On August 31, 2017 Aptevo Therapeutics Inc. (Nasdaq:APVO), a biotechnology company focused on developing novel immuno-oncology and hematology therapeutics, reported the end of its partnership with MorphoSys AG for the joint worldwide development and commercialization of MOR209/ES414, a targeted immunotherapeutic for the treatment of metastatic castration resistant prostate cancer (mCRPC) (Press release, Aptevo Therapeutics, AUG 31, 2017, View Source [SID1234520353]). Aptevo will regain worldwide development and commercialization rights for MOR209/ES414 (now known as APVO414) and intends to continue to advance APVO414 through the completion of Stage 1 of an ongoing Phase 1 continuous infusion, dose-escalation clinical study evaluating the safety, tolerability and clinical activity of escalating doses of APVO414 in patients with mCRPC.
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"We’re encouraged by the latest preliminary data from the ongoing Phase 1 clinical study of APVO414," said Dr. Scott Stromatt, Senior Vice President and Chief Medical Officer at Aptevo. "The data suggest that administration of APVO414 by continuous infusion, rather than weekly intravenous (IV) dosing, is effective at reducing the titer of anti-drug antibodies (ADA) previously observed in the initial weekly IV dosing cohorts."
In the initial cohorts of the Phase 1 dose escalation study, twelve patients with mCRPC were treated with weekly intravenous infusions of APVO414. Seven of these patients (58%) developed ADA with very high titers (as high as 1:250,000). None of the patients had any adverse reactions due to the ADA, but patients with high ADA titers cleared the drug from their blood to undetectable levels.
The amended protocol utilizes continuous intravenous infusion and two cohorts of patients have completed dosing without any dose limiting toxicities. Three of six patients (50%) developed ADA but with markedly lower titers of ADA (1:160 or 1:320). Additionally, drug was detected in the serum of all patients.
"These results clearly demonstrate that the administration regimen markedly reduced the generation of ADA. Additionally, we have seen early pharmacodynamic effects of the drug such as redistribution of T cells. We are encouraged and plan to continue dose escalation in order to determine the maximum tolerated dose and to examine the clinical activity of APVO414," said Dr. Stromatt.
APVO414 is a first-generation bispecific antibody candidate, developed using Aptevo’s ADAPTIR protein therapeutic platform. APVO414 is engineered to simultaneously target PSMA on prostate cancer cells, and CD3 on T-cells, and functions by redirecting cytotoxic T cell activity towards PSMA-expressing tumor cells.
Promising preclinical data demonstrating the ability of APVO414 to induce target-dependent tumor cell killing as well as target-dependent T cell proliferation were previously presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and recently published in the Journal of Molecular and Cellular Biology (2016 Mol Cancer Ther; 15(9); 2155–65). In addition, APVO414 demonstrated lower levels of T cell dependent cytokines compared to other bispecific formats, which, if confirmed in clinical studies, could offer the potential for enhanced safety and tolerability compared to other immuno-oncology bispecific antibody approaches.
"Aptevo has made a number of significant improvements to our ADAPTIR platform since the development of our first-generation bispecific candidates, like APVO414," commented Jane Gross, Ph.D., Senior Vice President and Chief Scientific Officer. "Our next generation ADAPTIR technology platform has been optimized to enable the development of bispecific antibody candidates with highly-desirable drug-like properties, including, enhanced potency and stability, prolonged half-life, and excellent manufacturing attributes – similar to traditional antibodies. Importantly, we have utilized state-of-the-art technologies to examine our next generation bispecific candidates and believe that we identified and eliminated the root cause of the ADA seen with APVO414. We look forward to obtaining additional information from the ongoing APVO414 clinical trial and advancing next generation ADAPTIR bispecific molecules into clinical development."
About Prostate Cancer
Although screening, radiation, surgery and hormone ablation therapy have greatly improved the detection and treatment of early-stage prostate cancer, the relapse rate following initial anti-androgen therapy remains high, and there remains a significant unmet medical need for patients with metastatic castration resistant prostate cancer for whom current therapies have demonstrated only a limited increase in overall survival. The global market for CRPC therapeutics is expected to reach $9.5 billion by 2020
About the ADAPTIR Pipeline
Two first generation ADAPTIR molecules are currently in clinical development: APVO414, which is being investigated in a Phase 1, dose escalation, continuous infusion study to evaluate safety and tolerability in patients with metastatic castration resistant prostate cancer; and, otlertuzumab, a monospecific antibody targeting CD37 under investigation for the treatment of chronic lymphocytic leukemia. In addition, Aptevo has several ADAPTIR candidates in preclinical development, including: APVO436, an optimized, next generation bispecific antibody candidate designed to simultaneously target CD123 and CD3 and redirect T cell cytotoxicity for the treatment of acute myelogenous leukemia (AML), a form of blood and bone marrow cancer; ALG.APV-526, a bispecific antibody candidate, partnered with Alligator Bioscience, featuring a novel mechanism of action designed to simultaneously target 4-1BB (CD137) and an undisclosed tumor antigen, and, APVO210 – a bispecific ADAPTIR candidate with a novel mechanism of action based on cytokine delivery currently in preclinical development for autoimmune and inflammatory diseases.