rivipansel (GMI-1070) / GlycoMimetics - LARVOL DELTA

Biologic Assessment of RBC Biology and Neutrophil Activation: Correlation with Sickle Cell Disease Activity (ASH 2023) - "A subset of samples were examined for RBC reactive oxygen species (ROS) content and adhesivity to laminin with and without stimulation by epinephrine...Interestingly, we also found that RBC [ATP] was lower in the RBCs of patients with higher total Hb, while it was higher in individuals with higher retic counts, suggesting that more long-lived RBCs have diminished [ATP], despite the fact that both [ATP] and total Hb have been reported to rise substantially after treatment with pyruvate kinase activators etavopivat and mitapivat...Similarly, senicapoc, which also reduces hemolysis, although by a different mechanism, failed to lessen VOE frequency...Anti-adhesive agents (crizanlizumab, rivipansel, sevuparin) have thus far failed to yield marked improvements in VOE frequency, but our results suggest that, in order to decrease the frequency of VOEs, it is not sufficient to reduce sickling and hemolysis. On the other hand, higher HbF levels were associated with lower admission..."

Cardiovascular • Genetic Disorders • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • Sickle Cell Disease • MMP9

Multi-Omics discovery and clinical validation of IGFBP2, B2M, and CST3 as a serum biomarker panel for diabetic kidney disease progression. (PubMed, Gene) - "Through a multi-omics approach, we identified IGFBP2/B2M/CST3 as a non-invasive biomarker panel for DKD progression, highlighting their roles as both diagnostic markers and therapeutic targets."

Biomarker • Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • B2M • CST3 • IGFBP2

GMI-1687-101, A PHASE 1A FIRST IN HUMAN TRIAL OF SECOND-GENERATION E-SELECTIN ANTAGONIST GMI-1687 (EHA 2024) - "Pan-selectin inhibitor rivipanselshortened IV opioid duration and length of stay in hospitalized SCD patients treated early in VOE, comparedwith placebo (Dampier, et al. Single ascending SC doses of second-generation E-selectin antagonist GMI-1687 (3. 3 to 80 mg) are safe andwell tolerated in healthy subjects. Pharmacokinetics results support testing of fixed-dose SC GMI-1687 in SCDpatients."

P1 data • Addiction (Opioid and Alcohol) • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • Sickle Cell Disease

Analogues of the pan-selectin antagonist rivipansel (GMI-1070). (PubMed, Eur J Med Chem) - "The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLex mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Genetic Disorders • Hematological Disorders • Oncology • Reperfusion Injury • Sickle Cell Disease • SELP

Glycomimetic drugs targeting E-selectin for inflammatory disease and as a major cause of progression and chemoresistance in cancer (ACS-Sp 2024) - "Rivipansel inhibits selectins by mimicking sialyl Lex and the tri-sulfated domain of PSGL-1...GMI-1687 binds E-selectin with a K D of 2.3 nM, is bioavailable through a subcutaneous route, and has recently entered Phase 1 clinical studies...As of August 2023, the reported median survival in this placebo-control blinded study with Uproleselan is over 30 months. Here, data are presented to demonstrate that E-selectin plays a major role in chemoresistance among many cancers and is susceptible to treatment with a potent glycomimetic drug."

Acute Myelogenous Leukemia • Genetic Disorders • Hematological Disorders • Oncology • Pain • Sickle Cell Disease • SELP

Revisiting the structural basis for biological activity of GMI-1070, a sialyl Lewis mimetic. (PubMed, Carbohydr Res) - "Our results for sialyl Lewis are in agreement with and expand upon prior work. As for the mimetic, our results indicate that, in spite of its conformational restriction, GMI-1070's behavior in solution deviates from what had been proposed, highlighting thus some features that could be optimized, as the development of sialyl Lewis mimetics continues, and new candidates emerge."

Journal • Oncology

[VIRTUAL] Early Initiation of Treatment with Rivipansel for Acute Vaso-Occlusive Crisis in Sickle Cell Disease (SCD) Achieves Earlier Discontinuation of IV Opioids and Shorter Hospital Stay: Reset Clinical Trial Analysis (ASH 2020) - P3 | "Pre-treatment variables were well balanced, including concomitant hydroxyurea use, genotype, chronic opioid use, gender, and country. These findings suggest the utility of early treatment to shorten or interrupt acute VOCs, analogous to thrombolysis for heart attack or stroke. This could change the VOC treatment paradigm from deferral of hospitalization to one of early intervention to reduce length of hospitalization and IV opioid requirement, relieve VOC symptoms, and possibly mitigate end-organ damage from tissue ischemia."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Myocardial Infarction • Pain • Pediatrics • Sickle Cell Disease

A Randomized Clinical Trial of the Efficacy and Safety of Rivipansel for Sickle Cell Vaso-occlusive Crisis (VOC). (PubMed, Blood) - P3 | "Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE)."

Clinical • Journal • Pain

Population Pharmacokinetic Analysis of Rivipansel in Healthy Subjects and Subjects with Sickle Cell Disease. (PubMed, Drugs R D) - "The pharmacokinetics of rivipansel was well characterized by a two-compartment population pharmacokinetic model. Our results illustrate the important role of simulations in optimizing a potential drug dosing regimen for patients with sickle cell disease and progressive renal impairment."

Clinical • Journal • PK/PD data • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Nephrology • Pain • Pediatrics • Renal Disease • Sickle Cell Disease

[VIRTUAL] Glycomimetic drugs: From rational design to clinical trials (ACS-Sp 2021) - P3 | "GMI-1070 (rivipansel) was designed to inhibit E, P, and L-selectins by incorporating a mimic of sialyl Lex together with that of the tri-sulfated domain of PSGL-1...In animal models of VOC, GMI-1687 blocked occlusion and normalized blood flow at 0.04 mg/kg BID...Based on positive phase 2 data, the FDA granted uproleselan “Breakthrough Therapy Designation”...Animal models of bone metastasis treated with GMI-1359 and chemotherapy show reduction of tumor volume and significant improvement in survival. GMI-1359 is now being studied in breast cancer patients at Duke University."

Clinical • Breast Cancer • Genetic Disorders • Hematological Disorders • Oncology • Pain • Sickle Cell Disease • Solid Tumor • CXCR4

[VIRTUAL] Restoration of Normal Blood Flow in Mouse Models of Sickle Cell Vaso-Occlusion Following Intravenous or Subcutaneous Administration of a Highly Potent E-Selectin Specific Inhibitor (ASH 2020) - "These data demonstrate that the administration of the potent and E-selectin specific compound GMI-1687 was effective in restoring blood flow in two mouse models of SCD, and support the development of GMI-1687 formulated for SC use and self-administration with the potential for early intervention of VOC."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

New Supportive Efficacy Data for GlycoMimetics’ Rivipansel in Sickle Cell Acute Vaso-Occlusive Crisis Presented at 62nd ASH Annual Meeting and Exposition (Businesswire) - P3, N=345; RESET (NCT02187003); Sponsor: GlycoMimetics; "...Dr. Wun reviewed key findings from several post hoc analyses of the Phase 3 RESET trial and a subsequent pre-planned analysis of the OLE trial. Specifically, these included the achievement of statistically significant improvements in primary and key secondary endpoints, with early treatment in the pediatric subgroup as well as the all-ages treatment group and importantly, on several key secondary endpoints, including time to discharge (TTD) and time to discontinuation of IV opioids (TTDIVO)."

P3 data • Sickle Cell Disease

GlycoMimetics Program Data to be Highlighted Via Three Oral Presentations and Two Posters at 62nd American Society of Hematology Annual Meeting and Exposition (Businesswire) - "Of particular note are primary and key secondary endpoint data from additional analysis of the Phase 3 RESET study evaluating the efficacy of rivipansel in VOC. These findings point to the potential benefits, clinical improvements and improved outcomes associated with early treatment with GlycoMimetics’ wholly-owned product candidate, which include shorter hospital stays for patients and reduced need for IV opioids to treat pain. A second presentation includes data from two different preclinical models of VOC using GlycoMimetics’ highly potent and specific E-selectin antagonist, GMI-1687. This presentation will highlight the product candidate’s potential for intravenous and subcutaneous administration to treat VOC by inhibiting occlusions and restoring blood flow."

P3 data • Preclinical • Sickle Cell Disease

New Pediatric and Secondary Endpoint Data from Rivipansel Phase 3 RESET Trial Presented at The Annual Scientific Conference on Sickle Cell and Thalassemia (ASCAT) Meeting (Businesswire) - P3, N=345; RESET (NCT02187003); Sponsor: GlycoMimetics; "GlycoMimetics...announced that new post hoc analyses of the Phase 3 RESET study evaluating the efficacy of rivipansel, its wholly-owned product candidate, in VOC show that pediatric patients treated with rivipansel within approximately 30 hours of the onset of acute crisis pain experienced statistically significant improvements in the primary efficacy endpoint of time to readiness for discharge (TTRFD) compared to placebo as well as in two key secondary endpoints, namely time-to-discharge (TTD) and time-to-discontinuation-of-IV opioids (TTDIVO)."

P3 data • Sickle Cell Disease

FDA Grants GlycoMimetics Rare Pediatric Disease Designation for Rivipansel for Treatment of Sickle Cell Disease (GlycoMimetics Press Release) - "GlycoMimetics...announced that the U.S. Food and Drug Administration (FDA) has granted the Company a Rare Pediatric Disease designation for rivipansel for the treatment of sickle cell disease in patients 18 years old and younger. This designation recognizes the significant needs in pediatric patients....'We plan to roll out the full data set from the Phase 3 RESET program at upcoming medical meetings, based on the acceptance of abstract submissions.”"

FDA event • P3 data • Hematological Disorders • Sickle Cell Disease

Lectin antagonists in infection, immunity, and inflammation. (PubMed, Curr Opin Chem Biol) - "This evolution has culminated in the transition of the small molecule GMI-1070 into clinical phase III. In this opinion article, an overview of the most important developments of lectin antagonists in the last two decades with a focus on the last five years is given."

Journal • Review • Immunology

Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel. (PubMed, Clin Pharmacol Drug Dev) - P1 | "The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment."

Clinical • Journal • PK/PD data • Complement-mediated Rare Disorders • Hematological Disorders • Renal Disease

New efficacy and biomarker data from rivipansel phase 3 RESET trial to be presented at Sickle Cell Meeting (Businesswire) - P3, N=345; RESET (NCT02187003); Sponsor: GlycoMimetics Incorporated; "GlycoMimetics...announced that a post hoc analysis of the Phase 3 RESET study evaluating the efficacy of rivipansel , its wholly-owned development candidate, in acute vaso-occlusive crisis (VOC) shows that patients treated with rivipansel within approximately 26 hours of the onset of pain in their crisis experienced statistically significant improvements in the primary efficacy endpoint of time to readiness for discharge compared to placebo."

P3 data • Sickle Cell Disease

Effect of Renal Impairment on the Pharmacokinetics and Safety of Rivipansel in Subjects with Renal Impairment and in Healthy Subjects (ASH 2018) - "Conclusion s: Greater rivipansel exposure and decreased clearance were observed in subjects with renal impairment compared with subjects with normal renal function. A single 840-mg IV dose of rivipansel was well tolerated in all groups."

Clinical • PK/PD data • Biosimilar • Gene Therapies • Genetic Disorders • Hematological Disorders • Renal Disease

A Study to Evaluate the Effect of IV Doses of GMI-1070 on Qtc Intervals in Healthy African-American Adult Subjects (clinicaltrials.gov) - P1; N=48; Completed; Sponsor: Pfizer; Active, not recruiting -> Completed

Trial completion • Acute Coronary Syndrome • Biosimilar

Efficacy and Safety of Rivipansel (GMI-1070) in the Treatment of Vaso-Occlusive Crisis in Hospitalized Subjects With Sickle Cell Disease (clinicaltrials.gov) - P3; N=350; Not yet recruiting; Sponsor: Pfizer; Initiation date: Jun 2015 ->Sep 2014

Trial initiation date • Biosimilar • Hematological Malignancies • Pain

Efficacy and Safety of Rivipansel (GMI-1070) in the Treatment of Vaso-Occlusive Crisis in Hospitalized Subjects With Sickle Cell Disease (clinicaltrials.gov) - P3; N=350; Not yet recruiting; Sponsor: Pfizer; Initiation date: Sep 2014 ->Jun 2015

Trial initiation date • Biosimilar • Hematological Malignancies • Pain

Safety Of Rivipansel (GMI-1070) In The Treatment Of One or More Vaso-occlusive Crises In Hospitalized Subjects With Sickle Cell Disease (clinicaltrials.gov) - P3; N=153; Terminated; Sponsor: Pfizer; Trial completion date: Jun 2021 ➔ Nov 2019; Active, not recruiting ➔ Terminated; Trial primary completion date: Jun 2021 ➔ Nov 2019

Clinical • Trial completion date • Trial primary completion date • Trial termination

Safety Of Rivipansel (GMI-1070) In The Treatment Of One or More Vaso-occlusive Crises In Hospitalized Subjects With Sickle Cell Disease (clinicaltrials.gov) - P3; N=153; Active, not recruiting; Sponsor: Pfizer; Recruiting ➔ Active, not recruiting; N=250 ➔ 153

Clinical • Enrollment change • Enrollment closed

"GlycoMimetics craters as @pfizer says rivipansel flunks phase 3 #sicklecell crisis trial https://t.co/U93T9PUZyU" (@pharmaphorum)