Currently it has been approved in about 18 countries, initially it is mainly used for the treatment of high-risk myelofibrosis, however, interestingly, myelofibrosis combined with vitiligo patients in the use of a period of time after rucotinib found that their own vitiligo symptoms have improved, so the researchers used this to develop rucotinib ointment, has been approved by the U.S. FDA in 2022 as the treatment of vitiligo for the topical use of drugs. The drug is approved by the FDA in 2022 as a topical treatment for vitiligo. In addition, the indications for rucotinib have since expanded to include the treatment of atopic dermatitis, graft-versus-host disease, true erythrocytosis, and dozens of other conditions.
According to global best-selling drug data, rucotinib sales were only $156 million in 2012, reaching $1.910 billion in 2017 and $3.970 billion in 2022. In addition, the drug's domestic sales increased 23% year-on-year, reaching $400 million overall. The drug was included in the national health insurance varieties (Class B) in 2021, limited to patients with intermediate-risk or high-risk primary myelofibrosis (PMF), myelofibrosis secondary to true erythrocytosis (PPV-MF), or myelofibrosis secondary to primary thrombocythemia (PET-MF), and is available at around $3,000 per box for the 5mg*60-tablet size of the drug.
JAK kinase was initially named "just another kinase", meaning "just a kinase". Eventually, however, scientists published the name by which it is now known, calling it JAK kinase or Janus kinase (JAK). Originating from Janus, the god of doors in Roman mythology, it is also known as the god of two faces, or the god of time, because Janus had a face in front of him and a face in back of him, looking at the past on one side and the future on the other. And JAK kinase has two almost identical structural domains for transferring phosphate groups, one for activation and the other for shutdown.
The JAK family currently consists of four proteins, JAK1, JAK2, JAK3, and Tyk2, which conduct different signals. JAK1 and JAK3 are more responsible for immune regulation, while JAK2 is mainly associated with erythrocyte and platelet production, and a strong correlation has been found in myeloproliferative neoplasms (MPNs) with a JAK2 mutation. The high structural similarity of their four proteins has led to a dichotomy in the treatment with JAK inhibitors, i.e., on the one hand, they can treat the disease, but on the other hand, they can lead to strong side-effects, such as viral infections and thrombosis, due to their inevitable inhibition of the four proteins.
The non-selective inhibition of the first generation of JAK inhibitors posed significant safety concerns, and in 2021 the FDA even gave tofacitinib (a JAK inhibitor used in the treatment of rheumatoid arthritis) a black-box warning for its potential to cause serious infections, blood clots, and other side effects. Inevitably, the development of selective JAK inhibitors, which inhibit the disease-causing JAK proteins and avoid inhibiting the ones that cause side effects, became a hot topic for the major players, and the second generation of JAK inhibitors was born.
Eli Lilly and Incyte are developing baricitinib, a JAK1/JAK2 inhibitor, and AbbVie's upapatinib, a JAK1-selective inhibitor, both marketed for the treatment of rheumatoid arthritis. Deucolexitinib, a Tyk2 inhibitor developed by BMS, was approved by the FDA in September 2022 for the treatment of plaque psoriasis.
And in the field of myeloproliferative neoplasms, in August 2019, BMS-developed fidzotinib was approved by the FDA for the treatment of myelofibrosis, a highly specific JAK2 inhibitor that inhibits JAK2 more effectively than JAK1, JAK3 and TYK2, thus allowing for a reduction in other side effects while treating it. The drug's launch has not been smooth sailing, however, as trials were repeatedly halted early on in the development process due to side effects that could lead to encephalopathy, and even now the launch is still burdened with a black box warning of serious and fatal encephalopathy.
In 2022, the FDA approved pacritinib for the treatment of adults with intermediate- or high-risk primary or secondary myelofibrosis with platelet counts below 50 x 109/L. The drug was also the first to specifically target thrombocytopenic myelofibrosis. In addition, Zejing Pharmaceutical's Jacketinib is the first domestic originator JAK inhibitor to be declared on the market in China, and it has submitted a marketing application for the drug for the treatment of intermediate- and high-risk myelofibrosis on September 28, 2022 to the NMPA. Jacketinib has a significant inhibitory effect on four JAK kinases, and the strongest inhibitory effect on JAK2 and TYK2. Moreover, the drug can reduce ferredoxin transcription by inhibiting activin receptor 1 (ACVR1) activity, lowering the incidence of anemia and reducing transfusion dependence in myelofibrosis patients.
However, although the safety issues of second-generation JAK inhibitors have been reduced, on the one hand, because of the similarity of the mechanism of action of some of the drugs, the FDA has given a black box warning to baricitinib and nipatinib, which are two JAK inhibitors, as well as tofacitinib; on the other hand, the strength of selectivity of the JAK inhibitors varies, so that the FDA's scrutiny of a variety of JAK inhibitors will be even more stringent.
Finally, JAK inhibitors, as the name Janus suggests, are a mixed blessing, and cytokines are involved in most of the reactions in the body, leading to an extremely wide range of applications for JAK inhibitors, with myeloproliferative neoplasms being one of the indications. However, in addition to JAK, there are other cytokine drugs being researched, and it is believed that there will be other drugs that can be applied to MPN as well. In addition, with the launch of domestic generic products and the increase in the number of drugs included in the medical insurance, more patients will be able to use rucotinib as a class of drugs, so that more people can benefit.
