Starpharma focuses on the use of dendrimers as drugs in their own right, in contrast to dendrimers as drug delivery vehicles or diagnostics. This contextual review describes how dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and how the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. Using Starpharma's work on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates as an example, the process from which SPL7013 emerged as a development candidate is described. Following a range of preclinical studies, Starpharma submitted an investigational new drug application (IND) for SPL7013 gel (VivaGel) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer-based drug. The first clinical trial under this IND was completed in 2004.
An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal (irreversible) activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC 50 ) for i) reducing virus-induced cytopathic effect of 0.002 to 0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019 to 0.032 mg/mL in Vero E6 cells and 0.031 to 0.037 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, irreversibly reducing SARS-CoV-2 infectivity by >99.9% (>3 log 10 ) within 1 minute of exposure, and up to >99.999% (>5 log 10 ) shown at astodrimer sodium concentrations of 10 to 30 mg/mL in Vero E6 and Calu-3 cell lines. Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to irreversible inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a topically administered agent for SARS-CoV-2 therapeutic applications.
Strategies to combat COVID-19 require multiple ways to protect vulnerable people from infection. SARS-CoV-2 is an airborne pathogen and the nasal cavity is a primary target of infection. The K18-hACE2 mouse model was used to investigate the anti-SARS-CoV-2 efficacy of astodrimer sodium formulated in a mucoadhesive nasal spray. Animals received astodrimer sodium 1% nasal spray or PBS intranasally, or intranasally and intratracheally, for 7 days, and they were infected intranasally with SARS-CoV-2 after the first product administration on Day 0. Another group was infected intranasally with SARS-CoV-2 that had been pre-incubated with astodrimer sodium 1% nasal spray or PBS for 60 min before the neutralisation of test product activity. Astodrimer sodium 1% significantly reduced the viral genome copies (>99.9%) and the infectious virus (~95%) in the lung and trachea vs. PBS. The pre-incubation of SARS-CoV-2 with astodrimer sodium 1% resulted in a significant reduction in the viral genome copies (>99.9%) and the infectious virus (>99%) in the lung and trachea, and the infectious virus was not detected in the brain or liver. Astodrimer sodium 1% resulted in a significant reduction of viral genome copies in nasal secretions vs. PBS on Day 7 post-infection. A reduction in the viral shedding from the nasal cavity may result in lower virus transmission rates. Viraemia was low or undetectable in animals treated with astodrimer sodium 1% or infected with treated virus, correlating with the lack of detectable viral replication in the liver. Similarly, low virus replication in the nasal cavity after treatment with astodrimer sodium 1% potentially protected the brain from infection. Astodrimer sodium 1% significantly reduced the pro-inflammatory cytokines IL-6, IL-1α, IL-1β, TNFα and TGFβ and the chemokine MCP-1 in the serum, lung and trachea vs. PBS. Astodrimer sodium 1% nasal spray blocked or reduced SARS-CoV-2 replication and its sequelae in K18-hACE2 mice. These data indicate a potential role for the product in preventing SARS-CoV-2 infection or for reducing the severity of COVID-19.
An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC50) for i) reducing virus-induced cytopathic effect of 0.002 to 0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019 to 0.032 mg/mL in Vero E6 cells and 0.031 to 0.037 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, reducing SARS-CoV-2 infectivity by >99.9% (>3 log10) within 1 minute of exposure, and up to >99.999% (>5 log10) shown at astodrimer sodium concentrations of 10 to 30 mg/mL in Vero E6 and Calu-3 cell lines. Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a nasally administered or inhaled antiviral agent for SARS-CoV-2 prevention and treatment applications.
An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will require a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 cells when added to cells 1-hour prior to or 1-hour post infection, with 50% effective concentrations reducing virus-induced cytopathic effect (EC50) ranging from 0.090 to 0.742 μM (0.002 to 0.012 mg/mL). The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also effective in a virucidal evaluation when mixed with virus for 1 hour prior to infection of cells (EC50 1.83 μM [0.030 mg/mL]). Results from a time of addition study, which showed infectious virus was below the lower limit of detection at all time points tested, were consistent with the compound inhibiting early virus entry steps. The data were similar for all investigations and were consistent with the potent antiviral activity of astodrimer sodium being due to inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial association of the virus with heparan sulfate proteoglycans on the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a nasally administered or inhaled antiviral agent for SARS-CoV-2 prevention and treatment applications.
Astodrimer sodium is a dendrimer molecule with antiviral and virucidal activity against SARS-CoV-2 and other respiratory viruses in vitro, and has previously been shown to be safe and well tolerated, and not systemically absorbed, when applied to the vaginal mucosa. To investigate its potential utility as a topical antiviral, astodrimer sodium has been reformulated for application to the nasal mucosa to help reduce viral load before or after exposure to respiratory infection. The current investigation assessed the safety, tolerability and absorption of astodrimer sodium 1% antiviral nasal spray. This was a single-centre, double-blinded, randomized, placebo-controlled, exploratory clinical investigation. Forty healthy volunteers aged 18 to 65 years with no clinically significant nasal cavity examination findings were randomized 3:1 to astodrimer sodium nasal spray (N = 30) or placebo (N = 10) at an Australian clinical trials facility. An initial cohort of participants (N = 12 astodrimer, N = 4 placebo) received a single application (one spray per nostril) to assess any acute effects, followed by a washout period, before self-administering the spray four times daily for 14 days to represent an intensive application schedule. Extent of absorption of astodrimer sodium via the nasal mucosa was also assessed in this cohort. A second cohort of participants (N = 18 astodrimer, N = 6 placebo) self-administered the spray four times daily for 14 days. The primary endpoint was safety, measured by frequency and severity of treatment emergent adverse events (TEAEs), including clinically significant nasal cavity examination findings, in the safety population (all participants randomized who administered any spray). Participants were randomized between 6 January 2021 and 29 March 2021. TEAEs occurred in 8/10 (80%) participants in the placebo arm and 19/30 (63.3%) participants in the astodrimer sodium arm; all were of mild intensity. TEAEs considered potentially related to study product occurred in 5/10 (50%) participants receiving placebo and 10/30 (33.3%) of participants receiving astodrimer sodium. No participants experienced serious AEs, or TEAEs leading to withdrawal from the study. No systemic absorption of astodrimer sodium via the nasal mucosa was detected. Astodrimer sodium nasal spray was well tolerated and is a promising innovation warranting further investigation for nasal administration to potentially reduce infection and spread of community acquired respiratory virus infections.Trial Registration: ACTRN12620001371987, first registered 22-12-2020 (Australia New Zealand Clinical Trials Registry, https://anzctr.org.au/).
Docetaxel (Taxotere®) and cabazitaxel (Jevtana®) are mitotic inhibitors that function as effective cytotoxic agents and are widely used in many chemotherapy regimens. However, treatment with taxanes is limited by serious adverse toxicities, notably bone marrow toxicity (neutropenia, leukopenia and anemia) and hepatotoxicity. Taxanes are poorly water soluble and must be formulated with surfactants such as polysorbate, which can cause systemic adverse events (e.g. anaphylaxis and fluid retention) requiring predosing with corticosteroids. These combined drug and excipient toxicities limit clinical use and make them ideal candidates for improvement using dendrimer technology. Starpharma's novel dendrimer nanoparticle DEP platform has broad applicability in drug delivery through improved drug solubility, efficacy and pharmacokinetics, reductions in certain toxicities (e.g. bone marrow toxicity) and generation of intellectual property. The DEP platform has shown reproducible benefits across a wide range of drug classes including small molecules, peptides and proteins. Currently there are three DEP candidates in the clinic; DEP docetaxel (DEP DTX), DEP cabazitaxel (DEP CTX), and DEP irinotecan. The fourth DEP candidate, AZD0466, is a promising Bcl-2/Bcl-xL inhibitor, partnered with AstraZeneca, and is currently transitioning into clinical trials in the US. Starpharma's DEP DTX and DEP CTX are both PEGylated polylysine dendrimers with the drug conjugated to the surface via a hydrolytically labile linker. Both products have demonstrated superior efficacy and survival compared to the standard drug formulations in a range of xenograft cancer models in immunocompromised mice: breast (MDA-MB-2231), prostate (DU145), and pancreatic (CAPAN-1). In the CAPAN-1 pancreatic xenograft model, the DEP taxanes were superior to Nab paclitaxel (Abraxane®) when dosed either as monotherapy or in combination with gemcitabine. Abraxane inhibited tumor growth by 85% (monotherapy) and 81% (combination with gemcitabine) compared to complete inhibition for DEP CTX and DEP DTX treated groups (at day 37). DEP CTX induced complete regression of tumors over the duration of the study. Treatment with DEP taxanes significantly extended survival compared to Abraxane as monotherapy (P= 0.004, DEP DTX; P <0.0001, DEP CTX), and in combination with gemcitabine (P<0.0001, DEP DTX; P<0.0001, DEP CTX). In summary, both DEP taxanes are well tolerated and show significant efficacy and survival benefits compared to current standard of care therapies when used either as a monotherapy or in combination. DEP CTX and DEP DTX are two of four clinical stage products from Starpharma's DEP platform. DEP DTX is currently in a P2 clinical trial at Guy's and St Thomas', NUTH, The Leeds Teaching Hospital, UCLH, The Christies and The Beatson while DEP CTX is in a phase 1/2 adaptive trial at Guy's and St Thomas', UCLH, Velindre Cancer Centre and ICLH. Citation Format: Brian D. Kelly, Victoria McLeod, Rachael Walker, Jeannette Schreuders, Susan Jackson, Michael Giannis, Christine Dietinger, Pauline Reitano, Rashmi Pathak, Shirley Xia, Anne Cargill, Aynaz Seta, Richard Hufton, Graham Heery, Carleen Cullinane, David J. Owen. Anticancer activity of the taxane nanoparticles, DEP® docetaxel and DEP® cabazitaxel [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1716.
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