How many problems can acute myeloid leukemia IDH inhibitors solve?

the | Drug mad acute myeloid leukemia (AML) is a common acute leukemia in adults, accounting for about 70% of adult leukemia.
20,000 new AML cases in the U.S. by 2020, compared with a five-year relative survival rate of 28.7 percent, according to the National Cancer Institute (NCI).
, there are an estimated 19,700 new AML cases in China in 2018 and 24,200 by 2030.
, after decades of no new drugs on the market, therapeutic drugs in the field have emerged in recent years, and IDH inhibitors seem to be proving this clinical value! Leukemia and AML Characteristics Briefly introduced leukemia and acute myeloid leukemia in 1827, French doctors reported a case of 63-year-old man, symptoms of bloating, fever, fatigue, etc. , after repeated fever, and soon after hospitalization died.
autopsy found that his liver and spleen were visibly swollen and his blood was sticky, "like white porridge."
is the world's first case of accurate description of leukemia patients, and it comes down to an increase in white blood cells.
In 1845, British pathologists observed under a microscope a 28-year-old male with swelling of the liver and spleen, with many "colorless small bodies" in the blood, different from the previously described "white blood cell growth", known as "white blood cell disease".
1847, officially named "Leukemia", and then divided chronic leukemia into "spleen type" and "lymph type", in 1913, leukemia was divided into acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.
· AML cancer-causing genes are classified according to the currently discovered AML cancer-causing genes, mainly as follows: 1) gene mutations associated with important signaling path paths related to cell proliferation (59% incidence of AML patients); 2) tumor suppression related gene mutations (16% incidence of AML patients); 3) DNA methylation-related gene mutations (44% incidence of AML patients); 4) gene mutations related to bone marrow differentiation (incidence of AML patients 2) 2%);5)Chromosomal modification-related regulatory factor mutations (30% in patients with AML); 6) mutations in genes associated with adhesive complexes (13% in patients with AML); 7) shuttle protein NPM gene mutations (27% in patients with AML) transported inside and outside the cytocytes; 8) mutations in genes associated with scissors complex (14% in patients with AML), etc.
AML's listed drugs and target distribution The treatment of AML is still mainly based on combination chemotherapy and hematopoietic stem cell transplantation, and in the past 40 years, AML standard treatment has made little progress until the approval of some targeted drugs in recent years.
the traditional AML standard scheme is based on "7 plus 3", that is, 7 days of glycosine and 3 days of erythromycin and other cyclic chemicals for induction and mitigation, 1 to 2 courses of treatment can obtain CR, and then repeatedly give a large dose of Ara-C for post-remission treatment, or the same allogeneic stem cell transplant.
to 2017, arguably a landmark year in the history of AML targeted therapy, the FDA has approved several AML treatments, such as FMS-like tyrosine kinase (FLT3) inhibitors midostaurin, erythromycin, and glycosine liposome CP X351, IDH2 inhibitor enasidenib, etc.;
, the clinical effects of IDH inhibitors have received more attention.
2.1 Recently approved drugs for the treatment of AML Source: Clinical Lymphoma, Myeloma and Leukemia June 2020IDH Target Features For IDH, or isocric acid dehydrogenase, mutations are found later... In 2009, IDH2 mutations at R172-bits were found in gene screening in patients with gliomas, and further studies showed that 15 to 20 percent of AML patients developed IDH2 mutations at R172-bit or R140-bits.
the physiological effects of IDH, mainly in the process of energy metabolism, that is, in the cyclic metabolism of tricelic acid, can catalyz isocitric acid into a-ketone diacid (a-KG); Levels are too high in the body, and 2-HG is able to competitively inhibit a-KG-dependent bioxygenases, including histoprotein demethylase and DNA demethylase, so that hismoglobin and DNA are supermethylated, leading to abnormal behavioral regulation of histogenetics, thus blocking cell differentiation and promoting the proliferation of tumor cells.
And with the in-depth study of the target, IDH mutations have been found in a series of malignant tumors, in addition to AML, including the more common bone marrow abnormal hyperplision syndrome, vascular immune T lymphocytic cancer, cartilage, bile tube cancer, hepatocellular carcinoma, colon cancer, prostate cancer, stomach cancer, melanoma and so on.
3.1 IDH Physiological Function Characteristics Source: Annals of Oncology 27: 599-608, 2016 IDH two listed drugs introduced at present, for IDH this target, the world has been listed two drugs, are the new base company and Agios jointly developed IDH inhibitors Enasidenib (2017 listing) and Ivosidenib (2018 listing), adaptive diseases are acute myeloid leukemia.
· Enasidenib (listed 2017) Enasidenib, an oral IDH2 targeted inhibitor developed by New Base in cooperation with Agios Pharmaceuticals, extended the overall survival time from 3.3 months to 9.3 months for adult patients with recurring or refractic AML with IDH2 mutations compared to standard treatments.
was eligible for the U.S. Orphan Drug in June 2014 for AML and green channel for treatment of AML in August 2014.
was approved by the FDA in August 2017 for the treatment of IDH2 gene mutations in adult recurrence or refragsive AML, the product is called Idhifa ®, a total of 2 specifications to 50mg, 100mg.
adverse reactions, it is worth noting that the clinically occurring differentiation syndrome and biliary erythrene elevation.
and clinically developed allergies, as well as liver function decline, cartilage sarcoma, bile tube cancer, glioma and so on.
· Ivosidenib (2018 available) Ivosidenib, also developed in collaboration with Celgene and Agios Pharmaceuticals, is an oral IDH1 targeted inhibitor for the treatment of acute myeloid leukemia in 2015 Eligible for FDA Fast Track and Orphan Drugs, approved by the FDA in July 2018 for the treatment of adult patients with recurring or refragsive AML, the trade name Tibsovo ®.
clinically developed allergies are also liver function decline, cartilage sarcoma, bile tube cancer, glioma, and myeloid proliplation syndrome.
IDH in the study of important varieties in addition to the above two listed IDH inhibitors, currently entering the clinical phase III IDH inhibitors are still developed by Agios Company and Xinji Company Vorasidenib, the variety has entered the clinical phase III of the adaptation for glioma, blood tumors, bile tube cancer.
this shows the level of investment in this direction by Agios and New Base and the coverage of the target (which is very much in line with The New Base's approach to product layout).
the development of domestic IDH inhibitors, has entered the clinical stage of the variety of Hutchison Whampoa products HMPL-306, as well as Sanhe Pharmaceuticals SH1573, adaptive diseases are used to treat blood cancer.
HMPL-306, Hutchison Whampoa's 9th innovator, targets highly selective IDH1/2 new dual small molecule inhibitors, and a multi-center clinical trial has been conducted to assess the safety, pharmacological, pharmacological and efficacy of HMPL-306 in patients with recurring or refrectable malignant blood tumors with IDH1 and/or IDH2 mutations.
to determine the maximum to-dosage and/or the recommended dose for phase II, and the second stage dose is extended to further assess the safety, toerability and clinical efficacy of RP2D.
SH1573 capsule, is an independent research and development of Sanhe Pharmaceuticals, with independent property rights of IDH2 inhibitors, chemical drugs 1 class of new drugs, the main adaptive disorder is IDH2 mutation of acute myeloid leukemia (AML).
According to the official website, in 2019 San and Pharmaceuticals adopted the "SH1573 capsules in the IDH2 mutation recurrence or recurring acute myeloid leukemia patients in the safety, pharmaconodynamics and effective phase I/II clinical research" clinical program seminar;
the future? In summary, this is the main information developed for AML and IDH inhibitors.
two listed drugs that initially addressed much-needed unsealed clinical needs, and while global sales have not yet reached the top, they are an important step forward.
china, there is no IDH inhibitors approved for listing, so the domestic two varieties are very worth looking forward to, hope that can make significant clinical characteristics to solve the real clinical problems.
and the overall development of IDH inhibitors, especially in the exploration of other cancer species (such as glioma), is worthy of the attention of the pharmaceutical community, if a breakthrough, will bring great good news! References: 1. AML: New Drugs but New Challenges. Clinical Lymphoma, Myeloma and Leukemia June 20202.Annals of Oncology 27: 599-608, 20163.Cancer Cell 34, August 13, 2018 Elsevier Inc. 4.NCT042729575. National Cancer Institute (NCI) Data 6. Data