andecaliximab (GS-5745) / Gilead - LARVOL DELTA

āshibio Doses First Patient in ANDECAL study, a Phase 2/3 Trial of Andecaliximab for Treatment of Fibrodysplasia Ossificans Progressiva (FOP) (Businesswire) - "āshibio...today announced the dosing of the first participant in its ANDECAL study, a Phase 2/3 clinical trial evaluating the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of andecaliximab in patients with fibrodysplasia ossificans progressiva (FOP).'"

Trial status • Genetic Disorders

Systematic Literature Review (SLR) of Randomized Controlled Trials (RCTs) of Treatments for First-Line (1L) Gastric Cancer/Gastroesophageal Junction Adenocarcinoma (GC/GEJ) in Adult Patients (ISPOR-EU 2024) - "Among trials of PD-1/PD-L1 inhibitors (tislelizumab, nivolumab, pembrolizumab, sugemalimab, sintilimab), improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were observed for PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone at median follow-up times ranging from 11.6 to 54.3 months, with median OS, median PFS, and ORR ranging from 12.5 to 17.45 months, 6.9 to 10.94 months, and 47.3% to 68.6%, respectively...Among other targeted therapies, response and survival benefits compared to chemotherapy were mixed; improvements in response and survival were seen with the CLDN18.2 inhibitor zolbetuximab and the FGFR inhibitor bemarituzumab, while benefits compared to chemotherapy were not seen with cetuximab, ramucirumab, andecaliximab, onartuzumab, rilotumumab, pazopanib, or ipatasertib... PD-1/PD-L1 inhibitors showed improved efficacy compared to chemotherapy for the treatment of 1L GC/GEJ; while other..."

Clinical • IO biomarker • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CLDN18 • CTLA4 • HER-2

A Study of Andecaliximab in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P2/3 | N=92 | Recruiting | Sponsor: Ashibio Inc | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of Andecaliximab in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P2/3 | N=92 | Not yet recruiting | Sponsor: Ashibio Inc | Initiation date: Aug 2024 ➔ Dec 2024

Trial initiation date

Inhibition of MMP9 as a novel treatment strategy for Fibrodysplasia Ossificans Progressiva (FOP): Safety analysis of the anti-MMP9 antibody Andecaliximab in development for FOP (ASBMR 2024) - No abstract available

Clinical • Late-breaking abstract • Musculoskeletal Diseases • Orthopedics • MMP9

A Study of Andecaliximab in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P2/3 | N=92 | Not yet recruiting | Sponsor: Ashibio Inc

New P2/3 trial

“METABOLISM AND RESPONSE TO STRESS” (MARS) GENE SIGNATURES REVEAL HETEROGENEITY IN PATIENTS WITH ULCERATIVE COLITIS AND IDENTIFY CHARACTERISTICS OF PATIENTS WITH INCREASED RESPONSE TO THERAPY (DDW 2024) - P2/3, P3 | " Two clinical trial datasets including patients with moderate to severe UC with mucosal biopsy RNA-Sequencing analysis were used: a phase /3 study of andecaliximab (anti-matrix metalloproteinase-9 NCT0 5 0 84) and a phase 3 study of ustekinumab (anti-interleukin-1 / 3 UNIFI NCT0 407 36). We describe the MARS signatures which characterize the heterogeneity of participants with UC clinical trials and identify participants most likely to respond to ustekinumab at baseline. These signatures may be generally useful to predict patient response match therapeutics to patient profiles or identify pathways to target in difficult-to-treat patients."

Clinical • Gene Signature • Heterogeneity • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • MMP9

"Metabolism and Response to Stress" (MARS) gene signatures reveal heterogeneity in patients with Ulcerative Colitis and identify characteristics of patients with increased response to therapy (ECCO-IBD 2024) - P2/3, P3 | "Methods Two clinical trial datasets including patients with moderate to severe UC with mucosal biopsy RNA-Sequencing analysis were used: a phase 2/3 study of andecaliximab (anti-matrix metalloproteinase-9, NCT02520284) and a phase 3 study of ustekinumab (anti-interleukin‑12/23, UNIFI, NCT02407236). Conclusion We describe the MARS signatures which characterise the heterogeneity of participants with UC clinical trials and identify participants most likely to respond to ustekinumab at baseline. These signatures may be generally useful to predict patient response, match therapeutics to patient profiles, or identify pathways to target in difficult-to-treat patients."

Clinical • Gene Signature • Heterogeneity • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • IL12A • MMP9

Text Mining and Drug Discovery Analysis: A Comprehensive Approach to Investigate Diabetes-Induced Osteoporosis. (PubMed, Int J Med Sci) - "After DGI analysis, we identified 7 genes targeted by 11 drugs, which represent candidates for treating DOP. This study unveils ANDECALIXIMAB, SILTUXIMAB, OLOKIZUMAB, SECUKINUMAB, and IXEKIZUMAB as promising potential drugs for DOP treatment, demonstrating the significance of utilizing text mining and pathway analysis to investigate disease mechanisms and explore existing therapeutic options."

Journal • Diabetes • Metabolic Disorders • Orthopedics • Osteoporosis • Rheumatology

Identification of key genes in colorectal cancer diagnosis by co-expression analysis weighted gene co-expression network analysis. (PubMed, Comput Biol Med) - "Taken together, the results of the current study indicated that seven hub genes including COL1A2, COL5A1, COL5A2, SERPINH1, MMP9, SPARC, and COL1A1 which were upregulated in CRC could be used as a diagnostic and progression biomarker of CRC. On the other hand, miR-940 which targets SERPINH1 could be used as a potential biomarker of CRC. More ever, Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, Bevacizumab, Ocriplasmin , and Collagenase clostridium histolyticum were introduced as therapeutic agents for CRC which their therapeutic potential should be evaluated experimentally."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • COL1A1 • COL1A2 • COL5A1 • COL5A2 • MMP9 • SERPINH1

Promising targeted approaches (DGHO 2019) - "The combination of trifluridine/tipiracil (TAS-102) is a new oral anticancer drug with activity in gastrointestinal cancer...Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits the VEGFR-2 tyrosine kinase...The recent results from a large phase 3 trial with andecaliximab, a monoclonal antibody that inhibits matrix-metalloproteinase-9 (MMP-9), failed to replicate the positive data from a previous study of andecaliximab in combination with chemotherapy in untreated HER2-negative gastric or gastroesophageal junction adenocarcinoma...Randomized clinical studies with zolbetuximab are ongoing. Data on new targeted therapy options (excluding immunotherapy) will be discussed."

Immune monitoring of blood in advanced gastroesophageal adenocarcinoma patients treated with an anti-MMP9 monoclonal antibody in combination with nivolumab. (ASCO-SITC 2020) - P1b; "Background: A phase 1b study was conducted in Japanese patients with >2nd line advanced gastroesophageal adenocarcinoma (GEA) to evaluate the safety, tolerability and explore efficacy and biomarkers, of andecaliximab (ADX), an anti-MMP9 monoclonal antibody, in combination with nivolumab (nivo). The observation that baseline levels of LAG3+CD8+ T cells and DCs were higher in responders is consistent with a prior anti-tumor immune response. Transient decreased peripheral CD8+ T cells might reflect T-cell trafficking into tumor in response to immunotherapy, and increased peripheral CTLA-4+ CD4+ T cells may also relate to tumor-localized response. Although in a very small number of patients, the observations are consistent with early changes in peripheral immune cells that may relate to response to immunotherapy."

Clinical • Combination therapy • IO Biomarker • CD8 • MMP9

Effect of MMP9 inhibition on effector T-cell responses in a PD1-axis refractory model. (ASCO-SITC 2017) - P2; "Inhibition of MMP9 reduces tumor burden and promotes cytotoxic T cell infiltration in a PD1-axis refractory mouse model. The combination of nivolumab and GS-5745, a humanized anti-MMP9 inhibitory antibody, is currently being evaluated in gastric cancer (NCT02864381)."

Preclinical • Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Oncology

Exploratory evaluation of baseline tumor biomarkers and their association with response and survival in patients with previously treated advanced gastric cancer treated with andecaliximab combined with nivolumab versus nivolumab. (ASCO-GI 2019) - P2; "Neither CD8+ cell density nor IFNg, Teff or ActT gene signatures were associated with response or survival to checkpoint blockade. While TC was low, IC intermediate and TC + IC ≥ 1% PD-L1+ groups trended toward better survival for the ADX+N arm, consistent with the hypothesis that ADX potentiates N activity; this did not translate into better outcome."

Biomarker • Clinical • IO Biomarker • PD(L)-1 Biomarker

Phase Ib study of andecaliximab (GS-5745, ADX) in combination with S-1+platinum chemotherapy in Japanese subjects with advanced gastric or GEJ adenocarcinoma. (ASCO-GI 2019) - P1b; " The safety and efficacy of ADX in combination with S-1+cisplatin (SP) or S-1+oxaliplatin (SOX) were evaluated in subjects with systemic chemotherapy naïve advanced gastric or GEJ adenocarcinoma. Preliminary safety data demonstrate a manageable safety profile for ADX in combination with S-1+platinum, and the combination appears to show promising response rates."

Clinical • Combination therapy • P1 data

A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma. (ASCO-GI 2019) - P2; "Addition of ADX to NIVO did not improve ORR, PFS, or OS compared with NIVO alone in patients with pre-treated metastatic gastric or GEJ adenocarcinoma. Combination of ADX with NIVO had a favorable safety and tolerability profile."

Clinical • IO Biomarker • P2 data • PD(L)-1 Biomarker

Phase 1b study of andecaliximab (GS-5745, ADX) as monotherapy and in combination with nivolumab (nivo) in Japanese subjects with gastric or GEJ adenocarcinoma. (ASCO-GI 2019) - P1b; "Preliminary safety data demonstrate a manageable safety profile for ADX alone and in combination with nivo. The combination appears to be promising."

Clinical • Combination therapy • Monotherapy • P1 data • PD(L)-1 Biomarker

Evaluation of intratumoral T cells in biopsies from advanced gastric cancer patients treated with andecaliximab and nivolumab. (ASCO-GI 2019) - P2; "In the PD-L1+ ADX/N group, there was a significantly greater magnitude of CD8+ cell density increase, which was associated with gene signatures of T cell activation. More ADX/N-treated patients had an increase in tumor-associated CD8+ cells. Longer PFS was observed for patients in which CD8+ cells increased by ≥ 300%."

Clinical • IO Biomarker • PD(L)-1 Biomarker

A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of andecaliximab combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma (GAMMA-1). (ASCO-GI 2019) - P3; "Oxaliplatin was administered on Days 1 and 15 of each 28-day treatment cycle (total of 6 cycles), followed by leucovorin and 5-fluorouracil dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. Additionof ADX to mFOLFOX6 does not improve OS in pts with untreated HER2-negative gastric or GEJ adenocarcinoma."

Clinical • P3 data

A phase II, open-label, randomized study to evaluate the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma. (ASCO 2017) - P2; "Exploratory biomarkers correlated with study drug response will also be evaluated. Enrollment opened September 2016."

Checkpoint inhibition • Head-to-Head • Biosimilar • Esophageal Cancer • Gastric Cancer

Inhibition of MMP9 improves anti-tumor immunity by changing the tumor microenvironment to promote T cell trafficking and activation (AACR 2017) - P3,P2; "These analyses show that MMP9 is expressed in a variety of human tumors. Our data suggest that inhibition of MMP9 promotes anti-tumor immunity and enhances a Th1 immune response. GS-5745, a humanized anti-MMP9 inhibitory antibody, is being evaluated in gastric cancer in phase 3 and 2 studies with chemotherapy and nivolumab, respectively (NCT02545504, NCT02864381)."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology

Exploratory serum biomarker analysis in gastric cancer patients treated with GS-5745, an MMP9 Inhibitor, in combination with mFOLFOX6 (AACR 2017) - P1; "Modulation of these systemic biomarkers may reflect inhibition of MMP9 activity in the tumor consequent with reduced suppression of anti-tumor immunity; however, conclusions from this study are limited by the fact that all patients were treated with GS+chemo. Confirmation of these findings will require a controlled prospective study."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Immunology • Oncology

A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma. (ASCO-GI 2019) - P2; "Addition of ADX to NIVO did not improve ORR, PFS, or OS compared with NIVO alone in patients with pre-treated metastatic gastric or GEJ adenocarcinoma. Combination of ADX with NIVO had a favorable safety and tolerability profile."

Clinical • IO Biomarker • P2 data • PD(L)-1 Biomarker

Phase Ib study of andecaliximab (GS-5745, ADX) in combination with S-1+platinum chemotherapy in Japanese subjects with advanced gastric or GEJ adenocarcinoma. (ASCO-GI 2019) - P1b; " The safety and efficacy of ADX in combination with S-1+cisplatin (SP) or S-1+oxaliplatin (SOX) were evaluated in subjects with systemic chemotherapy naïve advanced gastric or GEJ adenocarcinoma. Preliminary safety data demonstrate a manageable safety profile for ADX in combination with S-1+platinum, and the combination appears to show promising response rates."

Clinical • Combination therapy • P1 data

Characterization of Active MMP9 in Chronic Inflammatory Diseases Using a Novel Anti-MMP9 Antibody. (PubMed, Antibodies (Basel)) - "It is detected around sites of active tissue remodeling, including fistulae of inflammatory bowel and dermal fissures in hidradenitis suppurativa, and is expressed by myeloid cells, including macrophages and neutrophils. Together, our findings provide insights into the distribution and potential role of MMP9 in inflammatory diseases."

Journal • Dermatology • Gastroenterology • Hidradenitis Suppurativa • Immunology • Inflammation • MMP9