The science of pharmaceutical discovery has enjoyed a long, rich history of innovation, profitability, and patent protection. However, the process of introducing a new drug is long, expensive, and given global governmental pressure to reduce cost, at risk of maintaining profitability in the future. Currently, the number of new compounds being introduced into the pipeline has been decreasing over time, and for those that reach regulatory approval, many are still at risk not being able to obtain governmental certification. For example, drugs that were initially determined to be effective in animal models and pre-clinical studies are later proven to have detrimental effects on critical human tissues. However, the biggest concern continues to be the inability to target unhealthy cells like cancer. As many have noted, companies have great drug pipelines with high opportunities for use. However, the ability to effectively use these portfolios of compounds remains limited.
Consequently, major pharmaceutical companies have turned their attention from introducing new compounds into the drug pipeline and instead have returned to their existing portfolios with the hopes of harvesting maximum value. Estimates for monetized in-use drug formulations have been estimated to be in excess of $100 billion. In this case, it is anticipated that new drug delivery platforms offer the greatest opportunity to have drugs repositioned to have new indications for usage by the medical industry. The implications for this type of approach are numerous. These include extended product life-cycles, creation of new chemical entities (NCEs), and in some instances, an approach to have patent protection extended.
Peptineo has identified the following market-critical requirements:
Ac-DEX nanoparticles overcome many known delivery barriers, and have demonstrated significant advantages over conventional formulations as follows: (1) Formulations facilitate passive targeting of host macrophages and Ac-DEX’s acid sensitivity results in a triggered release intracellularly once phagocytosed. Thus, intracellular delivery of drug limits systemic side effects as well as overcomes drug solubility issues. (2) Controlled release of active compounds is achievable with Ac-DEX because it has tunable release kinetics that can range from days to months. (3) The acid sensitivity of Ac-DEX also facilitates dose sparing, in that less drug is required for equal drug activity. (4) Ac-DEX nanoparticles display stable storage outside the cold chain to facilitate stockpiling. (5) The pH neutral by products of Ac-DEX (dextran, acetone, and ethanol) are unique in comparison to other ubiquitously used polymers like polyesters (e.g. PLGA, PCL) which have damaging acidic by-products.
Currently, Peptineo has several products in its development pipeline:
Peptineo's objective is to develop a versatile and tunable antibiotic drug delivery platform; Current customers require identification of antimicrobial formulations with capability of eradicating a broad range of mainstream bacterial infections. Formulations based on Acetalated Dextran (Ac-DEX) microparticles (MPs) have been successfully been demonstrated for the delivery of aerosolized antimicrobial agents. It is fully expected that current customer initiatives will provide novel broad antimicrobial formulation leads with high drug repurposing potential. In summary, the long-term goal for Peptineo is to establish a sustainable delivery pipeline with the potential of expansion beyond mainstream bacterial infections by moving into wound care management and other medically relevant chronic conditions treated with antibiotics.
A key area under active investigation is to design shorter, more effective therapies against tuberculosis. Currently, the basic treatment for tuberculosis involves four antibiotics and a long drug course (up to six months). Although mainstream protocols kill a major portion of the bacterial population quickly, many cells are able to tolerate treatment for extended periods of time and thus, require long therapeutic exposure. As a result, this basic protocol has remained largely unchanged for many years and has contributed to the emergence of drug-tolerant bacteria. It is anticipated that Ac-DEX will accelerate time to pathogen clearance by providing metabolic activation of TB persisters and resisters ( thereby increasing pathogen susceptibility) and by allowing for modified dosing strategies as necessary to quickly eliminate bacterial infections.
Subunit vaccines have been identified by the National Institutes of Allergy and Infectious Disease as the safest form of a vaccine available to the general population. Formulation of a subunit vaccine employing a particle based system based on acetalated dextran have already been demonstrated and continue to be under evaluation in several areas. As a platform, Ac-DEX is quickly being recognized for having numerous technical advantages over traditional subunit formulations. First, Ac-Dex particles have been shown to stabilize proteins and retain functional activity outside the cold chain - unlike mainstream vaccines. Second, Ac-DEX formulations facilitate needle-free vaccine delivery and increased potential for patient acceptance. Thus, is in anticipated that vaccines based on acetalated dextran will have an industry-wide impact and shape the way in which modern vaccine formulations are delivered.
The promise of small interfering RNAs siRNAs and their ability to knock-down or attenuate diseased genes has yet to be realized - as demonstrated by their absence in mainstream pharmaceutical applications. A key hurdle to widespread adoption and use of RNA interference is the lack of drug delivery carriers that deliver RNAi inducing molecules, including plasmid DNA and siRNAs systemically and efficiently. Customers investigating the use of Ac-DEX for therapeutic delivery of nucleic acids recognize the following: biocompatibility of Ac-DEX; protection afforded to genetic cargoes as it traverses to the site of therapeutic delivery; efficient cellular uptake; limited opsonization by the reticuloendothelial system (RES); avoidance of rapid elimination via the kidney; and efficient release of negatively charged genetic cargoes.
Currently, a wide variety of carriers have been explored to address siRNA delivery challenges. These include lipids, viral vectors, and polymers. However, each strategy comes with advantages and limitations. For example, viral vectors are efficient in transfection, but introduce numerous safety concerns including immune activation and oncogenesis. As result, lipid-based and polymer-based delivery systems have emerged as leading candidates for delivery of siRNA. Polysaccharides, for instance, offer low toxicity, are biodegradeable, and minimally activate the immue system. However, many delivery systems, including those based on chitosan have been tested and none have emerged for routine delivery in clinical siRNA applications. As a result, a formulation of a carrier based on Ac-DEX for the delivery of siRNA has already been demonstrated and continues to be under evaluation in several therapeutic areas. It is anticipated that Ac-DEX will form the basis of novel siRNA therapeutic delivery strategies in the near future.
Injectable biomaterials, including hydrogels and nanoparticles, are under intense evaluation in the development of therapeutic strategies that deliver biologics. Acetalated dextran has recently been used as the basis for a novel vaccine and has been employed to develop and deliver therapeutic compounds in response to heart injury. This ground-breaking study sought to demonstrate that biomaterials could be employed to facilitate healing at the site of injury in the heart. In this study, the strategy was to deliver, via sustained release, therapeutic compounds that promote healing - without repeated therapeutic intervention. Other materials including poly(lactic-co-glycolic acid) (PLGA) have been evaluated for delivery in cardiac applications. However, these delivery systems include inherent limitations such as an acidic microenvironment for biologically-based cargoes and necessarily have the potential to disrupt proper therapeutic function of the delivered biologic. Ac-Dex is currently under evaluation for the delivery of a number of biologically-based compounds - with applications including vaccines, cardiac intervention and restoration, inflammation, and others.