Open Label Extension (OLE) for the Patients Treated in the ISD002-P144-07 Study With P144 Topical Adminsitration for Skin Fibrosis in Patients With Systemic Sclerosis

Transforming growth factor-beta 1 is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts(25, 26). Activation of TGF-beta receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-beta 1 i one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-beta1 mRNA and protein levels has been described in these processes. Peptide 144 (P144)is a acetic salt of a 14mer peptide from human TGF-beta1 type III receptor (betaglycan). P144 TGF-beta1-inhibitor has been specifically designed to block the interaction between TGF-beta1 and TGF-beta1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated sucutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The aim of the study is to asses the long-term safety of topical application of P144 cream in the treatment of skin fibrosis in patients with systemic sclerosis in an extension open-label treatment period of 6 additional months.

Start Date01 Jul 2008

Sponsor / Collaborator

ISDIN SA

[+1]

NCT00574613

/ CompletedPhase 2

Phase II, Multicenter, Randomized, Double-blind, Intraindividually Placebo Controlled Clinical Trial, to Evaluate Efficacy and Safety of p144 Topical Administration for Skin Fibrosis in Patients With Systemic Sclerosis

Transforming growth factor-beta 1 (TGF-β1) is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts. Activation of TGF-β receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-β1 is one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-β1 mRNA and protein levels has been described in these processes. Peptide 144 (P144) is the acetic salt of a 14mer peptide from human TGF-β1 type III receptor (betaglycan). P144 TGF-β1-inhibitor has been specifically designed to block the interaction between TGF-β1 and TGF-β1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated subcutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The purpose of this study is to asses the efficacy and safety of topical application of P144 in the treatment of skin fibrosis in patients with systemic sclerosis.

Start Date01 Sep 2007

Sponsor / Collaborator

ISDIN SA

[+1]

NCT00656825

/ CompletedPhase 1

Multicentre, Placebo-Controlled, Multi-Dosis, Phase I Clinical Trial to Evaluate the Tolerability and Bioavailability of TGF β1 Inhibitor Peptide 144 After Topical Administration in Healthy Volunteers.

Transforming growth factor-beta 1 (TGF-β1) is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts. Activation of TGF-β receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-β1 is one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-β1 mRNA and protein levels has been described in these processes. Peptide 144 (P144) is the acetic salt of a 14mer peptide from human TGF-β1 type III receptor (betaglycan). P144 TGF-β1-inhibitor has been specifically designed to block the interaction between TGF-β1 and TGF-β1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated subcutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The purpose of this study is to assess the tolerability and safety of topical application of P144 in healthy volunteers.

Start Date01 Mar 2007

Sponsor / Collaborator

ISDIN SA

[+1]

100 Clinical Results associated with Disitertide

100 Translational Medicine associated with Disitertide

100 Patents (Medical) associated with Disitertide

Literatures (Medical) associated with Disitertide

01 May 2024·Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology

TGF-β1 inhibitor P144 protects against benign restenosis after esophageal stenting through TGF-β1/Smads signaling pathway inhibition

Article

Author: Zhang, Jin-Xing ; Yang, Wei ; Wu, Jun-Zheng ; Zhou, Wei-Zhong ; Liu, Sheng ; Zhou, Chun ; Shi, Hai-Bin

BACKGROUND AND STUDY AIMS:

Esophageal restenosis is a serious complication after esophageal stent placement, which influences the clinical prognosis of stent implantation and the patient's quality of life. TGF-β1/Smads signaling pathway plays an important role in the development of the eosinophilic esophagitis and scar repair after skin trauma. However, the role of TGF-β1/Smads in the development of esophageal restenosis after esophageal stent placement remains unknown. Our study aimed to investigate whether TGF-β1/Smads plays an important role in the development of esophageal restenosis after esophageal stent, and whether the exogenous TGF-β1 inhibitor supplement could ameliorate the esophageal restenosis after esophageal stent.

MATERIAL AND METHODS:

We established the model of esophageal restenosis after esophageal stenting in rats, and determined the expression levels of TGF-β1/Smads signaling pathway and the relevant markers of fibroblast activation by immunochemistry (IHC), Western Blot and real time qPCR. Those all the indicators were also determined in esophageal fibroblast when exposed to rhTGF-β1 with or without TGF-β1 inhibitor P144.

RESULTS:

The serum level of IL-1β and TNFα were significantly increased in stent implantation group compared to blank control group, and obviously ameliorated when treated with P144. The TGF-β1/Smads signaling pathway and the relevant markers of fibroblast activation were significantly increased in stent implantation group compared to blank control group, and obviously ameliorated when treated with P144. Those all the indicators were significantly increased when exposed to rhTGF-β1, and obviously decreased when treated with P144.

CONCLUSIONS:

TGF-β1 Inhibitor P144 could protect against benign restenosis after esophageal stenting by down-regulating the expression levels of relevant markers of fibroblast activation through TGF-β1/Smads signaling pathway inhibition, and may be used as a novel therapy for benign restenosis after esophageal stenting.

01 Oct 2022·Cell proliferation

TGF‐β1 peptide‐based inhibitor P144 ameliorates renal fibrosis after ischemia–reperfusion injury by modulating alternatively activated macrophages

Article

Author: Yan Tong ; Delun Li ; Jijun Li ; Tian Sang ; Jian Zhang ; Ran Liu ; Chao Wang ; Siyu Yuan ; Jiakai Chang ; Lili Li ; Qing Ouyang ; Xiangmei Chen

Abstract:

Objectives:

Ischemia–reperfusion injury (IRI) is a major cause of chronic renal fibrosis. Currently, numerous therapies have shown a minimal effect on the blockade of fibrosis progression. Here, the therapeutic potential of peptide‐based TGF‐β1 inhibitor P144 in IRI‐induced renal fibrosis and the underlying mechanism were analyzed.

Materials and Methods:

The unilateral ischemia–reperfusion injury with the contralateral nephrectomy model was established, and the P144 was administered intravenously 1d/14d after the onset of IRI. The histopathology and immunofluorescence staining were used to detect renal fibrosis and macrophage infiltration. The in vivo fluorescence imaging was used to measure the bio‐distribution of P144. The transwell assays were used to observe the migration of macrophages. RT‐qPCR and western blot were used to analyze TGF‐β1 signaling.

Results:

P144 ameliorated the accumulation of extracellular matrix in the kidney and improved the renal function in the unilateral ischemia–reperfusion injury plus contralateral nephrectomy model. Mechanistically, P144 downregulated the TGF‐β1‐Smad3 signaling at both the transcriptional and translational levels and further reduced the TGF‐β1‐dependent infiltration of macrophages to the injured kidney. Additionally, P144 blocked the polarization of macrophages to an M2‐like phenotype induced by TGF‐β1 in vitro, but showed no effect on their proliferation.

Conclusions:

Our study showed that the TGF‐β1 peptide‐based inhibitor P144 decreased renal fibrosis through the blockade of the TGF‐β1–Smad3 signaling pathway and the modulation of macrophage polarization, suggesting its potential therapeutic use in IRI‐induced renal fibrosis.

01 Sep 2021·Arteriosclerosis, thrombosis, and vascular biologyQ1 · MEDICINE

Anti-TGFβ (Transforming Growth Factor β) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome

Q1 · MEDICINE

Article

Author: Durán, Karina ; Berraondo, Pedro ; Campuzano, Victoria ; Jiménez-Altayó, Francesc ; Egea, Gustavo ; Fabregat, Isabel ; De Rycke, Karo ; Rodríguez-Rovira, Isaac ; Arce, Cristina

Objective::

We investigated the effect of a potent TGFβ (transforming growth factor β) inhibitor peptide (P144) from the betaglycan/TGFβ receptor III on aortic aneurysm development in a Marfan syndrome mouse model.

Approach and Results::

We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFβ signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfβ1 and Tgfβ2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFβ signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfβ1 and Tgfβ2 mRNA levels.

Conclusions::

P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFβ signaling during the early stages of aortic disease progression.

100 Deals associated with Disitertide

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Phase 2	Germany	ISDIN SA	01 Sep 2007
Fibrosis	Phase 2	Hungary	ISDIN SA	01 Sep 2007
Fibrosis	Phase 2	Italy	ISDIN SA	01 Sep 2007
Fibrosis	Phase 2	Poland	ISDIN SA	01 Sep 2007
Fibrosis	Phase 2	Spain	ISDIN SA	01 Sep 2007
Fibrosis	Phase 2	United Kingdom	ISDIN SA	01 Sep 2007
Limited Scleroderma	Phase 2	Germany	ISDIN SA	01 Sep 2007
Limited Scleroderma	Phase 2	Hungary	ISDIN SA	01 Sep 2007
Limited Scleroderma	Phase 2	Italy	ISDIN SA	01 Sep 2007
Limited Scleroderma	Phase 2	Poland	ISDIN SA	01 Sep 2007

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