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Niche tumors usher in new treatments, what other new drugs are worth looking forward to in the field of intrahepatic cholangiocarcinoma?

 Last Update: 2022-11-04
 Source: Internet
 Author: User

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Recently, Japan's Taiho Pharmaceutical and its subsidiary Taiho Oncology announced that the FDA has accelerated the approval of its product, Lytgobi (Futibatinib), for the treatment of treated adults with FGFR2 gene fusion or other rearrangements of unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma
.
This is the fourth new drug approved by the FDA to treat intrahepatic cholangiocarcinoma since 2020, and the third targeted drug
for FGFR2 abnormalities.

Lytgobi(Futibatinib)

Intrahepatic cholangiocarcinoma (Intrahepatic Cholangiocarcinoma, ICC), refers to malignant tumors originating from the bile ducts above the confluence of the left and right liver ducts, and is one of the types of primary liver cancer, accounting for only 10%~15%
of all primary liver cancer cases.
However, the incidence of intrahepatic cholangiocarcinoma is increasing and the mortality rate is high
.
According to relevant data, in 2018, 84,000~126,000 people were newly diagnosed with ICC in the world, and the incidence of intrahepatic cholangiocarcinoma in China is about half of the world
.
The age-standardized incidence rate from 2008 to 2012 was about 0.
63 per 100,000 people, and it increased
at a rate of about 11% per year.
In addition, due to the insidious onset and strong aggressiveness, surgical resection and chemotherapy are currently the main treatment methods, but the effect of anti-cancer measures is relatively poor, and the average survival time of patients does not exceed one year
.

Major breakthroughs have been made in FGFR2 and IDH1 targeted therapy

According to statistics, the common mutation types of intrahepatic cholangiocarcinoma include FGFR, IDH1, IDH2, BRAF, etc.
, in recent years, the treatment of FGFR2 and IDH1 two mutant subtypes has made significant breakthroughs, opening a new track
for the research and development of targeted drugs for intrahepatic cholangiocarcinoma.

So far, in addition to the just-approved Futibatinib, the FDA has approved 2 new drugs
targeting FGFR2 and 1 targeting IDH1.
According to relevant data, FGFR2 gene fusion is found in 13%~17% of intrahepatic cholangiocarcinoma patients, and IDH1 mutation occurs in about 20% of intrahepatic cholangiocarcinoma, which is a very important therapeutic target for intrahepatic cholangiocarcinoma
.

▲Table 1 Up to now, a total of 4 new drugs for ICC treatment have been approved Source: Compiled by the author

Treatment of intrahepatic cholangiocarcinoma can be expected in the future

In addition to the two major targets of FGFR2 and IDH1, what other therapeutic targets and new drugs are under development in the future?

Author via Clinical Trial, drug clinical trial registration and information disclosure platform, sorting out new drugs under development for intrahepatic cholangiocarcinoma, FGFR-targeted drugs are still the research focus of pharmaceutical companies, Hutchison Whampoa, Beijing Tiancheng, Basilea Pharmaceutica and other pharmaceutical companies have all layouts
.

▲Table 2 Global Intrahepatic Cholangiocarcinoma New Drug Development Source: Clinical Trial, Drug Clinical Trial Registration and Information Disclosure Platform, organized by the author

2.
1 Novel FGFR inhibitors

Relay's new drug under development, RLY-4008, is a highly specific oral inhibitor
of FGFR2.

Small molecules that inhibit FGFR2 activity often also inhibit the activity of FGFR1 and other members of the FGFR family, and this off-target effect has brought many toxic side effects in clinical applications, and Relay's proprietary technology platform developed the FGFR2-specific inhibitor RLY-4008
through detailed analysis of the dynamic equilibrium of protein conformation 。 Compared with other FGFR inhibitors, RLY-4008 exhibits FGFR2-dependent anticancer activity in cancer cell lines, and has minimal effect on other targets (including other proteins of the FGFR family) while shrinking tumors, and has good anti-off-target properties
.

Figure 1 RLY-4008 has very high FGFR2 specificity Source: Relay Company Presentation 2022

2.
2 Attacking the virus with poison, immunotherapy is worthy of attention to oncolytic viruses

At present, VG161, a class of innovative drug developed by Sinopharm China Biologics Biotechnology (Shanghai) Co.
, Ltd.
, is in clinical phase II for the treatment of advanced intrahepatic cholangiocarcinoma
.

VG161 is an oncolytic virus product, oncolytic virus is one of the tumor immunotherapy methods, oncolytic virus is a natural or artificially modified can selectively replicate in tumor tissue, thereby killing tumor cells, but has no killing effect on normal tissues
.
In addition to directly killing tumor cells, oncolytic viruses can participate in multiple stages of anti-tumor immunity and exert their anti-tumor activities, and oncolytic viruses can induce a strong immune response and enhance the body's anti-tumor response
.

Figure 2 Principle of oncolytic virus Source: Sullivan

VG161 also carries genes
for IL12, IL15/15RA (IL15 and IL15 receptors α subunits) and PD-L1 blocking peptide (PDL1B).
VG161 enters the tumor tissue through intratumoral injection, and the virus replicates and lyzes tumor cells in tumor cells, and the four immunostimulating factors carried are effectively expressed, realizing the synergy
between oncolytic activity and immune stimulation.
At the same time, further synergy between the four immunostimulatory factors expressed by the virus also occurs, thereby transforming the antiviral immune response into a specific anti-tumor immune response
.

Since 2015 Since the approval of the world's first product, four oncolytic virus products have been approved by the FDA for indications involving melanoma, head and neck tumors, and glioma (two of which are also indicated for melanoma), which marks the technological maturity of oncolytic viruses and the recognition
of their treatment of cancer.
At present, oncolytic virus technology is mainly used to treat refractory solid tumors, in addition to intrahepatic cholangiocarcinoma, the future oncolytic virus may bring new hope
for the treatment of patients with malignant tumors such as pancreatic cancer and glioblastoma.

2.
3 New targets emerge: PPT1, Sk2, HER2.
.
.

In September this year, Genoscience Pharma's new drug under development, GNS561, was granted orphan drug designation by the FDA for the treatment of intrahepatic cholangiocarcinoma
.

In advanced intrahepatic cholangiocarcinoma, autophagy is activated in tumor cells to accelerate tumor development
.
The orphan drug GNS561 is a PPT-1 (palmitoyl protein thioesterase-1) inhibitor that inhibits advanced autophagy and expands the dose-dependent accumulation of lysosomes by interacting with PPT1, thereby blocking cancer cell multiplication
.

According to the phase I clinical study data of GNS561, after one month of GNS561 treatment, PPT1 expression in malignant liver tissue was reduced
.
The effectiveness of GNS561 will be further verified in future clinical trials, and at present, GNS561 is a promising drug
candidate.

Figure 3 PPT-1 expression Source: First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers

ABC294640 is a sphingosine kinase 2 (Sphk-2) inhibitor
.
SPHK can use sphingosine, which has pro-apoptotic effects (Sphingosine, Sph) is metabolized to Sphingosine-1-phosphate (S1P),
which has a proliferative effect.
The study found that Sphk is overexpressed in many tumors and has the effect of promoting tumorigenesis and development, which is a new target for
tumor treatment.
There are two isomers of Sphk, namely Sphk1 and Sphk2, and Sphk2 is expressed higher
in cholangiocarcinomas.
ABC294640 is a new type of Sphk2 small molecule inhibitor, which has the advantages of strong specificity, good oral absorption and low side effects, and has entered phase II clinical trials
.

ZW25 (Zanidatamab) is a bispecific HER2-targeted antibody
.
In November 2020, ZW25 received breakthrough therapy designation
from the FDA.
At 2021 ASCO Phase I clinical data of the drug were presented at the GI meeting, and the objective response rate of 21 biliary tract cancer patients included in the study was 40%, the disease control rate was 65%, and the median duration of response was 7.
4 months
.

epilogue

There is a huge clinical unmet need for intrahepatic cholangiocarcinoma, and due to the high detection rate in intrahepatic cholangiocarcinoma, FGFR2-related drugs have been pinned on high expectations, and major breakthroughs have been made in recent years and have developed rapidly
.
In the future, more mechanism studies and targets will be explored, bringing hope
for the treatment of patients with intrahepatic cholangiocarcinoma.
In addition, the authors believe that the current detection methods for intrahepatic cholangiocarcinoma are very limited, and the current detection methods have pain points
.
Puncture is not suitable for preoperative patients and early diagnosis, imaging examination has the risk of misdiagnosis or missed diagnosis, poor diagnostic performance of tumor markers and other problems, with the deepening of the mechanism of intrahepatic cholangiocarcinoma, not only a leap in the treatment link, but also is expected to develop diagnostic products with a clear pathological mechanism, at that time, the intrahepatic cholangiocarcinoma diagnosis-treatment industry chain will also be reshaped
.

【Reference】

【Reference】【Reference】

1.
Clinical Trial, drug clinical trial registration and information disclosure platform

2.
"Treatment of cholangiocarcinoma, innovative precision therapy with accelerated FDA approval," WuXi AppTec, October 2022

3.
"Status and progress of diagnosis and treatment of intrahepatic cholangiocarcinoma", International Journal of Surgery, No.
6, 2020

4.
"The Men Chase the Deer!" 2021 Targeted Therapy for Cholangiocarcinoma, Potential Targets Open a New Track of New Cholangiocarcinoma Targeted Drugs", Liuji Xing Research Press, 2021

5.
《2021 ASCO GI | Inventory of blockbuster research in the field of liver cancer and cholangiocarcinoma", Yimaitong, 2021

6.
"China's first oncolytic virus product VG161 obtained clinical trial approval", Biologics Circle, 2020

7.
White Paper on the Development of Oncolytic Virus Industry in China, Sullivan, 2021

8.
"Oncolytic virus 3.
0, Funuojian has absorbed more than 140 million US dollars in half a year, and the first product has entered the clinic", Health Circle, 2021

9.
Harding JJ, Awada A, Roth G, etal.
First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers.
Liver Cancer.
2022 Feb 15; 11(3):268-277.

10.
"Precision treatment of cholangiocarcinoma, preliminary clinical results of highly specific FGFR2 inhibitors are positive", WuXi AppTec, 2021

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