If we have a similar platform technology (to destroy viruses) to that of BIND Therapeutics (for cancer), we may be using similar, if not the same source, for specialized/high tech equipment/instruments.
BIND Therapeutics has the patented Accurins(R) and NanoViricides Inc, has the patented nanoviricides(R).
BIND History
BIND Therapeutics was launched in 2007 as BIND Biosciences with the vision of revolutionizing the treatment of life-threatening diseases through the application of nanotechnology.
After two decades of research at MIT in the area of biomaterials and nanoparticle engineering, a number of critical technologies converged in the laboratory of Professor Robert Langer that would enable the development of therapeutic polymeric nanoparticles. Building on this convergence, Professor Omid Farokhzad of Harvard Medical School began collaborating with Professor Langer to apply combinatorial strategies to develop targeted nanoparticles for specific therapeutic applications.
This research, conducted in collaboration with the Koch Institute at MIT and Brigham and Women's Hospital-Harvard Medical School resulted in a the development of the Medicinal Nanoengineering platform, which enables the identification of the precise characteristics of an optimally engineered targeted nanoparticle for clinical applications. BIND Therapeutics was cofounded by Drs. Langer and Farokhzad for the purpose of developing and commercializing innovative and impactful pharmaceutical products based on the medicinal nanoengineering platform. . . . www.bindtherapeutics.com/about/history.html
Microfluidic Platform for Combinatorial Synthesis and Optimization of Targeted Nanoparticles for Cancer Therapy (2013)
Taking a nanoparticle (NP) from discovery to clinical translation has been slow compared to small molecules, in part by the lack of systems that enable their precise engineering and rapid optimization. In this work we have developed a microfluidic platform for the rapid, combinatorial synthesis and optimization of NPs. The system takes in a number of NP precursors from which a library of NPs with varying size, surface charge, target ligand density, and drug load is produced in a reproducible manner. We rapidly synthesized 45 different formulations of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs of different size and surface composition, and screened and ranked the NPs for their ability to evade macrophage uptake in vitro. Comparison of the results to pharmacokinetic studies in vivo in mice revealed a correlation between in vitro screen and in vivo behavior. Next, we selected NP synthesis parameters that resulted in longer blood half-life and used the microfluidic platform to synthesize targeted NPs with varying targeting ligand density (using a model targeting ligand against cancer cells). We screened NPs in vitro against prostate cancer cells as well as macrophages, identifying one formulation that exhibited high uptake by cancer cells yet similar macrophage uptake compared to non-targeted NPs. In vivo, the selected targeted NPs showed a 3.5-fold increase in tumor accumulation in mice compared to non-targeted NPs. The developed microfluidic platform in this work represents a tool that could potentially accelerate the discovery and clinical translation of NPs. . . . We reported a new microfluidic platform for the rapid, combinatorial synthesis of targeted polymeric NPs. It was first demonstrated that NPs with a wide range of properties can be generated by making a small library comprised of NPs with size from 25-200 nm, zeta potential from -20 to +20 mV, ligand density from 0 to ~105 ligands/µm2, and drug loading from 0 to 5%. Subsequently, we showed the rapid NP development capabilities of the system by synthesizing 45 NP formulations of different sizes and PEG coverage, and screened them against macrophage uptake in vitro. Finally we investigated the relation between in vitro macrophage uptake and in vivo pharmacokinetics, where low macrophage uptake correlated with longer circulation time. Building upon the in vitro macrophage uptake screen, we synthesized and screened targeted NPs to identify a formulation that maximized specific uptake in vitro while minimizing macrophage uptake. We also investigated the tumor accumulation of TNPs versus NT-NPs of essentially identical biophysicochemical properties, where the TNPs showed 3.5-fold accumulation in tumor versus non-targeted ones. Three key advantages of our system over existing bulk synthesis include (i) from a small set of NP precursors one can rapidly synthesize a NP library with a wide range of distinct physicochemical properties; (ii) the NPs prepared have high batch-to-batch reproducibility; (iii) NPs can be prepared at different scales (e.g. microgram versus milligram) without varying substantially the NP properties. These advantages allow for both in vitro and in vivo screening with the goals of either accelerating the clinical translation of a specific formulation or obtaining deeper fundamental understanding on the correlation of NP properties and biological behavior. . . . www.ncbi.nlm.nih.gov/pmc/articles/PMC3963607/
April 22, 2015
BIND Therapeutics Presents Data Highlighting Ability of Accurins to Control Biodistribution and Accumulate in Target Tissue at AACR Annual Meeting 2015 . . . CAMBRIDGE, Mass.--(BUSINESS WIRE)-- BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine platform company developing targeted and programmable therapeutics called Accurins™, today announced that clinical and preclinical data from its oncology pipeline, including proprietary and collaboration programs, were presented at the American Association of Cancer Research (AACR) Annual Meeting 2015. The presentations include data from the Company's lead proprietary Accurin drug candidate, BIND-014, and the Accurin drug candidate AZD2811, which is being developed in collaboration with AstraZeneca. . . . In a poster entitled, "Imaging Accurin-AZD1152 hQPA nanoparticle accumulation in pre-clinical tumours," data were presented that show the Accurin nanoparticle AZD2811 accumulates in tumors and achieves prolonged tumor drug exposure. This is the first time distribution of nanoparticles in tumors has been demonstrated.
-Imaging mass spectrometry analysis demonstrated that Accurin nanoparticle AZD2811 accumulates in preclinical tumor models and confirmed that the Accurin accesses the tumor and provides prolonged drug exposure and retention in the target tissue.
-Multiple imaging techniques demonstrated Accurin nanoparticle AZD2811 is still detected at nine days after nanoparticle administration, while no drug was detected 24 hours after the prodrug AZD1152 was administered. . . . http://ir.bindtherapeutics.com/releasedetail.cfm?ReleaseID=907878
...about two months later...
June 23, 2015
BIND Therapeutics Announces FDA Authorization of First-in-Human Clinical Trial with AstraZeneca's Aurora B Kinase Inhibitor Accurin AZD2811 . . . - Collaboration with AstraZeneca results in second Accurin candidate to enter clinical development - - Promising AZD2811 Data Demonstrating Tumor Growth Inhibition and Prolonged Drug Exposure Recently Presented at 2015 American Association of Cancer Research (AACR) Annual Meeting -
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine company developing targeted and programmable therapeutics called Accurins™, today announced that the U.S. Food and Drug Administration (FDA) has authorized the use of AstraZeneca's Accurin AZD2811 in clinical trials under an investigational new drug (IND) application. BIND is collaborating with AstraZeneca on the development of AZD2811, an Aurora B Kinase inhibitor that has been shown to be active in both solid and hematological tumors in preclinical models, and the companies anticipate enrolling patients in a phase 1 clinical trial with AZD2811 in the fourth quarter of this year. BIND will earn a $4 million milestone payment upon first dosing a patient in a phase 1 clinical trial with AZD2811.
Preclinical data on AZD2811 were presented at the 2015 American Association of Cancer Research (AACR) annual meeting in April 2015, including data demonstrating promising in vivo and in vitro tumor growth inhibition as monotherapy in models of diffuse large B-cell lymphomas (DLBCL) and small cell lung cancer (SCLC). Additional data showed that AZD2811 delivers prolonged exposure to active drug while having the potential to adapt the dosing regimen, potentially achieving an improved therapeutic index. In addition, using mass spectrometric imaging, AZD2811 was shown to accumulate in tumors and achieve prolonged tumor drug exposure. This represents the first time distribution of nanoparticles in tumors has been demonstrated. Previously, preclinical tumor model data were presented showing that AZD2811 minimizes the bone marrow toxicity seen with the parent compound, which has limited the clinical utility of Aurora B kinase inhibitors as a class. . . . BIND and AstraZeneca expect to enroll the first patient in a phase 1 clinical trial with AZD2811 in the fourth quarter of 2015. Under terms of the collaboration, AstraZeneca is responsible for clinical development and commercialization and BIND is responsible for conducting clinical manufacturing through at least the end of phase 2 clinical trials. . . . ir.bindtherapeutics.com/releasedetail.cfm?ReleaseID=919006
About BIND Therapeutics factsheet:
»We design combinatorial libraries of targeted nanoparticles with precise and systematically varied biophysicochemical properties such as particle size, surface properties, ligand density, API load and release profile, using a unique self-assembly nanoparticle fabrication process to optimize each product-for example, to balance circulation time with effective targeting and binding for a particular cell or tissue target.
»We engineer product candidates with optimal performance properties using an iterative process that includes in vitro drug release and cell binding along with in vivo PK, tolerability, biodistribution, targeting, and efficacy studies.
»We manufacture candidate Accurins from gram-scale laboratory experiments through kilogram-scale GMP clinical batches using robust, reproducible, and scalable processes www.bindtherapeutics.com/pdfs/BINDfactsheet.pdf Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study.(2014)
Abstract
Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13-150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies.
FROM THE CLINICAL EDITOR:
Applications of nanoparticle synthesis with microfluidic methods are typically limited to in vitro studies due to low production rates. The team of authors of this proof-of-principle study reports on the successful parallelization of NP synthesis by 3D hydrodynamic flow focusing using a multilayer microfluidic system to enhance production rate without losing the advantages of reproducibility, controllability, and robustness.
www.ncbi.nlm.nih.gov/pubmed/23969105
Optimizing the discovery and clinical translation of nanoparticles: could microfluidics hold the key?
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Since the first demonstration of a liposomal drug carrier in 1970s [1], tremendous efforts have been directed at developing nanoparticle (NP) platforms for therapy and diagnosis of major diseases. A few US FDA-approved NPs have emerged, including liposome-based Doxil and albumin-based Abraxane for chemotherapy, and iron oxide NPs Feridex and Resovist for MRI [2,3]. Several other NP platforms are in clinical trials, including a targeted polymeric NP for treatment of prostate cancer [2–4]. Yet, there exist major bottlenecks that retard discovery and clinical translation of NPs [2–3,5]. First, rational design of NPs is nontrivial because of limited knowledge of how the physicochemical properties of NPs correlate with in vivo behavior. Therefore, current technology for optimization of NPs requires intensive in vitro and in vivo screening. Second, conventional batch-type bulk reactors are limited in their ability to reproducibly prepare high-quality NPs while tuning their physicochemical properties. Third, in vitro screens do not adequately model in vivo environments, considerably increasing the cost of in vivo screening.
In the past decade, the intersection of nanomedicine and the rapidly growing field of microfluidics – the science and technology of manipulating nanoliter to picoliter volumes of fluids in microscale channels [6] – has provided fresh approaches to tackle these challenges [5]. Microfluidic systems enable precise control of microscale environments, which finds use in chemical synthesis, chemical and biomolecular analysis, tissue engineering, and other applications. Now, microfluidics is playing a key role in synthesis and screening of NPs and in elucidating the interaction of NPs with cells and tissues, promising to accelerate the clinical translation of NPs [5].
The first major application of microfluidics for nanomedicine was for improving the quality of NPs though control of the reaction environment [5,7–8]. Microfluidic reactors enable rapid mixing of reagents, control of temperature, and precise spatiotemporal manipulation of reactions that are difficult, if not impossible, in larger reactors [7,9]. For example, amphiphilic molecules self-assemble into NPs by mixing with a nonsolvent in a process known as nanoprecipitation [2,5]. In this process, mixing time has a strong influence on the average NP size and the size distribution. In conventional bulk synthesis methods, mixing is heterogeneous and typically occurs on a time scale longer than the characteristic time scale for self-assembly, which results in large and polydisperse NPs. Controlled and homogeneous mixing in microfluidic synthesis methods results in smaller and uniform NPs [5,8]. Microfluidic control of reactions on the millisecond timescale has also enabled rapid nucleation followed by controlled growth and rapid quenching, leading to the synthesis of various inorganic NPs with improved spectral response for imaging applications [7,9]. This fine spatiotemporal control was achieved by using monodisperse droplets that serve as identical microscale reactors [9]. Droplets can be generated, combined, mixed and split in a controlled manner using microfluidic units. Since the reaction time of reagents directly correlates to residence time of the droplet in microchannel, it can be precisely controlled by tuning the residence time in a reaction area (e.g., heating zone) [10] or by adding a quenching agent at precise downstream locations [11]. Although microfluidics typically deals with small volumes, parallelized and high-throughput micro/millifluidic systems have also been developed to enable synthesis of high-quality NPs at larger scales [12–14]. Unlike batch reactors that require process optimization for scale-up, microfluidic devices typically operate in continuous process mode and do not require intensive process optimization for larger-scale production. These developments in synthesis and scale-up make a strong headway towards addressing the need for improved quality and consistency of NPs.
Microfluidics also enables precise and reproducible manipulation of the physicochemical properties of NPs, opening new avenues for high-throughput combinatorial NP synthesis and screening. For example, Chen et al. prepared a library of siRNA-containing lipid NPs with different chemical structures using a microchannel with groove structures for rapid and effective mixing of reagents [15]. This approach enabled in vitro and in vivo screening of lipid NP-mediated siRNA delivery to discover optimal lipids for silencing factor VII expression in mouse liver. Valencia et al. developed a microfluidic platform for rapid, combinatorial synthesis of a library of polymeric NPs by combining a multi-inlet micromixer for premixing NP precursors in a specified ratio and a downstream mixing unit for rapid nanoprecipitation [16]. Using high-throughput screening, this combinatorial synthesis method identified a targeted NP formulation that exhibited enhanced tumor accumulation in a mouse model of prostate cancer compared with an otherwise identical nontargeted NP. These results illustrate the potential of high-throughput microfluidic synthesis and screening to reduce costs by consuming smaller volumes of reagents while exploring a large parameter space of the physicochemical properties of NPs. . . .
NanoViricides President Dr. Diwan Presented FluCide Data at the 3rd Annual Influenza Conference held by GTC Bio on Friday, July 11
WEST HAVEN, CONNECTICUT -- Monday, July 14, 2014 -- NanoViricides, Inc. (NYSE MKT: NNVC) reports that its President, Dr. Anil Diwan, was invited to present the FluCide™ data at the 3rd Annual Influenza Research and Development Conference on Friday, July 11, at 0850 am. The Conference ran from July 9-11 at the Hyatt Regency in Boston, MA, and was held by GTC Bio (https://www.gtcbio.com/conferences/influenza-research-and-development-agenda).
Dr. Diwan discussed the nanoviricides® technology platform, and presented the pre-clinical data on the Company's first drug candidate, NV-INF-1, Injectable FluCide™, to treat all influenza infections in hospitalized patients. Influenza A H1N1 infected animals treated with FluCide survived the full 21-day observation period, whereas animals treated with 40mg/kg/d oseltamivir phosphate (Tamiflu®) survived only 8 days in this highly lethal study. Influenza A/WS/33/ (H1N1) virus was used in this study. The highly lethal infectious dose of 1M viral particles at time 0 h followed by another 1M virus particles at 23h that was employed caused uniform lethality in 5 days in untreated mice. Body weight began to decline in the infected, untreated mice, by days 2-3 days and continued to decline until death. The Oseltamivir-treated mice maintained body weight only through day 5, which declined thereafter until death. Similar to the survival results, the mice treated with NV-INF-1 maintained their body weight substantially longer, through day 14. NV-INF-1 demonstrated an unparalleled 1,000-fold reduction in lung viral load compared to untreated animals on day 4 in this lethal animal model study. Moreover, the lung viral load was suppressed to this baseline level through 13 days or longer, with a slight increase on day 19. In contrast, the current standard of care, oseltamivir, (Tamiflu®, Roche) exhibited only a 2-fold reduction in lung viral load at day 4, that rapidly rose by approximately 2X on day 7. Similar to the reduced virus titers, on day 4 the lungs from mice that were treated with NV-INF-1 showed a substantially lower lung weight (healthy) and displayed a markedly reduced presence of virus-induced lesions as compared to the untreated control and oseltamivir. Also similar to lung virus titers, the reductions in lung lesions in animals treated with NV-INF-1 were maintained at least through 13 days.
Dr. Diwan also discussed the extremely high safety of NV-INF-1 observed in preliminary safety/toxicology studies. He noted that no significant changes in all observed parameters were found even at the maximum feasible dose of approximately 2,700 mg/kg/d repeatedly given for five consecutive days.
He also presented the data on NV-INF-2, the Company's current oral anti-influenza drug candidate. NV-INF-2 has the same antiviral ligand as NV-INF-1, but a different polymeric backbone that has enabled significant oral effectiveness. NV-INF-2 has been evaluated in a mouse model of influenza virus infection using two different influenza virus a strains, A/WS/33/ (H1N1) and A/W/67 (H3N2v). NV-INF-2 treated mice survived as long as 14.5 days in an H1N1 lethal infection study, and for 15.6 days in an H3N2 lethal infection study. Oseltamivir treated animals died in only 7.6 days in H1N1 infection study, and in 9.6 days in the H3N2 study. The lethal infection viral dose and protocol was chosen such that the untreated animals died in 5 days in both H1N1 and H3N2 studies. Similar to substantially increased survival, NV-INF-2 also exhibited substantially superior reduction in lung viral titer and protection of lungs from lesions.
The data indicate that both NV-INF-1 and NV-INF-2 are highly effective, broad-spectrum, anti-influenza drugs. The Company has shown that they are effective against both group I and group II influenza A viruses.
Dr. Diwan also reported that the Company is successfully scaling up production of NV-INF-1 for the GLP Safety/Toxicology study at its current facilities. In addition, he reported that construction of the Company's new facility capable of cGMP production of all of the Company's nanoviricides drug candidates for human clinical batches is now complete. Facility testing and validation are in progress.
The market size for an effective influenza drug for treating severely ill hospitalized patients has been estimated in the billions of dollars, worldwide, depending upon the therapeutic value and cost savings. Currently, there is no effective therapeutic available for this indication. The Company believes that it could supply a substantial portion of the demand for this drug from its new small scale cGMP clinical drug facility. This drug is currently in IND-enabling studies.
This broad-spectrum FluCide drug is expected to work against most, if not all, forms of influenza virus, including epidemic, pandemic (e.g. H1N1/2009), high path influenzas such as H3N2, H7N9, and "bird flu" such as H5N1.
The total market size addressed by the Company's current drug programs is estimated at about $50 billion. In addition to Injectable FluCide, the Company is working on five more commercially important drug candidates, namely: DengueCide™, HerpeCide™, HIVCide™, Oral FluCide™ for out-patients, and a broad-spectrum antiviral drug for viral diseases of the external eye. All of our programs are for therapeutics to treat viral infections. Our drugs are expected to be useful as prophylactics as well. DengueCide has recently received orphan drug designation by the US FDA as well as the European EMA.
NanoViricides recently received an important international award, the "IAIR Award 2014 for Leadership in Nanomedicines in the North American Sector".
The Company currently has approximately $41 million cash-in-hand and cash-like-instruments. These funds are estimated to be sufficient for taking at least one of our drug candidates through initial human clinical trials, and possibly take another drug candidate into human clinical trials. . . .
How fast could the Clinical Trials in Australia be?
"by the way, I'm sure that when you think human trials for drugs you think of hundreds of millions of dollars and years of time, well in this case because the disease only lasts a week, two weeks,...that it is possible to complete human trials in the space of a few short months...four parts to the human trials" ~ Dr. Eugene Seymour, CEO Nanoviricides, Inc.
...then on the CEO letter to shareholders he went on to explain how would this be possible:
The number of patients that need to be enrolled in a clinical trial depends upon how good the drug is. If the drug effect is very easily separated from the placebo, and more so, from the standard of care, then the trial would require fewer patients to reach the clinical end point of determining that the drug is indeed effective or superior, as the case may be. Therefore we believe, based on the very strong efficacy observed in our animal studies, that our influenza clinical trials will be short, and will be relatively inexpensive.
