Delving into the Latest Updates on TGF-alpha/epiregulin monoclonal antibody(Eli Lilly) with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

EPIREG/TGFa MAB, Fepixnebart

+ [2]

Target

EREG x TGF-α

Mechanism

EREG inhibitors(Epiregulin inhibitors), TGF-α inhibitors(Transforming growth factor alpha inhibitors)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesEndocrinology and Metabolic Disease+ [1]

Active Indication

Chronic PainDiabetic peripheral neuropathic painLow Back Pain+ [1]

Inactive Indication

Diabetic Nephropathies

Originator Organization

Eli Lilly & Co.

Active Organization

Eli Lilly & Co.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 126428H

Source: *****

Sequence Code 126431L

Source: *****

This study is being done to test the safety and efficacy of the study drug LY3016859 for the treatment of diabetic peripheral neuropathic pain. This trial is part of the chronic pain master protocol H0P-MC-CPMP (NCT05986292) which is a protocol to accelerate the development of new treatments for chronic pain.

Start Date15 Jul 2020

Sponsor / Collaborator

Eli Lilly & Co.

NCT04456686

/ CompletedPhase 2

Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3016859 for the Treatment of Osteoarthritis

This study is being done to test the safety and efficacy of LY3016859 for the treatment of osteoarthritis pain. This trial is part of the chronic pain master protocol H0P-MC-CPMP (NCT05986292) which is a protocol to accelerate the development of new treatments for chronic pain.

Start Date01 Jul 2020

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with TGF-alpha/epiregulin monoclonal antibody(Eli Lilly)

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100 Translational Medicine associated with TGF-alpha/epiregulin monoclonal antibody(Eli Lilly)

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100 Patents (Medical) associated with TGF-alpha/epiregulin monoclonal antibody(Eli Lilly)

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3

Literatures (Medical) associated with TGF-alpha/epiregulin monoclonal antibody(Eli Lilly)

01 Sep 2018·Clinical Pharmacology in Drug DevelopmentQ4 · MEDICINE

Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy After Single and Multiple Dosings of LY3016859 in Healthy Subjects and Patients With Diabetic Nephropathy

Q4 · MEDICINE

Article

Author: Eli, Michelle ; Raddad, Eyas ; Deeg, Mark A. ; Flynt, Amy ; Sloan‐Lancaster, Joanne ; Tumlin, James

AbstractTwo phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF‐α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1–750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10–750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50–750 mg intravenously) or placebo. Pharmacokinetics, pharmacodynamics, anti‐LY antibodies, and change in proteinuria and albuminuria were evaluated. Single and multiple doses of LY administered 3 weeks apart were well tolerated. Pharmacokinetics were nonlinear in healthy subjects and patients with DN, indicating target‐mediated drug disposition. Epiregulin level increased in both studies, and TGF‐α levels increased in the TGAB study, consistent with target engagement; however, LY treatment did not significantly reduce proteinuria or albuminuria in patients with DN. There was no obvious effect of LY on the disease‐related biomarkers monocyte chemoattractant protein‐1, synaptopodin, or transferrin. Although LY administration resulted in a high frequency of anti‐LY antibodies, pharmacokinetics, target engagement, and efficacy were not impacted.

01 Nov 2016·Protein ScienceQ4 · BIOLOGY

Structural basis of selectivity and neutralizing activity of a TGFα/epiregulin specific antibody

Q4 · BIOLOGY

Article

Author: Boyles, Jeffrey S. ; Druzina, Zhanna ; Witcher, Derrick R. ; Atwell, Shane ; Heuer, Josef G.

AbstractRecent studies have implicated a role of the epidermal growth factor receptor (EGFR) pathway in kidney disease. Skin toxicity associated with therapeutics which completely block the EGFR pathway precludes their use in chronic dosing. Therefore, we developed antibodies which specifically neutralize the EGFR ligands TGFα (transforming growth factor‐alpha) and epiregulin but not EGF (epidermal growth factor), amphiregulin, betacellulin, HB‐EGF (heparin‐binding epidermal growth factor), or epigen. The epitope of one such neutralizing antibody, LY3016859, was characterized in detail to elucidate the structural basis for ligand specificity. Here we report a crystal structure of the LY3016859 Fab fragment in complex with soluble human TGFα. Our data demonstrate a conformational epitope located primarily within the C‐terminal subdomain of the ligand. In addition, point mutagenesis experiments were used to highlight specific amino acids which are critical for both antigen binding and neutralization, most notably Ala41, Glu44, and His45. These results illustrate the structural basis for the ligand specificity/selectivity of LY3016859 and could also provide insight into further engineering to alter specificity and/or affinity of LY3016859.

01 May 2014·The Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Generation and Activity of a Humanized Monoclonal Antibody That Selectively Neutralizes the Epidermal Growth Factor Receptor Ligands Transforming Growth Factor-α and Epiregulin

Q3 · MEDICINE

Article

Author: Breyer, Matthew D. ; Yang, Derek D. ; Harlan, Shannon M. ; Datta-Mannan, Amita ; Johnson, Robert L. ; Ellis, Bernice ; Petrovan, Ramona J. ; Heuer, Josef G. ; Chu, Shaoyou ; Conner, Elaine M. ; Witcher, Derrick R. ; Beidler, Catherine B. ; Stauber, Anja ; Boyles, Jeffrey S.

At least seven distinct epidermal growth factor (EGF) ligands bind to and activate the EGF receptor (EGFR). This activation plays an important role in the embryo and in the maintenance of adult tissues. Importantly, pharmacologic EGFR inhibition also plays a critical role in the pathophysiology of diverse disease states, especially cancer. The roles of specific EGFR ligands are poorly defined in these disease states. Accumulating evidence suggests a role for transforming growth factor α (TGFα) in skin, lung, and kidney disease. To explore the role of Tgfa, we generated a monoclonal antibody (mAb41) that binds to and neutralizes human Tgfa with high affinity (KD = 36.5 pM). The antibody also binds human epiregulin (Ereg) (KD = 346.6 pM) and inhibits ligand induced myofibroblast cell proliferation (IC50 values of 0.52 and 1.12 nM for human Tgfa and Ereg, respectively). In vivo, a single administration of the antibody to pregnant mice (30 mg/kg s.c. at day 14 after plug) or weekly administration to neonate mice (20 mg/kg s.c. for 4 weeks) phenocopy Tgfa knockout mice with curly whiskers, stunted growth, and expansion of the hypertrophic zone of growth plate cartilage. Humanization of this monoclonal antibody to a human IgG4 antibody (LY3016859) enables clinical development. Importantly, administration of the humanized antibody to cynomolgus monkeys is absent of the skin toxicity observed with current EGFR inhibitors used clinically and no other pathologies were noted, indicating that neutralization of Tgfa could provide a relatively safe profile as it advances in clinical development.

100 Deals associated with TGF-alpha/epiregulin monoclonal antibody(Eli Lilly)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Pain	Phase 2	US	Eli Lilly & Co.	30 Jan 2020
Chronic Pain	Phase 2	PR	Eli Lilly & Co.	30 Jan 2020
Diabetic peripheral neuropathic pain	Phase 2	PR	Eli Lilly & Co.	30 Jan 2020
Diabetic peripheral neuropathic pain	Phase 2	US	Eli Lilly & Co.	30 Jan 2020
Low Back Pain	Phase 2	PR	Eli Lilly & Co.	30 Jan 2020
Low Back Pain	Phase 2	US	Eli Lilly & Co.	30 Jan 2020
Osteoarthritis, Knee	Phase 2	PR	Eli Lilly & Co.	30 Jan 2020
Osteoarthritis, Knee	Phase 2	US	Eli Lilly & Co.	30 Jan 2020
Diabetic Nephropathies	Phase 2	US	Eli Lilly & Co.	01 Mar 2013
Diabetic Nephropathies	Phase 2	BG	Eli Lilly & Co.	01 Mar 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04476108 (CTgov)	Phase 2	Chronic Pain \| Diabetic peripheral neuropathic pain	125	LY3016859 (750 Mg-500 mg LY3016859)	oxvxazmesr(yblagptcbp) = wwmgblgxct bywfrwbmyz (kjyndlrpsr, wkxchtaxho - wlhrfvljog) View more	-	03 Aug 2022
				Placebo (Placebo)	oxvxazmesr(yblagptcbp) = znkpeaoutl bywfrwbmyz (kjyndlrpsr, itcpcvtoqv - xqogbiyqql) View more
NCT04456686 (CTgov)	Phase 2	Osteoarthritis \| Chronic Pain	117	LY3016859 (750 Mg-500 mg LY3016859)	ysomfmgkqv(ftelyucgmx) = slsdzviyfx pvxzfwcvko (brblqmmtjm, lgvbuceaah - npeqxmmyeu) View more	-	23 Jun 2022
				Placebo (Placebo)	ysomfmgkqv(ftelyucgmx) = zzkyaluiye pvxzfwcvko (brblqmmtjm, xnlztsehdn - uuzgjtvtsr) View more
NCT04529096 (CTgov)	Phase 2	Low Back Pain \| Chronic Pain	149	LY3016859 (750 Mg-500 mg LY3016859)	vmqvmbcryy(cesgkcpucc) = csrolhupkn dgdcvrqxij (kftzuiiqkf, dodokytuph - cqplnklspo) View more	-	23 Jun 2022
				Placebo (Placebo)	vmqvmbcryy(cesgkcpucc) = heodejfkpo dgdcvrqxij (kftzuiiqkf, mwsmztafsn - kbjrrcnhvy) View more
NCT01545583 (CTgov)	Phase 1	-	56	Placebo (Placebo IV)	(kexubwmiol) = babwffutjd dtquojqiwi (uzfyoqofgd, arvnhldkfa - yogcqwgzch) View more	-	19 Jul 2018
				Placebo (Placebo SC)	(kexubwmiol) = nhrwrgmtkf dtquojqiwi (uzfyoqofgd, hnalsbfpno - wjlrucbjnw) View more
NCT01774981 (CTgov)	Phase 1/2	Diabetic Nephropathies	60	Placebo (Placebo (Part B))	yaivaokygj(tfmhqbhmha) = ljaiibmmmm geekwlribv (qwxxmpmmht, hwuxxvehie - lqqebfuwma) View more	-	15 Aug 2017
				LY3016859 (50 mg LY3016859 (Part B))	yaivaokygj(tfmhqbhmha) = cnhfjqceyy geekwlribv (qwxxmpmmht, ohvfrhctxz - hdhucduryu) View more