Nellik? The results of phase I/II clinical studies were published in the international authoritative journal "Journal of Hematology & Oncology", verifying the potential of best-in-class

Ascentage Pharma (6855.
HK) announced on September 21 that the phase I and phase II clinical results of the company's core variety orebatinib (HQP1351, trade name: Nerix) in the treatment of drug-resistant chronic myeloid leukemia (CML^{) have been officially published in the internationally renowned oncology journal Journal of Hematology & Oncology (hereinafter referred to as JHO journal), further verifying its long-lasting efficacy and safety in CML patients ®}
。

The JHO journal is the world's leading journal in hematology and oncology, and the journal publishes top research covering the full range of hematology and oncology fields with an impact factor of 23.
168 ^[1].

。 The study, published in the journal Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial^[2]
。 Professor Huang Xiaojun, principal investigator of the ^{clinical trial of Nellix ®} China, director of the Institute of Hematology of Peking University and director of the Department of Hematology of Peking University People's Hospital, is the corresponding author of the article; Professor Jiang Qian, principal investigator of the Chinese clinical trial and deputy director of the Department of Hematology, Peking University People's Hospital, is the first author
of the paper.
^®

The study published the results
of a clinical trial ^{of Nelik ®} in 165 Chinese CML patients who had previously received multiple lines of TKI.
The cohort of participants included TKI-resistant CML patients with T315I mutations, with a median follow-up of nearly 3 years
.
The data showed that in patients with the chronic phase (CP) of CML, the 3-year cumulative response rates of major cytogenetic responses and major molecular responses were 79% and 56%, respectively; In patients with the accelerated phase of CML (AP), the 3-year cumulative response rates for major cytogenetic responses and major molecular responses were 47% and 45%, respectively, in addition, cytogenetic and molecular response rates increased further with prolonged treatment
.
In terms of safety, common non-hematological adverse events are mainly skin pigmentation, hypertriglyceridemia, etc.
, mostly grade 1-2; Hematologic adverse events resolved
after temporary suspension of treatment or supportive care.
Adverse events were mostly manageable and tolerable
.
Especially with the prolongation of the treatment time, side effects such as thrombocytopenia continue to decrease
.
This shows that Nerix ^® is well tolerated in TKI-resistant patients with CML-CP or CML-AP and has stable and durable
efficacy.
In addition, this variety has shown high activity against the BCR-ABL1T315I mutant and has shown encouraging antitumor activity in patients with complex mutations, for whom there is currently no standard treatment
regimen.

CML is a malignancy
associated with white blood cells.
With the introduction of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL, CML treatment has revolutionized
.
Despite the significant clinical benefits of first- and second-generation TKIs for the treatment of CML, TKI resistance has been a major challenge
in CML treatment.
BCR-ABL kinase region mutation is one of the important mechanisms of TKI resistance, among which T315I mutation is one of the common types of drug resistance mutations, and the incidence rate in drug-resistant CML can reach about
25%.
Chronic patients with T315I mutations are resistant to all current first- and second-generation BCR-ABL inhibitors
.
There is a great
clinical demand for third-generation BCR-ABL inhibitors that can safely and effectively treat patients with T315I mutant CML chronic granules.

Nellix ^® is a potential best-in-class new drug developed by Ascentage Pharma, and is a special support variety
for the national "major new drug creation".
As the first and only third-generation BCR-ABL inhibitor approved for marketing in China, the emergence of Nellix ^® has broken the dilemma
of long-term drug-free CML patients with T315I mutation in China.
At present, Nelik ^® has been recommended by the guidelines of the Chinese Society of Clinical Oncology (CSCO) and the Chinese Anti-Cancer Association "Chinese Guidelines for Integrated Diagnosis and Treatment of Oncology (CACA)" to treat patients with previous TKI resistance chronic granules with T315I mutation (CACA guidelines also recommend this variety for the treatment of chronic granules who have received more than 2 TKIs resistance or intolerance).

At the global level, although another BCR-ABL inhibitor has been approved before, there is still an incomplete clinical need
for the treatment of drug-resistant CML due to drug accessibility, drug-related adverse events, etc.
Because of this, the clinical progress of the drug has attracted the attention
of the global hematology community in recent years.
Since 2018, Nelik's ^® clinical progress has been selected for four consecutive years as an oral presentation at the American Society of Hematology (ASH) Annual Meeting and nominated
for "Best Study" at the 2019 ASH Annual Meeting.
At present, Nelik ^® has entered phase Ib clinical trials in the United States for the treatment of drug-resistant CML
.
In addition, Nellik ^® has received 1 US Food and Drug Administration (FDA) Fast Track designation, 3 FDA orphan drug designations and 1 European Medicines Agency (EMA) EU orphan drug designation
.

Professor Huang Xiaojun said: "As a Chinese clinician who has been studying in the field of hematological oncology for more than 30 years, and as the principal investigator of the clinical trial of Nelik, I am very pleased to see the clinical progress of this innovative drug published in JHO journal, ^® which once again proves that ^{the original product of Nelik ®} is expected to bring Chinese solutions
to the global CML ^{treatment field.
®} It is hoped that more and more local innovative drugs ^{like Nelik ®} will emerge, giving more Chinese clinicians the opportunity to lead the clinical trials of new drugs, accumulate Chinese data and experience in the process and transform them into internationally forward-looking evidence-based medical results for publication, and ultimately enhance China's international academic influence
in the world.
"

Professor Jiang Qian said: "Currently, 20-30% of CML patients are resistant to or intolerant to existing TKIs, leading to disease progression, and many of them will fail to meet the expected milestone due to new mutations or other complications after switching to a second or third TKI, resulting in treatment failure
.
It can be said that TKI resistance is a global challenge for
CML treatment.
The data published in the journal JHO show that Nelik has good efficacy for CML and can effectively overcome the T315I mutation, while showing encouraging clinical activity
against BCR-ABL kinase domain complex mutations ^{for which there is currently no effective ®} treatment.
This means that Nellix ^® is a promising CML treatment
.
"

Dr.
Yifan Zhai, Chief Medical Officer of Ascentage Pharmaceutical, said, "Nelik is an original Class 1 new drug with the potential of "best-in-class", and its clinical development is the implementation of Ascentage Pharma's global innovation strategy
.
^® The Phase I/II clinical progress of Nelik was awarded the Journal of Hematology & Oncology, which not only reflects the therapeutic potential of this product in the field of global drug-resistant CML, but also represents another success in the company's global innovation strategy
.
^® We eagerly look forward to starting from China to bring a definitive and safer treatment
option to drug-resistant CML patients around the world.
" ^® In the future, we will continue to adhere to the mission of 'solving the unmet clinical needs of patients in China and even around the world, accelerate the clinical development of the company's research products at the global level, and benefit patients
as soon as possible.
" "

The main points of the research conducted ^{by Nerik ®} in the Journal of Hematology & Oncology are as follows:

       Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial

Orebatinib -- A safe and effective tyrosine kinase inhibitor in patients with T315I-mutated chronic myeloid leukemia: a study in an open-label, multicenter phase I/II clinical trial

Research Methods:

This is an open-label, multicenter phase I/II study
.

The Phase I study used a standard design of "3+3" dose escalation and dose expansion, with orebatinib being an oral, alternate-day, 28-day cycle with 11 dose groups
ranging from 1 to 60 mg.
The primary endpoint of the Phase I study was the Phase II study recommended dose (RP2D).

The Phase II study partially evaluates the efficacy and safety
of orebatinib in patients with T315I mutant CML-CP and CML-AP at RP2D.
The primary endpoints of the Phase II study were orebatinib in CML-CP patients with major cytogenetic response (MCyR) and CML-AP in patients with CML-AP (MaHR).

Characteristics of enrolled patients

Between October 26, 2016 and October 08, 2019, a total of 165 patients
were enrolled.
It included 127 patients with CML-CP and 38 patients
with CML-AP.
66.
7% (110 patients) of patients were male
.
The median age was 42 (range: 20~74) years
.
The median time from diagnosis of CML to treatment with orebatinib was 5.
7 (0.
3~23.
2) years
.

More than 80% of patients had received 2 or more TKIs in the past: 54.
5% (90 patients) had received 2 prior TKIs; 27.
3% (45 patients) received at least 3 TKIs
.

Sanger sequencing results showed that 61.
8% of patients had T315I point mutations, 15.
2% with T315I and additional mutations, and 8.
5% with mutations
other than T315I.

Phase I study

Between October 26, 2016 and December 12, 2018, a total of 101 TKI-resistant CML patients were enrolled in the Phase I study
.
Among them, 86 patients had CML-CP and 15 had CML-AP.

In 11 dose groups (1~60 mg QOD, 28-day cycle), dose-limiting toxicity (DLT) was observed in the 60 mg cohort, and the maximum tolerated dose (MTD) was 50 mg
.
Based on preliminary safety and efficacy results, RP2D was determined to be 40 mg QOD.

Phase II study

After the RP2D was identified, two pivotal studies were initiated in 10 research centers in China, enrolling 41 patients with T315I mutant CML-CP and 23 patients with T315I mutant CML-AP, of which more than 60% received second-line therapy
.

As of September 30, 2021, the median follow-up time was 34.
3 (4.
8~58.
6) months, and 69.
0% (114 cases) of patients were still receiving orebatinib treatment
.

security

The median duration of treatment was 30.
7 (1.
2~58.
6) months
.
The common non-hematologic TRAE was skin pigmentation, which occurred in 139 patients (84.
2%), followed by hypertriglyceridemia (57.
6%), proteinuria (50.
9%), hyperbilirubinemia (41.
8%), hypocalcemia (38.
8%), and elevated hepatic transaminases (35.
8%)
.

Grade 3/4 hematology TRAE include thrombocytopenia (51.
5%), anemia (23.
0%), leukopenia (20.
6%), and neutropenia (11.
5%)
.
Myelosuppression occurs in the early stages
.
Most TRAE resolve after suspension of treatment or supportive care, including platelet or red blood cell transfusions or dose adjustment
.

Orebatinib related cardiovascular events (CVEs) were observed in 53 patients (32.
1%) during treatment, mainly including hypertension (13.
3%), pericardial effusion (8.
5%), etc.
, of which grade 3/4 CVEs accounted for 11.
5%, and the incidence of arterial occlusion and venous thromboembolism was 5%, far lower than the 31%
reported by the world's first third-generation BCR-ABL inhibitor.

With the exception of skin pigmentation and proteinuria, the incidence of TRAE decreases progressively over
time during follow-up.
Decreased
renal function in patients with persistent proteinuria was not observed.
Serious adverse events (SAEs) with >1% incidence included thrombocytopenia (9.
0%), anaemia (6.
0%), pneumonia (3.
0%), fever, or atrial fibrillation (2.
0% each); and acute myocardial infarction, cholelithiasis, pericardial effusion, upper respiratory tract infection, and urinary tract infection (1% each).

Most SAEs resolve
after temporary suspension of treatment or dose reduction.

efficacy

       Efficacy

In patients with CML-CP, the median follow-up period of 126 evaluable patients was 37 (7~58) months
since the start of receiving the effective dose (≥30 mg QOD).
100% of patients achieve a complete hematological response (CHR).

MCyR and CCyR were 79.
3% and 69.
4%,
respectively.
55.
6% of patients achieved deep molecular biology response (MMR), 44.
4% achieved MR4.
0, and 38.
9% achieved MR4.
5
.
With the prolongation of treatment time, cytogenetic and molecular response rates further increased, and the cumulative 3-year incidence rates of MCyR, CCyR, MMR, MR4.
0 and MR4.
5 were 78.
6%, 69.
0%, 55.
9%, 43.
5% and 38.
6%,
respectively.
The 3-year progression-free survival (PFS) and overall survival (OS) rates were 92.
0% and 94.
0%,
respectively.

In patients with CML-AP, the median follow-up time of 38 evaluable patients was 27 (5~56) months
since the start of receiving the effective dose.
78.
4% of patients achieved MaHR; CHR was achieved in 73% of patients; The incidence of MCyR and CCyR was 47.
4%.

44.
7% and 36.
8% of patients achieved MMR and MR4.
0, and 34.
2% achieved MR4.
5
, respectively.
With the extension of treatment time, the cytogenetic and molecular response rates also further increased, reaching the 3-year cumulative incidence rates of MCyR, CCyR, MMR, MR4.
0 and MR4.
5 of 47.
4%, 47.
4%, 44.
7%, 39.
3% and 32.
1%, respectively, and the 3-year PFS rate and OS rate of 60.
0% and 71.
0%,
respectively.

Conclusion of the study

       Conclusions

Orebatinib is well tolerated in TKI-resistant patients with CML-CP or CML-AP, and the efficacy is stable and durable; It is worth mentioning that this variety shows high activity against the BCR-ABL1T315I mutant and shows encouraging antitumor activity
in patients with complex mutations.

Resources

       1.
2-Year Impact Factor (2021) as released by ClarivateTM

2.
Jiang Q, Li Z, Qin Y, et al.
Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.
J Hematol Oncol.
Aug 18 2022; 15(1):113.
doi:10.
1186/s13045-022-01334-z