FDA grants priority review to futibatinib, FGFR inhibitor tripartite situation may be broken

On March 30, Taiho Oncology and Taiho Pharmaceutical announced that the FDA has accepted a New Drug Application (NDA) for futibatinib for previously treated locally advanced or metastatic cholangiocarcinoma (CCA) harboring FGFR2 fusions, including gene fusions
.

At the same time, the FDA also granted the application priority review status with a PDUFA date of September 30, 2022

futibatinib (TAS-120) is an oral, selective FGFR1-4 inhibitor that irreversibly covalently binds to the ATP-binding "pocket" of FGFR1-4, inhibiting FGFR-mediated signaling, thereby reducing FGFR1-4 Proliferation of genetically altered tumor cells
.

In May 2018, futibatinib was granted orphan drug designation by the FDA for the treatment of cholangiocarcinoma

The NDA is based on positive results from the pivotal Phase 2b clinical study FOENIX-CCA2 of futibatinib
.

The study is a single-arm, multicenter study to evaluate futibatinib in patients with locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 gene rearrangements, including gene fusions, who have failed at least one therapy.

The results of the study, published in the American Association for Cancer Research (AACR) in April 2021, showed that the ORR of futibatinib treatment was 41.
7%, meeting the primary endpoint of ORR > 20% determined by an independent central review assessment
.

Secondary endpoints: mDOR was 9.

In terms of safety, common treatment-related adverse events in the study were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%)
.

The most common grade 3 TRAE was hyperphosphatemia (30%), but symptoms resolved with appropriate treatment

FGFR, the fibroblast growth factor receptor, is one of the subgroups of receptor tyrosine kinases, including four subtypes, FGFR1, FGFR2, FGFR3, and FGFR4
.

Signal transduction pathways mediated by FGFR, such as RAS-RAF-MAPK, PI3K-AKT, signal transducer and activator of transcription (STAT), and phospholipase Cγ (PLCγ), are necessary for normal cell growth and differentiation, and are involved in new blood vessels.

When FGFR is mutated or overexpressed, the FGFR signaling pathway will be overactivated, causing normal cells to become cancerous
.

A study published in Clinical Cancer Research in 2015 showed that FGFR aberrations were found in about 7.

At present, global pharmaceutical companies have developed a number of drugs around FGFR targets, among which Johnson & Johnson's Balversa (erdafitinib), Incyte/Innovent Bio's Pemazyre (pemigatinib), BridgeBio/Helsinn's Truseltiq (infigratinib) have been approved for marketing
.

Balversa, a once-daily oral FGFR kinase inhibitor discovered by Astex Pharmaceuticals, was approved by the FDA in April 2019 for the treatment of individuals with susceptible FGFR3 or FGFR2 genetic alterations during or after receiving at least one platinum-containing chemotherapy (including Adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with disease progression within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy
.

In 2008, Johnson & Johnson entered into an exclusive global license and collaboration agreement with Astex Pharmaceuticals to jointly develop and commercialize the drug

Pemazyre is a potent, selective, and oral small molecule inhibitor of FGFR isoforms 1, 2, and 3 developed by Incyte, which was approved by the FDA in April 2020 for the treatment of previously treated patients with FGFR2 fusions Or rearranged, unresectable locally advanced or metastatic cholangiocarcinoma
.
In 2018, Innovent and Incyte reached an exclusive licensing agreement to obtain the license for the clinical development and commercialization of 3 drugs, including this drug, in single-agent or combination therapy in Mainland China, Hong Kong, Macau and Taiwan
.

Truseltiq is an innovative oral FGFR 1-3 selective and potent inhibitor with a clear novel chemical structure and pharmacological effect.
It was approved by the FDA in May 2021 for the treatment of previously treated locally advanced patients with FGFR2 fusions or rearrangements or metastatic CCA patients
.
The drug was introduced by BridgeBio from Novartis.
Currently, BridgeBio and Helsinn are jointly responsible for the US market, Helsinn is responsible for the market outside the United States (excluding Greater China), and Liantuo is responsible for clinical development and registration in Greater China (Mainland China, Hong Kong, Macau).
Development and commercialization of the Chinese market for applications and future commercial operations
.

According to the company’s financial report, Pemazyre’s sales in 2020 and 2021 will be US$25.
9 million and US$68.
5 million, respectively
.
The sales of the other two products are unknown, but Nature Review Drug Discovery predicts that Balversa will have sales of about $1.
2 billion in 2024
.

In addition, there are a number of FGFR inhibitors currently in clinical trials, as detailed in the table below
.
Among them, Rogaratinib is a highly effective and selective FGFR1-4 inhibitor developed by Bayer with oral activity.
The clinical trial for urothelial carcinoma is in Phase 3 clinical trials
.
Bemarituzumab is an anti-FGFR2b monoclonal antibody developed by Five Prime Therapeutics.
It has been granted breakthrough therapy designation by the FDA and CDE successively.
It is combined with an improved FOLFOX6 chemotherapy regimen (mFOLFOX6: fluoropyrimidine + folinate calcium + oxaliplatin), first-line treatment Fibroblast growth factor receptor 2b (FGFR2b)-overexpressing, HER2-negative, metastatic and locally advanced gastric and gastroesophageal junction (GEJ) cancer patients
.
In December 2017, Zai Lab reached a licensing agreement with Five Prime to acquire the rights and interests of bemarituzumab in Greater China
.
Derazantinib is a potent, oral, pan-FGFR inhibitor developed by ArQule.
Signaling is important for maintaining tumor-promoting macrophages and has been identified as a potential target for anticancer drugs) and has been granted orphan drug designation by the FDA and EMA for the treatment of intrahepatic cholangiocarcinoma
.
In February 2018, Roivant Sciences reached a cooperation with ArQule to obtain the authorization of the drug in Greater China
.

Looking at the above-mentioned FGFR inhibitors, in addition to pan-FGFR inhibitors, companies have begun to deploy FGFR4 inhibitors
.
Moreover, the indications of FGFR inhibitors are more extensive, in addition to cholangiocarcinoma and urothelial cancer, it has been expanded to hepatocellular carcinoma, gastric and gastroesophageal junction cancer, and mesothelioma
.
Chinese pharmaceutical companies are also actively deploying the FGFR inhibitor market.
In addition to introduction, they are also actively researching and developing independently.
For example, Betta Pharmaceuticals has not only developed pan-FGFR inhibitors, but also developed FGFR4 inhibitors
.