Incyte Surges 44% YTD on Jakafi's Strong Performance

JAK1抑制剂GVHD三期临床失败

2020-01-03 10:26:51 YAHOO!FINANCE

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Incyte today announced that its selective JAK1 inhibitor, itacitinib, failed to reach the trial endpoint in a phase III clinical trial of acute graft-versus-host disease (GVHD) called GRAVITAS-301. This trial compared the 28-day response rates of itacitinib and placebo to patients who had not previously been treated on a steroid hormone background. As a result, the response rates for the two groups were 74% and 66%, respectively, failing to reach statistical differentiation. A key secondary endpoint and 6-month non-relapse mortality did not differentiate between the two groups. Incyte traded down 10% after the close today. GVHD is a serious side effect of allogeneic stem cell transplantation, and is the most common non-recurring lethal factor, because the donor's immune cells cause multiple tissue attacks on the recipient. Acute GVHD has many symptoms, including the digestive tract, skin, and liver, while chronic GVHD is mainly an allergic skin reaction. This is a relatively rare disease with a specific incidence rate unknown. It is estimated that 10-50% of stem cell transplant patients will have GVHD. Currently, there is no reliable biomarker for assessing risk. Itacitinib also has a Phase III clinical program called GRAVITAS-309 for chronic GVHD. Incyte already has a dual inhibitor of JAK1 / JAK2, ruxolitinib, that has been approved for second-line acute GVHD patients with hormone recurrence through an accelerated approval channel. This product is also in the phase III clinical trials of chronic GVHD and acute GVHD. JAK1 is the earliest kinase inhibitor marketed for non-tumor diseases. Pfizer's tofacitinib was approved for rheumatoid arthritis in 2012. But this compound also has JAK3 activity, which may also play a role in curative effect. It is interesting that tofacitinib was later found to have a hair growth effect. JAK2 itself is a drug target, and Ruxolitinib is also approved for bone marrow fibrosis because of this activity. Another well-known JAK2 inhibitor, fedratinib Sanofi, was abandoned by Impact Biomedicines after being abandoned, which was acquired by Singi 1.1 billion, and fedratinib was successfully listed last year. There is also a member of the JAK family called TYK2. There are also drugs in Phase III, but they are mainly used for psoriasis. Bristol-Myers Squibb is a leader in this field, so when it acquired Sinki last year, the FTC was asked to auction the blockbuster drug Otezla to prevent a monopoly on the psoriasis market. The second-line GVHD has about 3,000 new patients in the United States and the first-line has 15,000, so the first-line is clearly a larger market. Ruxolitinib has shown a 55% response rate in the second-line population, so it is more confident to enter the first-line. However, there are not many patents left for this product and it expires in 2028. In addition, Novartis has rights outside the United States of this product, so Incyte has the incentive to develop a second-generation drug. This is the advantage of this type of cooperation for the researcher. When Bayer and Onyx developed Sorafenib, Bayer developed a derivative with only one fluorine atom, Regorafenib, and also played a lawsuit. Although Ruxolitinib differs from itactinib by more than one fluorine atom, the parent nucleus of the two molecules is the same. Itacitinib has a larger side chain that reduces binding to JAK2, so the selectivity is better, but this selectivity may also have a price. These kinases have complex functions, and in particular, homologous protein functions may complement each other, making it difficult to predict where the efficacy will come from. Incyte started from Ruxolitinib, but because of its anti-inflammatory and immune-activated IDO inhibitor Epac's reputation, it has had strategic cooperation with many major pharmaceutical companies, and cooperation with Merck has started the first-line and third-phase clinical trials of multiple solid tumors. Unfortunately, ECHO301 failed later, and now this mechanism is no longer beautiful. Disadvantageous at the beginning of the new year is a little disappointing, but winning and losing is a routine thing. Kinases are still a relatively stable and relatively complete field. The overall success rate of many kinase inhibitors in the Incyte product line should exceed that of new IO products like IDO.
今天Incyte宣布其选择性JAK1抑制剂itacitinib在一个叫做 GRAVITAS-301 的急性移植物抗宿主病(GVHD)三期临床未能达到试验终点。这个试验在甾体激素背景上比较itacitinib和安慰剂对此前未接受治疗患者28天的应答率,结果两组应答率分别为74%和66%、未能达到统计区分。一个关键二级终点、6个月非复发死亡率两组也无区分。Incyte今天收盘后交易下滑10%。 GVHD是异体干细胞移植的一个严重副作用、是最常见的非复发致死因素,因为供体的免疫细胞对受体的多种组织袭击造成。急性GVHD症状较多、包括消化道、皮肤和肝脏,而慢性GVHD主要是皮肤过敏反应。这是一类相对罕见疾病,具体发病率未知、估计10-50%干细胞移植患者会有GVHD,目前没有评价风险的可靠生物标记。Itacitinib还有一个叫做GRAVITAS-309 针对慢性GVHD的三期临床在进行中。Incyte已经有一个JAK1/JAK2双抑制剂ruxolitinib通过加速审批通道被批准用于激素复发的急性GVHD二线患者,这个产品也在慢性GVHD和急性GVHD的验证三期临床试验中。 JAK1是最早上市治疗非肿瘤疾病的激酶抑制剂,辉瑞的tofacitinib在2012年被批准用于风湿性关节炎。但这个化合物也有JAK3活性,可能也对疗效起了一定作用。有趣的是tofacitinib后来发现有生发的疗效。JAK2本身也是一个药靶,Ruxolitinib也因为这个活性被批准用于骨髓纤维化。另有一个著名的JAK2抑制剂fedratinib赛诺菲放弃后被Impact Biomedicines廉价收购,后者被新基11亿收购、fedratinib去年成功上市。JAK家族还有一个叫做TYK2的成员,现在也有药物在三期临床、但主要用于银屑病。施贵宝是这个领域的领导者,因此去年收购新基时被FTC要求拍卖重磅药物Otezla以防止垄断银屑病市场。 二线GVHD美国约有3000新增患者而一线有1.5万,所以一线显然是更大的市场。Ruxolitinib因为已经在二线人群显示55%应答率,所以进入一线更有把握。但这个产品专利期所剩不多、2028年到期,另外诺华拥有这个产品的美国以外权益、所以Incyte有动力开发一个二代药物。这是这类合作对研究方的有利之处,当年拜耳与Onyx开发Sorafenib后拜耳又开发了只加一个氟原子的衍生物Regorafenib还打了一阵官司。Ruxolitinib虽然与itacitinib差别不止一个氟原子、但二者分子母核是一样的。Itacitinib有一个较大的侧链可以降低与JAK2的结合,所以选择性更好、但这个选择性看来可能也有一定代价。这些激酶功能复杂,尤其同族蛋白功能可能相互补充、很难预测疗效到底来自哪里。 Incyte从Ruxolitinib起家,但因为抗炎的反面、免疫激活IDO抑制剂Epac名声大震,曾与多家大药厂有战略合作、与默沙东的合作曾同时开始多个实体瘤的一线三期临床。遗憾的是后来ECHO301失败,现在这个机理已经风光不再。新年伊始便出师不利有点令人失望,但胜败兵家常事。激酶还是一个相对稳健、理解相对完整的领域,现在Incyte产品线中的诸多激酶抑制剂总体成功率应该超过IDO那样的IO新产品。

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