BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to ADCETRIS (brentuximab vedotin) for the treatment of patients with CD30-expressing mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) who require systemic therapy and have received one prior systemic therapy. MF and pcALCL are the most common subtypes of cutaneous T-cell lymphoma (CTCL), accounting for more than 75 percent of the disease. ADCETRIS has been evaluated in CD30-expressing CTCL in investigator- and corporate-sponsored clinical trials, including the phase 3 ALCANZA study. The positive topline results of the ALCANZA trial were announced in August 2016 and an abstract was accepted for oral presentation at the upcoming American Society of Hematology (ASH) annual meeting, December 3-6, 2016 in San Diego, California. 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.
The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies on one or more clinically significant endpoints.
“The decision by the FDA to grant ADCETRIS Breakthrough Therapy Designation further reinforces our belief that ADCETRIS represents a meaningful advance in the treatment of CD30-expressing CTCL,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “The Breakthrough Therapy Designation supports our goal to expedite the review and approval process to make ADCETRIS available to patients in this setting who may benefit. We look forward to presenting the data from our phase 3 ALCANZA trial in an oral session at the upcoming ASH annual meeting and intend to submit a supplemental Biologics License Application to the FDA in the first half of 2017 for approval in this setting.”
This Breakthrough Therapy Designation was based on data from the phase 3 ALCANZA clinical trial. The phase 3 ALCANZA trial evaluated ADCETRIS in CD30-expressing CTCL and met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). This randomized trial, which received a Special Protocol Assessment (SPA) agreement from the FDA and scientific advice from the European Medicines Agency (EMA), compared the use of single-agent ADCETRIS to a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in 131 patients with CD30-expressing CTCL who received prior systemic or radiation therapy.
The title of the phase 3 ALCANZA abstract accepted for oral presentation at the ASH Annual Meeting is below and can be found at www.hematology.org:
- 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 on Saturday, December 3, 2016 at 2:15 p.m. PT)
Phase 3 ALCANZA Clinical Trial Design
The ALCANZA trial is a randomized, open-label phase 3 study designed to evaluate single-agent ADCETRIS versus a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in patients with CD30-expressing 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. Key secondary endpoints are complete response rate, progression-free survival and reduction in the burden of symptoms during treatment. The clinical trial enrolled 131 patients at 50 sites globally. 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. Patients received ADCETRIS every three weeks versus investigator’s choice for up to approximately one year. This international multi-center trial has been conducted in North and South America, Europe and Australia under operational responsibility of Takeda Pharmaceuticals.
ADCETRIS received orphan drug designation from the FDA for the treatment of MF, which is the most common type of CTCL. ADCETRIS also received orphan drug designation from the European Commission for CTCL, including subtypes pcALCL and MF.
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 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.
ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including two phase 3 studies, ECHELON-1 in frontline classical Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing 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-expressing 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.
In June 2016, the European Commission extended the current conditional approval 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 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 has 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
ADCETRIS (brentuximab vedotin) U.S. Important Safety Information
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
- Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
- Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
- Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
- Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
- Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
- Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
- Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
- Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
- Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
- Pulmonary toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
- Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
- Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
- Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, the most common adverse reactions (≥20%), regardless of causality, were: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.
In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).
Use in Specific Populations
MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.
Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.
Forward Looking Statements
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic and commercial potential of ADCETRIS, including ADCETRIS’ potential as a treatment for CTCL, the anticipated benefits of Seattle Genetics’ ADCETRIS clinical development program, and the potential submission of applications (e.g., a supplemental Biologics License Application in the U.S.) seeking label expansion for ADCETRIS use in the CTCL setting. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks of adverse events associated with ADCETRIS use, the possibility that data from the ALCANZA study may not be deemed sufficient by regulatory agencies to support approval of ADCETRIS for use in the CTCL setting, and adverse regulatory actions affecting ADCETRIS, all of which could result in Seattle Genetics being unable to expand ADCETRIS’ labeled indications of use for CTCL or any other settings. Seattle Genetics may also experience delays in submission or review of its supplemental Biologics License, in each case for a variety of reasons, including the inherent difficulty and uncertainty of pharmaceutical product development or regulatory action. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.