miridesap (GSK2315698) / GSK - LARVOL DELTA

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders. (PubMed, Open Biol) - "These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective."

Biomarker • Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

The Yin and Yang of Serum Amyloid P Component in Candidiasis and Other Fungal Infections (ASM Microbe 2023) - "When the inoculum was decreased 33% to 3.0 x 104 yeast/gm, the miridesap treatment doubled the median time to death, and two of five treated mice survived the disease challenge. Thus, SAP binding to fungal surface amyloid passivated the immune system and decreased inflammatory responses to prolong survival, but removal of SAP led to improved survival, and in some cases to resolution of systemic candidiasis."

Candidiasis • Dermatology • Infectious Disease • Inflammation • CRP • IFNG • IL10

The Paradoxical Effects of Serum Amyloid-P Component on Disseminated Candidiasis. (PubMed, Pathogens) - "SAP administered early in the septic process provided short-lived benefit to mice, probably by blunting cytokine secretion associated with disseminated candidiasis. The most important finding was that removal of SAP with miridesap led to prolonged survival by removing SAP and preventing its dampening effects on the host immune response."

Journal • Candidiasis • Infectious Disease

Blocking Serum Amyloid-P Component from Binding to Macrophages and Augmenting Fungal Functional Amyloid Increases Macrophage Phagocytosis of Candida albicans. (PubMed, Pathogens) - "Blocking the binding of SAP to macrophage FcγR1 receptors increases phagocytosis of yeast cells; seeding a pro-amyloid-forming peptide on the yeast cell surface also increases phagocytosis of yeasts by macrophages; and, lastly, miridesap, a small palindromic molecule, prevents binding of SAP to yeasts and removes SAP that is bound to C. albicans thus, potentially increasing phagocytosis of yeasts by macrophages. Some, or all, of these interventions may be useful in boosting the host immune response to disseminated candidiasis."

Journal • Candidiasis

An observational, non-interventional study for the follow-up of patients with amyloidosis who received miridesap followed by dezamizumab in a phase 1 study. (PubMed, Orphanet J Rare Dis) - P1 | "No further development of miridesap/dezamizumab is planned in amyloidosis. However, long-term follow-up of these patients may provide insight into whether active removal of amyloid deposits has an impact on disease progression."

Journal • Observational data • P1 data • Amyloidosis • Cardiovascular • APOA1

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study. (PubMed, BMC Cardiovasc Disord) - P1, P2 | "Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)."

Journal • P2 data • PK/PD data • Amyloidosis • Cardiovascular • Vasculitis

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Intravenous Dose of Miridesap in Healthy Japanese Subjects. (PubMed, Clin Pharmacol Drug Dev) - "Rapid depletion of circulating serum amyloid P component was observed after the initiation of miridesap infusion. Serum amyloid P component concentrations fell in a dose-dependent manner following administration of miridesap."

Clinical • Journal • PK/PD data

Identification, preclinical profile and clinical proof of concept of an orally bio-available pro-drug of miridesap. (PubMed, Br J Pharmacol) - "Using a preclinical screening cascade, we identified a pro-drug for a palindromic molecule with unique pharmacology (miridesap). The pro-drug depleted circulating SAP with a time course and extent similar to that of parenterally-administered miridesap."

Journal

The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs. (PubMed, Front Immunol) - "Meanwhile, the obligate therapeutic partnership of miridesap, to deplete circulating SAP, and dezamizumab, a humanized monoclonal anti-SAP antibody that targets residual SAP in amyloid deposits, produces unprecedented removal of amyloid from the tissues and improves organ function. The present personal and critical perspective on the pentraxins reports, for the first time, the key role of serendipity in our work since 1975. (345 words)."

Journal

Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698 (clinicaltrials.gov) - P2; N=7; Terminated; Sponsor: GlaxoSmithKline; N=30 ➔ 7; Trial completion date: Sep 2021 ➔ Jan 2019; Suspended ➔ Terminated; Trial primary completion date: Sep 2021 ➔ Jan 2019; Change in benefit/risk profile

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination