Professor Byung
Chul Cho MD, "TRX-221, top among all drug candidates"
CEO
Koo Lee PhD mentioned, "Preclinical results will be disclosed at AACR
2023... IND Application in June"
The requirements for a fourth-generation EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) can be summarized into three aspects: First, it should exhibit mutant selectivity, acting specifically on certain mutations to achieve accurate effects. Second, the drug itself must possess high potency. Third, it should be permeable to the blood-brain barrier to exert therapeutic effects on brain metastases. From these three aspects, Therapex's "TRX-221" can be considered among the top-tier candidates that are currently under development.
Professor Byung Chul Cho MD, Head of the Lung Cancer Center at Yonsei Cancer Hospital, recently evaluated Therapex's fourth-generation EGFR TKI candidate "TRX-221" in an interview with the press.
TRX-221 is a fourth-generation EGFR TKI candidate that not only targets the resistance mutation "C797S", which emerges after treatment with third-generation EGFR TKIs widely used in the treatment of EGFR-mutant non-small cell lung cancer, such as "Tagrisso" (ingredient name: Osimertinib), but also inhibits mutations targeted by first to third-generation EGFR TKIs (Del19, L858R, T790M, etc.).
Therapex has confirmed dose-dependent anticancer activity of TRX-221, not only in C797S mutation animal models but also in various EGFR-mutant tumor models. They plan to present the first preclinical research results at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2023.
In the interview, Professor Cho emphasized the
remaining unmet needs in the current treatment of EGFR-mutant non-small cell
lung cancer and the potential of TRX-221 based on these needs, as a member of
Therapex's clinical advisory board.
Professor Byung Chul Cho MD, Head
of the Lung Cancer Center at Yonsei Cancer Hospital
Professor Cho remarked, "Currently, third-generation EGFR TKIs have become the gold standard treatment for EGFR-mutant non-small cell lung cancer. However, after 17-20 months, resistance develops, and there is no established treatment strategy for patients who develop resistance."
He continued, "To address the issue of resistance, there are two approaches: biomarker-driven and non-biomarker-driven. A prominent approach based on biomarkers is the development of fourth-generation targeted anticancer agents."
He then mentioned the three characteristics that fourth-generation EGFR TKIs should possess in the future, including mutant selectivity, efficacy, and intracranial effects.
He emphasized that a fourth-generation drug should not only act specifically on certain mutations to achieve targeted effects but also demonstrate potency of the drug itself. Additionally, it should exhibit therapeutic effects on brain metastases, which develop in approximately 30% of lung cancer patients.
Professor Cho stated, "After using third-generation EGFR TKIs, patients may have a various spectrum of mutations such as C797S, Del19, L858R, and T790M. This ‘tumor heterogeneity’ is a challenging factor in clinical treatment. So far, the accumulated data suggests that recently developed fourth-generation EGFR TKIs show efficacy against a broad range of mutations."
He added, "While it's already known that third-generation drugs have better blood-brain barrier (BBB) permeability than first and second-generation drugs, there is no comparative data between third and fourth-generation drugs yet. However, at least in preclinical stages, fourth-generation agents with comparable BBB permeability to third-generation drugs are emerging."
Professor Cho anticipated that these characteristics of fourth-generation drugs would increase their potential for use as monotherapy or combination therapy compared to existing first to third-generation drugs.
He evaluated TRX-221 as having excellent mutant
selectivity and efficacy. He emphasized, "Among the preclinical studies of
fourth-generation EGFR TKI candidates under development, TRX-221 is evaluated
as a top-tier candidate."
Meanwhile, Therapex CEO Koo Lee PhD, who was
present at the interview, shared the development history of TRX-221 and future
clinical development strategies.
CEO Koo Lee PhD stated, "We plan to apply for Investigational New Drug (IND) of a TRX-221 Phase 1 clinical trial with the Ministry of Food and Drug Safety of the Republic of Korea (MFDS) by June this year." He emphasized, "Considering the typical timeline of over two years from drug candidate registration to IND application in new drug development, TRX-221 has only taken nine months." He stressed that this rapid pace in drug development is unprecedented in Korea.
Considering that it usually takes more than two years from the registration of a drug candidate to the submission of an Investigational New Drug (IND) application, it is indeed a fact that TRX-221 has shown remarkably rapid progress.
This has been made possible by the confidence and bold decisions of Therapex CEO Koo Lee PhD. He said that as soon as he saw the data for TRX-221, he got "a feeling". This "sixth sense" stems from his extensive experience with the drug candidate BBT-176, which laid the foundations for TRX-221, whilst he was Head of Drug Discovery at Bridge Biotherapeutics,
With a firm belief in TRX-221, the CEO swiftly
proceeded to contract with the Chinese global CRO WuXi AppTec for manufacturing,
toxicology tests, and other preclinical research. All the tests were then
conducted simultaneously.
Due to the substantial costs involved in the
preclinical process, it would have been safer in normal circumstances to
evaluate the potential after completing one process and then proceed to the
next stage. However, the CEO opted for the adventurous path of conducting all
these processes in parallel.
Reflecting on this decision, the CEO
reminisced, "Of course, there was no guarantee of 100% success, but the belief
in TRX-221 was strong. Therefore, the decision was made not to fall behind in
the current competition of fourth-generation EGFR TKIs under development."
The CEO emphasized that the market for the
treatment of EGFR-mutant non-small cell lung cancer continues to have high
demand for new drug development.
As a standard treatment, targeted cancer
therapy remains an area where continuous development of new treatment methods
is essential, as disease progression due to resistance ultimately necessitates
the development of new therapies.
CEO Koo Lee PhD also emphasized the advantages of TRX-221’s wide spectrum of target mutations. This includes those targeted by first and second-generation drugs such as Del19 and L858R, to the T790M mutation targeted by third-generation drugs, and even the C797S mutation, which emerges after treatment with third-generation drugs.
CEO Koo Lee PhD mentioned, “We expect TRX-221
to demonstrate maximum strength in terms of safety, with reduced off-target
toxicity.”
He also stated, “Although toxicity can only be determined accurately through clinical trials, the results shown in mouse models indicate that even with increased dosage, there was no significant weight loss, suggesting potential benefits in terms of safety.” He added, “Once safety is demonstrated in clinical trials, we can explore clinical strategies for combination therapy.”
CEO Koo Lee PhD plans to present the
preclinical results of TRX-221 at the upcoming AACR Annual Meeting 2023 himself.
In particular, the data to be presented this time will include research results
from the “PDX model".
The Patient-Derived Xenograph (PDX) model is
known as the animal model that best predicts actual patient outcomes by
transplanting tissue from actual cancer patients into mice with human immune
systems.
In the field of EGFR-mutant non-small cell lung
cancer, CEO Koo Lee PhD explained that TRX-221 is the first fourth-generation
EGFR TKI candidate to derive data using the PDX model.
CEO Lee stated, "The ultimate goal of
TRX-221 development is out-licensing," adding, "The final goal is to
have the stamp of approval on the out-licensing agreement by 2025, when interim
results from Phase 2 clinical trials are expected."
Source: "Cheongnyeon Doctor News",
Reporter Kim Yoon-mi