On January 2, 2018 Syros Pharmaceuticals (NASDAQ:SYRS), a biopharmaceutical company pioneering the development of medicines to control the expression of disease-driving genes, reported that it has entered into a clinical supply agreement with Janssen Research and Development, LLC (Press release, Syros Pharmaceuticals, JAN 2, 2018, View Source [SID1234522806]). Under the agreement, Janssen will supply daratumumab for a recently added combination dosing cohort in Syros’ ongoing Phase 2 clinical trial of SY-1425, a first-in-class selective retinoic acid receptor alpha (RARα) agonist, in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Daratumumab (DARZALEX) is an anti-CD38 antibody approved for use in various multiple myeloma populations.
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"We are delighted to work with Janssen to investigate the potential of SY-1425 in combination with daratumumab to benefit AML and MDS patients with the RARA or IRF8 biomarkers," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "By inducing expression of CD38 in these patients’ tumors, we believe SY-1425 may sensitize them to treatment with daratumumab, which is believed to induce tumor cell death in CD38-positive cells through multiple immune-mediated mechanisms. Based on preclinical data supporting this hypothesis as well as CD38 induction seen in the bone marrow of AML and MDS patients treated with SY-1425, we added a cohort to our ongoing Phase 2 clinical trial of SY-1425 and look forward to starting to enroll patients early this year."
In exchange for providing daratumumab, Janssen will receive access to data from the cohort evaluating the safety and efficacy of SY-1425 in combination with daratumumab for its research and development programs related to daratumumab. The study will continue to be sponsored solely by Syros.
Syros is assessing the safety and efficacy of SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy, and in combination with daratumumab in patients with relapsed or refractory AML or higher-risk MDS, in an ongoing Phase 2 clinical trial. All patients enrolled or to be enrolled in this clinical trial are prospectively selected using the Company’s proprietary RARA and IRF8 biomarkers. Enrollment in the combination cohort with azacitidine began last year and is ongoing. Syros expects to begin enrolling patients in the combination cohort with daratumumab in early 2018. Syros expects to present initial clinical data on both combinations in 2018.
Analysis of bone marrow biopsies from relapsed or refractory AML and higher-risk MDS patients enrolled in the ongoing clinical trial showed increased CD38 expression in 11 out of 13 (85 percent) of evaluable patients. Preclinical studies showed that SY-1425 induced CD38 in RARA biomarker-positive AML cells comparable to levels of CD38 seen in multiple myeloma cells that are known to be responsive to daratumumab, as well as in an in vivo model of biomarker-positive AML. Notably, AML cells do not normally express high levels of CD38. Preclinical studies also showed that SY-1425 in combination with daratumumab triggered robust activation of natural killer cells and immune-cell mediated tumor cell death in biomarker-positive AML cells.
DARZALEX is the first CD38-directed monoclonal antibody approved to treat patients with multiple myeloma. It was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent. DARZALEX is also approved in Europe, Canada and several other countries for a similar patient population. DARZALEX was more recently approved by the FDA in November 2016 for use in combination with lenalidomide (an immunomodulatory agent) and dexamethasone, or bortezomib (a PI) and dexamethasone, for multiple myeloma patients who have received at least one prior therapy. Daratumumab received Breakthrough Therapy Designation from the FDA for this indication in July 2016. In June 2017, the FDA approved a supplement for DARZALEX use in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. Janssen licensed daratumumab from Genmab A/S in August 2012 and is responsible for all global development, marketing and manufacturing.