Projects

Padcev (enfortumab vedotin) for the Treatment of Urothelial Cancer

Padcev™ (enfortumab vedotin) is the first nectin-4-directed antibody-drug conjugate approved for the treatment of advanced urothelial cancer, the most common form of bladder cancer.

Drug Name

Padcev™ (enfortumab vedotin)

Developers

Astellas Pharma and Seattle Genetics

Therapy Class

Antibody-drug conjugate

Product Description

Nectin-4-directed antibody-drug conjugate

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Padcev (enfortumab vedotin) is the first nectin-4-directed antibody-drug conjugate approved for the treatment of advanced urothelial cancer, the most common form of bladder cancer.

The drug is indicated for locally advanced or advanced urothelial cancer patients previously treated with platinum-containing chemotherapy or PD-1 or PD-L1 checkpoint inhibitors.

Padcev was jointly developed by Astellas Pharma and Seattle Genetics, under an agreement signed in 2007, with collaboration expansion taking place in 2009. The drug received breakthrough therapy designation in March 2018.

Astellas submitted a biologics license application (BLA) for enfortumab vedotin to the US Food and Drug Administration (FDA) in July 2019. The BLA was accepted under Priority Review in September 2019, while the drug received accelerated approval in December 2019, three months ahead of its target action date.

Padcev is available as a lyophilised powder of 20mg and 30mg strengths in a single-dose vial for intravenous injection after reconstitution, provided free of cost to uninsured patients to meet the eligibility requirements under the Padcev Patient Assistance Program (PAP).

Urothelial cancer causes and symptoms

Approximately 90% of all the types of bladder cancer accounts for urothelial cancer, the most common bladder cancer in the US.

The cancer originates in the inner lining of the bladder cells, causing abnormal tumour growth. It can also occur in the other regions of the urinary tract drainage system such as ureter and urethra.

The most common symptoms of urothelial cancer are haematuria, pelvic pain and painful urination.

Mechanism of action of Enfortumab vedotin

The antibody-drug conjugate (ADC) enfortumab vedotin comprises a Nectin-4 directed human immunoglobulin G1 (IgG1) antibody and a microtubule-disrupting agent Monomethyl Auristatin E (MMAE). The antibody connects to the MMAE via a protease-cleavable linker.

Nectin-4 is a cell surface protein highly expressed in bladder cancer patients. The ADC binds to the Nectin-4-expressing cells, resulting in the internalisation of the ADC-Nectin-4 complex and release of the toxin MMAE by proteolytic cleavage. The release of MMAE into the microtubule network within the cell causes cell cycle inhibition and cell death.

Clinical studies on enfortumab vedotin

The FDA approved enfortumab vedotin from the pivotal, phase II, multi-centre, single-arm, open-label clinical study, EV-201. The study enrolled 125 advanced urothelial patients, who previously received platinum-based chemotherapy or PD-1 or PD-L1 inhibitors.

Anticancer activity and safety of Padcev were evaluated in the study with the primary goal to determine the objective response rate (ORR) in the patients.

“The drug is indicated for locally advanced or advanced urothelial cancer patients previously treated with platinum-containing chemotherapy or PD-1 or PD-L1 checkpoint inhibitors.”

At 10.2 months, the confirmed ORR was 44%; 12% of patients showed complete response, while 32% of patients exhibited a partial response to the drug. Median response duration was 7.6 months.

The most common adverse events observed in the patients during the study were fatigue, peripheral neuropathy, loss of appetite, baldness, rash, nausea, diarrhoea, dry eye, loss of taste, pruritus and skin dryness.

A global, phase III, multi-centre, open-label, randomised confirmatory clinical study, EV-301 is being carried out in 600 patients for supporting registrations worldwide. The study will determine the overall survival of patients receiving enfortumab vedotin compared to those on chemotherapy.

ADCs in the market

ADCs are the rising targeted cancer therapies with seven FDA approved ADCs currently available in the market.

Seattle Genetics’ Adcetris® (brentuximab vedotin) was the company’s first ADC to receive approval for the treatment of cHL and relapsed sALCL in 2011.

Other ADCs in the market are Pfizer’s Mylotarg® (gemtuzumab ozogamicin) and Besponsa® (inotuzumab ozogamicin), as well as Roche / Genetech’s Kadcyla® (trastuzumab emtansine), Polivy® (polatuzumab vedotin) and AstraZeneca’s Enhertu® (trastuzumab deruxtecan).

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