DUBLIN Bicycle Therapeutics Ltd. received another hefty dose of validation for its constrained peptide technology in the form of a £40 million (US$51.5 million) series B round, which will enable it to take multiple programs into clinical development. "What we would have hated to happen would be for the whole technology, the whole company, to be judged based on one spin of the cards," CEO Kevin Lee told BioWorld Today.
The Cambridge, U.K.-based firm is, after eight years honing its novel approach to developing drugs, finally nearing the start of its first trial. "I think the company was given something that not a lot of companies are given time to really optimize the platform, the engine," Lee said.
Its lead drug candidate, BT-1718, is due to enter a phase I trial in solid tumors in the fourth quarter of this year. Several others are being lined up to follow it. "We have quite an abundance of riches coming through," Lee said. "We have to make some hard decisions over the next six months about what the next clinical candidates will be."
Bicycle is, famously, the third startup to emerge from the lab of antibody engineering magus Greg Winter at Cambridge University. Its ambition is to combine the selectivity and affinity of antibody drugs with the flexibility and convenience of small molecules, and the elimination characteristics of peptides. The basic structure comprises a bicyclic peptide scaffold tethered to an organic core, but that can be altered in myriad ways in order to tune the target specificity and physicochemical properties of individual molecules.
"Selectivity can be an issue typically with the linear and monocyclic versions of peptides," Lee said. Bicyclic peptides sidestep that problem by being rotationally constrained in a fixed conformation. The molecules can hit a diverse range of target classes, including cytokines, enzymes, G protein-coupled receptors (GPCRs), receptor tyrosine kinases and protein-protein interactions. Depending on the application, they can act as inhibitors, activators, or carriers of toxic payloads.
"This platform has incredibly large applicability across many therapeutic areas," Lee said. Bicycle is focusing on oncology. Late last year it entered a broad alliance, worth up to $1 billion, with London-based Astrazeneca plc, which covers respiratory, cardiovascular and metabolic disorders. It is open to further collaborations with companies that offer complementary expertise, Lee said. (See BioWorld Today, Dec. 2, 2016.)
The B round marks a new stage in Bicycle's development. It has, Lee said, already demonstrated that it can generate high-affinity molecules that have drug-like properties and that can be manufactured at scale. It is now setting out to see how those molecules behave in the clinic.
The trial of BT-1718 will be performed in the U.K. through a collaboration with Cancer Research UK, the London-based cancer charity. The molecule targets membrane type 1 matrix metalloproteinase (MT1-MTP), an antigen that is expressed in solid tumors, including triple-negative breast cancer and non-small-cell lung cancer. It is thought to play a role in tumor invasion, by activating collagenase enzymes involved in the breakdown of the extracellular matrix. Bicycle is not seeking to inhibit that activity, however. It is using the antigen as a postcode for the delivery of a conjugated toxin, maytansinoid. The same molecule is also used in the HER2-positive breast cancer antibody-drug conjugate Kadcyla (ado-trastuzumab emtansine), which the Genentech unit of Basel, Switzerland-based Roche Holding AG markets.
Bicycles' small size they typically comprise 10 to 20 amino acids should offer advantages over antibodies in terms of onset of action. "We rapidly and instantaneously penetrate into tumors. Antibodies take a while," Lee said. That factor, combined with their rapid elimination through the kidneys, means that the company can afford to rethink the linker chemistry it uses, he said. Bicycle-drug conjugates need not be delivered internally, only to the tumor microenvironment, where tumor-secreted enzymes can cleave the toxin from the bicycle. The company is also exploring the ability of bicycles to hit immune checkpoints. Because of their shorter persistence, bicycles may avoid some of the autoimmune toxicities that are a feature of antibody-based checkpoint inhibitors. "Small molecules cannot drug those types of targets. Bicycles can," Lee said.
Bicycle has now raised about $94 million in total. It raised $32 million in its series A round in 2014 and began life with £7.8 million in seed funding. Vertex Ventures HC led the new round. Other new investors included Cambridge Innovation Capital (CIC) and Longwood Fund, while the company's existing backers, Novartis Venture Fund, SROne, SV Life Sciences and Atlas Venture, also participated. Christopher Shen, of Vertex Ventures, and Michael Anstey, of CIC, have joined the company's board. (See BioWorld Today, Oct. 14, 2014.)