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%。