Adcetris - Treatment for Relapsed or Refractory Hodgkin's Lymphoma

Adcetris (Brentuximab) is an investigational drug being developed by Seattle Genetics along with Millenium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical, for the treatment of relapsed or refractory Hodgkin's lymphoma and anaplastic large cell lymphoma (ALCL). It is an antibody-drug conjugate.

The biologics licence application of the drug filed by Seattle Genetics in February 2011 was accepted by the US FDA in May 2011.

A six month priority review has been granted for the two indications and the decision is expected to be announced by the end of August 2011.

Takeda and Millenium submitted the marketing authorisation application (MAA) for the drug by furnishing the Phase II trial data.

The MAA was accepted by the European Medicines Agency (EMA) in June 2011.

The drug has obtained orphan drug designation for both the indications in Europe and US.

Upon approval, it will be marketed in US by Seattle Genetics and globally by Takeda.

Hodgkin's lymphoma

Lymphoma is a type of blood cancer occurring in the white blood cells. Hodgkin's and Non-Hodgkin's lymphoma are the two types of lymphoma.

The white blood cells are made up of T-lymphocytes (T-cells) which provide immunity against bacterial infections and B-lymphocytes (B-cells) which provide immunity against viruses.

Increased and abnormal growth in the number of lymphocytes results in lymphoma.

Hodgkin's lymphoma is usually observed in young people aged 15 to 35 or adults aged above 50.

The patients become relapsed if the cancer returns after the primary treatment or refractory when the primary treatment is not effective.

Mechanism of action of adcetris (brentuximab)

Hodgkin Reed-Sternberg cells are present in the white blood cells of Hodgkin's lymphoma patients. These cells express a protein called CD30.

Adcetris is an antibody-drug conjugate (ADC) consisting of the drug monomethyl auristatin E (MMAE) linked to a monoclonal antibody anti-CD30. The ADC binds to the CD30 of Reed-Sternberg cells and forms an ADC-CD30 complex.

This complex moves towards lysosome where the MMAE is released. MMAE causes breakdown of the microtubules resulting in the G2/M cell cycle arrest and cell death (apoptosis).

Clinical trials on Hodgkin's lymphoma patients

Phase I trials to evaluate the safety and efficacy of the drug on the cardiac system in patients with CD30 positive cancer were initiated in January 2010.

Phase I trials, to evaluate the safety and efficacy of the drug when used in combination with chemotherapy for treating newly diagnosed Hodgkin Lymphoma patients, were initiated in February 2010.

Around 70 patients have been enrolled who will be administered brentuximab in combination with chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or brentuximab in combination with  AVD (doxorubicin, vinblastine, dacarbazine) The study is expected to be completed by November 2012.

A Phase II trial was conducted to evaluate the safety and efficacy of brentuximab as a single agent in patients with relapsed or refractory Hodgkin's lymphoma. The study was initiated in February 2009 with a primary completion achieved in August 2010.

Phase III trials called Aethera is being conducted to evaluate the safety and efficacy of the drug in comparison with placebo.

The study is being conducted in patients with high risk of residual Hodgkin's lymphoma following a stem cell transplant. The enrolled patients are being administered either brentuximab or placebo intravenously every 21 days.

The study which was initiated in April 2010 is expected to be completed by June 2013.

Clinical trials on anaplastic large cell lymphoma patients

Phase I trials to evaluate the safety of the brentuximab in combination with chemotherapy in ALCL patients were initiated in February 2011.

The trial will enrol around 52 patients. The entire study is expected to be completed by December 2012.

Phase II trials to evaluate the safety and efficacy of the drug as single agent in patients with ALCL is currently ongoing and has enrolled 58 patients.

The trial was initiated in February 2009 and had a primary completion date of August 2010.

Patients were administered 1.8mg/kg of brentuximab every 21 days.

Another Phase II trial to asses the effect of brentuximab in controlling the ALCL, lymphomatoid papulosis (LyP) or mycosis fungoides (MF) was initiated in June 2011 and is estimated to be completed by June 2013. The study will enrol 35 patients who will be administered 1.8mg/kg of brentuximab a day intravenously.

Marketing commentary

If approved, brentuximab will be the first drug in a new class of antibody-drug conjugates. The drug is expected to generate annual sales of $420m per annum by the end of 2015.