Pachyonychia Congenita

2023年，ADC（抗体偶联药物）全球销售已破百亿美元，以狂暴的规模增速宣告了其为名副其实最具投资价值的创新药主流赛道之一。中国作为全球ADC管线研发的领导者，机会黄金遍地。3月28日，国内领先的ADC Biotech乐普生物发布2023年业绩报告：公司实现收入2.25亿元，同比增长1347.2%；年度亏损0.22亿元，相比2022年亏损6.89亿元的幅度大幅减少（缩减幅度96.8%），经调整年内净亏损减少至2.5亿元。众所周知，在国内投融资寒冬的背景下，亏损的收窄减缓现金消耗是未盈利Biotech公司的生命线之一。乐普生物2023年亏损大幅收窄，是通过多元化的收入结构实现的，具备十足的含金量：1）公司PD-1普特利单抗爬坡放量迅速，上市首个完整年度收入1.01亿元（2022年11月上市）；2）其次，2023年内公司与康诺亚合作CLDN18.2 ADC管线CMG901完成了一项对外授权，BD及技术服务费收入1.24亿元，而随着AZ推进大三期，未来有望收到后续里程碑。另外，公司通过减持皓阳生物股权实现投资收益约1.04亿元、以及所持长期股权投资武汉滨会因股权被动稀释录得收益约1.16亿元，补充现金流的同时净亏损大幅收窄；3）公司降本增效成果显著，在研发费用方面采取资源聚焦战略，创新药价值高效转化，费用从2022年5.24亿缩减为2023年4.58亿；行政开支从2022年的1.38亿大幅缩减为0.87亿，销售及营销开支仅约为0.43亿元。潜龙在渊，尽管乐普生物的市场关注度不如全球市场头部的几家ADC Biotech，但投资者需意识到：属于乐普生物高光时刻，很快就会到来。1瞄准未满足临床需求和最难癌种2024年以来，针对创新药的鼓励政策全面而密集。监管机构不仅在2024政府工作报告中首次提到“创新药”，2024年3月国务院公布了《产业结构调整指导目录（2024年本）》，目录中指出：拥有自主知识产权的创新药及抗体偶联这类的医药核心技术突破均在鼓励项之列。同月，市场广泛传播的“全链条支持创新药”政策中，也明确鼓励聚焦原始创新药物，重点支持新靶点、新机制、新结构、新技术且有自主知识产权的药物。另一个角度而言，国家层面对国内未被满足临床需求愈发重视，最直接体现在对罕见病用药的支持上，如2023年新增126种药品中就包括15款罕见病药物，数量创近三年新高。无论政策鼓励的方向有多广，具备足够确定性的是：只有真正具备重大创新性的药物研发厂商，才能够充分受益政策的红利。在响应或受益创新药鼓励政策层面，乐普生物在众多国内Biotech公司中出类拔萃，其核心ADC管线从一开始就瞄准了国内未满足临床需求鼻咽癌、全球“癌王”胰腺癌。MRG003的鼻咽癌适应症2022年获得美国孤儿药认定及中国突破性疗法认定，2023年获得美国FDA快速通道资格；MRG004A在2023年12月获得FDA的孤儿药认定，2024年初用于治疗胰腺癌获的美国FDA快速通道资格。据2020全球癌症数据统计，全球鼻咽癌新发病例为13.3万例，其中我国新发6.24万例，占到每年新发病患数的46.92%。尽管鼻咽癌并不算一个大癌种，但其具备发病地区集中（全球近一半在中国、国内绝大部分病例在南方地区）、早期患者接受根治性手术后&局部晚期接受放化疗患者生存期普遍较长（5年生存率分别高于95%、75%）等特点。在鼻咽癌整体患者生存期较长的背景下，仍约有20%的晚期患者由于发生复发或远处转移而导致预后较差，现有治疗手段为姑息性化疗或免疫治疗。据2021版CSCO鼻咽癌诊疗指南，对于复发转移性鼻咽癌二线及以上治疗，推荐单药化疗或PD-1/PDL-1抑制剂治疗，客观缓解率仅20~30%，效果非常有限，急需新型药物填补临床治疗空白。乐普生物瞄准了复发转移性鼻咽癌后线未满足治疗需求，MRG003是一款新型的EGFR ADC，而EGFR在鼻咽癌中表达率非常高（50%过表达），高表达与肿瘤侵袭性、转移和放疗/化疗抵抗增加有关，MRG003针对经铂类化疗或PD-(L)1治疗失败的鼻咽癌患者治疗的二期数据显示：其治疗组的mPFS高达7.3个月，且因AE停药患者比例仅有4.9%，无因治疗死亡事件；这意味着MRG003大概率可取得较PD-1们数倍以上的销售峰值（独家定价不内卷、用药时间长、多适应症并进），同时未来还有望进军鼻咽癌的前线治疗，预估销售峰值在15-20亿元。胰腺癌又被称为“癌中之王”，由于胰腺癌起病隐匿、早期没有明显症状，而且诊断困难（早期发现率仅5%-7%，在所有癌症中最低），80%患者发现时已达局部晚期或者发生转移，失去了最佳手术机会。加上针对晚期患者治疗手段有限（目前以化疗为主），缺乏有效的靶向或免疫疗法，患者的总生存期仅6-9个月，致死率极高。根据世界卫生组织发布的全球癌症负担数据显示，2020年全球约有46.6万死亡病例，中国胰腺癌新发病例和死亡病例均超过12万例。治疗药物方面，以广谱性著称的PD-(L)1免疫疗法，对胰腺癌依旧束手无策，大部分临床都遭遇失败；即便是ADC中的药王选手DS-8201在面对HER2表达晚期胰腺癌时也束手无策，已有的二期数据确认ORR仅有4%，是所有适应症中疗效最差的。在NCCN指南也指出，一线治疗晚期胰腺癌mOS一般在10个月以内，接受二线治疗后mOS更是只有约6个月。不过，全球在研管线中只有极少数在研管线被认为具备治疗胰腺癌的潜力，TF ADC便是其中一类药物。目前，全球范围内Seagen/Genmab的TF ADC产品Tivdak获批上市，由于其在宫颈癌、卵巢癌、头颈癌等亦有潜力，机构预测其销售峰值可能超过12亿美金。乐普生物也是TF ADC赛道的领导者，其管线MRG004A正在中美进行一期临床，相比于已上市的Tivdak，MRG004A具备更长的半衰期、更好的耐受性，对应更宽的治疗窗，有望成为TF ADC赛道的同类最佳。2商业化与BD双重预期一分耕耘，一分收获。乐普生物持续押注市场核心赛道、攻克未满足临床需求，正向反馈将接踵而至，不仅公司现有ADC管线具备很强的授权潜力，同时部分ADC管线产品也进入商业化倒计时。MRG003是全球为数不多进入三期的EGFR ADC，也是国内在研进度最快EGFR ADC。EGFR这个靶点相信国内投资者耳熟能详，在小分子领域其诞生了众多替尼类重磅炸弹，随着EGFR-TKI耐药患者越来越多，靶向EGFR的ADC药物便成为了巨头们眼中的“香饽饽”。MNC中，艾伯维重金从外部引进了数个EGFR ADC，却屡屡以临床数据不及预期而折戟；另一边，AZ在与科伦博泰、第一三共合作后，也正在积极的扩展不同靶点的ADC版图，大热的EGFR ADC极有可能成为目标。乐普生物的MRG003不仅在全球进度领先，成药性已经让市场吃下了一颗“定心丸”。MRG003在PD-1及化疗经治的鼻咽癌患者IIa临床数据显示：2mg/kg的低剂量组ORR为39.3%，mPFS为7.3个月；2.3mg/kg的中高剂量组ORR为55.2%，mPFS仍不成熟。MRG003在后线鼻咽癌数据层面已展现远优于PD-1们的疗效，并且MRG003计划在2024年下半年报产。另外，MRG003在PD-1及化疗经治的头颈癌患者二期上录得了同样优异的疗效数据（ORR与mOS分别为43%、11.3个月），目前已经进入了三期临床阶段。MRG004A同样拥有浓烈的BD预期，组织因子TF同样是潜力很大的ADC靶点，其在乳腺癌、肺癌、结肠癌、胰腺癌等多种癌症上过表达。目前Seagen的Tivdak已经拿下了宫颈癌、卵巢癌两大适应症，但其较高的眼毒性和现有适应症空间构成了其当下的天花板；与Tivdak相比，乐普生物的MRG004A具备很强的差异化，不仅包括在前文提到拥有更好的耐受性、更大的治疗窗，而且公司在临床上已经观察到其胰腺癌（PC）、TNBC（三阴乳腺癌）及CC（宫颈癌）的治疗潜力。尤其在胰腺癌领域，一旦MRG004A在早期数据中展现出初步的疗效和安全性，届时压根不愁买家。同时，投资者不应该忽视的是，乐普生物的HER2 ADC管线MRG002离商业化也差临门一脚，目前除了针对HER2高表达乳腺癌肝转移患者正在进行二期临床外，针对HER2 高表达乳腺癌适应症正在进行临床三期。这么看来，乐普生物不仅拥有一般Biotech没有的多款管线强烈BD预期，同时最快在2025年公司将有2-3款产品在市销售（PD-1普特利单抗、MRG003或MRG002）。那么，可以预见乐普生物有望在未来几年收入规模快速提升，达到盈亏平衡并实现盈利指日可待。3优势扩围：联合疗法IO+ADC取代IO疗法成为未来各大实体瘤前线治疗的趋势已经无法阻挡，K药联合Nection-4 ADC（Padcev）治疗一线晚期膀胱癌已经挑战成功。同样来势汹汹的，还有IO+溶瘤病毒组合。在下一代疗法的革命浪潮中，乐普生物在国内创新药企甚至全球药企中拥有绝对的前瞻性。目前，乐普生物拥有了已商业化的PD-1普特利单抗，ADC也即将拥有MRG003、MRG002这样后期冲刺商业化产品，同时公司还有全球当下最稀缺的溶瘤病毒产品。对于IO、ADC和溶瘤病毒这三个领域有着全方位布局的企业，全球Biotech可能不超过3家（MNC除外）。实质上，溶瘤病毒是个“老药”并不稀缺，但成药且蕴含磅礴治疗潜力的溶瘤病毒无比稀缺，乐普生物通过与CG Oncology合作，在很早期拿到了溶瘤病毒CG0070其大中华区的权益。CG0070在其最新的针对高危BCG无反应非肌层浸润性膀胱癌临床三期中期分析中，CG0070治疗组患者的完全缓解率达到75.7%；用药3个月及6个月CR为68.2%及63.6%，其中74.4%患者完全缓解维持6个月以上。CG0070治疗的112例患者中，3级及以上副作用发生率为0，没有副作用导致的停药病例，没有死亡病例。更重要的是，在CG0070联合K药针对高危BCG无反应非肌层浸润性膀胱癌早期临床数据中，91%患者接受3个月联合治疗获得缓解，到了12个月仍有75%患者维持完全缓解。这意味着，两者联合用药患者完全缓解率数据较单药有着数倍以上的提升。这也是在这个适应症中目前看到的最好的一个治疗方案。CG Oncology的CG0070三期临床已进入尾声，目前，乐普生物CG0070正在进行国内的一期临床。对于公司而言，只需要在CG0070海外获批之前完成一期临床，由于有大量海外临床的确证性数据，做完一期临床后大概率可跟监管机构沟通直接开展小规模桥接三期临床，实现快速上市。IO、ADC和溶瘤病毒单品均处于商业化阶段后，其疗效和安全性经过充分验证，此时及后续公司想要布局绝大多数适应症的联用，可能相比其他大部分同行，在入组、监管沟通、审批等流程上将拥有更高的效率和优势。当然除了这个小算盘之外，在探索IO+ADC、IO+溶瘤病毒联合疗法方面，乐普生物也走在了国内创新药企业的最前头。目前，乐普生物正在进行两个方向的二期临床，分别是普特利单抗+MRG003探索鼻咽癌及头颈癌的治疗应用、普特利单抗+MRG002治疗HER2表达实体瘤的治疗应用。另外，普特利单抗与CG0070联合治疗高危BCG无反应非肌层浸润性膀胱癌的I/II临床也正计划开展。早期临床多瘤种潜力的初步探索和验证，其实也是为了乐普生物未来开展联合疗法大三期进行探路，也方便配合后续公司各个单药上市后能够迅速开展各个适应症的注册性临床，确保公司走在国内的最前沿。— 结语 —  乐普生物正在积极的通过不同手段快速抵御医药投融资寒冬带来的负反馈，这是一家优秀的Biotech所应该具备的行动策略和特质。但除了这些之外，我们更多的能看到公司所蕴含的潜力和商业化机会，价值修复可能仅仅需要时间的洗礼。对于乐普生物这样的“小而美”ADC Biotech选手，我想弹性之外，更多的或许是确定性。关于同写意 同写意论坛是中国新药研发行业权威的多元化交流平台，二十年来共举办会议论坛百余期。“同写意新药英才俱乐部”基于同写意论坛而成立，早已成为众多新药英才的精神家园和中国新药思想的重要发源地之一。同写意在北京、苏州、深圳、成都设立多个管理中心负责同写意活动的运营。尊享多重企业/机构会员特权 ● 分享庞大新药生态圈资源库；● 同写意活动优享折扣；● 会员专属坐席及专家交流机会；● 同写意活动优先赞助权；● 机构品牌活动策划与全方位推广；● 秘书处一对一贴心服务。入会请联系同写意秘书处 同写意创新链盟机构 （上下滑动查看更多）森西赛智 | 汇芯生物 | 申科生物 | 方拓生物 | 东抗生物 | 科盛达 | 依利特 | 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引言胰腺腺癌(PC)是一种侵袭性恶性肿瘤，治疗方案有限。不良预后主要源于晚期诊断和当疾病已成为治疗挑战。迫切需要确定癌症亚型和早期检测的特定生物标志物，以提高发病率和死亡率。2024年3月8日，上海交通大学崔玖洁、王理伟、苏州大学Yu Zhengyuan及同济大学Quan Ming共同通讯在Molecular Cancer (IF 37）在线发表题为“Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib”的研究论文，该研究发现通过ARNTL2激活PI3K/AKT信号通路可增强细胞糖酵解并使胰腺腺癌对厄洛替尼增敏。该研究检查了各种癌症标志的水平，并确定糖酵解是PC患者总生存的主要危险因素。随后，建立了糖酵解相关评分(GRS)模型，以准确区分高GRS的PC患者。通过筛选发现厄洛替尼对高GRS PC患者的治疗效果最强。此外，ARNTL2是一种新的预后生物标志物，也是PC患者厄洛替尼治疗反应性的预测因素。抑制ARNTL2表达降低了治疗效果，而增加ARNTL2表达可提高PC细胞对厄洛替尼的敏感性。不同ARNTL2表达水平的患者源性异种移植物(PDX-PC)体内验证表明，厄洛替尼单药治疗有效地阻止了高ARNTL2表达的PDX-PC模型的肿瘤进展。相比之下，缺乏ARNTL2的PDX-PC模型对厄洛替尼治疗反应不佳。在机制上，证明了ARNTL2/E2F1轴介导的细胞糖酵解通过激活PI3K/AKT信号通路使PC细胞对厄洛替尼治疗增敏。胰腺腺癌是一种高度恶性的肿瘤。由于目前还没有有效的针对PC的靶向治疗方法，化疗仍然是主要的治疗方法。可靠的预测和预后生物标志物以及战略性的癌症分层和标准化将极大地受益于PC的管理。几项大型随机研究表明，大多数接受手术和辅助治疗的患者并没有获得显著的总体生存获益，特别是在未选择的患者中。因此，迫切需要确定生物标志物和新的有效靶点，以便更好地选择患者进行既定的联合治疗。人表皮生长因子受体1型(HER1/EGFR)在胰腺癌中过表达，并与不良预后和肿瘤进展相关。因此，研究发现阻断HER1/EGFR酪氨酸激酶信号传导可抑制人胰腺肿瘤异种移植物的生长和转移，增强吉西他滨的抗肿瘤作用。厄洛替尼是一种口服HER1/EGFR酪氨酸激酶抑制剂，目前已被批准用于非小细胞肺癌患者。FDA批准胰腺癌(PC)患者的治疗是基于吉西他滨联合厄洛替尼与吉西他滨单药治疗相比，总生存率有统计学显著提高[。然而，由于临床反应有限，厄洛替尼用于晚期胰腺癌受到限制。因此，确定和表征患者分层的新靶点是至关重要的。此外，发现生物标志物作为胰腺癌患者的预测因子，以确定谁将特别受益于厄洛替尼治疗是重要的。模式图（Credit: Molecular Cancer）ARNTL2编码一种基本的螺旋-环-螺旋转录因子，称为芳烃受体核转运因子2，是昼夜节律和缺氧因子的生物学相关伙伴。越来越多的证据表明，在乳腺癌、结肠癌、肺癌和胰腺癌等多种癌症中，ARNTL2促进肿瘤细胞的迁移、侵袭和转移。然而，临床意义和ARNTL2与胰腺癌靶向治疗有效性的关联尚未报道。该研究确定了一个具有胰腺癌患者预后潜力的关键分类标准，并发现了一个有效的生物标志物，用于鉴别可能受益于厄洛替尼靶向治疗的PC患者。研究证明糖酵解，一种代谢途径，与PC患者总生存率下降有关。还建立了一个与糖酵解相关的基因标记来预测PC的预后。重要的是，高糖酵解相关基因特征(GRS)和较高的ARNTL2表达水平与胰腺癌患者对厄洛替尼治疗的更好反应显著相关。这种相关性通过一系列体外试验和患者来源的胰腺癌异种移植(PDX)模型的体内验证得到证实。在机制上，证明了ARNTL2介导的糖酵解通过激活胰腺癌中PI3K/ AKT通路增强厄洛替尼的反应性。总之，该研究确定了ARNTL2作为一种新的预后生物标志物和敏感性预测因子，能够识别厄洛替尼敏感的胰腺癌患者。原文链接https://doi.org/10.1186/s12943-024-01965-5责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

Highlights Clarity recently reported that in its diagnostic Phase 1/2 trial, COBRA, 64Cu-SAR-bisPSMA was found to be safe and highly effective in detecting prostate cancer (PC) lesions in patients with biochemical recurrence (BCR). In trial participants where standard of care (SOC) imaging was unable to detect any lesions, up to approximately 60% had lesions identified by same-day imaging with 64Cu-SAR-bisPSMA and up to 80% on next-day imaging, with high specificity on both days. The number of lesions identified by 64Cu-SAR-bisPSMA almost doubled from same-day (up to 80) to next-day imaging (up to 153). One of the reasons for the higher detection of lesions on next-day imaging was due to the ability of 64Cu-SAR-bisPSMA to detect much smaller lesions compared to other prostate specific membrane antigen (PSMA) agents, including a lesion with a diameter of less than 2 mm. For all lesions, regardless of their size, 64Cu-SAR-bisPSMA lesion uptake increased by more than 80% and lesion contrast increased almost 5 times when comparing same-day to next-day imaging. A key observation was the high uptake and contrast observed in lesions of less than 5 mm. More lesions and smaller lesions detected on next-day imaging could have a substantial impact on how patients are treated. The detection of lesions that are less than 5 mm in size by current PSMA positron emission tomography (PET) imaging agents (including PYLARIFY® and the generic product 68Ga-PSMA-11) is challenging, which possibly contributes to the low sensitivity of these agents. The information gathered from the Phase 1/2 COBRA trial, including the size of lesions that are detected by 64Cu-SAR-bisPSMA, will be used to inform the design of the registrational Phase 3 trial in patients with BCR of PC. SYDNEY, March 8, 2024 /PRNewswire/ -- Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, is pleased to share additional data from its diagnostic 64Cu-SAR-bisPSMA trial, COBRA (NCT05249127)[1]. COBRA was a multi-centre, single-arm, non-randomised, Phase 1/2 diagnostic imaging study of 64Cu-SAR-bisPSMA administered to participants with BCR of PC following definitive therapy and who had a negative or equivocal SOC scan at screening. The primary objectives of the trial were to investigate the safety and tolerability of 64Cu-SAR-bisPSMA as well as its ability to correctly detect recurrence of PC. Patients underwent PET/computed tomography (CT) scans with 64Cu-SAR-bisPSMA on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively), which were interpreted by three blinded central readers. Following the recent announcement of positive results from the COBRA trial[2], which began showcasing the many benefits of 64Cu-SAR-bisPSMA, further analysis of the data reveals additional advantages of this optimised PSMA product. 64Cu-SAR-bisPSMA was able to detect much smaller lesions than anticipated, including a lesion with a diameter of less than 2 mm. This compares favourably against the current SOC PSMA PET imaging agents, including PYLARIFY® and the generic product 68Ga-PSMA-11, with which the detection of lesions smaller than 5 mm is challenging. Sensitivity is a known challenge for the existing PSMA PET agents, particularly for lesions <5 mm[3]-[6]. This suggests that lesions are missed by current SOC imaging, which can have significant implications on accurate staging and subsequent treatment decisions. For those undergoing initial staging of their disease, missing lesions may lead to unnecessary surgery resulting in long-lasting side effects (e.g. impotence and/or incontinence following the removal of the prostate)[7]. In patients with BCR of PC, it is also crucial to identify their cancer early to avoid disease progression and the side effects of systemic treatments that accompany such therapies[8]. Clarity's Executive Chairperson, Dr Alan Taylor, commented, "The cornerstone of better therapy is better diagnosis, and we are incredibly excited about the substantial degree of improvement in detection of lesions with our bisPSMA product compared to SOC imaging. This difference is similar to comparing the old Hubble telescope to the new James Webb telescope, allowing us to visualise with much greater clarity, and to effectively change the paradigm of treatment to considerably improve the outcomes for patients with PC. Innovative products like 64Cu-SAR-bisPSMA may prevent many millions of men from receiving inappropriate treatments and suffering substantial debilitating side effects from surgery or other therapies. "When combining the optimised dual PSMA targeting agent with the ideal half-life of copper-64 (64Cu), we continue to observe higher uptake and retention of 64Cu-SAR-bisPSMA in PC lesions. We believe the ability of 64Cu-SAR-bisPSMA to detect such small lesions is due to the higher uptake and retention of the product over time with high contrast (parameters measured by mean standardised uptake value [SUVmean], maximum standardised uptake value [SUVmax] and tumour-to-background ratio [TBR]). Small lesions become more readily detectable if the uptake of the product in the lesion is high and the background noise on the image is low. This effect enhances the contrast, making the lesion easier to detect, providing clinicians with valuable information on how to best treat their patients." The size of the PC lesions detected by 64Cu-SAR-bisPSMA was recorded on the same-day (Day 0) and next-day (Day 1) imaging. Lesions with less than 5 mm in size were identified across readers among 14% (7/50) of patients (Figures 1 and 2). These lesions were located in the bone, pelvic and extra-pelvic lymph node regions. The smallest lesion (pelvic lymph node) identified in the study was 2.6 x 1.9 mm (Figure 3). The SUVmax, SUVmean and TBR were assessed in up to 25 lesions per patient on the same-day and next-day 64Cu-SAR-bisPSMA PET imaging. Mean SUVmean and SUVmax increased more than 80% (82% and 87% average increase across all readers, respectively) and TBR increased almost 5 times (4.8x average increase across all readers) comparing same-day with next-day imaging (ranges among readers, Day 0 and Day 1, respectively: SUVmean 6.6-9.9 and 14.7-15.8; SUVmax 13.9-14.0 and 22.2-33.4; TBR 23.2-25.4 and 118.1-181.7) (Graphs 1 and 2). Lesions of less than 5 mm in size had SUVmean, SUVmax and TBR value of 16.3, 16.8 and 90.1, respectively (mean values across all readers). The ability of 64Cu-SAR-bisPSMA to detect lesions less than 5 mm is a result of a few factors unique to the product. 64Cu has a longer half-life (12.7 h) than the isotopes used in currently approved PSMA PET agents, such as gallium-68 (68Ga) and fluorine-18 (18F) (<2 h), enabling next-day imaging, which is impossible with 18F- and 68Ga-based agents. Clarity's SAR Technology holds isotopes of copper securely inside a cage, preventing their leakage when administered to patients. Pre-clinical and clinical evidence has demonstrated that the optimised dual targeting molecule connected to the cage, bisPSMA, ensures increased targeting and retention of the product in PC tumours compared to its single targeting molecule counterpart and approved PSMA agents[9],[10]. Results from Clarity's Phase I PROPELLER trial substantiated this hypothesis as 64Cu-SAR-bisPSMA showed detection of additional lesions and 2-3 times greater uptake within the same PC lesions compared to the generic SOC imaging agent, 68Ga-PSMA-11. Furthermore, the initial positive results from the COBRA study, announced on the 15th of February 2024[2], showed that delayed imaging with 64Cu-SAR-bisPSMA is able to detect PC lesions in up to 80% of patients with BCR of PC, who demonstrated negative or equivocal SOC imaging at screening. It also showed that the number of lesions detected by 64Cu-SAR-bisPSMA almost doubled on delayed imaging compared to same-day imaging. "The COBRA trial was designed to showcase the true benefits of bisPSMA compared to current SOC imaging, implementing a high standard of study design to validate our findings and utilise an unbiased view of assessment. The results are nothing short of extraordinary, and as we continue to adhere to best practice in clinical development, our science at Clarity is clearly differentiating us from our competitors. Combined with our clinical and pre-clinical evidence to date, this data further validates SAR-bisPSMA as a potential best-in-class PSMA agent for the diagnosis (with 64Cu) and subsequent treatment (with copper-67 [67Cu]) of PC. The benefits of 64Cu-SAR-bisPSMA are now even more evident, given the highest scientific rigour applied to the COBRA study design, and confirmed by clinicians who reported that they would change their treatment plan in response to the 64Cu-SAR-bisPSMA scan results in approximately half of their trial patients. Our COBRA trial was an exploratory first-in-human Phase 1/2 trial in BCR to generate information to allow us to meticulously design a Phase 3 registrational trial. Now that we know what we are looking for, including lesions in the 2 mm range, we can structure a Phase 3 trial in the BCR of PC indication to clearly differentiate ourselves from the first-generation PSMA agents as we head towards our ultimate goal of improving treatment outcomes for people with cancer," Dr Taylor said. About SAR-bisPSMA SAR-bisPSMA derives its name from the word "bis", which reflects a novel approach of connecting two PSMA-targeting agents to Clarity's proprietary sarcophagine (SAR) Technology that securely holds copper isotopes inside a cage-like structure, called a chelator. Unlike other commercially available chelators, the SAR Technology prevents copper leakage into the body. SAR-bisPSMA is a Targeted Copper Theranostic that can be used with isotopes of copper-64 (Cu-64 or 64Cu) for imaging and copper-67 (Cu-67 or 67Cu) for therapy. 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA are unregistered products. The data outlined in this announcement has not been assessed by health authorities such as the US Food and Drug Administration (FDA). A clinical development program is currently underway to assess the efficacy and safety of these products. There is no guarantee that these products will become commercially available. About Prostate Cancer Prostate cancer is the second most common cancer diagnosed in men globally and the fifth leading cause of cancer death worldwide[11]. The American Cancer Institute estimates in 2024 there will be 299,310 new cases of prostate cancer in the US and around 35,250 deaths from the disease[12]. About Clarity Pharmaceuticals Clarity is a clinical stage radiopharmaceutical company focused on the treatment of serious disease. The Company is a leader in innovative radiopharmaceuticals, developing Targeted Copper Theranostics based on its SAR Technology Platform for the treatment of cancer in children and adults. References Clinicaltrials.gov Identifier: NCT05249127. clinicaltrials.gov/ct2/show/NCT05249127 Initial COBRA results announcement. 15 Feb 2024. claritypharmaceuticals.com/news/cobra_results/ Pienta et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate Specific Membrane Antigen PET/CT with 18F-DCFPyL in Prostate Cancer Patients (OSPREY). Journal of Urology, 2021. Hope et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection. JAMA Oncol, 2021. Petersen et al. 68Ga-PSMA PET/CT compared with MRI/CT and diffusion-weighted MRI for primary lymph node staging prior to definitive radiotherapy in prostate cancer: a prospective diagnostic test accuracy study. World Journal of Urology, 2019. Surasi et al. Diagnostic Performance and Safety of Positron Emission Tomography with 18F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE). European Urology, 2023. Stanford et al. Urinary and Sexual Function After Radical Prostatectomy for Clinically Localized Prostate Cancer. The Prostate Cancer Outcomes Study. JAMA, 2000. Shore et al. Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification. Prostate Cancer and Prostatic Diseases, 2023. Zia et al. A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention. Angew Chem Int Ed Engl. 2019. Lengyelova et al. 64Cu-SAR-bisPSMA (PROPELLER) positron emission tomography (PET) imaging in patients with confirmed prostate cancer. ASCO, 2023. Global Cancer Statistics 2020. GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21660 American Cancer Society Key Statistics for Prostate Cancer. cancer.org/cancer/prostate-cancer/about/key-statistics.html This announcement has been authorised for release by the Executive Chairperson. View original content to download multimedia: SOURCE Clarity Pharmaceuticals Company Codes: Australia:CU6