及研究者评估），骨折率，s-CTX及血清N-末端I型前胶原肽（s-P1NP）的相对变化百分比，安全性，药代动力学（PK），和免疫原性。
结果
在2022年6月17日至2024年6月5日期间，共有514例受试者被随机分配到HLX14组（256名）或欧盟市售原研地舒单抗（PROLIA）组（258名）。在第52周，来自PROLIA组的220例受试者再次随机分配，接收最后一剂HLX14（PROLIA/HLX14组，110名）或PROLIA（PROLIA/PROLIA组，110名）；HLX14组的220例受试者继续接受最后一剂HLX14（HLX14/HLX14组）。
在基线到第52周期间，HLX14组和PROLIA组的腰椎骨密度（LS-BMD）均有所增加。通过中央影像评估，从基线到第52周的平均（标准偏差）百分比变化分别为HLX14组6.10%（3.95%），PROLIA组5.90%（3.83%）。两组之间的调整平均差异为0.23%（90%置信区间[CI]：−0.36%，0.83%；95% CI：−0.48%，0.95%）。90%置信区间和95%置信区间均落在预设的等效性界限−1.45%到1.45%之间, 证明了两组疗效等效性。对于主要药效动力学（PD）终点，HLX14组和PROLIA组的AUEC0-26W几何均值（CVb%）分别为14075.1253（17.3%）day*%inhibition，13883.3613（17.9%）day*%inhibition。HLX14组和PROLIA组AUEC0-26W的几何均值比为1.01（90% CI：0.99, 1.04；95% CI：0.98, 1.05）。几何均值比的90%和95%置信区间均落在预设的等效性界限0.8到1.25之间，证明两组PD等效性。因此，本研究的共同主要终点已达到。所有敏感性、补充性和亚组分析结果也与主要分析一致。所有次要疗效终点的结果进一步支持了HLX14和欧盟市售原研地舒单抗（PROLIA）等效。
在基线到第52周期间，两组的安全性结果相当；HLX14组出现了69例（27.0%）与治疗相关的不良事件（TRAEs），而PROLIA组出现了82例（31.8%）。从第52周到第78周，PROLIA/HLX14、PROLIA/PROLIA、HLX14/HLX14各组之间的安全性特征仍相似；PROLIA/HLX14组报告了14例（12.7%）TRAEs，PROLIA/ PROLIA组报告了15例（13.6%），HLX14/HLX14组报告了25例（11.4%）。总体而言，安全性评估未发现HLX14和PROLIA之间存在显著差异，即使在单次治疗药物转换之后也是如此。各组在单次药物转换前后的抗药抗体和中和抗体的发生率也相当。
结论
综上所述，HLX14与欧盟市售原研地舒单抗在疗效上具有等效性，并且二者的安全性特征相似。本研究的结果支持 HLX14 作为地舒单抗的生物类似药，在获批上市后，将可以提高骨折风险的绝经后女性对抗骨质疏松症和骨质流失的有效治疗方法的可及性。
关于复宏汉霖
复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已有6款产品在中国获批上市，4款产品在国际获批上市，4个上市申请分别获中国药监局、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，公司商业化生产基地已相继获得中国、欧盟和美国GMP认证。
复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状®的肿瘤免疫联合疗法。截至目前，公司已获批上市产品包括国内首个生物类似药汉利康®（利妥昔单抗）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac®）、汉达远®（阿达木单抗）、汉贝泰®（贝伐珠单抗）、全球首个获批一线治疗小细胞肺癌的抗PD-1单抗汉斯状®（斯鲁利单抗，欧盟商品名：Hetronifly®）以及汉奈佳®（奈拉替尼）。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。
Phase 3 MRCT Results of Denosumab Biosimilar HLX14 Released at ORS 2025
On February 11, 2025, the results of the international multicenter phase 3 study (NCT05352516) of denosumab biosimilar candidate HLX14 were released at the 2025 Orthopaedic Research Society (ORS) Annual Meeting. The results were orally presented by Professor Li Xin from The Affiliated Hospital of Xuzhou Medical University, the leading principal investigator of NCT05352516.
Henlius independently developed denosumab biosimilar candidate HLX14 in accordance with the NMPA, EMA, FDA, and other international biosimilar guidelines. In 2022, Henlius entered into a license and supply agreement with Organon for the exclusive commercialization rights to two biosimilar candidates, including HLX14. The agreement covers markets such as the United States, the European Union, and Canada. An exception from the agreement is China. In April 2024, NCT05352516 met the primary endpoints. Based on a series of head-to-head comparison studies, the marketing applications of HLX14 have been accepted by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Health Canada in 2024.
The detailed results of the study released at ORS 2025 Annual Meeting are as follows:
Study design
In this randomized, double-blind, international multicenter, parallel-controlled phase 3 study, female subjects aged 60 to 90 years with confirmed postmenopausal status and lumbar spine or total hip bone mineral density (BMD) T-score of −4.0 < T-score ≤ −2.5 as assessed by central dual-energy X-ray absorptiometry scans were initially randomized 1:1 to receive two doses of HLX14 or EU-denosumab. At Week 52, the subjects receiving EU-denosumab were re-randomized 1:1 to receive either a third dose of HLX14 or EU-denosumab, subjects receiving HLX14 will be continue with a third dose of HLX14. The co-primary endpoints were the percent change from baseline at lumbar spine BMD (LS-BMD) at week 52 as assessed by the central imaging, and the area under the effect-time curve for percent change of serum type I collagen C-telopeptide (s-CTX) from baseline to Week 26 (AUEC0-26W). Secondary endpoints included efficacy endpoints of the percent change from baseline in BMD at lumbar spine (assessed by the investigator), at femoral neck and total hip (as assessed by central imaging and investigator), fracture rate, relative percent change in s-CTX and serum procollagen type I N propeptide, safety, PK, and immunogenicity.
Results
Between 17 June, 2022 to 05 June, 2024, a total of 514 subjects were randomized to the HLX14 (n= 256) or EU-denosumab (n=258) group. At Week 52, 220 subjects from the EU-denosumab group were re-randomized to receive a final dose of HLX14 (EU-denosumab/HLX14 group, n=110) or EU-denosumab (EU-denosumab/EU-denosumab group, n=110); 220 subjects in the HLX14 group continued to receive the final dose of HLX14 (HLX14/HLX14 group).
From baseline to week 52, an increase in LS-BMD was evident in both the HLX14 and EU-denosumab groups; the mean (standard deviation) percent change from baseline to Week 52 as assessed by central imaging were 6.10% (3.95%), and 5.90% (3.83%) for the HLX14, and EU-denosumab group, respectively. The adjusted mean difference between the two groups was 0.23% (90% confidence interval [CI]: −0.36%, 0.83%; 95% CI: −0.48%, 0.95%). The 90% CI and 95% CI for the difference both fell within the pre-specified equivalence margins of −1.45% to 1.45%, demonstrating the efficacy equivalence between the two groups. As for the primary PD endpoint, the geomean (CVb%) of AUEC0‑26W for subjects in the HLX14, and EU-denosumab group were 14075.1253 (17.3%) day*%inhibition, and 13883.3613 (17.9%) day*%inhibition, respectively. The geometric mean ratio of AUEC0‑26W for the HLX14 and EU-denosumab groups was 1.01 (90% CI: 0.99, 1.04; 95% CI: 0.98, 1.05). The 90% CI and 95% CI for the geometric mean ratio of AUEC0‑26W both fell within the pre-specified equivalence margins of 0.8 to 1.25, demonstrating the PD equivalence between the two groups. Henceforth, the co-primary endpoints in this study were met. All sensitivity, supplementary and subgroup analysis were also consistent with the primary analysis. The results of all secondary endpoints support the efficacy equivalence between HLX14 and EU-denosumab.
The safety findings were comparable between the two groups from baseline to week 52; treatment-related adverse events (TRAEs) were reported in 69 (27.0%) subjects in the HLX14 group and 82 (31.8%) in the EU-denosumab group. Importantly, the safety profiles of the EU-denosumab/HLX14, EU-denosumab/EU-denosumab, and HLX14/HLX14 groups remained comparable from week 52 to week 78; TRAEs were observed in 14 (12.7%) in the EU-denosumab/HLX14 group, 15 (13.6%) in the EU-denosumab/EU-denosumab group, and 25 (11.4%) subjects in the HLX14/HLX14 group. Overall, the safety evaluation did not indicate notable differences between HLX14 and EU-denosumab, even after the single transition between the treatment drugs. Lastly, the incidence of anti-drug antibodies and neutralizing antibodies were also comparable between the groups prior to and after the single transition.
Conclusion
The efficacy equivalence of HLX14 and EU-denosumab was demonstrated along with comparable safety profiles for HLX14 and EU-denosumab. Taken together, the findings from this study add to the totality of evidence supporting HLX14 as a proposed biosimilar to reference denosumab that, if approved by regulatory agencies, may improve access to effective therapies for osteoporosis and bone loss in postmenopausal women at high risk of fracture.
About Henlius
Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases and ophthalmic diseases. Up to date, 6 products have been launched in China, 4 have been approved for marketing in overseas markets, and 4 marketing applications have been accepted for review in China, the U.S. and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP.
Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as the backbone. To date, the company's launched products include HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab), HANBEITAI (bevacizumab), HANSIZHUANG (serplulimab, trade name: Hetronifly® in the EU), the world’s first anti-PD-1 mAb for the first-line treatment of SCLC, and HANNAIJIA (neratinib). What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.
联系方式
媒体：PR@Henlius.com
投资者：IR@Henlius.com
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