-Updated Data from Phase 1 Clinical Trials Support Further Clinical Evaluation of SGN-CD19A in Randomized Phase 2 Trials: Testing Novel Regimens for Frontline and Relapsed DLBCL-
-First Preclinical Data Presented for SGN-CD19B, a Novel Antibody-Drug Conjugate with PBD Dimer Payload; Phase 1 Clinical Trial in B-cell Malignancies to Begin in 2016-
ORLANDO, FL, USA I December 6, 2015 I Seattle Genetics, Inc. (Nasdaq: SGEN) today highlighted clinical data with denintuzumab mafodotin (SGN-CD19A; 19A) in B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphocytic leukemia (B-ALL), presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015. Preclinical data from a novel antibody-drug conjugate (ADC) program called SGN-CD19B in B-cell malignancies will also be featured in an oral presentation. About 85 percent of non-Hodgkin lymphomas (NHL) are B-cell lineage, and CD19 is broadly expressed across all subtypes of B-cell malignancies. These two ADCs, 19A and SGN-CD19B, both target CD19 and utilize two of Seattle Genetics’ proprietary payloads, monomethyl auristatin F (MMAF) and a pyrrolobenzodiazepine (PBD) dimer, respectively. The company has initiated the first of two planned phase 2 trials of 19A in DLBCL and plans to advance SGN-CD19B into a phase 1 trial in 2016.
“Data presented at ASH from our 19A phase 1 trial in non-Hodgkin lymphoma show encouraging objective response rates, particularly in relapsed DLBCL patients, and a tolerability profile that we believe supports further investigation as part of novel regimens. Based on these data, we recently initiated a phase 2 trial in relapsed DLBCL, and plan to initiate a phase 2 trial in frontline DLBCL during 2016,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “CD19 is an attractive target for NHL, and there is a clear need for potent, safe and convenient therapies that can be used to improve outcomes for patients.”
With more than 15 years of experience and innovation, Seattle Genetics is the leader in developing ADCs, a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. More than 25 ADCs in clinical development utilize Seattle Genetics’ proprietary ADC technology.
A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refractory B-Lineage Non-Hodgkin Lymphoma (Abstract #182, oral presentation on Sunday, December 6, 2015 at 7:45 a.m.)
Data were reported from 62 patients with relapsed or refractory NHL, including 54 patients with DLBCL, five patients with mantle cell lymphoma and three patients with grade 3 follicular lymphoma. Of the 62 patients, 37 patients (60 percent) were refractory to their last therapy and 25 patients (40 percent) were relapsed. Sixteen patients (26 percent) had received a prior autologous stem cell transplant. The median age of patients was 65 years.
The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and evaluate the safety and tolerability of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this study, patients receive 19A either every three weeks or every six weeks. Patients with stable disease or better are eligible to continue treatment with 19A. Key findings from an oral presentation by Craig Moskowitz, M.D. Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, include:
- The maximum tolerated dose was not exceeded after escalating to 6 milligrams per kilogram (mg/kg) every three weeks.
- Of the 60 patients evaluable for response, 23 patients (38 percent) achieved an objective response, including 14 patients (23 percent) with a complete remission and nine patients (15 percent) with a partial remission. Thirteen patients (22 percent) achieved stable disease and 24 patients (40 percent) had disease progression.
- Antitumor activity appeared to be higher in relapsed patients. Of the 25 relapsed patients, 15 patients (60 percent) achieved an objective response, including 10 patients (40 percent) with a complete remission. In the 23 relapsed patients who responded, median duration of response was 47.1 weeks. Among all relapsed patients, median progression-free survival was 25.1 weeks and median overall survival was 56.7 weeks.
- The most common adverse events of any grade occurring in more than 15 percent of patients were blurred vision (63 percent); dry eye (53 percent); fatigue, keratopathy and photophobia (39 percent each). Ocular symptoms were reported in more than 70 percent of patients. Symptoms were mostly Grade 1/2 and were managed with steroid eye drop treatment and dose modifications. Eighty-eight percent of patients with Grade 3 or 4 keratopathy experienced improvement and/or resolution within a median of five weeks.
A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Adults with Relapsed or Refractory B-Lineage Acute Leukemia (B-ALL) and Highly Aggressive Lymphoma (Abstract #1328, poster presentation on Saturday, December 5, 2015)
Data were reported from 72 adult patients with relapsed or refractory B-ALL and highly aggressive lymphomas, including B-cell lymphoblastic lymphoma (B-LBL) and Burkitt lymphoma. The median age of adult patients was 45 years and the median number of prior systemic therapies was two, with 20 patients (28 percent) having received a prior allogeneic stem cell transplant.
The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients received 19A in Schedule A (40 patients) at 0.3 to 3 mg/kg weekly or Schedule B (32 patients) at 4 to 6 mg/kg every three weeks. Key findings include:
- Of the 56 B-ALL adult patients evaluable for response, six patients (19 percent) treated weekly achieved a composite complete remission (complete remission or complete remission with incomplete platelet or blood recovery) and nine patients (38 percent) treated every three weeks achieved a composite complete remission. The median duration of response was 27 weeks. Fifty-four percent of patients across both schedules achieved cytoreduction of greater than 50 percent.
- In the ten patients with Philadelphia chromosome positive (Ph+) B-ALL, five patients (50 percent) achieved a complete remission and one patient (10 percent) had a partial remission. Ph+ B-ALL represents 20 to 30 percent of adult patients and carries a dismal prognosis, with higher rates of relapse and lower overall survival.
- The maximum tolerated dose was not reached in patients treated weekly and was identified at 5 mg/kg in patients treated every three weeks.
- The most common adverse events of any grade occurring in 25 percent or more of patients treated weekly (40 patients) or every three weeks (32 patients), respectively, were nausea (63 and 41 percent), fatigue (58 and 47 percent), fever (55 and 50 percent), headache (45 and 38 percent) and anemia (43 and 22 percent).
- In the study, 43 patients (60 percent) developed ocular symptoms, of which 91 percent were Grade 1/2. These included blurred vision (39 percent), dry eye (25 percent) and photophobia (19 percent). Ocular symptoms were managed with steroid eye drop treatment and dose modifications. Keratopathy was observed in 34 patients, of whom 22 patients had Grade 3/4 events. The majority of patients with Grade 3/4 events had improvement or resolution with a median time of approximately four weeks.
The 19A phase 1 clinical trials are ongoing. Separately, a randomized phase 2 trial has recently initiated evaluating 19A in combination with R-ICE chemotherapy for second-line DLBCL. In addition, a phase 2 clinical trial in frontline DLBCL is planned to begin in 2016. More information about the 19A clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.
SGN-CD19B, a Pyrrolobenzodiazepine (PBD)-Based Anti-CD19 Drug Conjugate, Demonstrates Potent Preclinical Activity Against B-Cell Malignancies (Abstract #594, oral presentation on Monday, December 7, 2015 at 11:45 a.m.)
A preclinical analysis evaluated the activity of SGN-CD19B, a new ADC consisting of an anti-CD19 antibody attached to a highly potent DNA binding agent called a PBD dimer, in multiple B-cell malignancy models. Data to be presented in an oral session demonstrate that SGN-CD19B exhibits antitumor activity against a broad panel of CD19-expressing B-cell malignancies, inducing durable tumor regressions and improved survival in multiple preclinical models of NHL and B-ALL. Based on these data, a phase 1 clinical trial evaluating SGN-CD19B in NHL is planned to start in 2016.
About Denintuzumab Mafodotin (SGN-CD19A)
Denintuzumab mafodotin (SGN-CD19A; 19A) is an ADC targeting CD19, a protein expressed broadly on B-cell malignancies. 19A is comprised of an anti-CD19 monoclonal antibody linked to a synthetic cell-killing agent, monomethyl auristatin F (MMAF). The ADC is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.
About Non-Hodgkin Lymphoma
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 NHL. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of NHL. According to the American Cancer Society, more than 71,000 cases of NHL were to be diagnosed in the United States during 2015 and more than 19,000 people would die from the disease.
About Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia, also called acute lymphocytic leukemia or ALL, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. In ALL, lymphoblasts, which are malignant, immature white blood cells, multiply and crowd out normal cells in the bone marrow. ALL is the most common type of cancer in children. According to the American Cancer Society, more than 6,000 people will be diagnosed with ALL during 2015 and more than 1,400 would die from the disease.
About Seattle Genetics
Seattle Genetics is a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer. Seattle Genetics is leading the field in developing antibody-drug conjugates (ADCs), a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS® (brentuximab vedotin) is a CD30-targeted ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available in more than 55 countries, including the U.S., Canada, Japan and members of the European Union. Additionally, ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials in CD30-expressing malignancies. Seattle Genetics is also advancing a robust pipeline of clinical-stage programs, including vadastuximab talirine (SGN-CD33A; 33A), denintuzumab mafodotin (SGN-CD19A; 19A), SGN-LIV1A, SGN-CD70A, ASG-22ME, ASG-15ME and SEA-CD40. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com.
SOURCE: Seattle Genetics
