CAMBRIDGE, Mass., OSAKA, Japan & BOTHELL, Wash.—Takeda Pharmaceutical Co. Ltd. and Seattle Genetics Inc. on June 26 announced that the Phase 3 ECHELON-1 clinical trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) vs. the control arm, giving some weight behind the value of Adcetris (brentuximab vedotin) as a frontline therapy in Hodgkin’s lymphoma—Adcetris is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin’s lymphoma.
Specifically, the multicenter ECHELON-1 trial was designed to evaluate Adcetris as part of a frontline combination chemotherapy regimen in 1,334 patients with previously untreated advanced classical Hodgkin’s lymphoma. Adcetris is currently not approved as a frontline therapy for Hodgkin’s lymphoma.
Patients in ECHELON-1 were randomized to receive either a combination of Adcetris+AVD (Adriamycin, vinblastine, dacarbazine) or ABVD (Adriamycin, Adcetris, vinblastine, dacarbazine). The results of the ECHELON-1 trial demonstrated that combination treatment with Adcetris resulted in a statistically significant improvement in modified PFS vs. the control arm, with the two-year modified PFS rate for patients in the Adcetris arm being 82.1 percent compared to 77.2 percent in the control arm. Interim analysis of overall survival (OS), the key secondary endpoint, also trended in favor of the Adcetris+AVD arm.
“We are excited about the positive result which shows a statistically significant improvement in the primary endpoint of modified PFS,” said Dr. Dirk Huebner, executive medical director of the Oncology Therapeutic Area Unit of Takeda. “The results of this trial signify an important step forward in the development of Adcetris and have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”
The safety profile of Adcetris+AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen. There was an increased incidence of febrile neutropenia and peripheral neuropathy in the Adcetris+AVD arm. Febrile neutropenia was reduced through the use of prophylactic growth factors in a subset of patients, and peripheral neuropathy was managed through dose modifications. The control arm had an increased rate and severity of pulmonary toxicity.
“The outcome of the Phase 3 ECHELON-1 trial represents a significant milestone for the Hodgkin lymphoma community,” commented Dr. Clay Siegall, president and CEO of Seattle Genetics. “Seattle Genetics’ goal is to establish Adcetris as the foundation of care for CD30-expressing lymphomas, including Hodgkin lymphoma. Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin.”
Takeda and Seattle Genetics plan to submit these results to regulatory authorities for approval in their respective territories.
Adcetris is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas, including three Phase 3 studies: the completed ECHELON-1 trial in frontline classical Hodgkin’s lymphoma, the completed ALCANZA trial in cutaneous T cell lymphoma and the ongoing ECHELON-2 trial in frontline mature T cell lymphomas.
Adcetris is an 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.
Adcetris for intravenous injection has received approval from the FDA for three indications:
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Regular approval for the treatment of patients with classical Hodgkin’s lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
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Regular approval for the treatment of classical Hodgkin’s lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation
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Accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted Adcetris approval with conditions for relapsed or refractory Hodgkin’s lymphoma and sALCL.
Adcetris was granted conditional marketing authorization by the European Commission in October 2012 for two indications: the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin’s lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option and for treatment of adult patients with relapsed or refractory sALCL. In June 2016, the European Commission extended the current conditional approval of the drug and approved it for the treatment of adult patients with CD30-positive Hodgkin’s lymphoma at increased risk of relapse or progression following ASCT.
In other Takeda news, the company announced on the same day the forming of a collaboration with Hyderabad, India-based Biological E. Limited (BE) to expedite the development and delivery of affordable combination vaccines, with BE commercializing the vaccine in India, China and low- and middle-income countries where large, unmet public health needs exist.
Takeda has sold both the measles and pertussis vaccines in the Japanese market for more than 20 years. In heavily populated countries like India, where 25.7 million births occurred in 2015, substantial opportunities remain to deliver critical vaccines to those who need them, Takeda notes. In the absence of access to vaccines in many parts of the world, this partnership “illustrates Takeda’s desire to forge the kind of collaborations needed to overcome this public health challenge in low- and middle-income countries.”
“Access to medicines is one of Takeda’s core values, and these agreements align with Takeda’s strategic goals to make high-impact contributions to global public health, either alone or through partners,” noted Rahul Singhvi, chief operating officer of the Takeda Vaccine Business Unit. “These two agreements along with our current vaccine pipeline underscore our global commitment to address important infectious diseases across the globe.”
Under these agreements, Takeda will conduct a transfer from Japan to BE its existing measles and acellular pertussis vaccine bulk production technology, including the provision of technical services such as support in infrastructure review, training for production and quality control, technical assistance in process development, preclinical study design and production of clinical batch and the first commercial batches. BE will scale up the bulk production technology transferred from Takeda and will be solely responsible for conducting and funding development activities for the combination vaccines.
