Focus on the clinical progression of drug target IDH target drugs and their accompanying diagnostic solutions

IDH Target Overview Isocitrate dehydrogenase (Isocitrate dehydrogenase, IDH) is the key enzyme needed for cellular respiration in the triamcilic acid cycle in the human body, with IDH1, IDH2 and IDH3 are three isomerase forms, where IDH1 and IDH2 mutations are closely related to tumor occurrence and development However, IDH3 mutation is not common, structurally, IDH1 and IDH2 are highly similar isomerases, which exist in cells in the form of isoenic isomers, each subunit of omogenous domnics has an active center, and IDH3 is a heterogenous tivomer structure.
IDH target-tumor relationship IDH1 and IDH2 hot mutations were first discovered by Professor Bohai and his partners in adult glioblastoma (a malignant brain tumor) patients, the results of which were published in Science and NEJM, respectively, from which IDH entered the field of vision of cancer genomics scientists.
In subsequent studies, the clinical significance of IDH1/2 gene mutations has been gradually discovered in a number of cancers, including acute myeloid leukemia (AML), intra-liver bile tube cancer, cartilage sarcoma, thyroid cancer, prostate cancer, subneural thyroid and melanoma.
2016 IDH1/2 was included in the WHO Classification of Central Nervous System Tumors guidelines, the first time in human history that molecular parting has been used as a gold standard for the diagnosis of brain tumors.
IDH1/2 mutations correspond to WHO partings have certain distribution laws, mainly distributed in II-III grade less protrusion glioma (69.2%), asstarycoma (79.8%), less astrogenic cell tumor (75.5%) and IV-grade secondary glioblastomas ( .
In 2018, Professor Bohai led a team that for the first time mapped the genetic spectrum of TERTpwt-IDHwt through genome-wide sequencing, the results of which were published in the journal Nature, on the basis that the molecular profing criteria for malignant brain tumors may be further updated.
in the field of blood cancer research, in most adult AML studies, the mutation frequency of IDH1 is about 5.5%-10.4%, while the frequency of IDH2 mutation is about 8.6%-17.7%.
potential effects of targeted therapy for IDH mutations in AML have been confirmed in several in vitro and in vivo preclinical studies.
August 2017, the FDA approved the new base and Agios IDH2 inhibitor enasidenib (trade name Idhifa, formerly used as AG-221) for the treatment of IDH2 variants, recurring recurring refractic AML, and Abbott's RealTime IDH2 test kit as an accompanying diagnosis.
Figure 1 IDH1/2 mutation and its carcinogenic pathogenic schematic map , the new enzyme mutIDH1/2 produced by the mutant can convert the product of the original wild type IDH1/2 α-ketone diacid (alpha KG) into carcinogenic metabolite 2-hydroxydephedic acid (2HG) in the plasma/mitochondrials.
2HG is able to competitively inhibit the dioxygenase α-ketone diacid dependence in the cytopseum/cell nucleo.
2HG-mediated 10-11 sublocation (TET) enzyme and histoprotein lysine demethylase (KDM) activity inhibition led to the whole cell for DNA and histogeneous metagenetic modification, which in turn led to permethylation phenomics.
inhibition of acrylamide hydroxylase and lysine hydroxyase (e.g. PLOD1-3) interferes with collagen maturation and the degradation pathway of hypoxia-induced factor 1 alpha (HIF-1 alpha), thus stabilizing HIF-1 alpha after translation.
, ALKBH, which is responsible for repairing DNA oxidation damage, also receives 2HG inhibition.
IDH global clinical trials carried out IDH inhibitors through the action of IDH mutation points in tumor cells, so that the body carcinogenic metabolite 2HG reduced, thereby inducing histoprotein de-methylation, to inhibit tumor development.
IDH inhibitors were divided into IDH1 inhibitors, IDH2 inhibitors and IDH1/IDH2 inhibitors according to the target of action.
Figure 2 has been on the market with the inhibitor illustration in the study of the AML targeted treatment of IDH2 mutations as early as 2013, the main target is IDH2R140Q, the candidate drug is AG-221 (enasidenib).
the drug was first developed by Agios Pharmaceuticals and named AGI-6780, in clinical 1/2 of its trials, the total response rate of 100 mg/day administration was 38.5% (42/109) and the total remission rate was 20.2 (22/109).
results led to an effective suppression of D2HG levels.
, also from Agios Pharmaceuticals' AGI-5198, also known as AG-120 (ivosidenib), can lower D2HG levels in glioma cells and promote histone de-methylation, thereby inhibiting IDH1 mutations in glioma cells.
the drug began clinical trials in 2014, with a full remission rate of 30.4 percent for AML patients and an effect of 8.2 months.
as of November 20, 2020, there were 112 clinical trials involving IDH.
mainly in North America, the European Union and China.
46 of these mutations involving the IDH1 gene and 32 of the IDH2 gene mutations.
representative part of the project is listed below: Figure 3 On IDH Clinical Trial Distribution Chart 1 Representative IDH Gene Mutations U.S. Approved IDH Accompanying Diagnostic Kits August 1, 2017, FDA Approves Idhifa (enasidenib, Celgene Corp.) Used to treat adult patients with recurring or incurable acute myeloid leukemia (AML) with specific gene mutations.
same time, the drug was approved for use in the RealTime IDH2 accompanying diagnostic kit, which can detect mutations in the IDH2 gene in AML patients.
if IDH2 mutations can be detected in a patient's blood or bone marrow, these patients are the right group to be recommended for treatment with Idhifa.
July 20, 2018, the FDA approved Tibsovo (ivosidenib, Agios Pharmaceuticals, Inc.) for the treatment of adult patients with recurring or refractic acute myeloid leukemia (AML) that may carry IDH1 mutations.
the accompanying diagnostic reagent that was approved on the same day as the Abbott RealTime IDH1 Assay.
May 2, 2019, the FDA further approved Tibsovo (ivosidenib, Agios Pharmaceuticals, Inc.) for the treatment of patients at least 75 years of age or whose co-diseases are excluded using intensive induced chemotherapy, newly diagnosed with relapsed or refractic acute myeloid leukemia (AML) that may carry IDH1 mutations.
the accompanying diagnostic reagents are Abbott's products, Abbott RealTime IDH2 Assay and Abbott RealTime IDH1 Assay, respectively.
Abbott RealTime IDH2 Assay is a PCR product that runs on the Abbott m2000rt system and can be used for qualitative testing of nine single nucleotide mutations (SNVs) coded IDH2 (R140Q, R140L, R140G, R140W, R172K, R172M, R172G, R172S and R172W, DNA to be tested can be extracted from blood (EDTA) or bone marrow (EDTA).
the difference between Abbott RealTime IDH1 Assay and its ability to detect five single nucleotide mutations (SNVs) encoded IDH1 R132 (R132C, R132H, R132G, R132S and R132L).
the first NMPA approved IDH kit (PCR method) in 2018, NMPA approved the human IDH1 gene mutation detection kit (PCR-fluorescent probe method) in IDH solution 20173401602) for qualitative detection of IDH1 (isocric acid dehydrogenase 1) gene mutation (R132HCGT-CAT) in neutral formaldehyde fixation, paraffin-encumbelisted glioma tissue samples in glioma patients.
This Aassy is the first approved adaptive glioma IDH test kit, the kit is not only an important result of the clinical transformation of pan-born children's scientific research technology, but also an important embodiment of Pansheng's in-depth promotion of the "service-product" model, which has been approved for clinical glioma pathological subtypes to provide important guidance and reference.
figure 4 Human IDH1 gene mutation detection kit (PCR-fluorescent probe method) IDH1 gene testing kit using ARMS-qPCR (mutation block amplification system - polyenzyme chain reaction) technology, based on the real-time fluorescent PCR platform, combined with specific citations and Taqman probe (fluorescent marker probe) two technologies.
the main advantages of this kit are as follows 1, high sensitivity can detect 10 ng/ sL DNA samples as low as 1% of the gene mutation.
2, the operation of convenient fluorescence quantitative PCR operation method standardization, a machine can detect up to 90 samples, detection time of about 1 hour.
a fully enclosed system to reduce the possibility of pollution.
3, the results of the reading of simple test results objective data, without the need for subjective judgment of the naked eye, easy to do.
the NGS platform-based expansion solution, using Vorasidenib, developed by Agios and Celgene, as an example, we can note that new IDH inhibitors are already moving towards multi-target, multi-adaptive trends.
is able to detect both IDH1 and IDH2, and even more potential target requirements are also available, and high-volume, accurate, fast-edged NGS technology can well meet the needs of this scenario, Pansheng son is currently for the clinical end of the promotion of a number of NGS panel covering IDH1/2 targets and tumor signaling path related important genes, can be used to provide solid tumor, blood tumor type, prognosis, drug and other multi-dimensional guidance.
IDH target with diagnostic registration strategy and recommendations in recent years, major domestic and foreign pharmaceutical companies in the IDH pipeline frequently shot, but also to promote IDH1/2 as a popular target with diagnosis.
The two Abbott IDH1/2 accompanying diagnostic reagents previously approved by the FDA are developed and approved in a synchronous development and synchronous approval form, in which the study of drug erration correlation, taking IDH2 as an example, Abbott's accompanying diagnostic reagents and drug IDHIFA carried out clinical trials AG221-C-0 01. The proportion of 199 IDH2 mutation patients who were completely relieved (CR) after receiving 100 mg/day dose IDHIFA treatment was evaluated by prospectively screening the subject's IDH mutation status into the group, or retrospectively confirming other tested group samples.
From the above approved cases, it is not difficult to see the work to be done to verify an IDH accompanying diagnostic reagent, including comprehensive analytical performance verification, which may include the minimum detection line (LOD), sample start, cross-reaction, internal/external interference substances, precision, reproducible, and other gold standards or recognized methods of mutual comparison series of trials, but also include drug efficacy related studies.
The former requires IVD manufacturers to be able to have deep research and development and improvement capabilities for the testing performance of accompanying diagnostic products, while the latter requires IVD manufacturers to have more comprehensive industry operational capabilities, including cooperation with external pharmaceutical companies, in a variety of clinical scenarios (including real-world data) to verify the clinical effectiveness of accompanying diagnostic products, and ultimately to obtain approval from the pharmaceutical regulatory department.
Pansheng is currently for IDH1/2 target has a sound multi-platform solution, we are willing to work with pharmaceutical partners to accelerate the progress of clinical trials targeting IDH drugs, as soon as possible for the vast number of patients to usher in drug treatment and benefit opportunities!