murepavadin (POL7080) / Spexis - LARVOL DELTA

Antibiotics and non-traditional antimicrobial agents for pseudomonas aeruginosa in clinical phases 1, 2, and 3 trials. (PubMed, Expert Opin Investig Drugs) - "Traditional agents in clinical development include β-lactam/β-lactamase inhibitors (funobactam, taniborbactam, QPX2014-xeruborbactam), aminoglycosides (apramycin), polymyxin derivatives (upleganan, MRX-8, and SPR741), fluoroquinolones (MP-376), and lipopolysaccharide transport inhibitors (murepavadin). Non-traditional antibiotics in clinical development include anti-virulence agents (fluorothiazinone), monoclonal antibodies (INFEX-702, TRL-1068, and CMTX-101), bacteriophages (AP-PA02, YPT-01, BX004-A, and WRAIR-PAM-CF1), and miscellaneous agents (AR-501, PLG-0206, SNSP-113, OligoG CF-5/20, and ALX-009). A considerable number of antimicrobial agents, some with novel mechanisms of action, are in clinical phases of development for treating Pseudomonas aeruginosa infections. The urgent need for more therapeutic options necessitates the rapid optimization of progress to introduce new agents into clinical practice."

Journal • Review • Infectious Disease

Unravelling the mechanisms causing murepavadin resistance in Pseudomonas aeruginosa: lipopolysaccharide alterations and its consequences. (PubMed, Front Cell Infect Microbiol) - "We aimed to explore genomic modifications and consequences underlying murepavadin and/or colistin susceptibility. Although GWAS identified one variant associated with the murepavadin-resistant phenotype, data revealed that there was no unique single genetic event underlying this phenotype. Our study provides insight into the mechanisms underlying murepavadin susceptibility."

Journal • Inflammation

Murepavadin Enhances the Killing Efficacy of Ciprofloxacin against Pseudomonas aeruginosa by Inhibiting Drug Efflux. (PubMed, Antibiotics (Basel)) - "In addition, the murepavadin-ciprofloxacin combination exhibits a synergistic bactericidal effect in an acute murine pneumonia model. In conclusion, our results identify an effective drug combination for the treatment of P. aeruginosa infections."

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

Synthesis of the Antimicrobial Peptide Murepavadin Using Novel Coupling Agents. (PubMed, Biomolecules) - "Finally, the antimicrobial activity of different synthetic batches was tested in three Pseudomonas aeruginosa strains, including highly resistant ones. All murepavadin batches yielded the same highly active MIC values and proved that the chiral integrity of the molecule was preserved throughout the whole synthetic procedure."

Journal

Murepavadin promotes the killing efficacies of aminoglycoside antibiotics against Pseudomonas aeruginosa by enhancing membrane potential. (PubMed, Antimicrob Agents Chemother) - "We further demonstrated that murepavadin enhances bacterial respiration activity and subsequent membrane potential, which promotes intracellular uptake of aminoglycoside antibiotics. In addition, the murepavadin-amikacin combination displayed a synergistic bactericidal effect in a murine pneumonia model."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Mutations in genes lpxL1, bamA, and pmrB impair the susceptibility of cystic fibrosis strains of Pseudomonas aeruginosa to murepavadin. (PubMed, Antimicrob Agents Chemother) - "Furthermore, we found that specific amino acid substitutions in histidine kinase PmrB (G188D, Q105P, and D45E) reduce the susceptibility of P. aeruginosa to murepavadin, colistin, and tobramycin, three antibiotics used or intended to be used (murepavadin) in aerosols to treat colonized CF patients. Whether colistin or tobramycin may select mutants resistant to murepavadin or the opposite needs to be addressed by clinical studies."

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

A novel synthetic method for backbone-cyclized polypeptide POL7080 with the help of hydrophobic-support materials. (PubMed, Org Biomol Chem) - "In this paper, we report a liquid-phase peptide synthetic route for this valuable candidate polypeptide assisted by hydrophobic-support materials (tags), which overcomes the difficulties of high cost and poor yield in the traditional solid-phase synthesis of macrocyclic peptides. Through the careful optimization of reaction conditions and the innovative strategy of synthetic post-treatment, we established a simple and efficient liquid-phase synthetic route suitable for POL7080 and other similar structures, with satisfactory yield, high purity and a production process not being controlled by scale."

Journal • Infectious Disease

Antibiotic therapy for nonfermenting Gram-negative bacilli infections: future perspectives. (PubMed, Curr Opin Infect Dis) - "Each of the novel molecules reviewed possesses an interesting range of in-vitro activity against NF-GNB. In addition, some of them have already been proved effective in vivo, underscoring their potential as future treatment options."

Gram negative • Journal • Infectious Disease • Nephrology

Murepavadin induces envelope stress response and enhances the killing efficacies of β-lactam antibiotics by impairing the outer membrane integrity of Pseudomonas aeruginosa. (PubMed, Microbiol Spectr) - "In addition, the combination of murepavadin and a β-lactam/β-lactamase inhibitor mixture (ceftazidime/avibactam) slowed down the resistance development of P. aeruginosa. Overall, this study demonstrates the bacterial response to murepavadin and provides a new combination strategy for effective treatment."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Spexis provides business update and announces financial results for the full year 2022 (GlobeNewswire) - "Lead Program: ColiFin®....COPILOT has study start-up activities ongoing and is expected to enroll its first patient in Q3 2023 with data expected in the first quarter of 2024....Spexis intends to advance iMPV into Phase 1b/2 studies in CF patients in 2023, with the potential to expand development efforts into moderate to severe non-CF bronchiectasis ('nCFBE'), a significant additional market opportunity....R&D expenditures are expected to increase in 2023 as the company launches the Phase 3 trial for ColiFin®...Spexis’ cash position as of December 31, 2022 was CHF 1.8 million (cash and cash equivalents)."

Financing • New P1/2 trial • P3 data • Bronchiectasis • Non‐Cystic Fibrosis Bronchiectasis

Lipid A modification in murepavadin-resistant Pseudomonas aeruginosa mutant strains: relevance for colistin cross resistance and inflammatory response (ECCMID 2023) - No abstract available

Inflammation

Current and Emerging Inhaled Antibiotics for Chronic Pulmonary Pseudomonas aeruginosa and Staphylococcus aureus Infections in Cystic Fibrosis. (PubMed, Antibiotics (Basel)) - "Inhaled tobramycin, aztreonam, levofloxacin, and colistin are the four most common discussed inhaled antibiotics targeting P. aeruginosa. Additionally, inhaled liposomal amikacin and murepavadin are also in development...The mechanism of action, efficacy and safety, current status, and indications of corresponding inhaled antibiotics will be summarized. Combination therapy and the strategies to select an optimal inhaled antibiotic protocol will also be discussed."

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

Chimeric Peptidomimetic Antibiotic Efficiently Neutralizes Lipopolysaccharides (LPS) and Bacteria-Induced Activation of RAW Macrophages. (PubMed, ACS Infect Dis) - "Murepavadin, MHM, and PMBN were incapable of neutralizing LPS in this assay, while PMB was less active compared to CPA...Finally, we showed that CPA-killed bacteria caused significantly less macrophage activation than bacteria killed with gentamicin, heat, or any of the other compounds. This indicates that the combined killing activity and LPS neutralization of CPA can prevent unwanted inflammation, which could be a major advantage over conventional antibiotics. Our data suggests that immunomodulatory activity can further strengthen the therapeutic potential of peptide antibiotics and should be included in the characterization of novel compounds."

Journal • Immune Modulation • Immunology • Infectious Disease • Inflammation • Septic Shock • IL10 • TNFA

Spexis reports solid safety and pharmacokinetics results from first-in-human study with inhaled murepavadin, a novel macrocycle compound (GlobeNewswire) - P1 | N=39 | "Inhaled murepavadin shown to be well tolerated at all dose levels....Data support moving forward to Phase 2 in cystic fibrosis and non-cystic fibrosis bronchiectasis lung infection...'The first clinical data with our inhaled murepavadin hold promise as we work to bring more efficacious and safe treatments for serious lung infections to patients in need, including people with cystic fibrosis and non-CF bronchiectasis'....At the highest single dose tested, systemic bioavailability of MPV was lower than 5%, and peak plasma concentrations were observed at 1-2 hours post start of inhalation. In the ELF, the concentration of MPV at the 24-hour timepoint was still above the concentration that would inhibit the growth of 90% of P. aeruginosa isolates (MIC90) obtained from people with CF."

P1 data • Bronchiectasis • Cystic Fibrosis • Non‐Cystic Fibrosis Bronchiectasis

Spexis provides business update and announces financial results for the first half of 2022 (GlobeNewswire) - "Lead program, ColiFin: The process of site initiation is proceeding well, and the COPILOT trial is now planned to start in H1 of 2023, and aims to provide dosing data for COPA, which is now expected to initiate in H2 2023....Inhaled murepavadin (iMPV)...is currently in a Phase 1 study in healthy volunteers to evaluate safety and tolerability of single and multiple ascending doses (SAD/MAD). The study is ongoing and top-line data are expected by the end of this year. Potential indications that could be eventually targeted with iMPV include CF, nCFBE and COPD in patients with chronic PA infection."

New P3 trial • P1 data • Cystic Fibrosis • Infectious Disease • Respiratory Diseases

Chemical Synthesis of a Potent Antimicrobial Peptide Murepavadin Using a Tandem Native Chemical Ligation/Desulfurization Reaction. (PubMed, J Org Chem) - "The synthetic peptide antibiotic showed potent activity against different clinical isolates of P. aeruginosa. This approach can be easily adapted for the production of murepavadin analogues and other backbone-cyclized peptides."

Journal

Polyphor and EnBiotix Announce Signing of Merger Agreement and Sale of Inhaled Murepavadin to EnBiotix (Issuer Direct) - "Polyphor...and EnBiot...announced that the companies have signed a merger agreement pursuant to which Polyphor acquires all of the outstanding capital stock of EnBiotix in exchange for shares of Polyphor common stock....Following closing, expected in Q4 2021, Polyphor will be renamed and is expected to trade under a new ticker symbol on the Swiss Stock Exchange....Initiation of a single Phase III trial of ColiFin(R) for the treatment of CF patients, upon completion of which the combined company plans to seek FDA approval in the US. Initiation of a Phase I trial of inhaled murepavadin for the treatment of CF patients...the companies have signed a definitive asset purchase agreement where EnBiotix acquires Polyphor's inhaled murepavadin at an agreed valuation of USD 10 million in exchange for 2'599'655 of common shares of EnBiotix (15.4% fully diluted of EnBiotix). The closing of this agreement is expected in September 2021 and prior to the expected closing of the merger."

M&A • Trial status • Cystic Fibrosis • Infectious Disease

Anti-biofilm activity of murepavadin against cystic fibrosis Pseudomonas aeruginosa isolates. (PubMed, J Antimicrob Chemother) - "Murepavadin demonstrated good activity against P. aeruginosa biofilms both in open and closed systems. The MBIC-ECOFF and the MBEC-ECOFF are proposed as new parameters to estimate the activity of antibiotics on biofilms."

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

Murepavadin, a Small Molecule Host Defense Peptide Mimetic, Activates Mast Cells via MRGPRX2 and MrgprB2. (PubMed, Front Immunol) - "The data presented herein demonstrate that murepavadin activates human MCs via MRGPRX2 and murine MCs via MrgprB2 and that MRGPRX2 is resistant to β-arrestin-mediated receptor regulation. Thus, besides its direct activity against P. aeruginosa, murepavadin may contribute to bacterial clearance and promote wound healing by harnessing MC's immunomodulatory property via the activation of MRGPRX2."

Journal • Immune Modulation • Infectious Disease • Inflammation • CCL3 • CXCL8

Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane. (PubMed, Elife) - "Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the cytoplasmic membrane of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes."

Journal • Infectious Disease

Polyphor Announces Financial Results for the Full-Year 2020 (GlobeNewswire) - "The start of patient enrollment in the Phase I study, evaluating safety, tolerability, and pharmacokinetic profile by using eFlow® Technology nebulizer (PARI Pharma GmbH) to administer murepavadin Inhalation Solution (MIS) in healthy volunteers, is expected in Q3 2021, to further optimize primary packaging providing better stability for later stages of development."

Enrollment status • Cystic Fibrosis

Murepavadin antimicrobial activity against and resistance development in cystic fibrosis Pseudomonas aeruginosa isolates. (PubMed, J Antimicrob Chemother) - "Murepavadin characteristics, such as its specific activity against P. aeruginosa, its unique mechanism of action and its strong antimicrobial activity, encourage the further clinical evaluation of this drug."

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

Polyphor Receives Approval to Start First-in-Human Clinical Trial of Inhaled Antibiotic Murepavadin (GlobeNewswire) - "Polyphor...today announced that the UK Medicines and Healthcare products regulatory agency (MHRA) has granted a CTA (Clinical Trial Authorization) to start the first-in-human Phase I study of its novel class antibiotic murepavadin, delivered via the oral inhalation route....The study is expected to enroll the first patient in the coming weeks....A Phase Ib/IIa trial in adults with CF, assessing safety and tolerability of ascending doses of inhaled murepavadin, is planned to be initiated following completion of the Phase I study in 2021....Phase I development in healthy volunteers is jointly funded by Polyphor and the European Innovative Medicines Initiative (IMI)."

Financing • New P1 trial • New P1/2 trial • Cystic Fibrosis

Polyphor receives award of up to USD $3.3 million from Cystic Fibrosis Foundation to support clinical development of inhaled antibiotic murepavadin (GlobeNewswire) - "Polyphor...today announced a funding agreement with the Cystic Fibrosis Foundation to advance clinical development of its novel class antibiotic, inhaled murepavadin, in cystic fibrosis (CF)....Under the terms of the agreement, Polyphor will be awarded up to USD $3.3 million to fund a Phase Ib/IIa clinical trial of inhaled murepavadin...planned to be initiated pending CTA (clinical trial application) approval....The Phase Ib/IIa trial in adults with CF, assessing safety and tolerability (both overall and local) of ascending doses of inhaled murepavadin, is planned to be initiated in Q4 2021 following completion of the Phase Ia study."

Financing • New P1/2 trial • Cystic Fibrosis • Infectious Disease

Multidrug-resistant gram-negative organisms: a review of recently approved antibiotics and novel pipeline agents. (PubMed, Int J Clin Pharm) - "Thus, from MEDLINE/PubMed, we found only 1 item referred to a novel chemical class (Murepavadin n = 1). From ClinicalTrials.gov a total of 4 citations were identified (Ftortiazinon n = 1, Zoliflodacin n = 1, Gepotidacin n = 1, ETX2514 + sulbactam n = 1)...There are limited novel drug classes targeting gram-negative infections in the pipeline. Providers must be vigilant with the use of current antibiotics, especially until research and development (R&D) advancements are made."

Journal • Review • Complement-mediated Rare Disorders