Takeda Pharmaceuticals

Vincent Ling

History- Traditional pharmaceutical research centers on the invention and development of new drug modalities. The pharmaceuticals industry had its roots in the chemical industry and hence small molecule drugs were the dominant class of therapeutics. In the past 30 years, many other substances have entered into the therapeutic space, most notably: nucleic acids (ASO, mRNA, DNA), biologics (proteins, peptides, antibodies), and cell / gene therapies (CAR-T, transplant / cell regeneration, viral vectors). Each of these modalities has vastly different size and chemical properties that pose a unique challenge for development. After the selection of the most potent candidate best-suited for the clinic, the drug compound is most often formulated for systemic delivery, either by tableting or by liquid injection – unless topical delivery is desired. Systemic delivery systems result in exposure of the body to the drug as it courses through the blood stream, and results in side effects and dose limiting toxicity. Such negative outcomes contribute to the high failure rates of drug candidates in clinical trials.

One can envision a future where off-target effects may be lessened by implementing refined drug delivery systems developed alongside the drug candidate. In recent years, the critical role of drug delivery systems was recognized at a global scale by the Covid-19 vaccines. Lipid nanoparticles were used to encapsulate the nucleic acid payload and to create the necessary immune response to help repel further exposure to virus. The world of drug delivery goes much further than formulation, as each drug class mentioned above can benefit from advanced drug delivery technologies as mentioned below.

Particle delivery – Lipid nanoparticles, liposomes, and polymers as drug delivery vehicles. These chemical structures can form carriers that effectively encase nucleic acids and biologics. In addition, modifications can be made into the macromolecule that help target specific markers on the surface of diseased sites. Redosable genetic delivery is a major interest in the field, after the massive success of the Covid-19 vaccine, but the ultimate impact that these delivery particles will have on future medicine remains to be seen. Also this class of particles includes viral particles, now engineered to afford the best targeting and permanent treatment, that carry nucleic acid payloads commonly referred to as Gene Therapy, now on the market for rare diseases. Many such viralparticle therapeutics are set to produce clinical outcomes in the coming years.

“Technology for energy-based therapy has advanced considerably in the past several years, especially in the field of ultrasound, thermal and more recently magnetic delivery systems”

Energy based delivery – Technology for energy-based therapy has advanced considerably in the past several years, especially in the field of ultrasound, thermal and more recently magnetic delivery systems. Focused ultrasound drug delivery has been used in blood brain barrier opening for years now, but systems were not clinically scalable to meet demands of a vast patient population. Miniaturization of ultrasound machines for drug delivery will render commercial application more widely acceptable. Thermal delivery of drugs has been gradually developed through the decades, and lately with the invention of robust thermo-liposomes that shields drug contents until it reaches the heated lesion. Localized drug delivery can be afforded by microwave array targeting of internal tumors, or used as an adjunct to interventional ablation where heatprobes placed next to tumors or spine. Magnetic delivery systems are a new entity to this space where magnetic force can push paramagnetic particles loaded with drugs in a guided trajectory through tissue, with better penetration.

Materials and Scaffolds – When the treatment modality reaches the size of therapeutic cells, it is clear that a method is necessary to retain the cells within the lesion area. Without a retention system, therapeutic cells spread to the rest of the body within days, leaving scant remainders to afford therapy utility at the location of interest. The two methods to help anchor cell placement involve encasing the cells, either into biocompatible hydrogels or by infiltrating cells within porous scaffolds which can better adhere into desired areas. In addition, such gels and scaffolds can be tuned for degradation for transient release of cells or placement as a solid immobile device.

Outlook- To best achieve the greatest odds of success in treating a disease, one needs to look beyond the reductionist approach that focuses on API potency – factoring drug delivery to the location of the disease lesion is equally important. For example, tumor targeting has been difficult to achieve due to the fibrotic core, central hypoxia, and altered immune state. These barriers to API entry are not related to drug mode of action, but such challenges can be addressed by application of advanced drug delivery technologies, with research honed to breach the malignant tumor architecture. As the discipline of drug delivery matures, we can appreciate both disciplines to synergize and yield a greater clinical impact on treating patient disease.