Bicycles: Regulation and Analysis for a New Class of Medium-Sized Molecules

What is a Bicycle molecule? 

Bicycle molecules are a novel bicyclic peptide platform from Bicycle Therapeutics that can target a range of diseases. These molecules can take on various formats including monomeric Bicycles, antibody-drug conjugates, or Bicycle-toxin conjugates, which can target a range diseases very specifically. Bicycle’s phage display discovery system is based on Nobel-winning science, with the ability to generate and progress a vast range of Bicycle molecules very quickly. 

Ranging from 1.5 to 2 kilodaltons, Bicycles are medium-sized molecules: larger than small compounds but smaller than most biologics. They can also be linked together, pushing their size into the 4 to 8 kilodalton range. Their ‘Goldilocks zone’ size is what gives them their high specificity, targeted delivery, and rapid tissue penetration and clearance. As a result, toxicity issues are very low with this class of compounds. 

Regulatory Challenges 

However, the unconventional size range of Bicycle molecules comes with regulatory challenges. Being between a small molecule and a biological, there is some ambiguity in the regulatory guidance. In practice, following ICH Q3a and Q3b guidelines, managing impurities within Bicycle molecules proves more challenging than it might for a traditional biologic or peptide, particularly in adhering to the limits set by USP 1503. 

Bicycle Therapeutics have opted for small molecule submission with the FDA and other regulatory agencies. The company are one of three inaugural companies to be enrolled into the FDA’s CMC Development Readiness Program (CDRP) which gives them increased contact with the regulatory agency as well as the potential for expedited development timeframes. 

Analytical Challenges  

The unique structural constraints of a Bicycle molecule offer notable advantages; the cyclisation results in a more rigid and defined structure, which enhances the interaction with the target compared to either a linear or even a simple cyclic peptide.  

This conformational rigidity not only benefits clinical outcomes and patient experience but also introduces analytical challenges. In particular, the process of elucidating the structure and identifying impurities becomes more complex due to this constrained architecture.