Programs

Bicycle Conjugates

Introduction

Bicycles can be used to reach a wide spectrum of targets and target classes, including many that have so far been undruggable with small molecules.

Our novel, proprietary phage display screening platform uses synthetic biology to display a vast range (>10²⁰) of peptides. This diversity is generated by changing the design of the Bicycle® at four key areas: first, each amino acid can be varied at each position within the rings; second, the number of amino acids can be changed in each ring; third the symmetry of the rings can be altered; and finally the choice of scaffold used profoundly changes the way the appended amino acids are presented. Collectively, this allows us to choose from over 300 different library configurations, enabling high chemical diversity and potentially increasing the probability of success in our screening campaigns.

Our screening platform can be deployed to screen for either soluble proteins or cell-based targets. In addition to being resource-efficient and rapid, the process uses an integral on-phage binding assay that informs structure-activity relationships. The process then tunes the molecule to perform a specific function, something extremely hard to achieve with biologics. The Bicycle structure is then assembled. The flexibility of our Bicycles – and our powerful screening platform – will, we hope, allow new therapeutics to be rapidly developed in the future with the potential to serve a wide range of indications across diverse therapeutic areas.

BT5528

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BT5528 (EphA2 Program)

Currently being evaluated in a Company-sponsored Phase I/II clinical trial

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.

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

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

BT5528 is currently being evaluated in a Company-sponsored Phase I/II clinical trial as a potential monotherapy and in combination with nivolumab. Most patients enrolled into the study are being pre-screened according to tumor type and their EphA2 IHC status is recorded for future assessment as a potential predictor for efficacy of BT5528.

Bicycle Strategy

Examples of high EphA2 expressing tumors
Non-small cell lung cancer
Triple negative breast cancer
Bladder cancer
Esophageal cancer
Gastric cancer
Ovarian cancer

EphA2 is an attractive target for cytotoxin delivery previously pursued by other companies as an antibody drug conjugate (ADC) target. Despite encouraging preclinical activity, these ADCs produced significant safety concerns, including liver toxicity and a disseminated intravascular coagulation in several species and in humans. Development of these ADCs was ultimately terminated. We believe EphA2 remains an attractive target for our Bicycle Toxin Conjugates^® due to the potential of Bicycles to overcome the safety concerns observed with ADCs. In our preclinical pharmacokinetics and toxicokinetic studies, we observed BT5528 exhibits a short half-life, rapid renal elimination, and volume of distribution that allows it to distribute to the tissues.

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BT8009

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BT8009 (Nectin-4 Program)

We are currently conducting a Company-sponsored Phase I/II trial of BT8009 as a monotherapy.

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.

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

Bicycle’s Nectin-4 toxin conjugates 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, BT8009 appeared to demonstrate superior anti-tumor activity, including complete regressions in both very large and small tumor models.

In our preclinical toxicity studies, BT8009 showed only a subset of the toxicities typically associated with the MMAE cytotoxin payload, avoiding liver, GI and renal toxicity.

We are currently conducting a company-sponsored Phase I/II trial of BT8009 as a monotherapy, with plans to evaluate BT8009 in combination with nivolumab. Some of the patients enrolled onto the study are pre-screened according to tumor type.

Bicycle Strategy

Nectin-4 is a validated target for cytotoxin delivery. The ADC against Nectin-4 PADCEV® (enfortumab vedotin) received US FDA approval in December 2019 for use in advanced urothelial cancer. We are developing a small, synthetic Bicycle Toxin Conjugate with a renal route of elimination that minimizes liver exposure. It may also be effective in numerous cancer types where Nectin-4 is expressed, including urothelial, breast, gastric, lung and ovarian. We plan to screen for specific tumor types that we may investigate with BT8009 in the clinic.

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BT1718

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BT1718 (MT1 Program)

Currently being evaluated in the Phase IIa portion of the trial sponsored by the Cancer Research UK Centre for Drug Development (CRUK).

BT1718 targets Membrane Type 1 Matrix Metalloproteinase (MT1-MMP, also known as MMP-14) which has an established role in cell invasion and metastasis and is linked to poor outcomes in cancer patients. It is generally expressed at relatively low levels in normal adult tissues but overexpressed in many solid tumors.

The molecule is composed of our MT1-MMP targeting Bicycle®, a hindered disulphide cleavable linker and a DM1 cytotoxin payload.

MT1-MMP is an attractive target for cytotoxin delivery due to high levels of expression on subsets of stromal and tumor cells in a range of cancers.

BT1718 is being investigated in an ongoing Phase I/IIa open label dose escalation and expansion clinical trial sponsored by CRUK.

BT1718 is currently being evaluated in the Phase IIa portion of the trial sponsored by CRUK.

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Immuno-Oncology^→

Bicycle Conjugates

Introduction

BT5528 (EphA2 Program)

Bicycle Strategy

BT8009 (Nectin-4 Program)

Bicycle Strategy

BT1718 (MT1 Program)

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