Roche launched a HER2-ADC price war, which domestic companies may stand out

Recently, the Liaoning Provincial Centralized Purchasing Network for Drugs and Medical Consumables issued the "Notice on the Implementation of the Result of Active Price Reduction of 20 Drugs including Enmet, Trastuzumab, etc.
".
-DM1) took active price reduction measures
.

At present, T-DM1 has a total of two dosage forms on the market, 160mg/bottle and 100mg/bottle.
According to the price announced this time, the 160mg/bottle dosage form has been reduced from the current online price of 27,632.
04 yuan to 13,184.
05 yuan, and the 100mg/bottle dosage form has been reduced from 19,282.
00 yuan.
The yuan dropped to 9200.
00 yuan, both of which fell by 52.
3%, and it was also the variety with the largest active decline among the 20 products announced this time
.

On January 21, 2020, T-DM1 was launched in China for the adjuvant treatment of patients with HER2-positive early breast cancer with residual invasive disease after receiving taxanes combined with trastuzumab-based neoadjuvant therapy It has become the first approved HER2-ADC drug in China, opening a new era of antibody-drug conjugate (ADC) therapy in China
.

01

       Introduction to HER2-ADC

       ADC is a new class of targeted drugs composed of monoclonal antibodies, cytotoxic drugs and linkers that connect the two.
It uses the targeting of antibodies to selectively deliver cytotoxic molecules to tumor cells.
It does not affect healthy cells while preventing cancer
.

The selection of antibodies and target antigens is the key to determining the indications of drugs

       HER2 stands for human epidermal growth factor receptor 2, and its overexpression or high levels of mutations are associated with the degree of cancer progression
.

Tumors with high HER2 expression show strong metastatic ability and infiltration ability, poor sensitivity to chemotherapy, and easy recurrence.

       HER2-ADC is an ADC drug targeting HER2.
Currently, two HER2-ADC drugs have been approved for marketing in the world , namely Kadcyla (T-DM1) from Roche and Enhertu (DS-8201) from AstraZeneca/Daisankyo.
, the former was approved by the FDA in 2013, and the approved indications include HER2-positive metastatic breast cancer and HER2-positive early breast cancer; the latter was approved by the FDA in December 2019, with indications for HER2-positive breast cancer, 2021 In January, the indication was expanded to HER2-positive gastric or gastroesophageal junction adenocarcinoma
.

       02

       Kadcyla (T-DM1)

       "Leader" of HER2-ADC drugs

       T-DM1 is composed of trastuzumab and DM1 (maytansine derivative) conjugated through a stable thioether linker.
Humanized trastuzumab is an IgG1-type antibody that expresses on the cell surface.
The HER2 has high affinity and can effectively exert the ability of humanized antibody to inhibit the growth of HER2 overexpressing cells
.

T-DM1 retains the effect of trastuzumab, inhibits HER2 receptor signaling, and induces antibody-dependent cell-mediated cytotoxicity (ADCC), which inhibits HER2 ectodomain expression in HER2-overexpressing human breast cancer cells.

       Based on the unique structural design and mechanism of action of T-DM1, T-DM1 exhibits strong antitumor activity in both preclinical and clinical studies
.

       Its pivotal phase III EMILIA clinical trial recruited a total of 991 patients with HER2-positive advanced breast cancer and were randomly assigned to the T-DM1 group and the lapatinib + capecitabine group.
The results showed that the median progression-free survival in the T-DM1 group was (mPFS) and median overall survival (mOS) were prolonged compared with lapatinib + capecitabine group (mPFS: 9.
6 months vs 6.
4 months, HR=0.
65, P<0.
001; mOS: 30.
9 months vs.
25.
1 months, HR=0.
68, P<0.
001), ORR was also significantly improved (43.
6% vs 30.
8%, P<0.
001), and the incidence of grade 3-4 treatment-related adverse events (TRAEs) was lower
.

In addition, the TH3RESA Phase III clinical study included 602 patients with HER2-positive advanced breast cancer who were randomly assigned to the T-DM1 group and the physician's choice of treatment group.

       03

       Enhertu (DS-8201)

       Exquisite design, better curative effect

       DS-8201 is a next-generation ADC that links trastuzumab to a novel topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd) via a 4-peptide linker, and deliver the drug to the inside of the cell
.

The activity of DXd is 10 times that of irinotecan (a topoisomerase I inhibitor, a chemotherapy drug suitable for multiple tumors), and it is less resistant to drug resistance and more effective than commonly used anti-microtubule drugs.

       In a head-to-head second-line Phase III clinical trial of DS-8201 versus T-DM1 in HER2-positive breast cancer (DESTINY-Breast03), an interim analysis showed that DS-8201 met the primary endpoint with significant improvement in progression-free survival, a key secondary endpoint Overall survival (OS) also trended toward improvement; safety was consistent with prior
.

This indicates that DS-8201 is about to end the role of T-DM1 in the second-line standard of care in the treatment of HER2-positive breast cancer and is expected to change the breast cancer treatment landscape
.

       In the face of the powerful efficacy of DS-8201, and since T-DM1 was approved for listing in China in January 2020, its domestic sales are not optimistic due to its high price.
It is a wise move to cut prices to grab more market share
.

       04

       Domestic HER2-ADC research and development

       According to Frost & Sullivan's forecast, the market prospect of HER2-ADC drugs in China is expected to reach 3.
281 billion yuan in 2024 and 3.
828 billion yuan in 2030
.
Attractive market prospects make HER2-ADC an important track for major pharmaceutical companies to compete for layout
.
However, facing the first-mover advantage of T-DM1 and the powerful curative effect of DS-8201, which domestic enterprises can emerge in this fierce competition?

       

       Table 1.
Some domestic HER2-ADC R&D companies, source: based on public information

       At present, there are many domestic HER2-ADC developers, but the innovation is not enough.
Most of them are me too products of T-DM1, and there is no major improvement in cytotoxic drugs, coupling methods, and antibody selection
.
However, there are still companies that have made differentiated products
.

       Rongchang Biology - RC48

       Rongchang Bio is the first innovative drug company to develop ADC drugs in China.
Its self-developed RC48 (veldicetumumab) has become the first self-developed ADC drug approved for marketing in China due to its breakthrough efficacy data
.

       Vidicitumab's antibody uses Disitamab, which has high affinity, lower dosage and fewer side effects
.
The small molecule toxin uses MMAE, which has higher membrane permeability, higher toxicity, and can better block tubulin polymerization; using a cleavable linker, it can kill adjacent tumor cells through the bystander effect
.

       On June 9, 2021, Vidicitumab was approved by the NMPA for marketing, and is indicated for patients with HER2-overexpressing locally advanced or metastatic gastric cancer who have received at least 2 kinds of systemic chemotherapy
.
The clinical trial showed that the ORR of vellicitumab in the third-line treatment of gastric cancer was 24.
4%, the mPFS was 4.
1 months, and the mOS was 7.
9 months
.
In addition, for patients with urothelial carcinoma who have undergone second-line or above systemic chemotherapy, vellicitumab treatment showed good efficacy and survival benefit, with ORR of 50%, OS of 14.
2 months, and mPFS of 5.
1 months
.

       Vidicitumab also has indications for breast cancer, urothelial cancer, biliary tract cancer, and non-small cell lung cancer
.
In the selection of indications, RC48 can be said to be comprehensive, and all indications related to the target of HER2 are tried to break through
.

       Kelun Pharmaceuticals - A166

       In addition, A166 of Kelun Pharmaceuticals is also differentiated in China, which is a very potential drug
.
A166 is the third-generation HER2-targeting ADC drug developed by Kelun Pharmaceuticals
.
At the 2021 American Society of Clinical Oncology (ASCO) annual meeting, the Phase I clinical study of A166 was included in the form of a poster discussion second only to oral reports, indicating that A166 has attracted the attention of foreign oncology peers
.

       A166 is special in its site-directed coupling of a novel toxin molecule (Duo-5, a tubulin inhibitor) to trastuzumab via a protease-cleavable linker
.
Toxin molecules (MMAF analogs) have membrane permeability.
After target cells die, MMAF analogs are in a free state and can enter surrounding tumor cells to exert a bystander effect
.

       The Phase I clinical study of A166 in China is divided into two phases: dose escalation and dose expansion :

       In the dose escalation phase, 25 patients with HER2-expressing solid tumors (IHC ≥ 1+) were enrolled;

       In the dose expansion phase, 32 patients with HER2-positive breast cancer (IHC 3+) were enrolled, and the primary endpoint was objective response rate (ORR)
.

       At the effective dose of 4.
8 and 6.
0 mg/kg, 36 patients with evaluable HER2-positive breast cancer had ORR of more than 70%, which was much higher than that of T-DM1 (ORR was about 40%) .
It showed clinically meaningful antitumor activity in cancer patients, and also showed preliminary efficacy in patients with low HER2 expression, possibly due to the bystander effect; in the 4.
8 mg/kg dose group, 1 patient received A166 treatment for more than 19 months
.

       The safety profile of A166 is also very good, with no dose-limiting toxicity (DLT) observed during the dose escalation phase
.
The A166 antibody binds stably to toxin molecules in the blood, and the overall safety is good and controllable.
The incidence and severity of hematological toxicity and gastrointestinal toxicity are low.
The main adverse reactions are ocular adverse events and peripheral neuropathy, ocular Some adverse events occurred early and could be recovered after pretreatment and symptomatic treatment
.
From the combination of efficacy and safety data, A166 is a very promising drug
.

       The research and development of A166 has made progress at home and abroad, and has attracted attention
.
A166 has been developed simultaneously in China and the United States, and has obtained orphan drug status for gastric cancer in the United States
.

       05

       summary

       ADC is a platform product with high technical barriers and great development potential.
As one of the hottest branches in the field of innovative drugs, it has attracted major pharmaceutical companies to enter the market
.
Overall, the development of domestic ADC drugs has further room for improvement compared with foreign countries in terms of indications and ADC structure design
.
For domestic ADC drug research and development, companies should continuously optimize technology, and improve product quality from the perspectives of optimization of cytotoxic drugs and optimization of coupling methods
.
It is also necessary to race against time to increase the speed of research and development.
In addition, it is necessary to focus on differentiated innovation to avoid the accumulation of indications
.

       At present, Roche has taken the lead in provoking the price war.
With its excellent clinical data, once DS-8201 is launched in China or reshapes the market competition pattern, there is not much time left for domestic companies
.
In the end, who can stand out in this war without gunpowder smoke, we will wait and see
.

       References:

       1.
Verma S, Miles D, Gianni L, et al.
Trastuzumab emtansine for HER2 positive advanced breast cancer.
N Engl J Med, 2012, 367(19):1783⁃1791.

       2.
Krop IE, Kim SB, González-Martín A, et al.
TH3RESA study collaborators.
Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.
Lancet Oncol.
2014 Jun;15(7):689-99.

       3.
Krop IE, Kim SB, Martin AG, et al.
Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial.
Lancet Oncol.
2017 Jun;18(6):743-754.

       columnist

       little time

       Biochemical and molecular biology background, once engaged in molecular typing of esophageal squamous cell carcinoma, familiar with the pathogenesis and drug regimens of various solid tumors
.
Now I take the discovery and dissemination of knowledge as a means of making a living, and I have no end to learn.
I hope that I will always maintain a humble attitude and plasticity, and welcome the golden age of the medical field with my colleagues
.