Bicycle Therapeutics Ltd.

Meditrina Building

Babraham Research Campus

Cambridge CB22 3AT UK

Phone: +44 (0)1223 497 415

Web Site: www.bicycletherapeutics.com

Contact: Jonathan Savidge, PhD, Director, Business Development

Industry Segment: Biotechnology

Business: Therapeutic peptides

Founded: June 2010

Founders: Sir Gregory Winter, PhD (Medical Research Council Laboratory of Molecular Biology); Christian Heinis, PhD (Ecole Polytechnique Fédérale de Lausanne [EPFL])

Employees: 8

Financing To Date: £7.7 million

Investors: Atlas Venture; Novartis Venture Fund; SR One; SV Life Sciences (SVLS); Astellas Venture Management

Employees: 18

Board Of Directors: Andrew Sandham, Chairman (Syncona Partners); Kate Bingham (SVLS); Bruce Booth, DPhil (Atlas Venture); Rolf Günther, MD, PhD, CEO; Deborah Harland, PhD (SR One); Anja König, PhD (Novartis Venture Fund); Gregory Winter

Scientific Advisory Board: Gregory Winter, Chairman; Jochen Knolle, PhD (formerly Jerini); Michel Aguet, MD (EPFL)

Some biologists call peptides nature’s medicines. That’s because they evolved for specific tasks in mediating protein-protein interactions. They’re extremely diverse, specific, and have high affinity for their large targets. Mimicking nature, numerous approved peptide drugs such as antibiotic vancomycin, immunosuppressant cyclosporine, and anticancer ocreotide, deliver powerful biological jolts. But natural peptides have plenty of drawbacks that have held them back when it comes to pharmaceutical applications. Principally, that’s due to their highly unstable amino acid chains that degrade too quickly to produce a therapeutic effect. Moreover, discovery has been difficult to industrialize and manufacturing complex and costly. However, emerging technologies for synthetically stabilizing peptide structures may eventually conquer most of natural peptides’ drawbacks as pharmaceuticals. That has stoked interest in biotechs possessing next-generation peptide platforms. (SeeAlso see "Peptide Therapeutics' Rising Tide" - Scrip, 1 May, 2010..) Cambridge, UK, start-up Bicycle Therapeutics Ltd. hopes its two-wheel “constrained” peptides it calls “bicycles” will ride off with the prize for exploiting nature’s medicines.

Constrained peptides are naturally occurring protein-binding domains into which synthetic linkers are introduced to “constrain,” or stiffen, them into stable shapes with potential therapeutic usefulness. Most of these new-generation peptides are cyclical in one form or another, which increases their half-life and enhances their target affinity. That’s thanks to the numerous molecular interactions formed at the relatively large contact interface between the cyclical peptide and its target, as well as the limited flexibility of the cyclic structures. Those improved characteristics lend them drug-like properties comparable to antibodies – though they are 100-fold smaller, making them closer to small molecule agents in their ability to reach and penetrate tissue.

A growing number of biotechs have engineered variations on the constrained peptide theme. Companies pursuing them include Aileron Therapeutics Inc., Encycle Therapeutics Inc., Ensemble Therapeutics Inc., and Ra Pharma Inc. Indicating the eagerness with which pharma is watching the field unfold, these and other companies in the space have the support of multiple corporate venture funds. Several have signed early-stage pharma deals. Their technologies all share either a stiffened linear or single-loop structure, with side chains for conjugating payloads such as antibodies, chemotherapeutic toxins, or some other bi-specific modality.

Bicycle’s founders suspect that two wheels would significantly expand on all those properties. Bicycle co-founder Sir Gregory Winter is a member of the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, where he spent most of his prolific scientific career. He is now Master of Trinity College, University of Cambridge. He invented techniques to humanize rodent antibodies for use as therapeutics and helped to industrialize their discovery. He applied his technologies to the founding of Cambridge Antibody Technology LLC and Domantis LLC, both of which were eventually acquired (by AstraZeneca PLC and GlaxoSmithKline PLC, respectively). Christian Heinis, now at the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland, spent two years as a post-doc in Winter’s lab, from 2006 to 2008. Together they came up with a method to systematically cyclize amino acid chains of differing lengths expressed on phage into linked loops anchored to a mesitylene core – in other words, engineering stiffened, interlinked cyclical peptide-binding domain in a predictable way.

This discovery enabled use of phage display to isolate macrocycles with demonstrated evidence in the lab for high affinity binding and great potency in inhibiting targeted protein-protein interactions. Since its founding in 2010, Bicycle has industrialized the technology into an automated high-throughput system, generating large libraries of bicycle molecules from which high affinity binders to targets of interest can be rapidly selected.

Bicycle thinks the platform based on the Winter and Heinis technology embodies key features that go beyond other constrained technologies in commercial development. Among them are the bicycle macrocycle’s tighter constraints, leading to higher affinity for its target and greater stability. Basically, according to the company, anchoring a peptide sequence “string” at three points on a scaffold to produce a bi-cyclic structure secures the string more firmly than the two anchor points in a monocycle, driving higher target affinity.

“The major determinant for binding is structural,” says Jonathan Savidge, Bicycle’s business development director. “You want the optimal shape and size peptide. We can vary the size of the two loops. That enables us to increase the diversity and range of the molecule we select from to fit precisely into different pockets to block protein-protein interactions.”

In addition, Bicycle can alter its macrocycles’ properties through chemical modification and conjugate functional groups via linkers without affecting that target affinity. This enables it to generate bi-specific molecules, potentially carrying targeting or drug payloads or binding to multiple targets. “There’s a great deal of flexibility to the chemistry,” says Savidge. “We can also modulate the half-life” for controlled-release formulations.

Bicycle adds another key advantage: the company’s platform combines the power of biological selection with the speed and scale of new chemical entity (NCE) discovery. “We express the peptides using phage display,” explains Christophe Bonny, PhD, Bicycle’s chief scientific officer “We can generate a library with 10¹² diversity with variable loop sizes and select the optimal size for targeting the protein-protein interactions. In many cases, this is something a small molecule is not likely to block.” And, unlike antibodies, the simple and economic chemical synthesis won’t vary between batches, even in scaled-up operations, according to Bonny.

Lab studies show that the company’s macrocycles can modulate many different types of protein-protein interaction. Bonny says that out of 50 protein-protein targets studied in company labs, Bicycle succeeded 70% of the time in identifying highly specific inhibitors. Many of these targets had previously proved resistant to inhibitors or are inadequately treated by existing agents, he says.

One of those targets Bicycle studied caught the eye of ThromboGenics NV, a Belgian ophthalmic company that developed JETREA (ocriplasmin), available in the EU and US for treatment of vitreomacular traction. That led to a deal with Bicycle to develop a bicycle against an unidentified ophthalmic disease drug target, such as diabetic macular edema (DME). [See Deal] Savidge says, “We identified some very potent and effective molecules against a target that has been a challenge to other modalities.” ThromboGenics paid an undisclosed up-front fee and will cover all development costs, as well as pay development and regulatory milestones and sales royalties for any product, in return for exclusive global development and marketing rights to the bicycle the UK company selects and optimizes.

Bicycle is also planning to build an internal pipeline, taking two to three of its own molecules focused on oncology targets into the clinic. Savidge says, “The high affinity and small size of bicycles make them excellent potential agents for reaching and penetrating tumor targets. They have better penetration than antibodies.”

To build its pipeline, the company plans to raise £10 million to £15 million in late 2014 on top of the close to £8 million it has raised to date from a group of blue chip investors. Atlas Venture and Novartis Venture Fund, which has backed a number of early-stage constrained peptide therapeutics ventures, were the company’s initial supporters, later joined by SR One, SVLS, and Astellas Venture Management. [See Deal] [See Deal]

Parallel to its internal program, the company hopes to add on other alliances to go with the Thrombogenics deal. “We can modulate a large number of targets in various therapeutic areas,” says Savidge. “We also offer a big advantage for collaborators because our industrialized system can rapidly identify molecules – typically within a couple months.”

Bicycle CEO Rolf Günther, came to the company in 2012 from Affimed Therapeutics AG, a German monoclonal antibody company, which he had helped lead since 2004. Scientific founder Sir Greg Winter remains in close touch with the 18-employee company, serving on the board of directors and heading the scientific advisory board.

If the bicycle molecules work, they could become a new therapeutic class, situated at the midpoint between small molecules and antibodies and combining the best qualities of both – and then Bicycle will indeed ride off with the prize.

Editor's note: this article was updated post-publication.

Bicycle Therapeutics Ltd.

Two-wheeled constrained peptides

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