filociclovir (MBX400) / Microbiotix - LARVOL DELTA

In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2. (PubMed, Viruses) - "Although it does not phosphorylate deoxynucleosides, this enzyme is involved in the first phosphorylation step of ganciclovir (GCV), a viral DNA polymerase inhibitor...Substitutions that induce cross-resistance to MBV and GCV may directly or indirectly affect the environment of D456 and N461 residues in the catalytic loop, with reduced viral replicative capacity. These results have implications for the clinical use of MBV as well as for the design of novel pUL97 kinase inhibitors."

Journal • Cytomegalovirus Infection • Infectious Disease

Anti-CMV therapy, what next? A systematic review. (PubMed, Front Microbiol) - "Maribavir and letermovir are the latest antivirals to have been developed with other targets...Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs...Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy...All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials."

Journal • Review • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease • Transplantation

Filociclovir is a potent inhibitor of human adenovirus F41. (PubMed, Antiviral Res) - "The activity of FCV was compared to 3 other known antivirals: cidofovir (CDV), ganciclovir (GCV) and valganciclovir (VGCV). This report provides timely and valuable methodologies to the research community for testing antivirals against HAdV-F41. Our findings also support the continued development of FCV for various therapeutic applications, including pediatric hepatitis, if a causal relationship is firmly established in the future."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Pediatrics • Transplantation

Filociclovir Is an Active Antiviral Agent against Ocular Adenovirus Isolates In Vitro and in the Ad5/NZW Rabbit Ocular Model. (PubMed, Pharmaceuticals (Basel)) - "The 50% effective concentrations (EC) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower eye titers, fewer numbers of positive eye cultures, and shorter durations of eye infection. FCV demonstrated anti-adenovirus activity in vitro and in vivo."

Journal • Preclinical • Ocular Infections • Ophthalmology

Filociclovir is a potent in vitro and in vivo inhibitor of human adenoviruses. (PubMed, Antimicrob Agents Chemother) - "Furthermore, FCV administered at the same dose after intranasal challenge with HAdV6 partially mitigated body weight loss, but significantly reduced pathology and virus replication in the lung. These findings suggest that FCV could potentially be developed as a pan-adenoviral inhibitor."

Journal • Preclinical • Conjunctivitis • Cytomegalovirus Infection • Dry Eye Disease • Infectious Disease • Ocular Inflammation • Ophthalmology • Pneumonia • Respiratory Diseases

A Phase 1b Trial to Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers. (PubMed, Antimicrob Agents Chemother) - P1 | "The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro."

Clinical • Journal • P1 data • PK/PD data • Cytomegalovirus Infection

In vitro comparison of currently available and investigational antiviral agents against pathogenic human double-stranded DNA viruses: A systematic literature review. (PubMed, Antiviral Res) - "Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC values. These findings could assist clinical practice and developmental research."

Journal • Review

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy. (PubMed, Curr Hematol Malig Rep) - "Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies...Vaccine development continues, with several promising candidates currently under study. No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes."

Journal • Review

The discovery and development of filociclovir for the prevention and treatment of human cytomegalovirus-related disease. (PubMed, Antiviral Res) - "Currently approved drugs for treating HCMV-related disease [including ganciclovir (GCV), valganciclovir (VGCV), cidofovir (CDV) and foscarnet (FOS)] all target the viral DNA polymerase and suffer from dose-limiting toxicity and resistance issues. The most recently approved drug, letermovir (LMV), was approved only for prophylaxis in adult HCMV-seropositive stem cell transplant recipients...Furthermore, FCV was shown to retain activity against a panel of GCV-resistant HCMV isolates, suggesting that it could be a useful alternative therapy for treating patients infected with some GCV-resistant HCMV strains. This review summarizes the early discovery work of FCV and highlights the recent advances in the continued development of this clinical candidate."

Journal • Review

In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus. (PubMed, Antiviral Res) - "Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance...We therefore tested select combinations of approved (GCV, CDV, letermovir (LMV)) and experimental (brincidofovir (BCV), cyclopropavir (CPV), maribavir (MBV), BDCRB) drugs with the hypothesis that combinations of drugs with different and distinct molecular mechanisms of action will produce an additive and/or synergistic enhancement of antiviral effect against HCMV in vitro. Using MacSynergy II (a statistical package that measures enhancement or lessening of effect relative to zero/additive), select drug combination studies demonstrated combination indices ranging from 160 to 372 with 95% confidence intervals greater than zero indicating that these combinations elicit a synergistic enhancement of effect against HCMV in vitro. These data suggest that..."

Journal • Preclinical

Modern ethiotropic chemotherapy of human cytomegalovirus infection: clinical effectiveness, molecular mechanism of action, drug resistance, new trends and prospects. Part 2. (PubMed, Vopr Virusol) - "A number of synthetic compounds, such as the nucleoside analog ganciclovir, its L-valine ester (a metabolic precursor of ganciclovir) and pyrophosphate analog foscarnet, are permitted for the treatment of HCMVrelated diseases in the WHO European Region...In this review, we focused on viral proteins of interest as new potential targets and their inhibitors, such as the inhibitor of human CMV terminology, lethermovir, which showed great activity in the third phase of clinical trials, inhibitors of viral cyclin-dependent kinase (maribavir, cyclopropavir) and a number of compounds exhibiting anti-HCMV-activity, undergoing only preclinical trials in the experiment. Inclusion of new anti-CMV agents that are active against GСV/PFA/CDV-resistant strains of CMV into standard prophylactic and therapeutic regimens, will allow to increase the effectiveness of anti-CMV therapy, including in cases when standard therapy is ineffective. Areas covered: the international databases such as..."

Clinical • Journal • Review