Bicycle Therapeutics plc (NASDAQ: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle®) technology, today announced that a research paper describing the mechanism of action for the Company’s first second-generation Bicycle Toxin Conjugate (BTC), BT5528, has been published in the American Association for Cancer Research (AACR) journal Molecular Cancer Therapeutics. The manuscript, titled “MMAE delivery using the Bicycle toxin conjugate BT5528,” discusses the preclinical profile of BT5528, which has physiochemical properties thought to enable more favorable safety and efficacy profiles than antibody drug conjugates (ADCs) with the same tumor antigen target and similar cytotoxic payload. The e-publication can be found here.
“Bicycles are a unique therapeutic modality designed to address clinical needs that can’t be met by biologic or small molecule approaches,” said Kevin Lee, Ph.D., Chief Executive Officer of Bicycle Therapeutics. “The preclinical data for BT5528 published in Molecular Cancer Therapeutics suggest that the key features of Bicycles, such as their low molecular weight, short systemic half-life and renal route of elimination, can result in a therapeutic candidate with an in vivo pharmacokinetic profile that yields a wider preclinical therapeutic index than that of a comparator ADC.”
BT5528 is a second-generation BTC, which uses a valine-citrulline cleavable linker and a cytotoxin MMAE payload, that targets EphA2, a tumor antigen that is overexpressed in a wide range of solid tumor types and is associated with poor outcomes, making it ideal for selective payload targeting using ADCs and other approaches. The manuscript published in Molecular Cancer Therapeutics describes the preclinical development of BT5528, which involved a suite of pharmacokinetic, efficacy and safety studies aimed at derisking the toxicology that limited development of MedImmune’s MEDI-547, an ADC comprised of an EphA2 targeted monoclonal antibody (1C1) conjugated to a cytotoxin MMAF.
Though MEDI-547 showed promising anti-tumor activity in preclinical models, its toxicology profile included bleeding and coagulation events in non-human species, which were later observed in a Phase I study, resulting in the discontinuation of clinical development. Unlike with MEDI-547, Bicycle did not observe coagulopathy, DIC-like syndrome or changes in closely monitored clotting parameters in preclinical toxicology studies of BT5528. Furthermore, BT5528 and a 1C1-mcMMAF ADC designed to approximate MEDI-547 showed broadly equivalent tumor regression in certain standard tumor models, but BT5528 demonstrated improved efficacy over the ADC in large, poorly vascularized tumor models that are more difficult to treat. These results support the hypothesis that low molecular weight peptide conjugates achieve faster and greater tumor penetration and thus greater efficacy than antibody conjugates.
BT5528 is being evaluated in a Phase I/II multi-center, open-label trial, which is currently enrolling patients with advanced solid tumors in indications associated with EphA2 expression into Phase I dose escalations of BT5528 as a monotherapy and in combination with nivolumab. To date, doses of BT5528 continue to appear well-tolerated with manageable adverse events as the dose escalations approach clinically relevant dose levels.
About Bicycle Therapeutics
Bicycle Therapeutics (NASDAQ: BCYC) is a clinical-stage biopharmaceutical company developing a novel class of medicines, referred to as Bicycles®, for diseases that are underserved by existing therapeutics. Bicycles are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycle’s lead product candidate, BT1718, a Bicycle Toxin Conjugate (BTC) that targets MT1-MMP, is being investigated in an ongoing Phase I/IIa clinical trial in collaboration with the Centre for Drug Development of Cancer Research UK. Bicycle is also evaluating BT5528, a second-generation BTC targeting EphA2, in a Company-sponsored Phase I/II study. Bicycle is headquartered in Cambridge, UK with many key functions and members of its leadership team located in Lexington, MA. For more information, visit bicycletherapeutics.com.
Article sourced from: https://investors.bicycletherapeutics.com/news-releases/news-release-details/bicycle-therapeutics-announces-publication-bt5528-mechanism
Published on: 12.05.2020
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