PTG-100 / Protagonist Therap - LARVOL DELTA

A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF THE ORAL, GUT-RESTRICTED Α4Β7 INTEGRIN PEPTIDE ANTAGONIST PN-943 IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS: RESULTS FROM THE IDEAL STUDY (UEGW 2022) - "PN-943 has ~3 times more potency than the first-generation candidate PTG-100 which demonstrated signs of clinical efficacy in a phase 2 ulcerative colitis (UC) study (Gastroenterol 2021; 161:1853-1864)...Key inclusion criteria were moderate to severe UC defined as a 3-component Mayo score (Stool Frequency Score (SFS), Rectal Bleeding Score (RBS), and centrally read Mayo Endoscopic Subscore (MES)), of 5-9; and prior inadequate response/intolerance to at least 1 conventional therapy, or a maximum of one biologic (excluding vedolizumab).  PN-943 at 150 mg BID, but not 450 mg BID, demonstrated concordant treatment effects across multiple secondary endpoints with nominal statistically significant differences in histologic remission/improvement and endoscopic improvement. These results suggest a novel mechanism of action for PN-943 affecting α4β7-MADCAM interactions in the local GI tissue environment and support further development of PN-943 in registrational UC trials."

Clinical • P2 data • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis. (PubMed, Gastroenterology) - "PTG-100 demonstrated local GI tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well-tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and demonstrated a dose response reflecting similar activities in preclinical models and healthy subjects. These data suggest local gut activity of an oral α4β7-integrin antagonist, distinct from full target engagement in blood, are important for efficacy and treatment of UC."

Journal • P1 data • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • ITGA4

THE IDEAL STUDY: A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTI-CENTER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF THE ORAL α4β7 INTEGRIN PEPTIDE ANTAGONIST PN-943 IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS (DDW 2022) - "PN-943, a second generation oral α4β7 peptide antagonist with approximately 3 times more in vitro and in vivo potency than PTG-100, has demonstrated dose dependent blood α4β7 receptor occupancy, as well as reduction in receptor expression in a phase 1 study in healthy volunteers (Clin Pharmacol Drug Dev...Key inclusion criteria are moderate to severe UC defined as an adapted 3-component Mayo score, comprised of Stool Frequency Score (SFS), Rectal Bleeding Score (RBS), and Mayo Endoscopic Subscore (MES), of 5-9; and prior inadequate response, loss of response, or intolerance of at least 1 of oral aminosalicylates, corticosteroids, immunosuppressives, or a biologic (excluding vedolizumab)...We will present key efficacy and safety analyses from the primary week 12 endpoint. The data will help elucidate the utility of a highly potent oral, peptide α4β7 inhibitor in UC."

Clinical • P2 data • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

PTG-100 for Patients With Celiac Disease (clinicaltrials.gov) - P1b | N=12 | Completed | Sponsor: Nielsen Fernandez-Becker | Active, not recruiting ➔ Completed | Trial completion date: Jul 2022 ➔ Apr 2022

Trial completion • Trial completion date • Celiac Disease • Immunology

PTG-100 for Patients With Celiac Disease (clinicaltrials.gov) - P1b | N=12 | Active, not recruiting | Sponsor: Nielsen Fernandez-Becker | Recruiting ➔ Active, not recruiting | N=30 ➔ 12 | Trial completion date: May 2022 ➔ Jul 2022

Enrollment change • Enrollment closed • Trial completion date • Celiac Disease • Immunology

Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): Insights into promising agents. (PubMed, Expert Opin Investig Drugs) - "This review summarizes efficacy and safety data from phase 1, 2 and 3 clinical trials on investigational drugs, including monoclonal antibodies (etrolizumab, abrilumab, ontamalimab) and oral small molecules (AJM300, PTG-100). Among the most exciting features of this class are the gut selectivity, the convenient subcutaneous and oral administrations and the reassuring safety profiles. Most of the new anti-integrins seem to improve outcomes in UC but not in CD, however these data are far from definitive and several pivotal trials are still under way."

Clinical • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

PTG-100 for Patients With Celiac Disease (clinicaltrials.gov) - P1b; N=30; Recruiting; Sponsor: Nielsen Fernandez-Becker; Trial completion date: Sep 2021 ➔ Mar 2022; Trial primary completion date: Jun 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Celiac Disease • Immunology

PTG-100 for Patients With Celiac Disease (clinicaltrials.gov) - P1b; N=30; Recruiting; Sponsor: Nielsen Fernandez-Becker; Not yet recruiting ➔ Recruiting; Initiation date: Sep 2020 ➔ Feb 2021

Clinical • Enrollment open • Trial initiation date • Celiac Disease • Immunology

Parent Caregiving Experiences and Posttraumatic Growth Following Pediatric Hematopoietic Stem Cell Transplant. (PubMed, J Pediatr Oncol Nurs) - "This study aimed to explore how parents experience caregiving and PTG 100 days after children's HSCT...Nurses are integral to the parents' experiences. Future work should focus on nursing interventions that enhance positive reinterpretation of parents' experiences after their children's HSCT."

Clinical • Journal • Critical care • Oncology • Pediatrics • Transplantation

[VIRTUAL] MEASUREMENT OF ULCERATED AND AFFECTED SURFACE OF THE COLON MAY PROVIDE MORE INSIGHT INTO RESPONSE COMPARED TO ENDOSCOPIC MAYO SCORE - A POST HOC ANALYSIS (UEGW 2020) - "Aims & Colonoscopies from the placebo and PTG-100 900mg dose group of the PROPEL study at week 0 and week 12 were assessed in back to back fashion by a single central unblinded reader... Our findings show that the endosocpic Mayo score lacks data granularity to highlight all changes in ulcerated and affected surface in ulcerative colitis. A validation process of a score measuring affected and ulcerated surface should be initiated."

Retrospective data • Dermatology • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

[VIRTUAL] MEASUREMENT OF ULCERATED AND AFFECTED SURFACE OF THE COLON MAY PROVIDE MORE INSIGHT INTO RESPONSE COMPARED TO ENDOSCOPIC MAYO SCORE - A POST HOC ANALYSIS (UEGW 2020) - "Aims & Colonoscopies from the placebo and PTG-100 900mg dose group of the PROPEL study at week 0 and week 12 were assessed in back to back fashion by a single central unblinded reader... Our findings show that the endosocpic Mayo score lacks data granularity to highlight all changes in ulcerated and affected surface in ulcerative colitis. A validation process of a score measuring affected and ulcerated surface should be initiated."

Retrospective data • Dermatology • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

[VIRTUAL] MEASUREMENT OF ULCERATED AND AFFECTED SURFACE OF THE COLON MAY PROVIDE MORE INSIGHT INTO RESPONSE COMPARED TO ENDOSCOPIC MAYO SCORE - A POST HOC ANALYSIS (UEGW 2020) - "Aims & Colonoscopies from the placebo and PTG-100 900mg dose group of the PROPEL study at week 0 and week 12 were assessed in back to back fashion by a single central unblinded reader... Our findings show that the endosocpic Mayo score lacks data granularity to highlight all changes in ulcerated and affected surface in ulcerative colitis. A validation process of a score measuring affected and ulcerated surface should be initiated."

Retrospective data • Dermatology • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

PTG-100 for Patients With Celiac Disease (clinicaltrials.gov) - P1b; N=30; Not yet recruiting; Sponsor: Nielsen Fernandez-Becker

New P1 trial • Celiac Disease • Immunology

Protagonist Therapeutics initiates phase 1 study with oral peptide PTG-100 (PRNewswire) - P1, N=70; "Protagonist Therapeutics...today announced that the company has initiated treatment of subjects with its lead drug candidate, PTG-100, in a Phase 1 clinical study...as a potential treatment for patients with inflammatory bowel disease (IBD)...Primary endpoints for the study are safety and tolerability of PTG-100."

Enrollment open • Inflammatory Bowel Disease

PTG-100: FDA discussion for P2b/3 study in ulcerative colitis in Q4 2018 (Protagonist Therapeutics) - Investor Presentation

FDA event • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

PTG-100: “PTG-100 shows clinical efficacy in UC patients based on Robarts re-reads” (Protagonist Therapeutics) - Investor Presentation: “PTG-100 has achieved Clinical POC and is safe and well tolerated”

P2b data • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

PN-943, AN ORAL α4β7 INTEGRIN ANTAGONIST, INHIBITS MADCAM1-MEDIATED PROLIFERATION AND CYTOKINE RELEASE FROM CD4+ T-CELLS INDEPENDENT OF TRAFFICKING (DDW 2020) - "Saturation of circulating T-cell α4β7 by vedolizumab is not sufficient for optimal efficacy (Ungar et al, Clin Gastroenterol Hepatol 2018); and PTG-100, a PN-943 analog, showed evidence of remission in Ulcerative Colitis patients at sub-saturating blood receptor occupancy (RO; Sandborn et al, UEGW 2018). Previous preclinical studies have shown PN-943 affects trafficking of CD4+ T cells (Mattheakis et al, DDW 2019). Here, we demonstrate the ability of PN-943 to inhibit MAdCAM1-mediated proliferation and cytokine release as another mechanism which may control chronic inflammation occurring in the gut of IBD patients. This finding supports an intervention strategy that is best exploited by an oral GI-restricted approach, whereby PN-943 is delivered locally and directly blocks α4β7 function in the GI"

Gastroenterology • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IFNG • IL17A • IL4 • IL6

PN-943, an oral α4β7 integrin antagonist, inhibits MAdCAM1-mediated proliferation and cytokine release from CD4+ T cells independent of trafficking (ECCO-IBD 2020) - "Saturation of circulating T-cell α4β7 by vedolizumab is not sufficient for optimal efficacy; and PTG-100, a PN-943 analogue, showed evidence of clinical and histological remission in ulcerative colitis patients at sub-saturating blood receptor occupancy (%RO). Consistent with the requirement for a locally acting drug, 30 mg/kg oral dosing in mice demonstrated high exposure (n = 6, 39 nM) and occupancy of T-cell α4β7 (n = 6, 92%) in the GI compared within the blood.Conclusion The α4β7-MAdCAM1 interaction promoted β7+CD4+ T-cell proliferation and cytokine release, which may contribute to chronic inflammatory responses occurring in the diseased gut of IBD patients independent of T-cell trafficking. PN-943 inhibition of MAdCAM1-mediated signalling through α4β7 supports the potential therapeutic advantages for an oral GI-restricted approach, whereby PN-943 is delivered locally and directly blocks α4β7 function in the GI."

IFNG • IL13 • IL17A • IL4 • IL6

Safety, Pharmacokinetics, and Pharmacodynamics of the Novel Oral Peptide Therapeutic PN-10943 (alpha4­beta7 Integrin Antagonist) in Normal Healthy Volunteers (ACG 2019) - "In the SAD portion of the study, 100, 300, 1000, and 1400 mg cohorts were dosed with no serious adverse events or dose-limiting toxicities. All adverse events were of mild to moderate severity and resolved without complication. In the MAD portion of the study doses studied were 100, 300, & 1000 mg for 14 days."

Clinical • PK/PD data

Challenging the sensitivity of HDX/MS with a large heterodimeric protein receptor: Characterization of the binding interactions of new generation integrin α4β7 inhibitors (ACS-Fall 2019) - "Despite this relevant finding, the characterization of the binding epitope of these new generation integrin inhibitors on the α4β7 receptor is still elusive.In this study, we report for the first time the molecular characterization of the binding interactions of clinical therapeutic disulfide-linked cyclic peptides PTG-100 against the integrin α4β7 receptor as probed by HDX/MS and computational approaches. The results of this study are of paramount importance to get a deeper insight into the involvement of α4β7 in autoimmune diseases and to guide the discovery of new chemotypes as inhibitors of this integrin receptor."

The Oral Α4Β7 Integrin Specific Antagonist Pn-10943 is More Effective Than Ptg-100 in Multiple Preclinical Studies (DDW 2019) - "Conclusions In these preclinical studies, we characterized the oral peptide PN-10943 and demonstrated its superiority to PTG-100 as measured by in vitro potency, in vivo PD response, and efficacy in a disease model of colitis. These data suggest PN-10943 has the potential to be clinically more effective than PTG-100 and support its further development in a planned Phase 1 study in normal healthy volunteers."

Preclinical

"Mattheakis with evidence of 2nd generation PTG-10943 superiority to 1st generation oral anti-integrin PTG100. PTG100 was ok in phase 21, but 943 looks better, primed for combo therapies. #IBD #DDW19" (@ibddoctor)

Head-to-Head

PTG-100: Patent expiry in US in 2035 (Protagonist Therapeutics) - Annual Report 2018

Patent