Islatravir

Gilead is awaiting a readout from a second pivotal trial later this year or early 2025 for a potential FDA filing for lenacapavir as PrEP. (Gilead) For the first time, an HIV PrEP drug candidate has shown zero infections in a phase 3 trial. The result came from the PURPOSE 1 trial evaluating Gilead Sciences’ twice-yearly, subcutaneous lenacapavir in cisgender women and adolescent girls ages 16 to 25 in South Africa and Uganda. Lenacapavir, a capsid inhibitor, is already approved by the FDA under the brand name Sunlenca for use alongside other antiretroviral medications to treat HIV in certain tough cases. The trial enrolled more than 5,300 individuals across 28 sites to receive lenacapavir or either one of Gilead’s daily oral PrEP drugs, Descovy and Truvada. While no infections happened during the trial period among more than 2,000 women in the lenacapavir group, the Descovy group recorded an incidence rate of 2.02 per 100 person-years and the Truvada group 1.69 per 100 person-years. “While we know traditional HIV prevention options are highly effective when taken as prescribed, twice-yearly lenacapavir for PrEP could help address the stigma and discrimination some people may face when taking or storing oral PrEP pills, as well as potentially help increase PrEP adherence and persistence given its twice-yearly dosing schedule,” Linda-Gail Bekker, Ph.D., director of the Desmond Tutu HIV Center at the University of Cape Town in South Africa and past president of the International AIDS Society, said in a statement. On the trial’s primary endpoint, which pitted lenacapavir against a background incidence rate of 2.41 per 100 person-years, the Gilead drug was found to be significantly better. The drug also achieved superiority against Truvada, a secondary comparator. As such, an independent data monitoring committee has recommended that Gilead stop the blinded phase of the PURPOSE 1 trial at this interim analysis, and that all participants be offered lenacapavir open label. Gilead is conducting multiple trials for lenacapavir under the PURPOSE program. The PURPOSE 2 trial is assessing the long-acting drug for PrEP mainly among cisgender men who have sex with men, transgender men and women in Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the United States. Results from that study are expected in late 2024 or early 2025. Gilead’s plan is to combine the data from both pivotal trials to seek an FDA approval. If approved, the twice-yearly drug could “provide a critical new choice for HIV prevention,” Bekker said. Lenacapavir’s success under a once-every-six-month schedule poses a major threat to GSK’s Apretude, an injection that so far can be administered only up to every two months. While GSK’s HIV-focused subsidiary ViiV Health was first to introduce a long-acting PrEP option, it’s behind Gilead on the ultralong-acting front. GSK plans to launch an every-four-month version of Apretude in 2026 and start a registrational study for a twice-yearly option in 2027, the company said during an investor update in September. By GSK’s estimate, the HIV PrEP market is expected to more than double in size to around 4 billion pounds to 5 billion pounds by 2031, with long-acting injectables taking up about 80% of the market value. “With current data from today (and assuming PURPOSE 2 holds), lenacapavir is probably well situated to garner a significant share” of the PrEP market, William Blair analyst Salim Syed wrote in a Thursday note. Besides efficacy, “compliance improvements (and we’ll see about any price premiums) could also be tailwind to sales,” he added. Wall Street’s consensus estimate has put lenacapavir’s global peak sales at around $3 billion across HIV prevention and treatment, Syed noted. The William Blair analyst suggest the drug could reach $4 billion without adjusting for any development risks.  The success of twice-yearly lenacapavir as PrEP also raises the bar for any future HIV vaccine, which remains elusive after multiple setbacks.  Following Apretude’s FDA approval, GSK has opened up the drug’s intellectual property to the United Nations-backed Medicines Patent Pool, working with generic manufacturers to make the PrEP option for certain poorer countries. Under the framework, licensing deals were signed with Aurobindo, Cipla and Viatris last year. Gilead also recognizes the importance of enabling access to achieve the broadest impact. The company on Thursday said it plans to make a public announcement “regarding its planned access approach for high-incidence, resource-limited countries, which are primarily low- and lower-middle-income countries.” Both Gilead and GSK are also working on ultralong-acting regimens for HIV treatment. Gilead looks to provide a phase 2 update later this year for lenacapavir in combination with the company’s broadly neutralizing antibodies. Lenacapavir is also being paired with Merck & Co.’s islatravir as a once-weekly oral candidate.   Editor's Note: The story has been updated with input from a Willaim Blair note.

，1整体表现GILD近几年用实际行动反向诠释了底蕴的重要意义，十几年前那笔Pharmasset震古烁今的巨大成功收购似乎耗尽了所有运势，从那之后KITE、FTSV、GLPG、IMMU，连续巨额出手是一个胜似一个的令人迷惑，现在陆续到研发和销售兑现的时候却挨个开始爆雷，业绩同比成长基本也就在5%左右，无怪乎市值回到$80b附近，等于把之前这几波预期又给跌没了。2已上市产品GILD赖以起家的抗病毒药物基本盘，现有品种也基本失去了增长动力，HIV系列年化在$18b确实遇到了瓶颈，丙肝市场早已被自己亲手剿灭，Remdesivir也只成追忆。肿瘤板块是GILD骚操作的重灾区，把抗病毒药物几十年赚来的钱砸进来，却连个响都不容易听到。先是两个CAR-T，看样子加起来年化峰值也就在$2b左右到头了，显然跟当初$12b的收购价相去甚远；然后是Trodelvy爬坡似乎有所放缓，目前LTM累计也就不到$1.2b，对于一家小公司而言已是不俗表现，但这可是个获批超过三年、花了$21b收购来的品种，想要值回票价还任重道远。3在研管线“出来混迟早要还”，最近好像就是GILD集中为此前各类离谱操作还债的大型“断舍离”现场。首先是已经被毒性打得千疮百孔的CD47单抗Magrolimab，总算是被彻底钉上了棺材板，2月7日宣布被FDA终止治疗AML和MDS所有试验、2月15日又宣布停止治疗实体瘤的研究，最终在季报中被证实扫地出门；捎带手，TIGIT单抗Domvanalimab的两个联用PD-(L)1治疗NSCLC的临床也消失在管线中。然后是Trodelvy备受关注的治疗2L+ NSCLC的三期临床EVOKE-01试验，年初宣布错失OS主要临床终点，后续蹲一下ASCO上的具体数据。再是肿瘤细胞治疗，同样砍掉了Brexu-cel的罕见B细胞肿瘤适应症以及CLL-1 CAR-T管线，又加进了一款新的CD19/CD20双靶点管线（是否又意味着之前版本的存在问题不得而知）。就怕，教训还并不够深刻。这个季度GILD的“重大操作”依然在继续，$4.3b收购Cymabay，获得旗下PPARδ激动剂Seladelpar，恕在下眼拙，这个在NASH里已经死过一户口本的靶点，不知道怎么就能在PBC这种适应症上值这个价；此外又从Xilio趁火打劫来IL-12前药，对价是$43.5m upfront + $604m milestone。最后看起来还是HIV老底子稍靠谱一些，特别是Lenacapavir与Islatravir联用的二期临床结果，这有可能成为首个HIV口服周制剂。除此以外，值得关注的进展还包括：α4β7整合素抑制剂GS-1427启动二期UC试验，以及PARP1抑制剂GS-0201和治疗IBD的PD1单抗GS-0151加入管线等。GILD过去十年左右的各种操作，真的颇有点崽卖爷田之感，将用幸运和辛苦挣来的真金白银，大量挥霍在一梦黄粱上，回头一看搞不好还不如老老实实搞抗病毒药物呢！