PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis

Sandborn, William J.; Mattheakis, Larry; Modi, Nishit B.; Pugatch, David; Bressler, Brian; Lee, Scott; Bhandari, Raj; Kanwar, Bittoo; Shames, Richard S.; D’Haens, Geert R.; Schreiber, Stefan; Danese, Silvio; Feagan, Brian G.; Pai, Rish K.; Liu, David Y.; Gupta, Suneel

doi:10.1053/j.gastro.2021.08.045

Cited by 25 publications

(15 citation statements)

References 27 publications

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“… 567 In recent years, novel chemotypes with high-quality orally bioavailable inhibitors have made large breakthroughs, such as carotegrast, 562 PLN-74809, 568 and PTG-100 . 569 Although PTG-100, an oral α4β7 antagonist peptide, initially did not meet the primary endpoint in a phase IIa study, it showed proof-of-concept efficacy in patients with moderate-to-severe active UC, and the related data also suggested that local gut activity of an oral α4β7 inhibitor is important for efficacy for UC treatment, which is different from full-target engagement in blood. Other orally bioavailable inhibitors under ongoing clinical studies include IDL-2965 and MORF-057, developed by EA Pharma, Pliant, Protagonist, Indalo, and Morphic, respectively (Table 4 ).…”

Section: Challenges and Opportunities: Integrin-targeting Drug Discov...mentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

250

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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Section: Challenges and Opportunities: Integrin-targeting Drug Discov...mentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

250

111

View full text Add to dashboard Cite

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“…PTG-100 is an orally administered, potent, and selective α4β7 peptide antagonist. It was already tested in a phase 2a RCT in patients with ulcerative colitis and showed high gastrointestinal exposure, limited systemic exposure, and a dose–response improvement in endoscopy and histology [ 104 ]. A phase 1b study (NCT 04524221) evaluating PTG-100 at a dose of 600 mg twice a day versus placebo in 30 CD patients on a gluten challenge was completed in April 2022.…”

Section: Pathophysiology-driven Strategies To Treat Celiac Diseasementioning

confidence: 99%

New Developments in Celiac Disease Treatment

Machado

2023

IJMS

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Celiac disease (CD) is a common autoimmune disease affecting around 1% of the population. It consists of an immune-mediated enteropathy, triggered by gluten exposure in susceptible patients. All patients with CD, irrespective of the presence of symptoms, must endure a lifelong gluten-free diet (GFD). This is not an easy task due to a lack of awareness of the gluten content in foods and the extensive incorporation of gluten in processed foods. Furthermore, a GFD imposes a sense of limitation and might be associated with decreased quality of life in CD patients. This results in gluten contamination in the diet of four out of five celiac patients adhering to a GFD. Furthermore, one in three adult patients will report persistent symptoms and two in three will not achieve full histological recovery when on a GFD. In recent years, there has been extensive research conducted in the quest to find the holy grail of pharmacological treatment for CD. This review will present a concise description of the current rationale and main clinical trials related to CD drug therapy.

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“…Presently, important progress has been made in the utilization of integrin antagonists for the treatment of inflammatory bowel disease (IBD) [ 94 ]. Some drugs including anti-α4β7 integrin antibodies (vedolizumab, abrilumab, etrolizumab) and small molecules (PTG-100, AJM300) have already been researched pre-clinically or clinically [ 95 , 96 , 97 , 98 , 99 ]. However, it is noteworthy that efalizumab, a recombinant monoclonal antibody against the αL-integrin chain, has previously been approved for the treatment of moderate-to-severe psoriasis.…”

Section: The Potential Of β2 Integrin Antagonists Serving As a Therap...mentioning

confidence: 99%

Effects of β2 Integrins on Osteoclasts, Macrophages, Chondrocytes, and Synovial Fibroblasts in Osteoarthritis

Zhang

Deng

et al. 2022

Biomolecules

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β2 integrins are transmembrane receptors that exist widely in human immune cells and participate in pathological processes such as chronic inflammation, thrombosis, and malignant tumor formation. They mainly mediate intercellular adhesion, coordinate the ingestion of extracellular matrix components, and regulate cytoskeleton formation, thereby regulating cell signaling. Osteoarthritis (OA) is a chronic joint disease that causes joint pain and increases disease burden; it has a high prevalence among populations worldwide. Previous studies have reported that β2 integrins are overexpressed in OA and may play an essential role in the occurrence of OA. The important roles of β2 integrins in the maturation and differentiation of osteoclasts, the regulation of bone homeostasis, and the polarization and migration of macrophages have also been reported. The present review aims to highlight the role of β2 integrins in OA pathogenesis and outline their potential for serving as therapeutic targets.

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PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis

Cited by 25 publications

References 27 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

New Developments in Celiac Disease Treatment

Effects of β2 Integrins on Osteoclasts, Macrophages, Chondrocytes, and Synovial Fibroblasts in Osteoarthritis

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