Technology

The DACRA Project

KeyBioscience's peptide platform focuses on discovering novel therapeutics for metabolic disorders, leveraging an extensive profiling platform inspired by naturally occurring peptide variants.

The KeyBioscience Peptide Platform

We are strongly committed to the discovery of novel peptide therapeutics for metabolic disorders. Building an extensive peptide profiling platform allows detailed investigation of molecules which are inspired by the evolution of naturally occurring peptide variants.
Utilizing this platform we have identified 3 peptides which have entered clinical development for Type 2 Diabetes, obesity and osteoarthritis. Two of these were licensed to Eli Lilly in 2017, and of these a second generation of the Lilly-KeyBio DACRAs is now in clinical development for Obesity. At KeyBioscience we are now focusing on the newest member of the KBP family, namely the long-acting KBP-336, which is under development as a once weekly injectable for metabolic osteoarthritis.

DACRAs – Dual Amylin And Calcitonin Receptor Agonists

Amylin and calcitonin are naturally occurring peptide hormones, which elicit a series of functions in mammalian systems, including regulation of appetite and weight, as well as some intriguing effects on pain sensation, and as such these peptides are nicely positioned as therapeutic candidates. Importantly, the amylin analogue Pramlintide was approved as an adjunct therapy to insulin for both type I and type II diabetes, despite needing multiple daily doses. Long-acting amylin analogies, such as cagrilintide, are in development, and while these clearly have a markedly improved efficacy compared to pramlintide, and especially as add-on to incretins are seen as the next level of obesity therapy, there is still room for more potent and better tolerated compounds.

Figure 1: Schematic structure of a DACRA.

Our early evidence indicates that DACRAs possess a superior mode of action compared to amylin analogues, with marked improved in potency and efficacy, and especially on pain-related outcomes. Hence, our focus is solely on Dual Amylin and Calcitonin Receptor Agonists and our platform is uniquely tailored for the development of these.

Peptide Evolution

When investigating naturally occurring peptides of the amylin/calcitonin family in search of modifications to the peptides allowing improved properties, we had our focus on non-mammalian species, such as fish, birds and amphibians. Intriguingly, in these species calcitonin and amylin functions are elicited by a single peptide, i.e. a DACRA (see figure), and hence, these peptides are important inspirations for the drug development at KeyBioscience. An additional attractive feature was also identified, namely a very high intrinsic potency on both receptors when compared to the mammalian peptides. These features have been carefully studied and utilized in the KBPs, which, to date, are the most potent amylin and calcitonin receptor agonists published, and as such are in a unique position as novel treatments for metabolic disorders, including metabolic osteoarthritis, which is a key unmet need.

Figure 2: The original DACRA – salmon calcitonin.

The Screening System

Initially, a series of screening assays focused on testing the potency of the DACRAs on the two target receptors was developed. These assays allow a thorough profiling of the potencies of the DACRAs with respect to different aspects of receptor binding and activation, an include accumulation of the downstream signalling molecules cAMP and β-arrestin, as well as competitive ligand binding studies on both the amylin and the calcitonin receptor. Additionally, we have implemented counter-screening tools, in the form of assays measuring the activation of the two closely related receptors, the CGRP-receptor and the adrenomedullin receptor. Activation of these is not desired as it will lead to off target effects on blood vessels, which could elicit migraine or other complications. Using this battery of profiling assays, we were able to identify peptides with potencies far exceeding the natural peptides on the two target receptors, and with no off-target activities.

Figure 3: Schematic illustration of the receptor outputs used to identify the optimal DACRA.

Additionally, as one of the challenges of the natural peptides is the duration of the receptor activation, we have carefully engineered the DACRAs to possess an additional property, namely prolonged activation of the target receptors, a phenomenon which translates directly to reduction of the number of injections required in vivo (see figure) to elicit a potent weight loss.

Figure 4: The unique ability of DACRAs to exert prolonged receptor activation and thereby elicit long lasting effects.

The Next Generation

The first generation of DACRAs were designed for daily dosing using injection; however, the metabolic field has moved on and now all the relevant peptide drugs are designed for once weekly dosing by injection. Hence, our focus was on transitioning the DACRAs from once daily to once weekly injections. To facilitate this acylations of the DACRA backbone were studied, and from this a series of DACRAs with the ability to bind to serum albumin allowing longer circulation half-life were identified. Of these the DACRA called KBP-336 stood out, due to a highly promising potency, stability and durability of response in the model systems.

Accordingly, it was tested across a range of metabolic models and it is, until this date, the most potent and efficacious DACRA identified, and the preclinical data clearly support that it can be dosed once a week in humans, and hence it was selected for clinical development.