Telomelysin

最近几个月，几家公司公布了新的临床数据，吹捧溶瘤病毒可能是治疗某些癌症的一种方法。然而，受积极结果的推动，免疫治疗领域仍然以基于检查点调控的药物为主。溶瘤病毒疗法可以使用经基因改造的病毒和非改造的病毒，它们都具有选择性地攻击和感染癌细胞的能力。最近几个月，其他形式的免疫疗法，如癌症疫苗，也取得了进展。相比之下，溶瘤病毒疗法在传递方面仍然受限于需要肿瘤内注射的限制。尽管如此，一些公司例如Repimune和Transgene最近分享了来自I期和II期临床试验的数据，突显出越来越多的早期阶段由公司主导的研究。2015年以来的放缓明尼苏达州弗里德利市明尼苏达肿瘤学中心的医学肿瘤学家Thomas Amatruda博士表示，目前使用溶瘤病毒进行癌症治疗仍然是一个小众领域。他说，虽然一些患者在使用安进公司的Imlygic（talimogene laherparepvec）时获得了显著效果，但在除了黑色素瘤领域之外，该治疗方法并未取得巨大的成功。Amatruda补充说，虽然在头颈癌和鳞状细胞癌等病症中进行了一些试验，但溶瘤病毒治疗到目前为止在黑色素瘤方面显示出更大的有效性。Thomas Amatruda在2005年11月，中国国家药品监督管理局（NMPA）批准了上海晨晖生物制药公司的Oncorine作为辅助化疗治疗鼻咽癌，这标志着溶瘤病毒治疗在一个重要市场上获得了首次批准。2015年10月，美国食品药品监督管理局（FDA）批准了Imlygic用于不能通过手术切除的转移性黑色素瘤患者的治疗。Imlygic使用一种经基因改造的疱疹病毒，可以直接注射在皮肤上、皮下或患者的淋巴结中。哈佛医学院的肿瘤外科医生和黑色素瘤研究员c博士表示，这一领域的发展速度令人稍感失望。他说：“从许多方面来看，[溶瘤病毒]是一项颠覆性的技术。这些东西需要一段时间才能获得更多的尊重。”尽管如此，他看到“越来越多的公司专注于这个领域，临床试验活动也越来越多。”早期开发阶段的溶瘤病毒领域概况Kaufman博士表示，对溶瘤病毒疗法缺乏关注部分原因是由于过去十年在检查点调节和细胞疗法方面取得的巨大进展。基于这些机制的药物已经彻底改变了整个治疗格局，而不仅仅是在单一癌症领域。GlobalData的药品分析师Kevin Marcaida表示，医学界也越来越倾向于个体化医学，这对于细胞和基因疗法是有益的。Marcaida解释说，现在溶瘤病毒的临床研究主要还处于早期阶段，在III期试验中的产品较少。然而，在亚洲的一些特定市场上可以看到令人鼓舞的活动。Oncolys USA总裁Talia Biran指出，这一点强调了日本的药品及医疗器械管理局（PMDA）愿意接受II期单臂临床研究以获得药物批准。Oncolys USA是日本公司Oncolys BioPharma的子公司。今年6月，Oncolys宣布了其溶瘤病毒治疗药物telomelysin与默沙东的Keytruda（pembrolizumab）联合治疗难治性胃食管腺癌的II期试验（NCT03921021）的初步数据。这一消息是在今年的美国临床肿瘤学会（ASCO）年会上发布的。根据公告，研究人员观察到在总计16名患者中，有3名患者出现了临床反应。Kaufmann表示，第一三共制药公司的Delytact（G47∆；teserpaturev）在日本获得用于治疗胶质母细胞瘤的条件批准是一个积极的进展。Transgene的首席医务官Maud Brandely Talbot表示，在中国，与当地合作伙伴合作有助于与中国国家药品监督管理局（NMPA）进行互动。Biran指出，亚洲国家如日本的批准也可以使总部位于美国的研发工作更加便利。Maud Brandely TalbotMarcaida解释道，根据GlobalData的估计，基于溶瘤病毒的药物销售收入预计将从2023年的1.14亿美元增长到2029年的24亿美元，增长约20倍。Marcaida称，Replimune的皮肤癌治疗药物RP1（vusolimogene oderparepvec）预计在同期将占据74%的市场份额。溶瘤病毒发展的关键日期Replimune在6月份的美国移植大会上展示了RP1单独治疗的初步数据，该数据来自于II期ARTACUS试验（NCT04349436），该试验针对局部晚期或转移性的皮肤恶性肿瘤患者进行。根据6月份的公告，RP1单独治疗显示出明显的抗肿瘤活性和良好的安全性。根据Replimune公司在五月份的公司更新报告，该公司计划在2023年第三季度公布RP1与Regeneron的Libtayo（cemiplimab）联合治疗皮肤鳞状细胞癌的注册II期CERPASS试验（NCT04050436）的最终数据。该公司计划在2024年第一季度向美国食品药品监督管理局（FDA）提交生物制品许可申请（BLA）。Transgene还在其产品组合中拥有一些癌症疫苗，例如TG4050。该类疫苗在今年的ASCO会议上发布了积极的数据，引起了人们的关注。Talbot表示，Transgene仍计划开发其溶瘤病毒，同时补充说其癌症疫苗产品组合仍处于早期阶段。在鼓励应用方面存在的几个挑战在开发溶瘤病毒方面的一个挑战是确定其理想的应用方式。Kaufman指出，Imlygic在早期阶段疾病和作为一线治疗时效果最好，这应该为临床上使用溶瘤病毒提供指导。Kaufman指出，将研究重点移至疾病的早期阶段可能有助于收集关于这些药物使用的更多数据。据Amatruda说，即使是在适当的时候正确使用Imlygic，医学界有时也会提出错误的问题。Kaufman解释说，需要改进的是选择对单一疗法或作为其他治疗的辅助治疗的溶瘤病毒治疗产生反应的患者。然而，这也带来了挑战。Amatruda表示，尽管在他的经验中，Imlygic单一疗法得到了很好的回报，但与其他治疗方法结合使用该产品的潜在应用更加困难。Marcaida表示，将肿瘤内注射作为溶瘤病毒治疗的给药途径仍然是一个障碍。Amatrada解释说，他的临床实践主要治疗的是淋巴结组织和皮肤病变的患者，这是一组有限的患者。根据Oncolys公司官网，在美国进行的一项I期黑色素瘤研究中，溶瘤病毒telomelysin展示了远端效应，即在注射部位之外的非注射病灶中也观察到了治疗效果。Talia BiranMarcaida表示，在开发不同的给药途径方面几乎没有进展，这成为商品化的限制因素。Talbot表示，虽然像Imlygic这样的治疗在注射部位具有活性，但在其他部位的效果并不明显。因此，Transgene正在投资研究静脉注射作为系统性治疗的手段。然而，Biran表示，静脉注射会增加病毒的生产成本，这是Oncolys公司决定不选择该途径的原因。Biran指出，中和抗体对静脉注射构成了挑战，因为在一定时间内，这些抗体可以清除注射的病毒。这意味着需要更多的病毒量。然而，Amatrada指出，静脉注射违背了Imlygic作为一种有趣的治疗选择的目的。Biran指出，溶瘤病毒可能会作为与其他免疫肿瘤学（IO）药物联合治疗的一种选择。她说：“我认为溶瘤病毒更多地是帮助其他免疫肿瘤学药物，并挽救其他免疫肿瘤学药物的复发。”由于平均只有20%的患者对抗PD-1疗法有反应，溶瘤病毒可以帮助增强对其他免疫肿瘤学药物的反应，并帮助将“冷瘤”转化为“热瘤”，她补充道。来源：https://www.pharmaceutical-technology.com/END

For the smaller companies attending the Biotechnology Innovation Organization's CEO and Investor Conference in New York, the mission was simple: find enough capital to keep going. Eli Lilly's Renee Williams arrived in New York City this week ready to mix and mingle with dozens of biotechs that had descended on the Big Apple itching to strike a deal. The draw was the Biotechnology Innovation Organization's CEO and Investor Conference, a business development bonanza centered on partnerships and dealmaking. For the smaller companies in attendance, the mission was simple: find enough capital to keep going. In a financing environment that remains perilous for new biotechs, the stakes are high.  Even so, Williams, who leads external innovation for Lilly's genetic medicine unit, cautioned against desperation.  “I definitely get the sense that people need to find a way to return for their investors, to return their own costs probably out of their pockets,” she said. “It's translating to perhaps maybe not typical business practices.”  While big-ticket licensing deals are at the top of the list for smaller biotechs, Williams highlighted Lilly's other offerings, such as data and strategy consulting in exchange for some royalties or commercialization rights. The proposal underscores how much the ball is in Big Pharmas court with respect to dealmaking—and what companies may need to give up in exchange for even a limited relationship with the industry's biggest players.  “Having dollars doesn't mean that you run your experiments in a way that necessarily we want to see them,” said Williams. Still, she emphasized the company is open for business, reiterating an often-heard call from pharma executives. But Big Pharmas need the biotech ecosystem just as much to top up their pipelines—hence why people like Williams were there, to meet the small biotech executives who could hold the next big thing.  The juxtaposition between Big Pharma's available cash to spend and the sheer volume of potential partnerships sets the scene for a competitive and dogged financing environment. It's been made even more difficult as IPOs have become increasingly difficult to pull off, M&A has not returned to expected volumes and trepidation has crept into private financing, particularly in follow-up raises. Yet the sentiment among conference attendees was largely hopeful.  That was certainly Talia Biran’s mood. As president of the U.S. subsidiary of the Japanese biotech Oncolys BioPharma, Biran is shopping for two distinct opportunities. The first is finding a commercial partner for the company’s soon-to-be-submitted oncolytic virus therapy, suratadenoturev, in Japan, with phase 2 data expected before the end of the year and an approval application slated to be submitted in 2024.  The other goal is to find a development partner in the U.S., where suratadenoturev is being tested in conjunction with chemoradiotherapy in a phase 1 trial and alongside Merck & Co.'s Keytruda in a phase 2 trial. The company has tried before with no luck. But this time is different, as Biran says Oncolys now has clinical data plus the prospect of bringing in revenue from Japan, bolstering the prospects of landing a coveted licensing deal. “I think the issue was that we didn't have data at the time that Oncolys tried a few years ago,” she said. “Now, four years fast forward, we have more convincing data that was generated in the U.S. that I feel more confident to showcase the virus and to get the licensing deal.” While Biran wishes Oncolys could commercialize the drug by itself, they simply can’t afford it. She guessed that before the end of the year, the company would at least be able to nail down a partner in Japan.  Ulrich Dauer, Ph.D., CEO of Vivoryon, finds himself in a similar situation as the company sets its sights on a phase 2 readout for Alzheimer’s disease treatment varoglutamstat in the first quarter of 2024. He says the goal is to find a partner to fund additional clinical development. His pitch comes as Alzheimer’s drug development is at a fever pitch, with Eisai’s lecanemab nabbing accelerated approval and Eli Lilly’s donanemab nearing a phase 3 readout. “Now having kind of the first successes, there seems to be an increasing interest to look on, you know, various approaches in the field and we are experiencing that,” said Dauer.  The inspired pursuit for more money that drove most companies at the conference means that the options for people like Williams were in abundance. Her pitch to them was succinct.  “People just have to come and ask—everything is not just give me a dollar. We have a lot to offer,” she said.