The fastest-growing antitumor drug pipeline in China, who do you pick?

In July last year, Insight compiled and released the 31 fastest-growing clinical-stage biological drug pipelines in China.
These new drugs, as drugs in the phase III research and development stage, are only one step away from being reported to the market
.

In the past six months, two PD-L1 mAbs have been declared for the market
.

According to the latest data from the Insight database, 9 new antibody drugs entered Phase III clinical trials in the past six months, and the development of new drugs in China is full of vitality

Antibody new drugs entering Phase III clinical stage after July 2021

From: Insight Database Project Progress Module (http://db.
dxy.
cn/v5/home/)

*Note: Phase II/III clinical and Phase I/III clinical project progress is counted in Phase III

Today, we are looking at the anti-tumor drugs that domestic pharmaceutical companies are in Phase III clinical development from the perspective of companies and targets
.

Target Top3: ALK, EGFR, CDK4/6

Target Top3: ALK, EGFR, CDK4/6

In terms of target dimension statistics, the most competitive targets in clinical phase III chemical drugs are ALK, EGFR and CDK4/6 targets
.

The common feature of these targets is that there are already marketed drugs, and there are also many latecomers.

In terms of target dimension statistics, the most competitive targets in clinical phase III chemical drugs are ALK, EGFR and CDK4/6 targets

ALK

ALK

There are currently 4 new domestic drugs in Phase III clinical trials for ALK targets
, from Shouyao Holding, Chia Tai Tianqing, Sihuan Pharma and Fosun Pharma .

ALK target

CT-707 (Conteltinib, SY-707) is a second-generation ALK inhibitor completely independently developed by First Pharmaceutical Holdings .
It has a good inhibitory effect on ALK, FAK, PYK2, IGF1R and other kinases.
Dosages (mostly tablets/capsules) are slightly different and are granules
.

Its main development indication is ALK-positive NSCLC

CT-707 (Conteltinib, SY-707) is a second-generation ALK inhibitor completely independently developed by First Pharmaceutical Holdings

At present, CDE has agreed that the second-line indication of CT-707 will be listed on the market after the completion of Phase II clinical and expected results, and the first drug is expected to be NDA in 2022; The first-generation ALK inhibitor crizotinib is evaluated in a head-to-head efficacy trial.
It is expected to complete enrollment in 2022Q1 and NDA in 2023
.

In addition, the drug was also approved for clinical use in February, and will be combined with Junshi Bio's PD-1 monoclonal antibody toripalimab to start a phase Ib/II clinical trial for pancreatic cancer

CT-707 Registered Clinical Registry

From: Insight database (http://db.
dxy.
cn/v5/home/)

First Pharmaceutical Holdings also owns a third-generation ALK inhibitor CT-3505 (SY-3505)
.

CT-3505 is a new ALK inhibitor obtained by further optimizing the branched molecular structure based on the parent nucleus structure of SY-707 molecule.

First Pharmaceutical Holdings also owns a third-generation ALK inhibitor CT-3505 (SY-3505)

CT-3505 Important Nodes in R&D

Chia Tai Tianqing also has two ALK inhibitors, TQ-B3139 and TQ-B3101 .
The former has progressed rapidly and is already in the phase III clinical stage, while the latter has launched 3 phase II clinical trials, which started in 2019
.

Chia Tai Tianqing also has two ALK inhibitors TQ-B3139 and TQ-B3101

TQ-B3139 (CT-1139) is a c-Met/ALK/ROS multi-target tyrosine kinase inhibitor jointly developed by Chia Tai Tianqing and Shouyao Holding.
Shouyao Holding is responsible for the design and optimization of the compound molecule.
The preclinical candidate compounds were transferred to Tianqing for clinical stage development, and both parties jointly owned the intellectual property rights
.

TQ-B3139 (CT-1139)

According to the Insight database, from the clinical development of indications, TQ-B3139 is consistent with other ALK inhibitors, and the fastest-growing Phase III clinical trial aims to compare the efficacy and safety of the drug with crizotinib in the treatment of ALK-positive advanced NSCLC, II Phase 1 clinical trials target two indications: ALK-positive advanced NSCLC after crizotinib resistance, and MET gene-abnormal NSCLC
.

According to the Insight database, from the clinical development of the indication, TQ-B3139 MET gene abnormal NSCLC

At the same time, another ALK/MET/ROS1 inhibitor TQ-B3101 developed in parallel has slightly different indications from TQ-B3139 .
Phase 2 clinical trials are aimed at ROS1 fusion-positive advanced NSCLC (CTR20191078)
.
The clinical study, with Professor Lu Shun and Professor Pan Hongming as the main PIs, has been selected for the 2022 European Lung Cancer Congress (ELCC), the ORR assessed by the Independent Review Committee (IRC) was 78.
4%, and the mPFS was 15.
6 months
.

The indication development of another ALK/MET/ROS1 inhibitor TQ-B3101 developed in parallel is slightly different from TQ-B3139

Chia Tai Tianqing ALK inhibitor original drug

From: Insight database (http://db.
dxy.
cn/v5/home/)

XZP-3621, developed by Xuanzhu Bio, a subsidiary of Sihuan Pharmaceutical, belongs to a new generation of ALK/ROS1 dual-target inhibitors and is intended to be developed for the treatment of non-small cell lung cancer
.
The results of in vitro studies show that XZP-3621 has excellent activity against multiple resistance sites of first- and second-generation ALK inhibitors
.
In preclinical in vivo pharmacodynamic model studies, XZP-3621 also showed good efficacy
.

XZP-3621 was developed by Xuanzhu Bio, a subsidiary of Sihuan Pharmaceutical, and belongs to a new generation of ALK/ROS1 dual-target inhibitors.

The results of clinical studies have shown that XZP-3621 has definite curative effect on both ALK inhibitor-naïve and ALK-rearranged advanced NSCLC patients with better safety
.
According to the Insight database, Xuanzhu Bio has initiated a Phase 3 clinical trial in November 2021 for the first-line treatment of patients with ALK-positive advanced non-small cell lung cancer
.

Phase III clinical trial details

From: Insight database (http://db.
dxy.
cn/v5/home/)

Furitinib (code: SAF-189) is an orally active ALK/ROS1 small molecule inhibitor developed by Fuchuang Pharma, which is intended to be developed for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer
.
ALK and ROS1 gene rearrangements are important predictive biomarkers and oncogenic drivers in advanced non-small cell lung cancer
.
In December 2021, Furitinib was registered on the CDE clinical trial platform to initiate a multicenter, open-label, randomized controlled Phase 3 clinical study to compare the candidate drug with a comparator in treatment-naïve ALK-positive advanced or metastatic non-cancerous patients.
Efficacy and safety in patients with small cell lung cancer
.

Public information shows that in early studies, feritinib succinate showed strong efficacy against ALK/ROS1 resistance mutations, had good anti-tumor effects, and was highly targeted to brain, lung and tumors tissue, with good pharmacokinetic profile and safety
.

According to the target competition pattern shown by the Insight database, 4 new drugs for ALK targets have been approved for marketing in China: the first-generation ALK inhibitor crizotinib, the second-generation ALK inhibitors ceritinib, alectinib, and ensa tinib
.
In addition, there are two second-generation ALK inhibitors brigatinib and Iluac, and a third-generation ALK inhibitor lorlatinib for listing.
Overall, the leading position is mainly occupied by foreign companies
.

Among the domestic innovative drugs, Betta Pharmaceuticals' ensatinib has made its first breakthrough and was approved for marketing in November 2020.
Currently, new indications for first-line therapy are also being applied for marketing.
According to Betta's official disclosure, the first three quarters of Ensatinib Satinib received sales revenue of 120 million yuan
.
Qilu Pharmaceutical's Iluak is the second domestic ALK inhibitor, and it also submitted a new drug marketing application in July last year
.

ALK target domestic competition pattern

EGFR

EGFR

EGFR inhibitors have been developed from one generation to four generations, and selective inhibitors for rare mutations such as Exon20 insertion mutations have been derived
.

EGFR inhibitors

EGFR target hierarchy (Insight)

*The Insight database contains new drugs under research with different levels of targets, and you can directly view the competition pattern of each subdivided target under EGFR, including EGFR-T790M
.

The degree of involution of the third-generation EGFR-TKI is almost well known.
Last year, 4 domestic pharmaceutical companies submitted new drug marketing applications, and 3 have been approved for marketing: AstraZeneca's osimertinib and Hansoh's almetinib and Ellis' fumetinib, both of which are covered by medical insurance
.
However, the huge market potential in the field of non-small cell lung cancer still leads companies to develop drugs for this indication one after another
.

Third-generation EGFR-TKIs

Domestic competition of third-generation EGFR inhibitors

The four EGFR inhibitors in Phase III clinical trials include two third-generation EGFR inhibitors, FHND9041 from Chia Tai Fenghai, and RX518 (olafertinib) from Runxin Bio
.

Both lelotinib developed by Sunshine Pharmaceuticals and maivatinib developed by Huadong Medicine are EGFR/HER2 inhibitors, but the clinical development strategies of the two companies are completely different
.
According to the Insight database, HEC is targeting esophageal cancer.
A total of 8 clinical trials of lelotinib have been launched so far.
Phase III clinical trials will be launched in May 2020, comparing chemotherapy to patients with advanced esophagus that have failed at least second-line therapy and have overexpressed EGFR.
Squamous cell carcinoma; Huadong Medicine focuses on NSCLC, phase III clinical comparison of gefitinib in the first-line treatment of advanced non-squamous NSCLC with sensitive EGFR mutations; Phase II clinical trials also investigated the treatment of advanced NSCLC with rare EGFR mutations (G719X, L861Q, S768I)
.

CDK4/6

CDK4/6

The competition of CDK4/6 inhibitors is similar to the above two targets.
Only Hengrui Medicine's Dalcilia was approved for marketing on December 31 last year
.
Simcere's tralacril has also submitted a marketing application (acceptance number: JXHS2101087), but it adopts a very different indication design from other CDK4/6 inhibitors
.

Looking at the research projects in the phase III stage, the competition is even more intense than the first two targets, and there are as many as 5 domestic drugs
.
Jiahe Bio, Sihuan Pharma, Fosun Pharma, Chia Tai Tianqing and Bibete have little difference in their latest progress.
They will enter Phase III from August 2021 to February 2022, and are expected to usher in the next phase.
Dense NDA of a wave of CDK4/6 inhibitors
.

Competitive landscape of CDK6 inhibitors in China

From: Insight database target module (http://db.
dxy.
cn/v5/home/)

In the face of intensified homogenization competition and generic drugs already on the market, the future of domestic CDK4/6 inhibitors remains to be tested by time
.
(Insight's previous article: The global sales of the three major CDK4/6 inhibitors were US$7 billion last year! Domestic generic drugs have been approved, are new drugs still fragrant?)

Chia Tai Tianqing leads the way, Hengrui, Fosun, Huadong.
.
.
are expected to usher in the NDA outbreak period

Chia Tai Tianqing leads the way, Hengrui, Fosun, Huadong.
.
.
are expected to usher in the NDA outbreak period

From the perspective of enterprises, Chia Tai Tianqing has the largest number of phase III anti-tumor drugs.
The three products are ALK inhibitors, third-generation EGFR-TKIs and CDK4/6 inhibitors, all of which are among the three popular targets mentioned above.
, and will not be repeated here
.
According to the Insight database, the group currently has 7 Phase III clinical projects, 11 Phase II clinical projects and 47 Phase I clinical projects
.

Distribution of research and development stages of new biopharmaceutical projects in China

From: Insight Database Enterprise Analysis Module (http://db.
dxy.
cn/v5/home/)

In addition to Tianqing, Hengrui Medicine, Huadong Medicine and Sihuan Medicine each have 2 Phase III anti-tumor drugs, as detailed in the table below:

Phase III clinical anti-tumor chemical drug projects of key enterprises (*supplement: Plinabulin has been declared for listing)

Hengrui Medicine

Hengrui Medicine

Famitinib Malate Capsules is a small molecule multi-target tyrosine kinase inhibitor independently developed by Hengrui Medicine
.
It has good inhibitory activity on various receptor tyrosine kinases such as c-Kit, VEGFR1/2/3, PDGFRα/β, FGFR2/3, etc.
, and belongs to multi-targeted anti-angiogenesis targeted drugs
.
According to the Insight database, the first IND application for famitinib was submitted as early as 2008, and so far 36 clinical trials have been registered
.
In combination with camrelizumab, famitinib has launched 12 clinical trials, with indications involving solid tumors such as NSCLC, cervical cancer, urinary system tumors, and gynecological tumors
.

Famitinib Malate Capsules

Plinabulin is a product introduced by Hengrui Medicine through a 1.
3 billion yuan cooperation with Wanchun Pharmaceutical on August 26, 2021.
It is a First-in-Class immune anti-tumor drug that activates the immune defense protein guanine nucleus.
Glycide exchange factor (GEF-H1), accelerates the maturation of dendritic cells (DC cells) and promotes antigen presentation, directly activates T cells to kill tumor cells, and acts as an "ignition agent of the immune system"
.
In addition, plinabulin can also prevent the damage of bone marrow neutrophils induced by chemotherapy drugs, achieve early protection, and prevent early CIN (chemotherapy-induced neutropenia)
.

Prinabrin 1.
3 billion

The mechanisms of plinabulin and G-CSF are complementary, and can form a good synergy with the company's tumor pipeline
.
Its research and development process has won many recognitions: both the FDA and NMPA have granted it breakthrough therapy designation, and China and the United States have submitted New Drug Application (NDA) simultaneously and have been included in priority review and approval by the regulatory agencies of both countries
.

However, on December 1 last year, Wanchun Pharmaceutical announced that it had received a Complete Response Letter (CRL) from the FDA, arguing that the Phase 3 clinical trial (106 studies) of plinabulin was not sufficient to support its marketing application, and additional supplements were required.
Clinical trials to demonstrate clinical benefit
.
After the news was released, Wanchun Pharmaceutical plummeted by more than 60%
.
Hengrui also quickly issued an announcement to clarify that Hengrui has paid Wanchun a down payment of 200 million yuan, but has not yet participated in clinical development; and the previously reached 100 million yuan equity investment has not yet completed payment and equity delivery.

.

Huadong Medicine

Huadong Medicine

In addition to the EGFR/HER2 inhibitor Maifatinib, Huadong Medicine has also developed the JAK2 inhibitor OB756 (bonritinib)
.
JAK inhibitors exert therapeutic effects by targeting the kinase activity of JAK2 V617F to block the JAK/STAT signaling pathway
.
According to a clinical study of OB756 in patients with myelofibrosis, more than 50% of the subjects had a ≥35% reduction in spleen volume from baseline at 24 weeks, which was significantly better than the efficacy of similar marketed drugs
.
In addition, OB756 also showed a good effect in reducing the constitutional symptoms of patients with myelofibrosis and improving the quality of life of patients
.

According to the Insight database, OB756 submitted an IND application for the first time in 2018 and started clinical trials for the first time in 2019.
Currently, 6 clinical trials have been registered, involving indications including rheumatoid arthritis and graft-versus-host disease
.

OB756 Project Details

From: Insight Database Project Progress Module (http://db.
dxy.
cn/v5/home/)