On December 18, 2017 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported that the first patient in its Phase 1/2 dose escalation and dose expansion clinical trial (see www.clinicaltrials.gov, identifier NCT03340883) has been dosed at Virginia Cancer Specialists in Fairfax, Virginia, the first site in this multi-center trial (Press release, Aduro Biotech, DEC 18, 2017, View Source;p=RssLanding&cat=news&id=2323132 [SID1234522686]). The study is designed to evaluate the safety and activity of BION-1301, a humanized anti-APRIL (A PRoliferation-Inducing Ligand) antibody, for adults with relapsed or refractory multiple myeloma.
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"Neutralizing APRIL is a differentiated approach in the treatment of multiple myeloma, and it has been shown to inhibit tumor growth and overcome drug resistance in preclinical studies," said Natalie Sacks, M.D., chief medical officer of Aduro Biotech. "BION-1301 is our wholly-owned novel antibody that has been shown in non-clinical studies to fully block the APRIL-induced signaling cascade at a critical juncture, and we are eager to further characterize its potential activity in the clinic. Until there is a cure for multiple myeloma which remains a debilitating disease, alternative treatments are needed."
Recently, two datasets on anti-APRIL were presented at the 59TH American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia. Data presented by Yu-Tzu Tai, Ph.D., of the Dana Farber Cancer Institute in an oral session at ASH (Free ASH Whitepaper) demonstrate that BION-1301 and its parental antibody blocked APRIL binding to both its receptors BCMA and TACI. Blocking APRIL with BION-1301 (or its parental antibody) not only inhibited proliferation and survival of multiple myeloma cells but it also alleviated drug resistance and immune suppression in preclinical models and cell culture, leading to enhanced anti-BCMA and daratumumab-mediated myeloma cell killing. Additionally, Dr. Tai and her colleagues demonstrated that regulatory T cells in the blood and bone marrow expressed TACI, and that APRIL blockade inhibited their function. Also, John Dulos, Ph.D., director and project team leader at Aduro Biotech, and his team conducted preclinical pharmacokinetic and pharmacodynamic studies indicating BION-1301 was well tolerated and binding of APRIL in preclinical models resulted in decreased IgA, IgG and IgM production in a dose-dependent fashion.
"We know that APRIL sets off a cascade of events that hinders the immune response to multiple myeloma cells, helping the disease escape immune attack. The data presented at ASH (Free ASH Whitepaper) indicate that blocking APRIL by targeting BCMA alone may not be sufficient for the treatment of multiple myeloma, as APRIL critically modulates regulatory T cell function via TACI, not BCMA," said Dr. Tai. "Importantly, BION-1301, as a fully-blocking monoclonal antibody, may have unique efficacy by inhibiting APRIL-induced proliferation of immune system components linked to multiple myeloma progression."
About Phase 1/2 Trial
The Phase 1/2 multi-center, open-label study is designed to evaluate the safety and activity of BION-1301 in patients with relapsed or refractory multiple myeloma whose disease has progressed after at least 3 prior systemic therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors, chemotherapies, or monoclonal antibodies. The Phase 1 part of the study will evaluate the safety, pharmacokinetics and pharmacodynamics of escalating doses of BION-1301 administered once every two weeks in a 28-day cycle. Once the recommended Phase 2 dose is determined, the Phase 2 part of the study will begin. It will assess safety and preliminary activity of BION-1301 at the selected dose, with a primary activity endpoint of objective response rate.
About APRIL and BION-1301
APRIL (A PRoliferation-Inducing Ligand) is a member of the tumor necrosis factor (TNF) superfamily and is primarily secreted by bone marrow and/or myeloid cells. APRIL is overproduced in patients with multiple myeloma and binds to BCMA (B cell maturation antigen) and TACI (Transmembrane Activator and CAML Interactor) to stimulate a wide variety of responses that promote multiple myeloma growth and suppress the immune system so that the tumor cells are allowed to proliferate. BION-1301 is a humanized anti-APRIL antibody that has been shown in preclinical studies to effectively neutralize APRIL, eliminate malignant cells and reduce resistance to therapy in models of multiple myeloma. In addition to multiple myeloma, APRIL’s role in other cancers and in B cell dependent autoimmune and inflammatory diseases indicate that BION-1301 may also be useful in treating chronic lymphocytic leukemia, colorectal cancer and Berger’s disease (caused by IgA antibody deposits in the kidneys).
About Multiple Myeloma
Lymphocytes (B cells and T cells) are the primary cell types within the immune system that work together to fight infection and disease. As B cells respond to normal infection in the body, they mature and change into plasma cells, which in turn make antibodies that help the body attack infection. While lymphocytes circulate throughout the body, plasma cells remain primarily in the bone marrow. Multiple myeloma is a blood cancer that occurs when malignant plasma cells proliferate uncontrollably. Approximately 50,000 new cases of multiple myeloma are expected to be diagnosed in the United States and Europe each year. While many new therapies have become available in recent years, multiple myeloma remains incurable and significant unmet needs exist among patients who relapse following, are resistant to, or cannot tolerate currently available agents.