China's first third-generation Gleevec orrebatinib is nearing approval, and Yasheng Pharmaceutical is about to commercialize

On November 11, the official website of NMPA showed that the marketing application (acceptance number: CXHS2000038) of Oribatinib (HQP1351) of Ascent Pharmaceuticals has entered the approval stage and is expected to be approved in the near future
.

This means that the first domestic tyrosine kinase inhibitor targeting the T315I mutation in BCR-ABL---oribatinib is about to be approved for marketing! Figure 1.
Orebatinib registration progress, source: NMPA official website Three years ago, the movie "I am not the god of medicine" starring Xu Zheng hit a hit with a box office of more than 3 billion yuan and won dozens of awards in the film industry.
Douban ratings are still ongoing 9 points or more; such a popular and popular movie, its plot is adapted from the true story of "Pharmaceutical Man" Lu Yong, the "life-saving medicine" in the film ---Glenin, the prototype in reality is Gleevec (Imatinib), a tyrosine kinase inhibitor developed by Novartis, Switzerland, was approved by the US FDA on May 10, 2001 for the treatment of chronic myelogenous leukemia (CML) and malignant stomach Intestinal stromal tumors and so on
.

The film has attracted great social attention, but when the human body develops resistance to Gleevec, is there any life-saving medicine available? Chronic myelogenous leukemia patients with T315I mutations are resistant to Gleevec and even the "second-generation Gleevec".
Before the emergence of oribatinib, they faced such a dilemma of no cure for a long time
.

The discovery and resistance of 01CML was as early as 1840, when chronic myelogenous leukemia was first discovered; but it was not until 1960 that two cytogeneticians David Hungerford and Peter Nowell worked together to determine that the leukemia was related to specific chromosomal abnormalities
.

Subsequently, Janet Rowley further refined this discovery in 1973
.

CML is characterized by the existence of the Philadelphia chromosome, a balanced mutual translocation between the long arms of chromosomes 9 and 22 [t (9;22) (q34;q11)], making the ABL gene on chromosome 9 and chromosome 22 Fusion of the BCR gene to obtain the BCR-ABL1 fusion gene, which encodes the BCR-ABL oncoprotein
.

Ph chromosome, as a genetic feature of CML, is found in 90%-95% of CML cases, and the protein it encodes is mainly P210
.

Compared with normal AbL protein, the fusion protein has stronger tyrosine kinase activity, which can promote cell division, reduce cell response to apoptosis signals, prolong cell survival time, disrupt normal cell signal transduction, and induce cell malignancy.
Lead to the occurrence of leukemia
.

The continuous proliferation of these highly differentiated stem cells is conducive to the production of mutations, which can produce resistance to standard therapies and have a negative impact on the prognosis
.

Figure 2.
The FDA-approved treatment for BCR-ABL inhibitor 02 targeting the ATP binding site (targeted drug for BCR-ABL) According to the above pathogenesis, some tyrosine kinase inhibitors (tyrosine kinase inhibitors) , TKI) can inhibit the kinase activity of BCR-ABL1, and the survival time of CML patients who achieve sustained remission through targeted BCR-ABL therapy is significantly prolonged
.

Certain point mutations in the BCR-ABL1 domain can lead to imatinib resistance.
The second and third generation of BCR-ABL inhibitors have a good effect on most patients who have failed imatinib treatment
.

The confirmed mutation sites include four types: P-loop (phosphate-binding loop; M244, G252, Y253, E255), gatekeeper residues (imatinib binding site; T315, F317), SH2 binding region And C-lobe (mutations near the catalytic domain; M351, F359), activation loop (H396)
.

Although the marketed BCR-ABL inhibitors can cover most drug-resistant mutations, the T315I mutation (mutation of threonine at position 315 to isoleucine) is still one of the mutations that is difficult to overcome at present
.

 Figure 3.
Asciminib's domestic research and development stage 03 Therapeutic strategy for T315I mutation.
T315I mutation, also known as "gatekeeper mutation", is located at the ATP binding site.
It is against imatinib, nilotinib, dasatinib and bosuti Nijun is resistant
.

Ponatinib is a third-generation BCR-ABL inhibitor.
It is effective against all current kinase point mutations, including T315I.
This drug has become a very important clinical choice
.

However, there are safety concerns for prnatinib: less than one year after the accelerated approval of prnatinib (October 31, 2013), the FDA announced that in view of prnatinib’s “life-threatening thrombosis and severe vascular stenosis” "The risk requires manufacturers to stop their sales and promotion.
This is also the first small-molecule kinase inhibitor anti-tumor drug to be withdrawn from the market
.

On December 20, 2013, since prnatinib was the only option for patients with T315I gene mutant chronic myelogenous leukemia, the FDA conducted a risk-benefit assessment for it, restricted indications, and added black box warnings related to treatment For the risk of arterial thrombosis and liver toxicity, the market was approved again under safety monitoring
.

At present, the fastest research and development stage of Pranatinib in China is in clinical phase II (indications are chronic myeloid leukemia, etc.
)
.

Today, Orebatinib is about to become the first three-generation BCR-ABL inhibitor in China and the second in the world to be approved for marketing
.

Effective for this T315I mutation, there are also Novartis' allosteric inhibitors
.

On October 29, 2021, the FDA approved Novartis’s BCR-ABL allosteric inhibitor Asciminib to be marketed for the treatment of chronic myeloid leukemia; however, according to the Yaodu database, the fastest domestic research and development stage of Asciminib is clinical phase II.
, The indication is myeloid leukemia; the indication of chronic myeloid leukemia is in the first clinical stage, and distant water is difficult to quench near thirst
.

Fortunately, the third-generation BCR-ABL inhibitor oribatinib developed by Ascent Pharmaceuticals will soon be available in China for indications for the accelerated and chronic phases of myeloid leukemia with T315I mutation; gastrointestinal stromal tumors are in clinical practice.
Phase one
.

At present, Orebatinib has been included in the CDE priority review and breakthrough treatment varieties
.

In addition, it has entered phase Ib clinical studies in the United States, and has also obtained the U.
S.
FDA review fast track and orphan drug certification qualifications
.

 Figure 4.
The domestic research and development stage of Orebatinib.
Figure 5.
The structure of the BCR-ABL inhibitor that has been approved by the FDA.
Drug resistance caused by non-BCR-ABL1 mutations, etc.
; we analyze it from point mutations
.

The residue Thr315 forms a hydrogen bond with imatinib, and when Thr315 is mutated to a larger residue Ile315, it hinders the binding of imatinib to the ATP binding pocket of the abl kinase domain; the T315I mutation accounts for about 25% of all point mutations
.

The mutation eliminates the key hydrogen bond interaction between imatinib and residues and changes the topological structure of the ATP binding pocket, resulting in structural inhibition of the binding of iamtinib to this region
.

Punatinib in the third-generation BCR-ABL inhibitor does not need to form a hydrogen bond with threonine 315 residue, and the alkyne group in the molecule can accommodate the T315I side chain, avoiding the space between the I315 side chain Steric conflict
.

The bicyclic skeleton containing 3 nitrogens occupies the adenine pocket of T315I kinase of BCR-ABL, the methyl phenyl occupies the hydrophobic pocket of the following residues, the trifluoromethyl phenyl tightly binds to the pocket induced by the outer conformation of DFG, and its N The -methylpiperazine group forms 2 kinds of extensive hydrogen bonds with ABL
.

By binding to the hydrophobic site of the BCR-ABL kinase, the configuration is inactivated instead of binding to the activated ATP site, thereby avoiding binding to the side chain of T315I of wild-type BCR-ABL, forming a heterogeneous complex that is conducive to binding to T315I.
Leucine mutates the van der Waals force of the side chain and changes the steric hindrance of the isoleucine mutant to inhibit T315I
.

The pre-clinical in vivo and in vitro activity data also reflect the rationality of this structure-based design
.

 Figure 6.
Part of the activity data in the patent 05 Discovery and potential of Orebatinib In 2010, Ding Ke, the dean of the School of Pharmacy of Jinan University, protected a class of heterocyclic acetylene benzene compounds and their medicinal use in the compound patent filed by Ding Ke, the dean of the School of Pharmacy of Jinan University The composition; and disclosed the inhibitory activity of the heterocyclic acetylene benzene compounds on various drug-resistant cell lines, among which D824 (GZD824, HQP1351) is the current oribatinib, which should be the first time for oribatinib The structure is disclosed; it can be seen from Figure 5 that the heterocyclic acetylene benzene compound has a significant inhibitory effect on K562 (chronic leukemia), in which the IC50 of oribatinib reaches 0.
494 nM, and the inhibition of MOLT cells is above 100 nM; in tumors The transplantation model can significantly inhibit the growth of tumors; the pharmacokinetics and bioavailability experiments in rats have confirmed that this type of acetylene benzene ring compound is very good as a drug
.

 Figure 7.
Orebatinib transformation strategy and predicted combination of Orebatinib and Bcr-Abl wild-type and mutant type.
In the 2013 JMC, Dink’s research group adopted the strategy of backbone transition and used 1H-pyrazole [3,4-b] Pyridinyl skeleton replaces imidazole [1,2-b] Pyrazinyl skeleton to obtain oribatinib, so that oribatinib can form a new hydrogen bond with Met318
.

The inhibitory activity of oribatinib on wild-type ABL protein kinase is equivalent to that of Pranatinib, and its activity on T315I and other mutants is better than that of Pranatinib
.

It also has excellent anti-tumor activity at the cellular level.
The IC50 for the BCR-ABL-positive leukemia cell line K562 and human CML cell line reached 0.
2nmol/L and 0.
13nmol/L
.

Orebatinib has good oral absorption in the rat model, with a bioavailability of 48.
7% and a half-life of 10.
6h
.

Oribatinib can completely inhibit tumor growth at an oral dose of 1.
0~20.
0 mg/(kg*d)
.

 Figure 8.
Orebatinib inhibits wild-type and mutant KIT enzymes.
Orebatinib is also a multi-kinase inhibitor against a wide range of mutated KIT kinases (doi.
org/10.
1186/s13578-019- 0351-6), can be used to treat imatinib-resistant gastrointestinal stromal tumors
.

In clinical trials and the selection of indications, oribatinib mainly targets mutant BCR-ABL and KIT (gastrointestinal stromal tumor related), including T315I
.

According to the information officially disclosed by Yasheng Pharmaceutical, clinical trials of oribatinib in the treatment of drug-resistant CML, gastrointestinal stromal tumors, and Philadelphia chromosome-positive acute lymphoblastic leukemia are underway
.

The summary of the 63rd ASH Annual Meeting was just announced a few days ago, and the research progress of Ascent Pharmaceuticals oribatinib was selected as an ASH oral report for four consecutive years
.

Among them, the latest results of the key registration phase II trial of subjects in the chronic phase and accelerated phase (CML-CP and CML-AP) of aoribatinib in the treatment of TKI-resistant BCR-ABLT315I mutant chronic myelogenous leukemia were displayed in the poster
.

HQP1351-CC201 and HQP1351-CC202 are an open, single-arm, multi-center key registration phase II clinical study conducted in China, respectively, which evaluated the CML-resistance of oribatinib to TKI (BCR-ABL1T315I mutation).
The safety and effectiveness of CP and CML-AP in adult subjects
.

Oribatinib is administered 40 mg orally, every other day, 28 days as a cycle
.

• As of August 25, 2020, a total of 41 CML-CP patients were enrolled in HQP1351-CC201, of which 32 (78%) completed ≥12 cycles, and the median follow-up time was 13 (3.
1-16.
3) months
.

Subjects who did not respond at baseline had a CHR of 100% after ≥12 treatment cycles
.

MCyR was 75.
6% (31/41), CCyR was 68.
3% (28/41), and MMR was 56.
1% (23/41)
.

The PFS rate of the subjects at the 12th month was 89.
3%, and the overall survival (OS) rate was 100%
.

• As of July 27, 2020, a total of 23 CML-AP patients were enrolled in HQP1351-CC202, of which 14 (61%) completed ≥12 cycles, and the median follow-up time was 13.
5 (1.
4-15.
2) months
.

In subjects who did not respond at baseline, after ≥12 treatment cycles, the hematological depth response rate (MaHR) reached 73.
9% (17/23), MCyR was 52.
2% (12/23), and CCyR was 47.
8%% (11 /23), MMR is 39.
1% (9/23)
.

The PFS rate of the subjects at the 12th month was 74.
1%, and the OS rate was 91.
3%
.

When oribatinib is used in the treatment of TKI-resistant CML-CP and CML-AP patients with T315I mutation, the most common hematological toxicity is thrombocytopenia, and most of the non-hematological toxicity is grade 1 to 2.
In general, the patient tolerated well
.

And with the extension of treatment time, the remission rate and depth of remission will further increase
.

At present, the marketing application of oribatinib (acceptance number: CXHS2000038) has entered the approval stage and is expected to be approved in the near future for the treatment of chronic phase (CML-CP) and accelerated phase (CML) of CML with T315I mutation -AP) Patients
.

It is believed that after the launch, oribatinib will break the treatment bottleneck for patients with T315I mutation resistance in China, solve the dilemma of no medicines available for Chinese patients, and extend the lives of patients with its excellent efficacy and safety
.

Figure 9.
Yasheng Pharmaceutical's logo, source: Yasheng's official website.
According to the public information disclosed by Yasheng Pharmaceutical, the product is actively expanding new indications and overseas clinical trials
.

In March of this year, Orebatinib has been included in the breakthrough therapy product by the Center for New Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) for the treatment of first- and second-generation tyrosine kinase inhibitor (TKI) resistance.
Patients with chronic myelogenous leukemia (CP CML) who are intolerant of drugs and/or intolerance
.

In the United States, Orebatinib has entered phase Ib clinical studies and has also obtained the fast track review and orphan drug certification granted by the US FDA
.

We also continue to pay attention to the follow-up performance of this product
.

Columnist Xinghu Xinghu has a medicinal chemistry background, has been engaged in target research, patent analysis and breakthroughs, and improved new drugs; now focuses on the molecular design of innovative drugs; loves the pharmaceutical industry, and is willing to learn from each other, make progress, and witness the best innovative drugs Good times
.

References: 1, Fabrício Freire de Melo et al; Chronic myeloid leukemia-from the Philadelphia chromosome tospecific target drugs: A literature review; World J Clin Oncol 2021 24; 12(2): 69-94.
2, Sara Malik, Shahzeb Hassan & Ahmet Emre Eşkazan; Novel BCR-ABL1 tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia; DOI: 10.
1080/17474086.
2021.
1990034.
3, Deepam Pushpam, Sameer Bakhshi; Pharmacology of tyrosine kinase inhibitors in chronic myeloid leukemia; a clinician's perspective; DARU Journal of Pharmaceutical Sciences (2020) 28:371–385.
4, Xuechao Liu,Dajun Yang and Yifan Zhai et al; Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors; Cell Biosci (2019) 9:88.
5, Cao Wenjing, Li Shuomin; Research progress in the efficacy and resistance mechanisms of BCR-ABL1 kinase inhibitors;Oncology Pharmacy, December 2020, Volume 10, Issue 6.
6, Zhang Fan, Min Qinwei, etc.
; Research progress of Bcr-Abl tyrosine kinase inhibitors and their drug resistance; 7, Ding Ke, Wang Deping; Heterocyclic acetylene benzene Compound and its pharmaceutical composition and application; CN101885722B
.

8, Ke Ding et al; GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo; Translational Oncology 13 (2020) 100766.
9, Ke Ding et al; Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region-Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib; J.
Med.
Chem.
2013, 56, 879−894.
10, Yasheng Pharmaceutical's official account: Yasheng Pharmaceutical's new drug for drug-resistant leukemia The clinical progress of oribatinib was selected as an oral report at the ASH annual meeting for the fourth time.
A total of three studies for this species were selected; 11, Yaodu Database; 12, Yaodu Series Books: Sheng Chunquan, Li Jian; "Drug Structure Optimization "
.

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