mongersen (GED-0301) / Nogra Pharma, BMS - LARVOL DELTA

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. (PubMed, Cardiovasc Diabetol) - "Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials...Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials...Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ABCA1 • ACACA • ACSL3 • BMP2 • CD36 • COL1A1 • CPT1A • CTGF • EHHADH • HMGB1 • IFNA1 • IL1B • IL6 • MALT1 • RUNX2 • SCARB1 • SMAD7 • TCF7L2 • TNFA

TGF-β1 signaling and Smad7 control T cell responses in health and immune-mediated disorders. (PubMed, Eur J Immunol) - "In this review, we highlight the roles of TGF-?1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)-17, and Th9 cells, thus contributing to amplifying or restricting T cell responses in health and human diseases (e.g. inflammatory bowel diseases, type I diabetes, asthma, and multiple sclerosis), In addition, we discuss the involvement of Smad7, an inhibitor of TGF-?1 signaling, in immune-mediated disorders (e.g. psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases), as well as the discordant results of clinical trials with mongersen, an oral pharmaceutical compound containing a Smad7 antisense oligonucleotide, in patients with Crohn's disease. Further work is needed to ascertain the reasons for such a discrepancy as well as to identify better candidates for treatment with Smad7 inhibitors."

Journal • Review • Asthma • Crohn's disease • Dermatology • Diabetes • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • Metabolic Disorders • Psoriasis • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Type 1 Diabetes Mellitus • SMAD7 • TGFB1

Smad7 Antisense Oligonucleotide in Crohn's Disease: A Re-Evaluation and Explanation for the Discordant Results of Clinical Trials. (PubMed, Pharmaceutics) - "The accumulating evidence highlights the need to maintain consistent manufacturing requirements for clinical AS, as well as the potential benefits of in vitro bioassays as a part of quality control. New clinical trials evaluating mongersen's impact on IBD using chemically homogenous batches will be needed to ascertain the therapeutic efficacy of such a drug."

Clinical • Discordant • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mucositis • Ulcerative Colitis • SMAD4 • SMAD7

Deletion of Smad7 Ameliorates Intestinal Inflammation and Contributes to Fibrosis. (PubMed, Inflamm Bowel Dis) - "Smad7 deficiency is associated with a decrease in intestinal inflammation and an increase in fibrosis. Targeting SMAD7 constitutes a potential new treatment option for IBD; progression of disease-associated fibrosis should be considered."

Journal • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Transplantation • MPO • SMAD7 • TGFB1 • TNFA

Smad7 Antisense Oligonucleotide-Based Therapy in Crohn's Disease: Is it Time to Re-Evaluate? (PubMed, Mol Diagn Ther) - "We illustrate the recent data indicating that the various batches of mongersen, used during the phase III program, are chemically different, with some of them being unable to downregulate Smad7 expression. Overall, these findings suggest the necessity of new clinical studies to further evaluate the efficacy of chemically homogenous batches of mongersen in patients with inflammatory bowel diseases (IBDs), and, at the same time, they can help understand the failure of other clinical trials with antisense oligonucleotides in IBD (i.e. alicaforsen)."

Clinical • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • SMAD7 • TNFA

Inhomogeneous Diastereomeric Composition of Mongersen Antisense Phosphorothioate Oligonucleotide Preparations and Related Pharmacological Activity Impairment. (PubMed, Nucleic Acid Ther) - "We tentatively suggest that this may be the origin of different biological activity. As similar manifolds are expected for other PS-based oligonucleotides, the protocol described here provides a general method to identify PS chirality issues and a chemometric tool to score each preparation for this elusive feature."

Journal • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease • SMAD4 • SMAD7

[VIRTUAL] Serological biomarkers of tissue remodeling are associated with endoscopic remission in Crohn’s disease patients treated with GED-0301 (mongersen) (ECCO-IBD 2021) - P1 | "Patients s who achieved remission based on endoscopic criteria showing greater suppression of these biomarkers relative to non-remitters. Collectively, these data suggest that biomarkers of tissue remodeling may be useful to monitoring disease activity and mucosal changes in CD patients."

Biomarker • Clinical • Crohn's disease • Immunology • Inflammatory Bowel Disease • SMAD7 • TGFB1

"Hello Dr. Do you recommend Mongersen for treat Cronh’s disease?" (@iishaabii)

A Pharmacological Batch of Mongersen that Downregulates Smad7 is Effective as Induction Therapy in Active Crohn's Disease: A Phase II, Open-Label Study. (PubMed, BioDrugs) - P2 | "The present findings support the clinical benefit of Mongersen in active CD and show that various batches manufactured during the GED0301 program differ in their ability to inhibit in vitro Smad7."

Clinical • Journal • P2 data • Colorectal Cancer • Crohn's disease • Gastroenterology • Gastrointestinal Cancer • Immunology • Inflammatory Bowel Disease • Oncology • Solid Tumor • PCR • PTPRC • SMAD7

TGF-β activity restoration and phosphodiesterase 4 inhibition as therapeutic options for inflammatory bowel diseases. (PubMed, Pharmacol Res) - "A recent phase 2 study has shown that oral administration of PD4 associates with clinical benefit in patients with ulcerative colitis. In this article, we review the rationale and the available data relative to the use of these two agents in IBD."

Journal • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • SMAD7 • TGFB1 • TNFA

Mongersen (GED-0301) for Active Crohn’s Disease: Results of a Phase 3 Study. (PubMed, Am J Gastroenterol) - "GED-0301 did not demonstrate efficacy vs placebo in active CD."

Journal • P3 data • Crohn's disease • Gastroenterology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Pneumonia • Respiratory Diseases

A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn's Disease. (PubMed, Biomedicines) - "This is the first study to show an association between Smad7 rs144204026 SNP and CD patients. Data indicate that such a variant does not negatively influence the in vitro inhibitory effect of Smad7 AS on Smad7."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • SMAD7

Celgene acquires late-stage product for Crohn’s disease and other gastrointestinal disorders (Businesswire) - "Celgene...entered into a global license agreement with Nogra Pharma Limited...to develop and commercialize GED-0301...for the treatment of moderate-to-severe Crohn’s disease and other indications."; P2, N=166; Sponsor: Giuliani SPA; EudraCT Number: 2011-002640-27; "The data have been submitted to a major medical journal and will be presented at an upcoming medical congress. Based upon these results, Celgene plans to initiate a phase III registration program by year-end 2014."

Anticipated conference • Anticipated new P3 trial • Anticipated P2 data • Anticipated phase shift • Licensing / partnership • Inflammatory Bowel Disease

A Study to Evaluate the Effect of Food, Formulation Strength, and a Proton Pump Inhibitor on GED 0301 Pharmacokinetics in Healthy Adult Subjects (clinicaltrials.gov) - P1; N=18; Not yet recruiting; Sponsor: Celgene Corporation

New P1 trial • Biosimilar

Effects of Mongersen (GED-0301) on Endoscopic and Clinical Outcomes in Patients With Active Crohn's Disease. (PubMed, Gastroenterology) - "No new safety signals were observed. These findings support a GED-0301 benefit in active CD."

Journal • Biosimilar • Crohn's disease • Immunology • Inflammation • Inflammatory Bowel Disease

A Randomized, Double-blind, Study to Explore the Effect of GED-0301 in Subjects With Active Crohn's Disease (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Celgene Corporation; Not yet recruiting -> Recruiting

Enrollment open • Biosimilar • Crohn's Disease • Inflammatory Bowel Disease

"This isn't about mongersen $CELG" (@JacobPlieth)

Biosimilar

Phase II data for Celgene's investigational oral GED-0301 for patients with active Crohn's disease published in New England Journal of Medicine (Celgene Press Release) - P2, N=166; "Celgene Corporation..today announced that results from...phase II trial of three doses of GED-0301 (mongersen) in patients with active Crohn's disease... a significantly greater proportion of patients with active Crohn's disease achieved the primary endpoint of clinical remission at both day 15 and day 28 with once daily GED-0301 40 mg (55 percent) or 160 mg (65 percent) than with GED-0301 10 mg (12 percent) or placebo (10 percent; P < 0.001)...with Crohn's disease, starting with advancing the phase III trial for GED-0301."

Anticipated new P3 trial • P2 data • Inflammatory Bowel Disease

"Looks good. However after #Mongersen trial experience I like to wait and watch for week 26/52 outcomes ! #UEGweek" (@rafeeq_rm)

Biosimilar

Pharmacodynamic Study of Mongersen in Patients With Crohn's Disease (clinicaltrials.gov) - P2; N=16; Not yet recruiting; Sponsor: Celgene Corporation

New P2 trial • Biosimilar • Crohn's Disease • Immunology • Inflammatory Bowel Disease

Celgene provides update on GED-0301 (mongersen) inflammatory bowel disease program (Businesswire) - P3, N=NA; NCT02596893 (REVOLVE); NCT02641392 (SUSTAIN); NCT02974322 (DEFINE); Sponsor: Celgene; "Celgene Corporation today announced that the GED-0301 (mongersen) phase III REVOLVE trial (CD-002) in Crohn’s disease (CD) and the extension trial (SUSTAIN, CD-004) will discontinue. Celgene has decided to stop the trials following an October recommendation of the Data Monitoring Committee, which assessed overall benefit/risk during a recent interim futility analysis...At this time, the phase III DEFINE trial (CD-003) in Crohn’s disease will not be initiated. Celgene is waiting to review the full dataset from the phase II trial with GED-0301 in ulcerative colitis (UC) to determine next steps."

Discontinued • Trial status • Immunology • Inflammation • Inflammatory Bowel Disease

Celgene: Conference Call on GED-0301 (Celgene) - Anticipated data from P2 UC-002 trial (NCT02601300) in ulcerative colitis in 2017; Anticipated data from P3 CD-002 trial (NCT02596893) in Crohn's disease in 2018; Anticipated data from P3 CD-003 trial in Crohn's disease in 2018

Anticipated P2 data • Anticipated P3 data • Inflammatory Bowel Disease

Celgene: Q3 2015 Earnings Conference Call (Celgene) - Anticipated completion of enrollment in P1 CD-001 trial (NCT02367183) for Crohn’s disease by end of 2015; Anticipated initiation of patient randomization in P3 CD-002 trial (NCT02596893) for Crohn's disease in Q4 2015; Anticipated initiation of registration trial CD-003 for Crohn’s disease in H1 2016; Anticipated initiation of proof-of-concept P2 trial in ulcerative colitis in Q4 2015

Anticipated enrollment status • Anticipated new P2 trial • Anticipated new trial • Trial status • Inflammatory Bowel Disease

Celgene: Conference Call on GED-0301 (Celgene) - "Clinical Remission at Week 12"; "Endoscopic Response: SES-CD Reduction by ≥25% by Subgroup"; "Change in Overall FCP and hsCRP in Patients With Elevated Baseline Levels"

P1 data • Inflammatory Bowel Disease

Celgene: J.P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Celgene) - Anticipated launch for Crohn's disease in 2019; Anticipated approval for inflammatory bowel diseases in 2019

Anticipated launch • Anticipated regulatory • Inflammatory Bowel Disease