Bicycle Therapeutics - Pipeline - Bicycle Therapeutics

Pipeline

Bicycle is developing several molecules in the clinic, and advancing many additional discovery-stage projects.

Bicycle® molecules are a novel class of medicines formed by constraining short linear peptides into a stabilized bi-cyclic structure using a central chemical scaffold.

The resulting structure enables Bicycle molecules to effectively mimic protein-protein interactions. Bicycle molecules combine the pharmacological properties normally associated with a biologic with the pharmacokinetic and synthetic advantages of a small molecule.

Bicycle molecules are fully synthetic and can be readily conjugated to other chemical payloads, or to other Bicycle molecules:

Bicycle® Drug Conjugates contain a Bicycle molecule targeted to a specific tumor antigen, a selectively cleavable linker, and a small molecule drug payload
Bicycle® Radioligands contain a Bicycle molecule targeted to a specific tumor antigen, a stable linker-chelator system, and either a highly potent therapeutic radioisotope or a low energy isotope for imaging
Bicycle molecules can be designed as immune cell agonists that are guided to the tumor under the direction of a tumor antigen targeting Bicycle molecule

Bicycle® Drug Conjugates

Preclinical

IND-enabling /
Human Imaging

Early Stage
Development

Late Stage
Development

nuzefatide pevedotin

Phase

Early Stage Development

Target

EphA2

Target

Nuzefatide pevedotin (formerly BT5528) targets EphA2 (or Ephrin type-A receptor 2), a member of the Ephrin superfamily of receptor tyrosine kinases, which regulates cell migration, adhesion, proliferation and differentiation during development. EphA2 is overexpressed in difficult to treat cancers, and expression of this kinase correlates with malignant progression and poor prognosis.

EphA2 is an attractive target for Bicycle® molecules due to the potential to overcome the safety concerns historically observed with antibody drug conjugates (ADCs). Significant safety concerns, including bleeding events and liver toxicity, were observed in preclinical studies and early clinical development of ADCs, which resulted in the discontinuation of development.

Molecule

The molecule is composed of our EphA2 targeting Bicycle®, a valine-citrulline (val-cit) cleavable linker and a monomethyl auristatin E (MMAE) drug payload.

Preclinical

Bicycle’s EphA2 drug conjugates have demonstrated promising target-dependent activity in preclinical models, including both cell- and patient-derived xenografts that are resistant to current treatments.

In preclinical studies, nuzefatide pevedotin was not observed to have any bleeding events in primates at toxin equivalent doses over 150 fold higher than the clinical dose of historical ADC therapeutics.

Clinical Plan

Nuzefatide pevedotin is currently being evaluated in a Company-sponsored Phase I/II clinical trial as monotherapy and in combination with immune checkpoint inhibitor and in a Phase II trial as monotherapy in adult patients with metastatic pancreatic ductal adenocarcinoma (PDAC). EphA2 IHC status for patient enrolled are being recorded for future assessment as a potential predictor of efficacy in each trial.

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zelenectide pevedotin

Phase

Late Stage Development

Target

Nectin-4

Target

Zelenectide pevedotin (formerly BT8009) targets Nectin-4, a cell adhesion molecule from the Nectin and Nectin-like family, which has been shown to be overexpressed in tumor cells and is believed to play a role in tumor cell growth and proliferation. High in normal embryonic and fetal tissue, Nectin-4 declines in adulthood, showing a limited distribution in healthy tissues.

Molecule

The molecule is composed of our Nectin-4 targeting Bicycle®, a valine-citrulline, or val-cit, cleavable linker, and an MMAE drug payload.

Preclinical

Bicycle’s Nectin-4 drug conjugate demonstrate promising target-dependent activity in preclinical models, including both cell- and patient-derived xenografts resistant to current standard of care treatments. In preclinical head-to-head comparisons with an ADC targeting Nectin-4, zelenectide appeared to demonstrate superior anti-tumor activity, including complete regressions in both very large and small tumor models. In preclinical studies, zelenectide showed only a subset of the toxicities typically associated with the MMAE drug payload, avoiding liver, GI and renal toxicity.

Clinical Plan

Zelenectide pevedotin is currently being evaluated in several Company-sponsored clinical trials. The Phase I/II Duravelo-1 trial is studying zelenectide in several Nectin-4 expressing tumors, while the Phase II Duravelo-2 trial is studying zelenectide as a treatment for metastatic urothelial cancer.

Program is being deprioritized, whilst evaluating potential regulatory options and next steps.

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BT7480

Phase

Early Stage Development

Target

Nectin-4 / CD137

Target

BT7480 is a novel, fully synthetic Bicycle tumor-targeted immune cell agonist® (Bicycle TICA®) that contains three Bicycle molecules. One targets Nectin-4, a cell adhesion molecule from the Nectin and Nectin-like family shown to be overexpressed on the surface of tumor cells. The others bind to and agonize CD137, a member of the TNFR family involved in the activation of several immune cell types, including T cells and NK cells.

Preclinical

In preclinical models, Nectin-4/CD137 Bicycle TICAs have shown powerful anti-tumor activity, enabled by potent and tumor antigen dependent CD137 agonism.

Clinical Plan

BT7480 is currently being evaluated in a company-sponsored Phase I/II clinical trial. Bicycle Therapeutics will no longer develop BT7480 internally and intends to seek a potential partner for future development.

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Bicycle Radioligands

Preclinical

IND-enabling /
Human Imaging

Early Stage
Development

Late Stage
Development

BT1702

Phase

IND-enabling / Human Imaging

Target

MT1-MMP

Target

BT1702 targets MT1-MMP (or Membrane type-1 matrix metalloproteinase), is a zinc-dependent transmembrane enzyme that plays a critical role in the degradation of the extracellular matrix (ECM) and the promotion of cell invasion and metastasis in cancers. MT1-MMP is overexpressed in a range of high value tumors.

Molecule

The molecule consists of an MT1-MMP targeting Bicycle® molecule coupled to a chelator cage which is used to coordinate ²¹²Pb, an alpha particle emitting radioisotope used as a therapeutic.

Preclinical

In pre-clinical models BT1702 showed an attractive biodistribution profile, with good localization to a range of tumor models and low uptake into other tissues. In pre-clinical efficacy studies, it showed promising target dependent activity.

Clinical Plan

The Company plans to initiate its first company-sponsored BRC® clinical trial in 2027.

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MT1-MMP Bicycle Imaging Agent

Phase

IND-enabling / Human Imaging

Target

MT1-MMP

Target

MT1-MMP Bicycle Imaging Agent targets MT1-MMP (or Membrane type-1 matrix metalloproteinase), is a zinc-dependent transmembrane enzyme that plays a critical role in the degradation of the extracellular matrix (ECM) and the promotion of cell invasion and metastasis in cancers. MT1-MMP is overexpressed in a range of high value tumors.

Molecule

The molecule is not designed as a therapeutic but as an agent to image the target in human. As such it consists of an MT1-MMP targeting Bicycle® molecule coupled to a chelator cage which is used to coordinate ⁶⁸Ga, a positron emitting short half-life imaging radioisotope used in PET imaging.

Preclinical

In pre-clinical imaging studies, BIA1701 localized to a range of MT1-MMP positive tumors, with low uptake in other tissues, and confirmed a renal route of elimination.

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EphA2 Bicycle Imaging Agent

Phase

IND-enabling / Human Imaging

Target

EphA2

Target

EphA2 Bicycle Imaging Agent targets EphA2 (or Ephrin type-A receptor 2), a member of the Ephrin superfamily of receptor tyrosine kinases, which regulates cell migration, adhesion, proliferation and differentiation during development. EphA2 is overexpressed in difficult to treat cancers, and expression of this kinase correlates with malignant progression and poor prognosis.

Molecule

The molecule is not designed as a therapeutic but as an agent to image the target in human. As such it consists of an EphA2 targeting Bicycle® molecule coupled to a chelator cage which is used to coordinate ⁶⁸Ga, a positron emitting short half-life imaging radioisotope used in PET imaging.

Preclinical

In pre-clinical imaging studies, BIA5501 localized to a range of EphA2 positive tumors, with low uptake in other tissues, and confirmed a renal route of elimination.

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Select targets

Bayer

Early human imaging

DKFZ and University Hospital Essen

Partnered Programs

Preclinical

IND-enabling /
Human Imaging

Early Stage
Development

Late Stage
Development

ION286/AZD4063

Phase

Early Stage Development

Target

TfR1

Partner

Ionis Pharmaceuticals

Target

Transferrin Receptor 1 (TfR1), one of the most studied transporter receptors. It is the primary mechanism for transporting iron into tissues which have a high iron requirement, such as cardiac and skeletal muscle, as well as the central nervous system (CNS). Bicycle Therapeutics has identified the first small molecules that can bind to the TfR1 transporter and are either internalized into cells or transited across the blood brain barrier by transcytosis and released into the brain.

Preclinical

This ability to deliver into a range of tissues, including across the blood brain barrier into the CNS, coupled with the ability to conjugate Bicycle® peptides to a range of payloads, unlocks multiple therapeutic opportunities. We have shown in pre-clinical models that we can use this conjugated system to deliver diverse, otherwise peripherally restricted therapeutic cargos, into a range of tissues, including the CNS, and that these cargos elicit pharmacodynamic activity.

Collaboration

Bicycle entered into a collaboration with Ionis Pharmaceuticals to explore the enablement of nucleic acid delivery into a range of tissue types using our TfR1-based precision guidance technology. Currently, the lead asset in this collaboration is for the treatment of cardiomyopathy and is undergoing phase 1 clinical trials.

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Expanded Access Policy

Bicycle is committed to developing innovative new medicines for patients with debilitating diseases.

As part of that commitment, Bicycle conducts, alone or with our partners, clinical trials of our investigational medicines to seek to demonstrate their safety and effectiveness for patients. The data generated from these clinical trials are integral to obtaining regulatory approval of our investigational medicines and such trials represent the best and most efficient way to develop our investigational medicines.

Patients who choose to participate in clinical trials play an essential role in developing new medicines. Clinical trials, including eligibility criteria, are listed at www.clinicaltrials.gov. Patients interested in learning if enrollment in a clinical trial is an option for them should consult with their treating physician.

As a general policy, Bicycle will not provide Expanded Access* to an investigational medicine until sufficient safety and efficacy information has been obtained in clinical trials. Therefore, Bicycle is currently unable to offer Expanded Access to any of its investigational medicines, as Bicycle is committed to conducting formal clinical trials.

Bicycle may update this Policy at any time, consistent with applicable law and regulations. The posting of this policy shall not serve as a guarantee of access to any specific investigational medicine for any patient. This website and policy may be updated with a hyperlink or other reference to an expanded access record on www.clinicaltrials.gov after such record becomes active.

For questions or additional information about this policy, please contact Bicycle’s Medical Information team at medinfo@bicycletx.com. Bicycle will endeavor to acknowledge any inquiries within five (5) business days of receipt.

* Expanded Access is a potential pathway for a patient with a serious or immediately life-threatening disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. Typically access is provided when a positive late stage trial has been reported or the Company has requested regulatory approval to go to market. Bicycle has no such products at this time and therefore it would be unsafe to offer such access.

Beyond^→

Pipeline

Bicycle® Drug Conjugates

Bicycle Radioligands

Partnered Programs

Expanded Access Policy

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