Fastest $1 billion ADC drug? Who can fight Enhertu for Breast cancer?

Daiichi Sankyo reported first-half sales of 79.5 billion yen, or $568 million (140 yen to $1), for its blockbuster ADC drug Enhertu (DS-8201) in partnership with Astrazeneca and raised its full-year results. It is estimated that Enhertu's global sales volume will reach 195.2 billion yen ($1.393 billion) in 22 years.

Of the 14 ADC drugs currently on the market, only Seagen/ Takeda's Adcetris and Roche's Kadcyla had global sales of more than $1 billion last year, according to incomplete statistics.

Seagen/ Takeda's Adcetris, which hit the $1 billion sales mark in nearly 10 years; Roche's Kadcyla took five years and Enhertu (DS-8201), the breast cancer blockbuster, may take just two years.

Fastest $1 billion ADC drug? What's the appeal of Enhertu, and who can compete with the HER2 ADC?

Breast cancer "god medicine" power again

Enhertu, a HER2-targeting antibody drug conjugated by Astrazeneca and Daiichi Sankyo, combines a humanized HER2-targeting monoclonal antibody trastuzumab (Trastuzumab) with a novel topoisomerase-1 inhibitor, an exatecan derivative (DX-8951 derivative), through a 4-peptide linker. DXd) are linked together for targeted delivery of cytotoxic agents into cancer cells.

It has four major advantages:

Higher drug loading: The hydrophobicity of ADC is reduced by using a unique hydrophobic ligon site-conjugate technique with cysteine residues. Each antibody of T-DXd (Enhertu) can carry 7-8 DXd molecules. The drug to antibody ratio (DAR) was 3-4 higher than that of T-DM1 (Kadcyla).

Warhead selection: DXd is more toxic than microtubule inhibitors, with a shorter half-life and shorter retention time of the toxin in the human body

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

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

In March 2019, Astrazeneca and Daiichi signed a global cooperative development and commercialization agreement to acquire Enhertu for an initial payment of $1.35 billion plus a potential milestone of $5.55 billion.

The $6.9 billion deal, in return for an equal share of global profits outside Japan with Daiichi Sankyo, is a big bet for Astrazeneca to expand its presence in oncology.

Now it's worth it.

In the third quarter, Enhertu's sales are expected to grow steadily as new indications are approved and market penetration increases.

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.

About 20% of them are HER2-positive breast cancer patients. The preferred therapy is HER2-targeted therapy, and a number of HER2-targeted drugs have been approved.

Her2-negative patients (about 80%) have relatively limited treatment options, and low HER2 expression is found in about 50% of breast cancer patients.

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 been treated with two or more anti-HER2 therapies.

Enhertu was approved by the FDA on a head-to-head basis with Kadcyla, a well-known ADC drug. According to a study published in NEJM (DESTINY-Breast03), the 12-month PFS rate of Enhertu vs. Kadcyla was 75.8% vs. 34.1%. The 12-month OS rate was 94.1%vs 85.9%; The ORR of Enhertu vs. Kadcyla was 79.7% vs. 34.2%, indicating that Enhertu showed far better 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 have been treated with an anti-HER2-targeted therapy.

Breast cancer with low HER2 expression

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

Among them, the 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 show a survival advantage in people with HER2-low, which is expected to redefine HER2-low breast cancer treatment.

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

In this trial, Enhertu reduced the risk of disease progression or death in patients with hormone-receptor-positive (HR +) or hormone-receptor-negative (HR-) metastatic breast cancer with low HER2 expression by 50% compared to doctor-selected chemotherapy, PFS: 9.9 months versus 5.1 months (HR: 0.50; 95% CI, 0.40 to 0.63; p< 0.0001). Patients treated with Enhertu had an OS of 23.4 months versus 16.8 months in the chemotherapy group, and Enhertu reduced the risk of death by 36% compared to chemotherapy (HR 0.64; 95% CI, 0.49 to 0.84; P = 0.001).

Cancer of the stomach

Enhertu was approved by the FDA in January 2021 for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, making it the first ADC drug to be approved for the treatment of HER2-positive gastric cancer.

Enhertu was approved for gastric cancer indications in the United States and Japan based on the results of an open-label, randomized Phase 2 DESTINY-Gastric01 trial. In the study, patients who had previously received 2 or more regimenes (including 5-FU, platinum-containing chemotherapy, and trastuzumab) but whose disease had progressed were randomly assigned to receive Enhertu (6.4mg/kg) or chemotherapy of the investigator's choice (paclitaxel or irinotecan monotherapy) once every three weeks in a ratio of 2:1. Results showed that the ORR was 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 pre-specified interim analysis, the Enhertu group had a 41% lower risk of death compared to the chemotherapy group (HR=0.59; 95% CI: 0.39 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 an active HER2 mutation. It is also the first drug approved by the FDA for the treatment of HER2-mutated NSCLC. The accelerated approved efficacy was based on DESTINY-Lung02. Patients with non-squamous non-small cell lung cancer with an unresectable or metastatic HER2 mutation and disease progression after prior systemic therapy received Enhertu 5.4mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression occurred. The results showed an objective response rate of 58% and a median duration of response of 8.7 months.

Who can fight Enhertu?

There are about 350 enterprise-led ADC drug clinical R&D projects in the world, among which 166 are conducted in China, accounting for about 47%. The top three ADC drug targets in the global research field are HER2, TROP2 and CLDN18.2.

HER2 is currently the number one target for ADC drug development in the world. There are nearly 50 ADC drugs targeting HER2 on the market or in development worldwide, among which 3 have been approved for market, namely Roche's Kadcyla, Daiichi Sanko's Enhertu and the first domestic ADC drug Roeglon Biotics' RC48 (Vidicetuzumab).

In the domestic market, HER2 is also the top target of ADC research and development, and the competition of Claudin-18.2, Trop-2 and other targets is also very fierce. From the research and development progress, most of the ADC drugs developed by domestic enterprises are in the early stage of research, and the rapid progress focuses on HER2 and TROP2 and other targets.

In China, the HER2ADC Vidicetuzumab independently developed by Rongchang Bio has been approved and marketed for the treatment of gastric cancer and uroepithelial carcinoma, and is also undergoing clinical trials for the treatment of a variety of solid tumors, such as breast cancer, non-small cell lung cancer, biliary tract cancer, gynecological malignancies, advanced melanoma, etc. In addition, SHR-A1811 of Hengrui and TAA013 of Dongyao Pharmaceutical have also entered phase 3 clinical trials...

Summary

ADC drugs are now one of the hottest tracks in the field of biomedicine, and Enhertu's sales will surely push the competition of this track to the white heat. The impact of DS-8201 on dimension reduction not only makes T-DM1 scared, but also makes it difficult for the following enterprises to get a share of the action under DS-8201.

Last year, Biaotec finally announced the end of its ADC project BAT8001, and Ambrx Biopharma announced that it would move the HER2 ADC ARX788 out of its internal pipeline due to the competitive landscape for HER2 targets. But we don't know if we can win head-to-head trials.

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

At present, there are indications and target pushing phenomenon in the whole ADC field both globally and in China, and the HER2 target is the focus. DS-8201's excellent performance makes all HER2 ADC track players on pins and needles. We will wait and see who is able to compete with one of them in the ADC field!