Commercial and Regulatory Progress under Brentuximab Vedotin Collaboration Between Seattle Genetics and Takeda

Nearly 7 years ago, in 2009, Seattle Genetics, a clinical stage biopharmaceutical company, and Takeda Pharmaceuticals, Japan’s largest pharmaceutical company with a 230+ year history, agreed to collaborate in the development of antibody-drug conjugates (ADC). At the time of signing the agreement, Takeda, which has a deep understanding of  unmet medical needs and the treatment environment in oncology and hematology, directed research efforts at optimizing and investigating novel oncology targets in related areas.[1]  With Takeda’s long-standing interest in the use of monoclonal antibodies, and specifically in the use of ADCs the companies entered into an agreement to jointly develop brentuximab vedotin (Adcetris®).

Under the terms of agreement Takeda is responsible for research, product development, manufacturing and commercialization of any ADC products resulting from the collaboration, while Seattle Genetics is entitled to receive progress-dependent milestone payments and mid-single digit royalties from Takeda on worldwide net sales of any resulting ADC products. Seattle Genetics also receives supply and annual maintenance fees as well as research support payments for assistance provided to Takeda.

Earlier this year the companies announced that based on there collaboration, Seattle Genetics will receive a one-time US $20 million milestone payment for their flagship drug brentuximab vedotin. The milestone was triggered when Takeda surpassed the annual net sales of $200 million for brentuximab vedotin in its assigned territory during 2015.

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Brentuximab vedotin is an antibody-drug conjugates (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily. In Hodgkin lymphoma, CD30 may be involved in tumor cell proliferation by interacting with immune cells in the tumor microenvironment.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

Anaplastic Large Cell Lymphoma (ALCL) is a type of aggressive T-cell lymphoma, comprising about 3% of all non-Hodgkin lymphomas (NHL) in adults and between 10 and 30% of all NHL in children. There are two distinct forms/types of ALCL, including primary cutaneous ALCL and systemic ALCL (sALCL). sALCL is a clinically aggressive, systemic lymphoma that primarily involves lymph nodes and expresses CD30.

Regulatory milestone
The milestone payment to be paid to Seattle Genetics will be recognized as royalty revenue in the first quarter of 2016.

Clay_Siegall_Seattle_Genetics
Photo 1.0: Clay B. Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics. Courtesy: Seattle Genetics.

This sales milestone and recent label update in Europe to include data on retreatment underscore the strong commercial and regulatory progress that Takeda has made in its territory,” explained Clay B. Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics (photo 2.0).

We and Takeda are focused on the goal of establishing [brentuximab vedotin] as the foundation of care for CD30-expressing lymphomas through global commercialization activities and a broad clinical development program that includes three phase II trials,” Siegall continued.

European Commission
In addition, the company announced that the European Commission (EC) recently approved a Type II variation that includes data on the retreatment of adult patients with relapsed or refractory (R/R) Hodgkin lymphoma or R/R systemic anaplastic large cell lymphoma (sALCL) who previously responded to brentuximab vedotin and who later relapse. The label update follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2015.[2]

The initial conditional marketing authorization was granted by the EC in 2012 for the treatment of R/R CD30+ Hodgkin lymphoma following autologous stem cell transplant (ASCT), or at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and for R/R sALCL.

The Summary of Product Characteristics (SmPC) variation includes an update to the clinical sections, including safety, to include data on retreatment of adult patients who have responded to previous treatment with brentuximab vedotin -Complete Response (CR) or Partial Response (PR)- under the existing indications, but later relapsed. [3]

The Type II variation is based on data from the Phase II SGN35-006 Part A study that demonstrated effective anti-tumor responses can be achieved in the majority of R/R Hodgkin lymphoma and sALCL patients with brentuximab vedotin retreatment. The safety and efficacy results from this trial were consistent with the positive profile demonstrated in the pivotal Phase II studies (SGN35-003 and SGN35-004).

Academisch_Medisch_Centrum,_Amsterdam
Photo 2.0: The Academic Medical Center or AMC in Amsterdam Southeast, The Netherlands is one of the foremost research institutions in The Netherlands, as well as one of its largest hospitals. Over 7,000 people work here to provide integrated patient care, fundamental and clinical scientific/medical research, and teaching. The AMC complex houses the university hospital and the faculty of medicine of University of Amsterdam as well as the Emma Children’s Hospital, the Netherlands Institute for Neuroscience, the medical department of the Royal Tropical Institute and the Amsterdam Institute for Global Health and Development. Courtesy: Vincent Steenberg [GFDL or CC BY-SA 3.0]
Transforming treatment
Brentuximab vedotin has transformed the treatment landscape for relapsed or refractory Hodgkin lymphoma and sALCL patients […], and has emerged as a most valuable tool to induce a remission. However, lymphoma is a relentless disease, and relapse occurs in some of these very difficult to treat patients. Now, with the opportunity for retreatment, we can offer patients with very limited options another chance to potentially benefit from brentuximab vedotin,” explained Professor Anton Hagenbeek, M.D., Ph.D., Professor of Hematology, Department of Hematology, Academic Medical Center (AMC) in the University of Amsterdam.

The European Commission’s decision to include data on retreatment in the [brentuximab vedotin] label is important in advancing care for patients battling these diseases,” noted Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda. “We look forward to continuing our ongoing clinical program of brentuximab vedotin in Hodgkin lymphoma and sALCL, as well as in a variety of other forms of lymphoma, with the goal of bringing this important therapy to patients who might benefit from it.”

Joint development program
Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize brentuximab vedotin in the rest of the world.

As part of the agreement, Seattle Genetics is entitled to royalties based on a percentage of Takeda’s net sales in its territory at rates that range from the mid-teens to the mid-twenties based on sales volume subject to offsets for royalties paid by Takeda to third parties. In addition, Seattle Genetics is entitled to receive progress- and sales-dependent milestone payments based on net sales of brentuximab vedotin within Takeda’s licensed territory.

Seattle Genetics and Takeda are funding joint development costs for brentuximab vedotin on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.