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Injectable PEG-like Conjugate for Sustained Delivery of a Peptide Drug for Type 2 Diabetes Treatment

Award Number: R01DK124276
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Injectable PEG-like Conjugate for Sustained Delivery of a Peptide Drug for Type 2 Diabetes Treatment - ABSTRACT The objective of this NIH R01 proposal is to develop a non-immunogenic, injectable depot of a PEG-like conjugate of a peptide drug for systemic drug delivery. This proposal is motivated by the fact that many peptide and protein drugs have a short plasma half-life on the order of minutes to a few hours. PEGylation —the conjugation of polyethylene glycol (PEG) moieties to biologics— is commonly used to overcome these limitations. Unfortunately, PEG is antigenic, which has led to the early termination of a Phase III clinical trial of a PEGylated drug candidate and withdrawal of several PEGylated drugs from the market because of severe allergic reactions in some patients. These problems have been traced to circulating anti-PEG antibodies that are found even in individuals who have not previously received a PEGylated drug. Furthermore, the improvement in pharmacokinetics (PK) and pharmacodynamics (PD) conferred by PEG and its branched derivatives are now at an asymptote. This proposal addresses the urgent, unmet need to develop the next-generation of PEGylation that overcomes these limitations. We hypothesize that we can solve the immunogenicity problem of PEG conjugates and further extend the half-life of PEG conjugates by a next generation PEG-like “stealth” polymer, poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) that presents short oligomeric ethylene glycol (OEG) side-chains on a backbone. This hypothesis is validated by our preliminary data that shows that reactivity towards patient-derived anti-PEG antibodies is eliminated by shortening the OEG side-chain length to ≤3 without compromising PK or PD, and that a copolymer with a mixture of two and three EG long side-chains also allows POEGMA to reversibly transition from a solution into an insoluble coacervate between 25-37 ºC, thereby enabling the creation of a sustained release depot. We will demonstrate the utility of this non-immunogenic, injectable drug depot by synthesizing POEGMA conjugates of exendin —a potent but short-acting clinically approved peptide drug for type 2 diabetes— and show that exendin-POEGMA conjugates are pharmacologically active, form a depot upon subcutaneous (s.c.) injection in diabetic mice, show zero-order release kinetics into the bloodstream from the depot, leading to sustained glucose control in diabetic (db/db) mice, while simultaneously eliminating PEG immunogenicity and antigenicity. The overall significance of this research is that it will solve the problem of PEG antigenicity and will also improve upon the PK and PD of PEG conjugates by creating an injectable PEG conjugate that forms a s.c. depot with sustained release of the drug. By doing so, it will breathe new life into an established drug delivery technology that is now beginning to show its age. More specifically, it will also enable improved management of type diabetes for the ~30 million Americans who are diabetic. Because the POEGMA conjugate technology can likely be applied to the many therapeutics —beyond exendin— that have a short plasma half-life and where anti-PEG antibodies are of concern, it has the potential to have broad impact.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $441,591 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/15/2024	NON-COMPETING CONTINUATION	$27,597
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/2/2024	NON-COMPETING CONTINUATION	$413,994
														Subtotal = $441,591

Issue Date FY: 2023 ( Subtotal = $460,492 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/30/2022	NON-COMPETING CONTINUATION	$414,445
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/5/2023	NON-COMPETING CONTINUATION	$46,047
														Subtotal = $460,492

Issue Date FY: 2022 ( Subtotal = $465,178 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/24/2022	NON-COMPETING CONTINUATION	$46,517
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/4/2021	NON-COMPETING CONTINUATION	$418,661
														Subtotal = $465,178

Issue Date FY: 2021 ( Subtotal = $512,934 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/8/2020	NEW	$512,934
														Subtotal = $512,934

Grand Total All Awards = $1,880,195

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Injectable PEG-like Conjugate for Sustained Delivery of a Peptide Drug for Type 2 Diabetes Treatment

Award Number: R01DK124276

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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