IBI-343

The investment in Fortvita, the market is highly concerned about the actions of innovative pharmaceutical companies, which is a supervisory force, which is also increasingly normal for innovative pharmaceutical companies. At the same time, a good company should be able to stand up to and respect multiple opinions. So can a persuadable creature of faith still be trusted? After the emotion, the debate has calmed down, or to return to the main line of investment growth logic. Innovent Biologics is facing three key changes: break-even, the birth of pharmaceutical king, and internationalization, which means value enhancement. After the PD-1 encountered obstacles at sea, Innovent Biologics had a deep sense of crisis, and pursued efficiency and fine management through a low-key bottom-up route, and miraculously supported a huge R&D pipeline with robust R&D expenditure. The product revenue of Innovent Biologics 2024Q3 exceeded 2.3 billion yuan, an increase of 40% year-on-year and 15% quarter-on-quarter. In the last four quarters, product revenue has climbed continuously, which is better than expected, verifying the excellent strength of domestic commercialization capability. Unlike most Biotech companies, Cinda no longer only looks at the situation of a single product, but wins with a diversified product matrix, which is similar to the robustness of traditional pharmaceutical companies Hengrui Pharmaceutical and China Biopharmaceutical. According to IQVIA statistics, in 2024H1, the total patient share of listed PD-(L)1 in China was the first for Xinda Biobasu, with a total share of 56% together with Beigene Beizan, and the market pattern was still relatively concentrated. As a cornerstone drug for cancer treatment, PD-1 market share is crucial, representing the right of pharmaceutical companies to speak in the field of cancer drugs. Innovent Biologics has crossed the death valley of the life cycle of innovative pharmaceutical companies, is sprinting to the break-even line, 2024H1 loss convergence to 393 million yuan, 2025 is expected to achieve adjusted EBITDA breakeven. This is all based on endogenous product revenue, rather than transient external BD licensing revenue. Cinda Bio-Mastal peptide is the world's first GLP-1R/GCGR dual-target agonist in the NDA stage, with NDA applications submitted in January 2024 for weight loss indications and NDA applications submitted in August 2024 for Type II diabetes indications, and both indications are expected to be approved for marketing in the first half of 2025 at the earliest. Compared with competing products (Simeaglutide, Tipotide), Maaldotide has a strong weight loss effect, and the 9mg group achieved a better weight loss benefit of 18.6% at 48 weeks when the average BMI and average body weight were higher at baseline. In addition to weight loss, Masidin is more worthy of expectation in terms of comprehensive metabolic benefits. The improvement of fatty liver was more obvious, activated liver GCGR, promoted fatty acid oxidation and lipopolysis, and the phase III clinical results showed that the liver fat content decreased by 80.2%, which was better than GLP-1R single agonist and other double-target agonists. Cinda has proven its commercialization efficiency, and Masaldopeptide as a super drug is about to explode the market. In the field of cardiovascular metabolism, there are high-potential products such as Symbila (PCSK9), which was approved for market last year, and Tetuzumab for thyroid ophthalmopathy, which is expected to be approved next year. Ophthalmology, free of large products are expected to be approved within 1-2 years. Tetuzumab (IGF-1R) was accepted as the NDA for the treatment of thyroid eye disease in May 2024, which is the first IGF-1R antibody to be declared for market in China, which will be a breakthrough variety exclusive to Cinda in this field; Piconcibezumab (IL-23p19) in the treatment of plaque psoriasis has potential better efficacy and advantages of long interval administration, and has been submitted for application. IBI302 is the world's first VEGF/ complement dual-target molecule in the treatment of stage 3 age-related macular degeneration. In recent years, we have also seen that Innovent Biologics is preparing for internationalization. The first is the layout of a new generation of innovative technology and self-research pipeline, involving ADC, double antibody, multi-antibody, small nucleic acid, in the first half of this year, self-developed varieties IBI343 (CLDN18.2 ADC) and IBI363 (PD-1/IL-2) disclosed preliminary clinical phase I data, showing positive early clinical signals. Secondly, the company invests more resources to simultaneously carry out overseas early clinical research and expand overseas research and development teams. It can be seen that the company attaches great importance and prudence to internationalization. From the appearance of the sea platform Fortvita, the company is still in a very early stage, the risk is extremely high, most of them are pre-clinical research and development projects, there is no pipeline assets to reach overseas POC, the layout is related to antibodies, involving tumor, non-tumor fields, similar to listed companies. It does not yet have production and sales functions. We seem to see that the muscle memory of the last failure is still dull, and Cinda Biology is extremely cautious about the first step of internationalization. Fortvita's current situation and direction are unclear, which precisely shows that internationalization is still in the exploratory stage. It is not ruled out to open other channels or ways to go to sea, License-out, NewCo model, cooperative development are all potential options, everything is full of variables. It is in the midst of uncertainty that management is prepared to demonstrate its commitment to internationalisation with real money, and that the market is too quick to judge the ethics of management. Even if the deal is withdrawn now, Fortvita's independent sea is still a proposition that Xinda and shareholders need to solve jointly. In any case, the internationalization of Innovent Biologics is also like an arrow from the string, there is no turning back, and it will eventually be achieved. China's new drugs are trekking a difficult road, fortunately has run out of a small number of leading companies, the fate is not tied to a clinical trial or business progress. Compared with the broad fundamentals of Xinda, this controversial event is just a small floating cloud, which will not shake the value of Innovent Biologics.

2024年9月26日，BMS公司宣布，美国FDA已批准口服药物COBENFY™（xanomeline和曲司氯铵）用于治疗成人精神分裂症。COBENFY是精神分裂症几十年来首款新型机制的药物，通过选择性靶向大脑中的M1/M4受体而不阻断D2受体。 在2022年5月的时候，礼新医药将LM-302/TPX-4589的全球权益（除大中华区和韩国地区）license out给了Turning Point Therapeutics公司，首付款为2500万美元，研发里程碑付款为1.95亿美元，潜在总金额为10亿美元。 紧接着，在2022年6月份的时候，BMS公司就以41亿美元收购了Turning Point Therapeutics公司，LM-302/TPX-4589这项资产也顺理成章地成为BMS公司的资产了。 该海外媒体ApexOnco猜测可能由于此项资产对于BMS公司的资产负债表影响较小，所以从未有公开的官方通告，同时也向BMS公司证实，与礼新医药的这项协议，其实早在2023年就已经终止了。 小结 对于这种“秘而不发丧”的退货消息，尤其是对大公司不痛不痒的资产，大公司都不屑于公布，而原研方的小公司却不急于公布，外界人士只能通过官网渠道查看管线权益的细微变化，来判断是否退货了。 这不是今年以来第一次关于CLDN18.2 ADC药物的坏消息。 2024年8月6日，Elevation Oncology公司披露CLDN18.2 ADC药物EO-3021的最新数据，简而言之，在CLDN18.2高表达的人群里，最新的美国地区人群数据不如之前的中国地区人群数据，同时CLDN18.2低表达的人群里是没效的，当天股价大跌63%。 在2022年7月份，石药集团将EO-3021全球权益（除大中华区）license out给了Elevation Oncology公司，首付款为2700万美元，开发监管里程碑付款为1.48亿美元，商业里程碑付款为10亿美元。 2024年8月19日，科伦博泰披露2024年中期业绩，里面提及默沙东将CLDN18.2 ADC药物SKB315/MK-1200的全球权益退还给科伦博泰。 在2022年7月份，科伦博泰将SKB315/MK-1200全球权益license out给了默沙东，首付款为3500万美元，开发里程碑付款为8200万美元，首次商业里程碑付款为3.34亿美元，销售里程碑付款为4.85亿美元。 过去几年CLDN18.2 ADC药物出海的很多，但如今仅剩下康诺亚/乐普生物的CMG901/AZD0901这一根独苗了。在2023年2月份，康诺亚/乐普生物将CMG901的全球权益license out给了阿斯利康，首付款6300万美元，潜在里程碑付款超过11亿美元。从阿斯利康近期的官方资料来看，已经将CMG901作为其肿瘤领域里的重要资产了。 提起CLDN18.2 ADC药物，当然离不开“内卷”这一关键词了，截至最新统计，目前临床在研的CLDN18.2 ADC药物已经有15家了，未来真正能够获批上市的，绝对要少于这个数，只要那些推进速度快的，或者有差异化的后来者，才有可能获批上市。 目前CLDN18.2 ADC药物的目标人群，主要集中在CLDN18.2高表达人群里，对于CLDN18.2中低表达人群其实仍存在巨大的治疗空白。而这次BMS的退货，或许在激烈竞争的情况下，对LM-302/TPX-4589在CLDN18.2中低表达人群的疗效信心不足。 目前公开披露的数据有限，礼新医药在2022年EORTC-NCI-AACR会议上发表了LM-302/TPX-4589的临床前数据，裸抗LM-102和ADC药物TPX-4589都对CLDN18.2低表达的细胞有较强的内吞作用，但接上了连接子和毒素之后的ADC药物TPX-4589明显要弱于裸抗LM-102。 而且里面只有CLDN18.2高表达的细胞杀伤数据，没有CLDN18.2低表达的细胞杀伤数据，这是不完整的。 还有在CLDN18.2低表达的胰腺癌动物模型里，剂量需要去到10mg/kg BIW×3才能将肿瘤消除。 而在CLDN18.2低表达的胰腺癌动物模型里，另一款CLDN18.2 ADC药物EO-3021的剂量需要9mg/kg QW×3也能将肿瘤消除，但总体用药量比LM-302/TPX-4589要减少了一半以上。 这两款药物的毒素都是MMAE，EO-3021的DAR值为2，LM-302/TPX-4589的DAR值不清楚，但若按照常规vc-MMAE及礼新的专利来看，其DAR值应为4。如此来看的话，相当于相同毒素当量下，两者在CLDN18.2低表达上要达到相似疗效，LM-302/TPX-4589的剂量将是EO-3021的4倍以上。 ▲ 临床在研CLDN18.2 ADC药物竞品图 ▲IBI343结构示意图 ▲LM-302结构示意图 ▲EO-3021结构示意图 ▲TORL-2-307-ADC结构示意图 ▲SOT102结构示意图 ▲ATG-022结构示意图 参考资料： 1.https://www.oncologypipeline.com/apexonco/bristol-changes-tack-claudin182 2.https://www.lanovamedicines.com/news-center/press-release/18.html 3.https://news.bms.com/news/details/2022/Bristol-Myers-Squibb-to-Acquire-Turning-Point-Therapeutics-a-Leading-Precision-Oncology-Company/default.aspx 4.https://www.szse.cn/disclosure/listed/bulletinDetail/index.html?427066fa-981b-403f-8672-b9eaaf43b8d7 5.https://www.szse.cn/disclosure/listed/bulletinDetail/index.html?4d23ef3c-6e88-4c03-be16-c28c300ec34d 6.https://investors.elevationoncology.com/2022-07-28-Elevation-Oncology-Expands-Pipeline-through-Exclusive-Licensing-of-EO-3021-SYSA1801-,-a-Clinical-Stage-Anti-Claudin18-2-Antibody-Drug-Conjugate,-From-CSPC-Pharmaceutical-Group 7.https://www.keymedbio.com/show-132-200-1.html 8.https://ir-upload.realxen.net/iis/6990/uploads/iis/2024/11328840-0.PDF 9.官方推介材料 免责申明 本公众号注明原创的内容权利均属九洲药业所有，未经授权，不得擅自使用或许可他人使用。如需获得授权，请和九洲药业提前联系。已获得授权的，应在授权范围内使用，并注明来源且不得再全部或部分转授权他人。 本公众号对转载、分享的内容、陈述、观点判断保持中立，不对所包含内容的合法性、准确性、可靠性或完善性提供任何明示或暗示的保证，该等内容版权归原作者所有，仅供学习参考之用，若对转载、分享的内容有任何权利疑问，烦请联系九洲药业。