Bicycle Therapeutics Stock

Bicycle Therapeutics plc, a clinical-stage biopharmaceutical company, engages in developing a class of medicines, which it refers to as Bicycles, for diseases that are underserved by existing therapeutics.

Bicycles are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycles are a unique therapeutic modality combining the pharmacology usually associated with a biologic with the manufacturing and pharmacokinetic, or PK, properties of a small molecule. The relatively large surface area presented by Bicycles allows targets to be drugged that have historically been intractable to non-biological approaches.

The company has a novel and proprietary phage display screening platform which it uses to identify Bicycles in an efficient manner. The company’s platform encodes quadrillions of potential Bicycles which can be screened to identify molecules for optimization to potential product candidates. The company has used this powerful screening technology to identify its portfolio of candidates in oncology and intend to use it in conjunction with its collaborators to seek to develop additional future candidates across a range of other disease areas.

The company’s product candidates, BT5528, BT8009, and BT1718, are each a Bicycle Toxin Conjugate, or BTCTM. These Bicycles are chemically attached to a toxin that when administered is cleaved from the Bicycle and kills the tumor cells. The company is evaluating BT5528, a second-generation BTC targeting Ephrin type A receptor 2, or EphA2, in a company-sponsored Phase I/II clinical trial and BT8009, a second-generation BTC targeting Nectin-4, in a company-sponsored Phase I/II clinical trial. In addition, BT1718 is being developed to target tumors that express Membrane Type 1 matrix metalloproteinase, or MT1 MMP, and is being investigated for safety, tolerability and efficacy in an ongoing Phase I/IIa clinical trial sponsored and fully funded by the Cancer Research UK Centre for Drug Development, or Cancer Research UK. In addition, its other product candidates, BT7480 and BT7455, are each a Bicycle tumor-targeted immune cell agonist, or Bicycle TICATM. A Bicycle TICA links immune cell receptor binding Bicycles to tumor antigen binding Bicycles. The company is evaluating BT7480, a Bicycle TICA targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial, and it is conducting IND-enabling studies for BT7455, an EphA2/CD137 Bicycle TICA. The company’s discovery pipeline in oncology includes Bicycle-based systemic immune cell agonists and Bicycle TICAs.

Beyond the company’s wholly owned oncology portfolio, it is collaborating with biopharmaceutical companies and organizations in additional therapeutic areas in which its proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need. The company’s partnered programs include collaborations in immuno-oncology, or I-O, anti-infective, cardiovascular, ophthalmology, dementia, central nervous system, neuromuscular and respiratory indications.

Bicycles are fully synthetic, short peptides consisting of nine to 20 amino acids constrained to form two loops which stabilize the structural geometry of the peptide and facilitate target binding with high affinity and selectivity. Bicycles represent a unique therapeutic class, combining the pharmacological properties normally associated with a biologic with the manufacturing and PK advantages of a small molecule, with no signs of immunogenicity observed to date.

The company has designed its molecules to be highly constrained by linking a chemical connector compound, also known as a scaffold, to particular amino acids in the peptide chain. The resulting cyclized molecule, which it refers to as a Bicycle, is locked in the preferred state to bind to the target proteins.

The company has expanded the diversity of the chemical space it can cover from approximately 1013 potential molecules in 2009 to in excess of 1020 potential molecules today. The company has applied its novel Bicycle modality to a growing range of targets, from a single target in 2009 to more than 130 today. The company can create a wide range of Bicycles by varying four parameters:

Bicycles have a large surface area available for target binding, which is designed to allow for high affinity and selectivity to the designated target. As short sequences of amino acids, or peptides, they have a low molecular weight, typically ranging from 1.5 kDa to 2.0 kDa.

The company utilizes its novel and proprietary phage display screening platform to identify Bicycles that are potentially useful in medicine. The company has used this technology to identify its pipeline and intends to leverage it to develop a broader portfolio of product candidates to address unmet medical needs across a wide range of diseases.

The company’s screening process self-selects for Bicycles that are amenable to attachment, commonly referred to as conjugation, to other molecular payloads, such as cytotoxins, innate immune agonists or other Bicycles. Bicycles can be linked together with synthetic ease to create complex molecules with combinatorial pharmacology. Alternatively, Bicycles in the form of multimers can also be used as standalone therapeutics, such as those that the company is exploring in its systemic and tumor-targeted immune cell agonist programs. The flexibility of the company’s Bicycles and its powerful screening platform allow new therapeutics to be rapidly conceived and reduced to practice to potentially serve diverse therapeutic applications across a wide range of indications. The company can readily identify Bicycles that may drug a wide spectrum of targets and target classes, including many that have so far been undruggable with small molecules, such as protein-protein interactions.

The company has optimized its proprietary Bicycle screening platform, enabling the technique to be applied to a diverse range of over 130 challenging targets to date, successfully identifying Bicycles for over 80% of these targets, some of which are intractable to small molecules. During these screens, Bicycles with diverse pharmacologies were identified, including enzyme inhibitors, receptor antagonists, agonists (partial, full and supra) and neutral site binders.

The company’s portfolio of internal product candidates is directed to oncology applications where they have the potential to treat a broad spectrum of cancers. The company is collaborating with biopharmaceutical companies and organizations in additional therapeutic areas, where its proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need.

Bicycles are an ideal vehicle to deliver small molecule payloads to tumors, both as potent cytotoxins in the case of BTCs, as well as small molecule agonists of the immune system in the case of the company’s Bicycle tumor-targeted immune cell agonists. Bicycle conjugates can offer improved performance as compared to antibody-mediated delivery.

In addition to their use as drug conjugates, Bicycles can be configured for use as standalone therapeutics. The company has identified Bicycles that have been observed to directly interact with CD137, a key immune cell co-stimulatory molecule. The company’s CD137-targeting Bicycles may overcome limitations inherent in antibody-mediated approaches and have the potential to be converted into simple tumor-targeted immune cell-engaging Bicycle molecules.

Within its BTC programs, the company is evaluating BT5528, a second-generation BTC that targets EphA2 and carries a monomethyl auristatin E, or MMAE, cytotoxin payload, in an ongoing, company-sponsored Phase I/II clinical trial to assess safety, pharmacokinetics, and preliminary clinical activity in patients with solid tumors. In October 2021, the company announced interim Phase I results from this clinical trial where it observed preliminary signs of anti-tumor activity and established a recommended Phase II dose range. In June 2022, the company announced that the first patient had been dosed in the dose expansion cohorts of the Phase I/II study of BT5528 which include urothelial and ovarian cancers, as well as a basket cohort of other solid tumors, including non-small cell lung cancer, triple-negative breast cancer, head and neck cancer, and esophageal cancer. Enrollment in these cohorts remains ongoing. In September 2022, the company announced top-line results from the completed dose escalation portion of the Phase I/II trial.

The company is evaluating BT8009, another second-generation BTC that targets Nectin-4 and carries an MMAE cytotoxin payload, in an ongoing company-sponsored Phase I/II clinical trial to assess to assess the safety, pharmacokinetics and preliminary clinical activity in patients with Nectin-4 expressing advanced malignancies. The company presented preliminary results from this clinical trial in October 2021 and in April 2022, it presented updated interim results where it presented confirmed signs of anti-tumor activity. In November 2022, the company announced updates from the Phase I/II trial, including that the Phase I dose escalation portion of the trial was complete and that the first patient had been dosed in the Phase II expansion cohorts. Results from the completed dose escalation portion of the trial were presented at the 2023 ASCO Genitourinary (GU) Cancers Symposium in February 2023.

In January 2023, the company announced that the U.S. Food and Drug Administration, or FDA, granted Fast Track Designation, or FTD, to its BT8009 monotherapy for the treatment of adult patients with previously treated locally advanced or metastatic urothelial cancer.

Strategy

The key elements of the company’s strategy are to progress its most advanced internal candidates, BT5528, BT8009, and BT7480 through clinical development; continue IND-enabling activities for BT7455; pursue clinical development of its discovery programs; leverage its powerful proprietary screening platform and novel Bicycle modality to grow its pipeline; collaborate strategically with leading organizations to access enabling technology and expertise in order to expand the application of its novel Bicycle modality to indications beyond oncology; and maximize the commercial potential of its product candidates, if approved, by either establishing its own sales and marketing infrastructure or doing so through collaborations with others.

Collaborations

Ionis

On December 31, 2020, the company entered into an evaluation and option agreement, or the Evaluation and Option Agreement, with Ionis Pharmaceuticals, Inc., or Ionis, pursuant to which Ionis had the option, or the Ionis Option, to obtain an exclusive license to its intellectual property for the purpose of continued research, development, manufacture and commercialization of products within a particular application of the company’s platform technology.

Genentech

On February 21, 2020, the company entered into a Discovery Collaboration and License Agreement with Genentech, or the Genentech Collaboration Agreement. The collaboration is focused on the discovery and development of Bicycle peptides directed to biological targets selected by Genentech and aimed at developing up to four potential development candidates against multiple I-O targets suitable for Genentech to advance into further development and commercialization.

Dementia Discovery Fund

In May 2019, the company entered into a collaboration with the Dementia Discovery Fund, or DDF, to use Bicycle technology for the discovery and development of novel therapeutics for dementia. DDF is a specialized venture capital fund focused on discovering and developing novel therapies for dementia. In October 2019, the collaboration with DDF was expanded to include Oxford University’s Oxford Drug Discovery Institute (ODDI). Under the terms of the agreement, Bicycle and DDF will collaborate to identify Bicycles that bind to clinically validated dementia targets.

Cancer Research UK

BT1718

In December 2016, the company entered into a clinical trial and license agreement with Cancer Research UK and Cancer Research Technology Ltd., a wholly owned subsidiary of Cancer Research UK that Cancer Research UK’s commercial activities operate through, or the Cancer Research UK Agreement. Pursuant to the agreement, as amended in March 2017 and June 2018, Cancer Research UK Centre for Drug Development will sponsor and fund a Phase I/IIa clinical trial of the company’s product candidate, BT1718, in patients with advanced solid tumors.

The company granted to Cancer Research UK a license to its intellectual property in order to design, prepare for, sponsor, and carry out the clinical trial. The company retains the right to continue the development of BT1718 during the clinical trial. Upon the completion of the Phase I/IIa clinical study, it has the right to obtain a license to the results of the clinical trial upon the payment of a milestone, in cash and ordinary shares, with a combined value in the mid-six digit dollar amount.

BT7401

In December 2019, the company entered into a clinical trial and license agreement with Cancer Research Technology Limited and Cancer Research UK. Pursuant to the agreement, Cancer Research UK Centre for Drug Development will fund and sponsor development of BT7401 from preclinical studies through the completion of a Phase IIa trial in patients with advanced solid tumors.

The company granted to Cancer Research UK a license to its intellectual property in order for Cancer Research UK to design, prepare for, sponsor, and carry out the clinical trial and all necessary preclinical activities to support the trial. The company retains the right to continue the development of BT7401 during the clinical trial. Upon the completion of the Phase I/IIa clinical study, the company has the right to obtain a license to the results of the clinical trial upon the payment of a milestone, in cash and ordinary shares, with a combined value in the mid six-digit dollar amount.

AstraZeneca

In November 2016, the comopany entered into a research collaboration agreement with AstraZeneca AB, or the AstraZeneca Collaboration Agreement. The collaboration focuses on the research and development of Bicycle peptides that bind to an undisclosed number of biological targets for the treatment of respiratory, cardiovascular and metabolic diseases. After discovery and initial optimization of such Bicycle peptides, AstraZeneca is responsible for all research and development, including lead optimization and drug candidate selection. AstraZeneca receives development, commercialization and manufacturing license rights with regard to any selected drug candidate(s).

Under the terms of the AstraZeneca Collaboration Agreement, the company granted to AstraZeneca the right and license (with the right to sublicense) to certain background, foreground and platform intellectual property, for the duration of the agreement, to the extent reasonably necessary or useful for AstraZeneca to conduct the activities that are assigned to it in the applicable research plan or that are reasonably necessary or useful or the purpose of researching, developing or exploiting resulting compounds and products.

Oxurion

In August 2013, the company entered into a research collaboration and license agreement, or the Oxurion Collaboration Agreement, with Oxurion NV, or Oxurion, which agreement was amended in November 2017. Under the Oxurion Collaboration Agreement, the company was responsible for identifying Bicycle peptides related to the collaboration target, human plasma kallikrein, for use in various ophthalmic indications. Oxurion is responsible for further development and product commercialization after the defined research screening is performed by it. THR-149 was selected as a development compound under the Oxurion collaboration agreement. The company granted certain worldwide intellectual property rights to Oxurion for the development, manufacture and commercialization of licensed compounds associated with plasma kallikrein.

Sales and Marketing

Subject to receiving marketing approval, the company intends to pursue the commercialization of its product candidates either by building internal sales and marketing capabilities or through opportunistic collaborations with others.

The company plans to build a marketing and sales management organization to create and implement marketing strategies for any products that it markets through its own sales organization and to oversee and support its sales force.

Company-Owned Intellectual Property

As of December 31, 2022, the company’s patent portfolio included 4 patent families directed to novel scaffolds and linkers, 12 patent families directed to its platform technology, 75 patent families directed to bicyclic peptides and related conjugates, and 12 patent families directed to later inventions relating to such bicyclic peptides and related conjugates, such as methods of making or using certain bicyclic peptide conjugates for treating various indications.

In total, as of December 31, 2022, the company owned about 326 patents in the United States and in foreign jurisdictions, such as Australia, Canada, China, Europe, Hong Kong, Japan, New Zealand, Russia and Singapore. In addition, as of December 31, 2022, the company had about 522 patent applications pending in the United States and in foreign jurisdictions, such as Argentina, Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, New Zealand, Russia, Singapore and Taiwan, as well as pending international applications under the Patent Cooperation Treaty, or PCT. These patents, as well as any patents that may be issued from these patent applications, are generally expected to have terms that will expire at various dates between February 2029 and December 2043, not including any patent term extensions and/or patent term adjustments.

In total, as of December 31, 2022, the company owned 67 registered trademarks across four territories (the United Kingdom, European Union, United States, and Japan), as well as a number of pending applications for new trademarks.

History

The company was founded in 2009. It was incorporated pursuant to the laws of England and Wales as Bicycle Therapeutics Limited in 2009 and re-registered as a public limited company named Bicycle Therapeutics plc in 2019.