Delving into the Latest Updates on KBP-042 with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

DACRA-042, UGP-302

Target

AMYR x CALCR

Mechanism

AMYR agonists(Amylin receptor agonists), CALCR agonists(Calcitonin receptor agonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2Obesity

Originator Organization

Unigene Laboratories, Inc.

Active Organization-

Inactive Organization

KeyBioscience AG

Nordic Bioscience A/S

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC149H246N44O48S2

InChIKeyWGPKKADKWIWSCQ-XTWYBNIISA-N

CAS Registry1432581-36-6

Gene Sequence

Sequence Code 144436

KBP-042 is a dual amylin and calcitonin receptor agonist that increases glucose tolerance and insulin action and reduces body weight in rat models of obesity and prediabetes. The objective of the present study was to 1) evaluate KBP-042 as a treatment of late-stage type 2 diabetes in a rat model and 2) assess the value of adding KBP-042 to the standard of care, metformin, to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention study and a prevention study. In the intervention study, treatment with 5 µg/kg KBP-042 was initiated in 11-week-old Zucker diabetic fatty (ZDF) rats, in which glucose tolerance, fasting glycemia, and glycated hemoglobin were assessed after 4 weeks. In the prevention study, either metformin (400 mg/kg), KBP-042 (5 µg/kg), or a combination of both were administered to ZDF rats for a total of 9 weeks. Glycemia, glucose tolerance, and insulin tolerance were tested. Furthermore, fasting plasma insulin and glucagon levels were evaluated. Finally, pancreatic content of insulin was assessed as a surrogate marker of beta-cell mass. It was found that KBP-042 was efficient in lowering fasting plasma glucose as well as improving glucose tolerance, both as prevention and intervention of disease progression. Furthermore, KBP-042 was efficient in combination with metformin and had additional effects compared with either therapy alone. In conclusion, KBP-042 is a highly relevant therapeutic candidate against type 2 diabetes, effective both as an add-on therapy to metformin and as a stand-alone therapy.

01 Sep 2015·European journal of pharmacologyQ3 · MEDICINE

KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

Q3 · MEDICINE

Article

Author: Gydesen, Sofie ; Karsdal, Morten A ; Hjuler, Sara T ; Andreassen, Kim V ; Henriksen, Kim

KBP-042 is a synthetic peptide dual amylin- and calcitonin-receptor agonist (DACRA) developed to treat type 2 diabetes by inducing a significant weight loss while improving glucose homeostasis. In this study the aim was to compare two different formulations: An oral formulation (1mg/kg) to subcutaneous formulations of KBP-042 (2.5μg/kg, 5.0μg/kg and 7.5μg/kg) with comparable pharmacokinetic profiles. Furthermore to examine if differences in mode of action between the two different routes of administration in high-fat fed Sprague-Dawley rats were present. It was established that the subcutaneous administrations of KBP-042 were able to dose-dependently cause a significant weight-loss, reduce food intake, and improve glucose homeostasis without increasing insulin secretion, effects comparable to those observed with oral administration. At the same time, s.c. KBP-042 suppressed the inappropriate glucagon response better than the oral formulation. Furthermore, KBP-042 was found to reduce incretins GLP-1 and GIP and considerably, improve gastric emptying, and to alleviate leptin resistance, as well as insulin resistance. In conclusion, the subcutaneous route of administration was found to have the same beneficial effects on blood glucose homeostasis and weight loss as well as resistance towards important insulin and leptin, albeit with a markedly lower variation in both exposure and biological responses. These data support the application of subcutaneously delivered peptide for mechanistic studies, and highlight the potential of developing s.c. KBP-042 as a therapy for T2D.

01 Jul 2014·American journal of physiology. Endocrinology and metabolismQ2 · MEDICINE

A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

Q2 · MEDICINE

Article

Author: Karsdal, Morten A. ; Gydesen, Sofie ; Andreassen, Kim V. ; Beck-Nielsen, Henning ; Henriksen, Jan Erik ; Feigh, Michael ; Henriksen, Kim ; Hjuler, Sara T. ; Christiansen, Claus

The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and β-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.

1

News (Medical) associated with KBP-042

10 Oct 2024

·endpts.com

Eli Lilly inks another obesity pact, doubling down on small Swiss partner

Eli Lilly is returning to KeyBioscience, a nimble Swiss biotech, seven years after originally linking arms with the startup to work on dual amylin calcitonin receptor agonists for obesity and other conditions. The world’s largest drugmaker by market capitalization will pay up to $1.4 billion to keep working with KeyBioscience on the potential new class of treatments also known as DACRAs. The companies didn’t say how much money was involved in the upfront payment. The tie-up includes an asset that is slated to enter Phase 2 testing by year’s end in people with obesity and osteoarthritis, the companies said Thursday morning. KeyBioscience said it will run the trial, which will include 600 people and look for both body weight reductions and changes in OA pain. Already one of the two GLP-1 leaders in the obesity drug landscape, Lilly continues to place further bets on other mechanisms of action and areas of research. It’s forged obesity pacts applying insights from the “ dark genome ,” the hibernation of the 13-lined squirrel and other areas. Beyond its hallmark tirzepatide franchise, the drugmaker has at least five other experimental medicines in late-stage or Phase 2 testing for obesity. If KeyBioscience follows through with its projected timeline, it could expand Lilly’s obesity pipeline to half a dozen drugs in mid- or late-stage trials by the end of 2024. KeyBioscience’s researchers think the dual agonists can help tamp down on body weight, control glucose levels and improve insulin action. Lilly already has an amylin receptor agonist known as eloralintide in Phase 2 for obesity. The Lugano, Switzerland-based biotech, which is a subsidiary of Danish drug developer Nordic Bioscience, had originally teamed with Lilly in 2017 for $55 million upfront. That pact included DACRAs known as KBP-042, KBP-089 and KBP-056. Lilly removed a Phase 2 of KBP-042/DACRA-042 for type 2 diabetes from its pipeline in the fourth quarter of 2018. Meanwhile, a study of KBP-089 for type 2 diabetes was terminated in 2020. On its website, KeyBioscience says in December 2019 it “reevaluated” its approach, which led to the “abandonment of once-daily injectable DACRAs” and switched to long-acting formulations that could be administered once a week. That pivot led to KBP-336, according to the biotech’s website. The drug entered human studies in the fall of 2021. A Phase 1b was completed in the spring of 2023. It wasn’t immediately clear if KBP-336 is the soon-to-be Phase 2 asset that KeyBioscience highlighted in Thursday’s press release. Editor’s note: This story was updated to include more details on the status of KBP-042 and KBP-089.

Phase 2Phase 1

100 Deals associated with KBP-042

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 2	DK	KeyBioscience AG	23 Aug 2017
Diabetes Mellitus, Type 2	Phase 2	PL	KeyBioscience AG	23 Aug 2017
Diabetes Mellitus, Type 2	Phase 2	RO	KeyBioscience AG	23 Aug 2017
Diabetes Mellitus, Type 2	Phase 2	GB	KeyBioscience AG	23 Aug 2017
Obesity	Discovery	DK	Nordic Bioscience A/S	22 Jun 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EASD2013	Not Applicable	Obesity	-	UGP302	tpmaahisnm(tvzprbaxti) = bxndpjyrta gwurpmryuv (oaewyzcyyb )	Positive	26 Sep 2013
				sCT	tpmaahisnm(tvzprbaxti) = pjbooiljor gwurpmryuv (oaewyzcyyb )
EASD2013	Not Applicable	Hyperglycemia	-	UGP302 1 mg/kg	pjoqlsgyoa(mllhhftqkm) = iphlcxakjc wmkjlvamfc (rqybfpkhvn )	-	25 Sep 2013
				UGP302 2 mg/kg	pjoqlsgyoa(mllhhftqkm) = xynmzhykhg wmkjlvamfc (rqybfpkhvn )