October 20, 2021

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The World first TF targeting ADC Tisotumab vedotin was approved by FDA

The World first TF targeting ADC Tisotumab vedotin was approved by FDA.

The world’s first! TF targeting antibody drug conjugate (ADC) Tisotumab vedotin was approved by the FDA



The World first TF targeting ADC Tisotumab vedotin was approved by FDA.

The world’s first! TF targeting antibody drug conjugate (ADC) tisotumab vedotin was approved by the FDA for marketing

On September 20, Seattle Genetics (Seagen) and Genmab A/S announced that its antibody-conjugated drug (ADC) tisotumab vedotin has been approved by the FDA for the treatment of recurrent or metastatic cervical cancer, becoming the first target TF Cervical cancer new drug is also the 12th ADC drug approved worldwide.

In addition, Agenus’s PD-1 monoclonal antibody balstilimab and Kangfang Bio-PD-1/CTLA-4 dual-antibody new drug Cadonilimab (AK104) have been accepted for new drug listing applications for cervical cancer, which also means that the field of cervical cancer is about to usher in A variety of targeted new drugs.

Cervical cancer is one of the common malignant tumors of the female reproductive system, and persistent high-risk human papillomavirus (HPV) infection is a key factor in the occurrence and development of precancerous lesions and cervical cancer. The global cancer statistics report shows that in 2020, there will be about 110,000 new cases of cervical cancer in some countries and about 59,000 deaths.

In recent years, comprehensive treatments such as surgery, radiotherapy and chemotherapy have enabled the 5-year survival rate of patients with early cervical cancer to reach more than 90%, but there is a lack of effective treatments for patients with advanced and recurrent cervical cancer, and the 5-year survival rate is still less than 20%. And 5%, it is urgent to explore new and efficient treatment strategies.

1. Only 3 cervical cancer targeted drugs are on the market in the world

At present, the development of targeted drugs for cervical cancer is still at an early stage. Among them, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mTOR, oncoprotein E6/E7, and immune checkpoints PD-1, CTLA- Grade 4 is a few major targets that have been studied more. However, the only targeted drugs for cervical cancer marketed worldwide so far are the anti-angiogenic drug bevacizumab, the tumor immune checkpoint inhibitor pembrolizumab, and the new ADC drug tisotumab vedotin.

Bevacizumab (Avastin) is a humanized IgG1 monoclonal antibody developed by Roche that specifically binds to VEGF, thereby blocking the binding of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells , To inhibit tumor angiogenesis. In 2004, the FDA approved its combination with 5-fluorouracil for the treatment of metastatic colorectal cancer, becoming the world’s first drug targeting VEGF. Subsequently, Avastin has been approved for non-small cell lung cancer, kidney cancer, colorectal cancer, Indications for glioma, breast cancer, ovarian cancer, and cervical cancer.

However, with the expiration of patents and the impact of biosimilar drugs, Avastin’s sales have dropped sharply from US$7.74 billion in 2019 to US$5.32 billion in 2020.

Pembrolizumab (Keytruda) is a humanized anti-PD-1 monoclonal antibody developed by Merck, which can block the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating possible T lymphocytes that affect tumor cells and healthy cells. In 2018, the FDA approved pembrolizumab for second-line treatment of recurrent or metastatic cervical cancer, and it requires PD-L1 positive or MSI-H (highly unstable microsatellite)/dMMR (mismatch repair defect), which is currently the only An approved PD-1 product for cervical cancer.

Based on Keytruda can be used for more than 10 indications, its sales in 2020 will increase to 14.380 billion US dollars, close to the sales record of drug king Humira.

On September 20, Seattle Genetics (Seagen) and Genmab A/S announced that their antibody-conjugated drug (ADC) tisotumab vedotin has been approved by the FDA for accelerated approval for the treatment of recurrent or metastatic cervical cancer.

Tisotumab vedotin is an antibody-drug conjugate (ADC) targeting tissue factor (TF), designed to target the TF antigen on cancer cells and deliver the cytotoxic agent MMAE (monomethyl auristatin E) directly Into the cancer cells. Among them, TF is expressed on cervical cancer cells and can promote tumor growth, angiogenesis and metastasis. It can be used as a single-drug therapy or combined with other therapies to treat recurrent and/or metastatic cervical cancer, ovarian cancer and other solid tumors.

Tisotumab vedotin is used in patients with relapsed or metastatic cervical cancer after treatment with two-drug chemotherapy combined with bevacizumab. The confirmed overall remission rate (ORR) is 24%, of which the complete remission rate is 7%, which is significantly higher than Standard therapy is less than 15% ORR; median duration of response (DOR) is 8.3 months.

2. Who will become the next blockbuster product?

In addition to the newly launched ADC drug tisotumab vedotin, there will also be two cervical cancer targeted drugs, namely Agenus’s PD-1 monoclonal antibody balstilimab (batilimumab), and Kangfang Bio’s PD-1/ CTLA-4 double anti-Cadonilimab (AK104).

(1) PD-1 monoclonal antibody balstilimab (batilimumab)

In June of this year, Agenus announced that the FDA has accepted its PD-1 monoclonal antibody balstilimab (batilimumab) for the treatment of recurrent or metastatic cervical cancer that has progressed during or after chemotherapy, and granted priority review status. .

Balstilimab (Batilimumab) is a new fully human monoclonal immunoglobulin G4 (IgG4) developed by Agenus. It is designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2. Developed as a monotherapy and combined anti-CTLA-4 therapy zalifrelimab (AGEN1884) to treat cervical cancer. From the current clinical data, the overall response rate (ORR) of Balstilimab single agent for cervical cancer is 11.9%, and the ORR of combined zalifrelimab is 20.6%.

(2) PD-1/CTLA-4 double anti-Cadonilimab (AK104)

On August 24, Kangfang Biological announced that its PD-1/CTLA-4 dual anti-Cadonilimab (AK104) new drug application for the treatment of recurrent or metastatic cervical cancer was officially accepted by the CDE and included in the priority review process.

Cadonilimab (AK104) is the first dual antibody product independently developed by Kangfang Bio based on its Tetrabody dual antibody platform. It is also the world’s first PD-1/CTLA-4 dual specific antibody to enter clinical trials. Its main indications include liver cancer and cervical cancer. Cancer, lung cancer, stomach cancer, esophageal squamous cell carcinoma and nasopharyngeal carcinoma, etc.

The results of a phase II clinical study showed that the overall response rate of AK104 to patients with recurrent or metastatic cervical cancer who failed platinum-containing chemotherapy was 47.6%, and the disease control rate was 66.7%. Compared with other clinical data for cervical cancer, AK104 shows the potential for better efficacy. In addition, preliminary data in the research of gastric cancer and other tumors show that AK104 can significantly reduce toxicity compared with the combination therapy of PD-1 and CTLA-4, and has obvious advantages in safety and efficacy.

It is worth mentioning that the approval of pembrolizumab also officially opened the door to cervical cancer immunotherapy. Up to now, pharmaceutical companies such as Roche, Daiichi Sankyo, Hengrui, Merck, Sanofi, etc. have completed the deployment of cervical cancer treatment through the use of immune checkpoint inhibitors alone or in combination with chemotherapy and targeted drugs.

According to the disclosed clinical results, Cemiplimab, a PD-1 inhibitor jointly developed by Regeneron and Sanofi; Karelizumab from Hengrui Pharmaceuticals combined with famitinib malate; and IBI310 ( Anti-CTLA-4 monoclonal antibody) combined with Sintilizumab; Merck’s PD-L1/TGF-β double antibody M7824 for cervical cancer clinical research and development are in the late stage and is expected to enter the marketing approval stage.


Summary

Keytruda can only be used for specific targets, which further limits its application in cervical cancer.

In addition to being used for cervical cancer, tisotumab vedotin and AK104 also have the potential to be applied to other solid tumors.

In addition, AK104 has a high remission rate and safety for recurrent or metastatic cervical cancer that has progressed after chemotherapy, and is expected to become the first choice for cervical cancer.

On the whole, no matter which new drug is approved for marketing, it will be a new choice for cervical cancer patients.

The World first TF targeting ADC Tisotumab vedotin was approved by FDA.

(source:internet, reference only)


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