OligoG CF-5/20 / AlgiPharma - LARVOL DELTA

Low Molecular Weight Alginate Oligosaccharides as Alternatives to PEG for Enhancement of the Diffusion of Cationic Nanoparticles Through Cystic Fibrosis Mucus. (PubMed, Adv Healthc Mater) - "In siRNA RTN transfections, OligoM is better than OligoG although 1% PEG is slightly better than both. The combination of cationic RTNs and alginate oligosaccharides represents a promising alternative to PEGylation for epithelial delivery of genetic therapies across the mucus barrier while retaining transfection efficiency."

Journal • Cystic Fibrosis • Gene Therapies • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 2b Randomised, Placebo Controlled Study of OligoG in Patients with Cystic Fibrosis (clinicaltrials.gov) - P2 | N=15 | Terminated | Sponsor: AlgiPharma AS | Phase classification: P2b ➔ P2 | Unknown status ➔ Terminated; Futility

Phase classification • Trial termination • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Alginate oligosaccharides exert protective effects on hydrogen peroxide-induced senescence in H9C2 cardiomyocytes by regulating the redox state of cells. (PubMed, Food Sci Biotechnol) - "A series of AOS molecules, including oligoM, oligoG, M-5, and G-5, were investigated...Furthermore, AOS treatment restored the expression of antioxidant enzymes in senescent H9C2 cells. Thus, our results show in vitro evidence that AOS alleviate senescence in H9C2 cells by regulating the redox state; thus, AOS may be an effective therapeutic agent that could protect against cardiomyocyte senescence."

Journal • Cardiovascular • CDKN1A

A chemo-enzymatic method for preparation of saturated oligosaccharides from alginate and other uronic acid-containing polysaccharides. (PubMed, Carbohydr Polym) - "In the case of alginate, the ratio of hydrolysis rate of Δ-G and Δ-M linkages to that of G-G and M-M linkages, respectively, was found to be approximately 65 and 43, at pH* 3.4, 90 °C. Finally, this method has been demonstrated to be superior in the production of α-l-guluronate oligosaccharides with a lower content of β-d-mannuronate residues compared to what can be achieved using chemical depolymerization alone."

Journal

Co-spray dried inhalable composite powders of ciprofloxacin and alginate oligosaccharide as anti-biofilm therapy. (PubMed, Int J Pharm) - "In this study, we designed new inhalable dry powders containing ciprofloxacin (CIP) and OligoG (Oli, a low-molecular-weight alginate oligosaccharide impairing the mucoid biofilms by interacting with their cationic ions) to combat respiratory bacterial biofilm infections. In contrast, the dry powders became non-inhalable following the storage at 20 ± 2 °C/53 ± 2 % RH for one month due to the hygroscopic nature of Oli, which could be largely prevented by incorporation of leucine. Collectively, this study suggests that the newly developed co-spray-dried powders composed of CIP and Oli might represent a promising and alternative treatment strategy against respiratory bacterial biofilm infections."

Journal • Infectious Disease • Respiratory Diseases

Structure-Activity Relationships of Low Molecular Weight Alginate Oligosaccharide Therapy against Pseudomonas aeruginosa. (PubMed, Biomolecules) - "While confocal laser scanning microscopy showed that both agents demonstrated similar dose-dependent reductions in biofilm formation, OligoG exhibited a stronger QS inhibitory effect and increased potentiation of the antibiotic azithromycin in minimum inhibitory concentration and biofilm assays. This study demonstrates that the anti-microbial effects of alginate oligosaccharides are not purely influenced by Ca-dependent processes but also by electrostatic interactions that are common to both G-block and M-block structures."

Journal

The alginate polymer OligoG alters susceptibility of biofilm-embedded non-typeable Haemophilus influenzae to ampicillin and ciprofloxacin. (PubMed, JAC Antimicrob Resist) - "OligoG shows promise as a potential adjuvant to antibiotics in NTHi infections, but strain-specific factors appear to affect drug interactions and may lead to antagonism. More research is needed to clarify the mechanisms of action of OligoG and interactions with antibiotics."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Influenza • Pulmonary Disease • Respiratory Diseases

Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms. (PubMed, Front Cell Infect Microbiol) - "Antimicrobial synergy between OligoG and nystatin against Candida spp. highlights the potential utility of this combination therapy in the prevention and topical treatment of candidal biofilm infections, to overcome the inherent tolerance of biofilm structures to antifungal agents."

Journal • Candidiasis • Infectious Disease

Polyguluronate simulations shed light onto the therapeutic action of OligoG CF-5/20. (PubMed, Bioorg Med Chem) - "This work, utilising molecular dynamics (MD) and Density-Functional Theory (DFT), has revealed that OligoG CF-5/20 interaction with the EPS is facilitated solely through bridging Ca ions, which are not liberated from their native EPS binding sites upon OligoG CF-5/20 dispersal, suggesting that OligoG CF-5/20 does not cause disruptions to mature P. aeruginosa biofilms through breaking EPS-Ca-EPS ionic cross-links. Rather it is likely that the therapeutic activity arises from sequestering free Ca ions and preventing further Ca induced EPS aggregation."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

SMR3372: A Dose-finding Study of Inhaled OligoG vs Placebo in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2/3 | N=0 | Withdrawn | Sponsor: AlgiPharma AS | N=120 ➔ 0 | Trial completion date: Jul 2022 ➔ Nov 2022 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Mar 2022 ➔ Oct 2022

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Alginate oligosaccharides enhance diffusion and activity of colistin in a mucin-rich environment. (PubMed, Sci Rep) - "Addition of alginate oligosaccharide (OligoG CF-5/20) significantly improved colistin diffusion by 3.7 times through mucin-rich AS medium (at 48 h; p < 0.05). These data support the use of this model to study drug and small molecule delivery across clinically-relevant diffusion barriers. The findings indicate the significant loss of colistin and reduced effectiveness that occurs with mucin binding, and support the use of mucolytics to improve antimicrobial efficacy and lower antibiotic exposure."

Journal • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Evaluating the alginate oligosaccharide (OligoG) as a therapy for Burkholderia cepacia complex cystic fibrosis lung infection. (PubMed, J Cyst Fibros) - "OligoG has previously shown potentiation of aztreonam against Burkholderia cepacia complex (Bcc) through biofilm disruption. There was a favourable safety profile for OligoG. Potential for reducing Bcc warrants further investigation of OligoG for the treatment of infection in CF."

Clinical • Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

Phenotypic and Genotypic Adaptations in Pseudomonas aeruginosa Biofilms following Long-Term Exposure to an Alginate Oligomer Therapy. (PubMed, mSphere) - "Interestingly, however, cross-resistance to other antibiotics (e.g., aztreonam) was reduced in the presence of OligoG CF-5/20. Here, a bead biofilm model with repeated exposure of P. aeruginosa to OligoG CF-5/20 (alone and in combination with azithromycin) was conducted to study these long-term effects and characterize the phenotypic and genotypic adaptations which result. These findings, over 6 weeks, show that long-term use of OligoG CF-5/20 does not lead to extensive mutational changes and may potentially decrease the pathogenicity of the bacterial biofilm and improve the susceptibility of P. aeruginosa to other classes of antibiotics."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Implementation of microbiota analysis in clinical trials for cystic fibrosis lung infection: Experience from the OligoG phase 2b clinical trials. (PubMed, J Microbiol Methods) - P2, P2b | "Despite the uniform pathogen culture-positivity status at recruitment, trial participants were highly heterogeneous in their lung microbiota. Understanding the microbiota profiles of individuals with CF ahead of future clinical trials would be beneficial in the context of patient stratification and trial design."

Clinical • Journal • P2b data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Exploiting Mannuronan C-5 Epimerases in Commercial Alginate Production. (PubMed, Mar Drugs) - "The alginates produced using either source showed similar antibiotic potentiation effects to the drug candidate OligoG CF-5/20 currently in development as a mucolytic and anti-biofilm agent. These findings clearly illustrate the value of using epimerases to provide an alternative production route for novel low-molecular-weight alginates."

Journal

Bi-Functional Alginate Oligosaccharide-Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections. (PubMed, Pharmaceutics) - "Both OligoG-colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro "time-to-kill" (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. Bi-functional OligoG-polymyxin conjugates have potential therapeutic benefits in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections, directly reducing toxicity whilst retaining antimicrobial and antibiofilm activities."

Journal • Infectious Disease

Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebo-controlled, crossover phase 2b study. (PubMed, ERJ Open Res) - "The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post hoc exploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified."

Clinical • Journal • P2b data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Cellulose nanofibril formulations incorporating a low molecular weight alginate oligosaccharide modify bacterial biofilm development. (PubMed, Biomacromolecules) - "These novel CNF formulations or bio-nanocomposites were able to modify bacterial growth, biofilm development and virulence factor production in vitro. These data support the potential of OligoG and CNF bio-nanocomposites for use in biomedical applications where prevention of infection or biofilm growth is required."

Journal

A Phase 2b Randomised, Placebo Controlled Study of OligoG in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2b; N=20; Active, not recruiting; Sponsor: AlgiPharma AS; Recruiting ➔ Active, not recruiting; N=33 ➔ 20; Trial completion date: Jul 2020 ➔ Jul 2021

Clinical • Enrollment change • Enrollment closed • Trial completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Targeted disruption of the extracellular polymeric network of Pseudomonas aeruginosa biofilms by alginate oligosaccharides. (PubMed, NPJ Biofilms Microbiomes) - "ITC demonstrated an absence of rapid complex formation between DNA and OligoG and confirmed the interactions of OligoG with Ca evident in FTIR and MD modelling. The ability of OligoG to diffuse into biofilms, potentiate antibiotic activity, disrupt DNA-Ca-DNA bridges and biofilm EPS matrix highlights its potential for the treatment of biofilm-related infections."

Journal • Biosimilar • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology

SMR3372: A Dose-finding Study of Inhaled OligoG vs Placebo in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2/3; N=120; Not yet recruiting; Sponsor: AlgiPharma AS; Trial completion date: Mar 2021 ➔ Jul 2022; Trial primary completion date: Dec 2020 ➔ Mar 2022

Clinical • Trial completion date • Trial primary completion date

A Phase 2b Randomised, Placebo Controlled Study of OligoG in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2b; N=33; Recruiting; Sponsor: AlgiPharma AS; Trial completion date: Feb 2020 ➔ Jul 2020

Clinical • Trial completion date

SMR3372: A Dose-finding Study of Inhaled OligoG vs Placebo in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2/3; N=120; Not yet recruiting; Sponsor: AlgiPharma AS; Trial completion date: Dec 2021 ➔ Mar 2021

Clinical • Trial completion date

SMR3372: A Dose-finding Study of Inhaled OligoG vs Placebo in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2/3; N=120; Not yet recruiting; Sponsor: AlgiPharma AS; Trial completion date: Jun 2021 ➔ Dec 2021

Clinical • Trial completion date

A Phase 2b Randomised, Placebo Controlled Study of OligoG in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2b; N=33; Recruiting; Sponsor: AlgiPharma AS; Not yet recruiting ➔ Recruiting; Trial completion date: Oct 2019 ➔ Feb 2020; Trial primary completion date: Sep 2019 ➔ Jan 2020

Clinical • Enrollment open • Trial completion date • Trial primary completion date