CAMBRIDGE, MA, USA & OSAKA, Japan & BOTHELL, WA, USA I December 3, 2016 I Takeda Pharmaceutical Company Limited (TSE:4502) and Seattle Genetics, Inc. (NASDAQ: SGEN) today announced that data from the Phase 3 ALCANZA clinical trial evaluating ADCETRIS (brentuximab vedotin) in patients with cutaneous T-cell lymphoma (CTCL) will be presented in an oral session at the 58th American Society of Hematology (ASH) annual meeting on Saturday, December 3 at 2:15 p.m. PT. Topline data were reported in August 2016 demonstrating the ALCANZA trial met its primary endpoint of achieving a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). Based on the study results, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to ADCETRIS for the treatment of the most common subtypes of CTCL, mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30 which is expressed on skin lesions in approximately 50 percent of patients with CTCL. ADCETRIS is currently not approved for the treatment of CTCL.
“CTCL is an incurable disease that severely impacts a patient’s quality of life and has a poor prognosis in advanced stages. The systemic therapies currently approved for treatment rarely provide reliable and durable responses, and to-date, no investigational systemic therapies have shown outcomes superior to standard of care therapies such as methotrexate or bexarotene in any clinical trials,” said Youn H. Kim, M.D., Stanford University School of Medicine, Stanford, Calif. “This is the first randomized Phase 3 clinical trial evaluating a novel agent versus standard of care options, including methotrexate or bexarotene, in CTCL. Data from the ALCANZA Phase 3 trial provide compelling evidence demonstrating that patients treated with ADCETRIS benefited in the clinical outcomes assessed in the study compared to the patients in the control arm treated with a standard of care agent. ADCETRIS was generally well-tolerated, consistent with prior studies, and the most common adverse event, peripheral neuropathy, was manageable with a modest rate of treatment discontinuation.”
“The data from the ALCANZA trial presented at this year’s ASH meeting provide evidence of the potential benefit of ADCETRIS in treating patients with CD30-positive CTCL. For patients with CTCL, there is a significant need for additional treatment options that increase the opportunity to achieve durable responses,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “The ALCANZA trial achieved its primary and secondary endpoints, all of which were highly statistically significant in favor of ADCETRIS. Treatment with ADCETRIS demonstrated a highly statistically significant improvement over the control arm in objective response rate lasting at least four months of 56.3 percent versus 12.5 percent and median progression-free survival of 16.7 months versus 3.5 months. Safety data were consistent with the currently approved label. We look forward to working with regulatory bodies around the world to bring a potential new treatment option to patients with CTCL.”
“The data from the Phase 3 ALCANZA clinical trial presented at ASH highlight improvements in the efficacy measurements experienced by the ADCETRIS treated patients with CD30-expressing CTCL over the standard of care agents methotrexate or bexarotene utilized in the control arm,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development of Seattle Genetics. “The ALCANZA clinical trial represents the fourth consecutive registrational trial with a positive outcome for ADCETRIS, which we are evaluating broadly as the foundation of care for CD30-expressing lymphomas. Based on the results of this trial, the FDA has granted Breakthrough Therapy Designation and we plan to submit a supplemental Biologics License Application in the first half of 2017 for approval in this setting.”
Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician’s Choice (Methotrexate or Bexarotene): The Phase 3 ALCANZA Study (Abstract #182, oral presentation at 2:15 p.m. PT on December 3, 2016 at the San Diego Convention Center, Room 6AB)
Key findings, which will be presented by Dr. Youn Kim, Stanford University, include:
- The trial achieved its primary endpoint and the ADCETRIS treatment arm demonstrated a highly statistically significant improvement in the ORR4 versus the control arm as assessed by an independent review facility. The ORR4 was 56.3 percent in the ADCETRIS arm compared to 12.5 percent in the control arm (p-value <0.0001).
- The key secondary endpoints specified in the protocol, including complete response (CR) rate, progression-free survival (PFS) and reduction in the burden of symptoms during treatment (per Skindex-29), were all highly statistically significant in favor of the ADCETRIS arm.
- The median PFS in the ADCETRIS arm was 16.7 months compared to 3.5 months in the control arm (HR 0.270; 95% CI, 0.169, 0.430; p-value <0.0001).
- The CR rate in the ADCETRIS arm was 15.6 percent compared to 1.6 percent in the control arm (p-value = 0.0046).
- The Skindex-29 symptom domain showed a mean max reduction of -27.96 in the ADCETRIS arm compared to -8.62 in the control arm (p-value <0.0001). There was a difference in mean maximum reduction of -18.9 (95% CI, -26.6, -11.2).
- Patients received a median of 12 cycles (36 weeks) of ADCETRIS versus 17 weeks of bexarotene or nine weeks of methotrexate.
- The safety profile associated with ADCETRIS from the ALCANZA trial was generally consistent with the existing prescribing information.
- The most common adverse events of any grade occurring in 15 percent or more of patients in the ADCETRIS and control arms were: peripheral neuropathy (67 and six percent, respectively), nausea (36 and 13 percent, respectively), diarrhea (29 and six percent, respectively), fatigue (29 and 27 percent, respectively), vomiting (17 and five percent, respectively), alopecia (15 and three percent, respectively), pruritis (17 and 13 percent respectively), pyrexia (17 and 18 percent, respectively), decreased appetite (15 and five percent, respectively) and hypertriglyceridemia (two and 18 percent, respectively). In the ADCETRIS arm, the most common grade 3 or 4 events were peripheral sensory neuropathy (no grade 4 events), fatigue, diarrhea, nausea, vomiting and pruritis. In the control arm, the most common grade 3 or 4 events were hypertriglyceridemia, pruritis, fatigue and pyrexia.
- The majority of the peripheral neuropathy events were grade 1 or 2 (26 percent and 32 percent, respectively). Peripheral neuropathy events were observed in nine percent at grade 3 and no grade 4 events were reported. Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the ADCETRIS arm at a median of 22.9 months of follow-up.
- Discontinuation due to adverse events occurred in 24 percent of patients in the ADCETRIS arm compared to eight percent in the control arm. Serious adverse events were comparable between the ADCETRIS arm and the control arm (29 percent in each). Four deaths in the ADCETRIS arm (three unrelated to study drug) occurred within 30 days of the last dose.
ALCANZA Trial Design
- ALCANZA is a randomized, open-label Phase 3 study designed to evaluate single-agent ADCETRIS versus a control arm of investigator’s choice of standard of care therapies, methotrexate or bexarotene, in patients with CD30-positive CTCL, including those with pcALCL or MF.
- The primary endpoint is ORR4 as assessed by Global Response Score in the ADCETRIS arm compared to the control arm. The results of the trial were assessed by an independent review facility.
- Key secondary endpoints are CR rate, PFS and reduction in the burden of symptoms during treatment.
- Patients with pcALCL must have received at least one prior systemic or radiation therapy and patients with MF must have received at least one prior systemic therapy.
- A total of 131 patients were randomized with 128 patients in the intent-to-treat population. Sixty-four patients were assigned to the ADCETRIS arm and 64 patients were assigned to the control arm.
- Patients received ADCETRIS every three weeks versus investigator’s choice of bexarotene or methotrexate for up to approximately one year.
- This international multi-center trial was conducted across 52 sites in North and South America, Europe and Australia under operational responsibility of Takeda Pharmaceuticals.
The ALCANZA trial received a Special Protocol Assessment (SPA) agreement from the FDA and scientific advice from the European Medicines Agency (EMA). Seattle Genetics plans to submit a supplemental Biologics License Application to the FDA in the first half of 2017. Takeda plans to begin to submit data from the ALCANZA trial to regulatory agencies in its territories in 2017.
About CTCL
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. Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. Progression from limited skin involvement may be accompanied by skin tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs. According to published literature, CD30 is expressed on skin lesions in approximately 50 percent of CTCL patients.
The standard treatment for systemically pretreated CTCL includes skin-directed therapies, radiation and systemic therapies. The systemic therapies currently approved for treatment have demonstrated 30 to 45 percent objective response rates, with low complete response rates.
About ADCETRIS
ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including three Phase 3 studies, the ongoing ECHELON-1 trial in frontline classical Hodgkin lymphoma and the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, as well as the completed ALCANZA trial in cutaneous T-cell lymphoma for which a supplemental BLA is planned in the first half of 2017. ADCETRIS is also being evaluated in many additional types of CD30-positive malignancies, including B-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-positive tumor cells.
ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin 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, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) 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 lymphoma and sALCL.
ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin 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 (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in 65 countries for relapsed or refractory Hodgkin lymphoma and sALCL.
In June 2016, the European Commission extended the current conditional marketing authorization of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT. See important safety information below.
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.
About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and central nervous system therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as our presence in Emerging Markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.
Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.
About Seattle Genetics
Seattle Genetics is an innovative biotechnology company that develops and commercializes novel antibody-based therapies for the treatment of cancer. The company’s industry-leading antibody-drug conjugate (ADC) technology harnesses the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. ADCETRIS® (brentuximab vedotin), the company’s lead product, in collaboration with Takeda Pharmaceutical Company Limited, is the first in a new class of ADCs commercially available globally in 65 countries for relapsed classical Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma (sALCL). Seattle Genetics is also advancing vadastuximab talirine (SGN-CD33A; 33A), an ADC in a Phase 3 trial for acute myeloid leukemia. Headquartered in Bothell, Washington, Seattle Genetics is developing a robust pipeline of innovative therapies for blood-related cancers and solid tumors designed to address significant unmet medical needs and improve treatment outcomes for patients. The company has collaborations for its proprietary ADC technology with a number of companies including AbbVie, Astellas, Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com
