Harmonizing physiochemical profiling for therapeutic oligonucleotides: an interview with Kohsaku Kawakami

[00:11] Kohsaku Kawakami: I graduated from Kyoto University, Department of Chemical Engineering, about 30 years ago. After that, I joined two pharmaceutical companies. The first one was Shionogi [which] is a Japanese pharmaceutical company where I was doing physiochemical characterization studies like DDS (drug delivery systems) studies. Later, I joined U.S. Merck to do preclinical developmental research, and there I was doing some physiochemical characterization and formulation development for clinical trials and so on. Then in 2006, I joined the current institute at the National Institute for Material Science in Japan. But I have many experiences in [different] companies, so I am still working with many pharmaceutical company people. Now I am leading a consortium where 11 pharmaceutical companies are participating. So this time, I introduced one of the results. It was done with the collaboration with the company in the consortium.

[01:35] Kohsaku Kawakami: Yes, our purpose is to establish the physiochemical profiling platform for nucleic acid drugs. In the case of small molecules — small drugs — the kind of evolution protocol is already established. [An] important point is, everybody knows how to look at the data, for example, so for the small molecule, everybody evaluates the polymorphism. Polymorphism is– so every drug molecule can have various crystal forms, and it will influence the physiochemical properties, so [they are] very important properties. But basically, it is important only for poorly soluble drugs. [This] is because it can change the solubility, so if your compound is highly soluble to water, you can be optimistic for the polymorphism program. In this way, everybody knows how to look at the data, depending on the property of the drug candidates.

[02:40] Kohsaku Kawakami: But such [an] idea is not available for nucleic acids yet. We do not have the generalized view. For our practical viewpoint, another important thing is we need to think about the amount of the drug that we can use for the evaluation because, in the very early stage of development, the amount of drug that we can use is very limited. So we need to care about that. Every method has good points and bad points. So every method has [its] complementary roles. We need to consider at which timing, which evaluation should be done. This is important. So, of course, the amount of drugs that we can use also influences. So such a practical viewpoint is required for establishing the physiochemical profiling platform. Now we are working with pharmaceutical companies. [This] is also [an] important point. We cannot do it alone. So we are doing it with the help of many pharmaceutical companies.

[03:55] Kohsaku Kawakami: Yes. Basically, the higher-order structure influences the solution properties, like viscosity [and] solubility. When a nucleic acid is administered to the body, in many cases a subcutaneous injection is used. If the viscosity is very high, we cannot inject and the higher order structure influences viscosity. We need to have a good understanding of higher-order structure. In the case of aptamers, so higher higher-order structure is directly related to the efficacy. So shape is very important for the aptamer. In that case, the high-order structure has [a] direct impact on their efficacy. In fact, EMA (European Medical Agency) recently published their guideline. In the guideline, it is recommended to evaluate the higher-order structure using UV or FT-IR (Fourier transform infrared spectroscopy) or CD (circular dichroism). It is recommended. In the case of aptamers, it is strongly recommended. So from this viewpoint, also we need a generalized view about the methodology for the profiling.

[05:22] Kohsaku Kawakami: The amount that we can use is very limited. Sometimes it is only a few milligrams [or] even less. So what we can do with such an amount is, basically, we can only do the spectroscopic measurement, like UV or CD. And if we do the UV measurement, we can have some information about the melting. We can determine the melting temperature, but the sensitivity is not that high. For investigating in more detail, we need maybe a DSC (differential scanning calorimetry), for which we need a larger amount. Then in the case of CD, we can have the information on the higher-order structure. But again, sensitivity is not so high. Basically, we see all these major structures. So if it is a mixture, we cannot detect the minor components, the minor structures. But if we combine [it] with other methods like NMR (nuclear magnetic resonance), we can have more detailed information. But in the early stage, what we can use is [a] spectroscopic method [as] it requires only a small amount. The important thing is we need to understand the ability and the limitations of the kind of method. Later, we can add more information, and those methods have [a] complementary role. So we need to consider what we can do with only a small amount, so it is a very important part of the developmental study.

[07:09] Kohsaku Kawakami: First of all, we need to recognize that physiochemical evaluation, it is not secret. In the case of drug discovery, it is secret. It is [a] competition. Every company has various, many secrets. But it is opposite to the physiochemical characterization. In this case, we need to disclose the information. For example, given that a certain company has very good technology for the evaluation, but if that is kept secret and if they use that evaluation method for the approval process, it may not be understood well. So they need to disclose their methodology to the outside [to enable] understanding by the people outside, for understanding by the regulatory people. It is important to disclose. And harmonization is also important. Everybody needs to have the generalized idea for the evaluation. So, by doing that approval process, development process, of course, will become very smooth. It is important to share the same idea with everyone for the quick development.