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The fastest to break $1 billion ADC drugs? The power of breast cancer "miracle drug" is once again revealed, who can fight Enhertu?

 Last Update: 2022-11-15
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Recently, Daiichi Sankyo released its second-quarter financial report, and its blockbuster ADC drug Enhertu (DS-8201), a blockbuster ADC drug cooperated with AstraZeneca, had first-half sales of 79.
5 billion yen, or about 568 million US dollars (140 yen to 1 US dollar), and raised its full-year results to forecast Enhertu Global sales in FY22 will reach 195.
2 billion yen (USD 1.
393 billion).

195.
2 billion yen (US$1.
393 billion)

Figure 1 Enhertu's sales by region Source: Q2 report (billion yen)

According to incomplete statistics, among the 14 ADC drugs currently on the market, only Seagen/Takeda's Adcetris and Roche's Kadcyla exceeded $1 billion
in global sales last year.

Seagen/Takeda's Adcetris, which surpassed the $1 billion sales mark in nearly 10 years; Roche Kadcyla took 5 years, while the breast cancer drug Enhertu (DS-8201) may only take two years
.

Nearly 10 years, 5 years and two years

The fastest to break $1 billion ADC drugs? What is the charm of Enhertu, the "miracle drug" of breast cancer, and who can compete with HER2 ADC?

01 The power of the "miracle drug" of breast cancer is once again visible

Enhertu is a HER2-targeting antibody drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo that links a humanized monoclonal antibody targeting HER2, trastuzumab (trastuzumab), with a novel topoisomerase 1 inhibitor, exatecan derivative (DX-8951 derivative, DXd), to target the delivery of cytotoxic agents into cancer cells
.

Figure 2 Composition of Enhertu Source: Specification

It has 4 major advantages:

Higher drug load: Using a unique hydrophobic linker and cysteine residue fixed-point coupling technique to reduce the hydrophobicity of the ADC, T-DXd (Enhertu) can carry 7-8 DXd molecules
per antibody.
The drug-to-antibody ratio (DAR) is 3-4
higher than that of T-DM1 (Kadcyla).

Higher drug load

Figure 3 Advantages of T-DXd over T-DM1 Source: Huachuang Securities

Warhead selection: DXd is more toxic than microtubule inhibitors, has a shorter half-life, and the toxin remains in the body for a shorter time

Warhead selection

linker design: The hydrophobic tetrapeptide linker of T-DXd can be degraded by highly expressed lysosomal enzymes in tumor cells to release DXd and avoid drug polymerization
.

Linker design

In addition, DXd has high membrane penetration, and the released DXd can penetrate to neighboring tumor cells and exert a killing effect through the "bystander effect
".

DXd has high membrane penetration

In March 2019, AstraZeneca and Daiichi Sankyo signed a global co-development and commercialization agreement to acquire Enhertu for an initial payment of US$1.
35 billion + a potential milestone of US$5.
55
billion.

The deal, which totals $6.
9 billion, will allow AstraZeneca to share global profits outside Japan on an equal footing with Daiichi Sankyo, a gamble
for AstraZeneca to expand its oncology impact.

Now it seems to be worth it
.

The third quarterly report mentioned that with the approval of new indications and the growth of market penetration, Enhertu sales are bound to achieve steady growth
.

Figure 4 Progress of Enhertu indication approval and sales in major regions Source: Second quarter report

breast cancer

Breast cancer patients can be divided into three categories based on the type of receptor expressed by the cancer cells: HER2-positive, HR-positive/HER2-negative, and triple-negative (ER-PR-HER2-) breast cancer
.

Among them, HER2-positive breast cancer patients account for about 20%, and the preferred therapy is HER2-targeted therapy, and a number of HER2-targeted drugs have been approved
.

Treatment options for HER2-negative patients (about 80%) are relatively limited, and breast cancer patients with low HER2 expression account for about 50%.

HER2-positive breast cancer

In December 2019, the FDA approved Enhertu for the treatment of patients
with unresectable or metastatic HER2-positive breast cancer who have received 2 or more anti-HER2 therapies.

Enhertu was approved by the FDA based on a head-to-head trial of the well-known ADC drug Kadcyla, according to a study published in NEJM (DESTINY-Breast03), Enhertu vs Kadcyla's 12-month PFS rate was 75.
8% vs 34.
1%; The 12-month OS rate was 94.
1% vs 85.
9%; Enhertu vs Kadcyla's ORR was 79.
7% vs 34.
2%, indicating that Enhertu had shown far more efficacy
than Kadcyla in head-to-head studies.

In May 2022, the FDA approved Enhertu for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who had previously received an anti-HER2-targeted therapy
.

HER2 is low in breast cancer

In August 2022, the FDA approved Enhertu for the treatment of adult breast
cancer with unresectable or metastatic HER2 low expression (immunohistochemical [IHC] 1+ or 2+/in situ hybridization [ISH]-negative).

Among them, breast cancer patients with low HER2 expression accounted for about 50%, and the treatment methods were limited
mainly chemotherapy.
Enhertu became the first HER2-targeted therapy to deliver a survival advantage in the HER2-low population, which is expected to redefine HER2-low breast cancer treatment
.

FDA approval is based on results from
the DESTINY-Breast04 Phase III trial.

In this trial, Enhertu reduced the risk of disease progression or death by 50% in patients with hormone receptor-positive (HR+) or hormone receptor-negative (HR-) HER2-expressing metastatic breast cancer by 50% compared with physician-selected chemotherapy, PFS: 9.
9 months versus 5.
1 months (HR: 0.
50; 95% CI 0.
40-0.
63; p<0.
0001).

Patients treated with Enhertu had an OS of 23.
4 months compared to 16.
8 months in the chemotherapy group, and Enhertu reduced the risk of death by 36 percent compared with chemotherapy (HR 0.
64; 95%CI 0.
49-0.
84; p=0.
001).

gastric cancer

In January 2021, the FDA approved Enhertu for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, and is the first ADC drug
approved to treat HER2-positive gastric cancer.

Enhertu's approval for gastric cancer indications in the United States and Japan is based on the results of the
open-label, randomized Phase 2 DESTINY-Gastric01 trial.
In the studies, patients (who had previously received 2 or more regimens (including 5-FU, platinum-containing chemotherapy, trastuzumab but whose disease progressed) were randomized in a 2:1 ratio to receive either Enhertu (6.
4 mg/kg) or chemotherapy of the investigator's choice (paclitaxel or irinotecan monotherapy) every
three weeks.
Results showed an ORR of 51.
3% (95% CI: 41.
9-60.
5%) in the Enhertu group and 14.
3% (95% CI: 6.
4-26.
2%)
in the chemotherapy group.
In a prespecified interim analysis, the risk of death was reduced by 41% in the Enhertu group compared with the chemotherapy group (HR = 0.
59; 95% CI: 0.
39 to 0.
88; p=0.
0097).

The median OS was 12.
5 months in the Enhertu group and 8.
4 months
in the chemotherapy group.

lung cancer

In August 2022, the FDA approved Enhertu for the treatment of patients
with unresectable or metastatic NSCLC who carry activating HER2 mutations.
It is also the first FDA-approved drug
to treat HER2-mutant NSCLC.
Accelerated approved efficacy is based on DESTINY-Lung02
.
Patients (with unresectable or metastatic HER2-mutated non-squamous non-small cell lung cancer and disease progression after prior systemic therapy) receive Enhertu by intravenous infusion 5.
4 mg/kg every 3 weeks until unacceptable toxicity or disease progression
.
The trial results showed an objective response rate of 58% and a median duration of response of 8.
7 months
.

02 Who can fight Enhertu?

There are about 350 enterprise-led ADC drug clinical research and development in the world, about 166 in China, accounting for about 47%, and the top three targets of ADC drugs under development in the world are HER2, TROP2 and CLDN 18.
2
.

HER2 is currently the number one target for global ADC drug development, and there are nearly 50 ADC drugs targeting HER2 that have been marketed or are under development worldwide, of which 3 have been approved for marketing, namely Roche's Kadcyla, Daiichi Sankyo's Enhertu, and the first domestic ADC drug Remegen's RC48 (vedicitumab).

In the domestic market, HER2 is also the number one target of ADC research and development, Claudin-18.
2, Trop-2 and other targets of competition is also very fierce, from the perspective of research and development progress, most of the ADC drugs developed by domestic companies are in the early stage of research, and the rapid progress is concentrated on targets such as HER2 and TROP2
.

Fig.
5 Proportion of global and Chinese ADC drug clinical stage targets Source: Soochow Securities

In China, the HER2ADC vedicitumab independently developed by Remegen has been approved for the treatment of gastric cancer and urothelial carcinoma, and is also conducting clinical trials for the treatment of a variety of solid tumors, such as breast cancer, non-small cell lung cancer, biliary tract cancer, gynecological malignant tumors, advanced melanoma, etc
.
In addition, Hengrui's SHR-A1811, Dongyao Pharmaceutical's TAA013, etc.
have also entered phase 3 clinical trials.
.
.

brief summary

ADC drugs are now one of the hottest tracks in the field of biomedicine and medicine, Enhertu's big sales will surely push the competition of the track to a fever pitch, DS-8201's dimensionality reduction blow not only makes T-DM1 terrified, but also the follow-up companies want to get a piece of the DS-8201 strangulation
.

Last year Bio-Thera finally announced the discontinuation of its ADC project BAT8001, and Ambrx Biopharma announced the introduction of HER2 ADCs in consideration of the competitive landscape for HER2 targets The ARX788 has moved out of the internal R&D pipeline, and although it will continue to cooperate with its partner XinmaBio to promote the development of the ARX788, it is not known
whether it will be able to win the head-to-head trial.

These stories are a wake-up call for all those who come after them
.

At present, both globally and in China there are indications and target pushes in the entire ADC field, and HER2 targets have become the focus, and the excellent performance of DS-8201 makes all HER2 The players of the ADC track are like pins and needles, who has the ability to fight against one in the ADC field, we will wait and see!

Resources

ADC outbreak, half-year revenue doubled, AstraZeneca.
.
.

Just! The blockbuster ADC drug DS-8201 was accepted by the NMPA, and AZ spent $6.
9 billion on it!

$6.
9 billion! AstraZeneca and Daiichi Sankyo have reached a strategic oncology cooperation to develop an antibody drug conjugate DS-8201
targeting HER2.

Daiichi Sankyo will introduce the DXd ADC portfolio at the 2022 ESMO Annual Meeting to fully promote progress in the field of oncology

The first three total second quarter report, Huachuang Securities, Soochow Securities, Guojin Securities, FDA and other online public information
.

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