Points of View Survey on modalities and indications in the drug development pipeline

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Hideyuki Kagii, Senior Researcher, Pharmaceutical Industry Policy Institute

1 Introduction

In recent years, drugs utilizing new drug discovery modalities, such as nucleic acid drugs, gene therapy, and gene-cell therapy, have emerged and are having a major impact in disease areas that were previously difficult to treat, such as cancer, genetic diseases, and most recently, new coronaviruses.

Although there is still much room for technological advancement in drug delivery, manufacturing methods, and production costs, compared to small molecule and antibody drugs, it is possible to strategically design optimal therapeutics from multiple modalities for a wide variety of diseases and drug targets. It is no exaggeration to say that the era has arrived.

In this study, we focused on nucleic acid drugs, gene therapy, tumor-soluble ^viruses1), gene cell therapy, and cell therapy as relatively new modalities that have been put into practical use in recent years, in addition to small molecule and antibody drugs, which are the main modalities of current pharmaceuticals. The survey also looked at what indications these pipelines are targeting.

2 Survey Methodology

New Molecular Entity ( ^NME2 )) from the listing information in the drug database EvaluatePharma (output on January 16, 2021). Information on disease areas by modality was extracted for products in the clinical development stage (P1-P3) and in the submission stage. If an NME that was already marketed or approved was undergoing clinical development for an additional indication, that NME was also included in the analysis, but not for indications that had already been approved.

(1) Classification and hierarchy of disease areas and count of applicable ingredients

EvaluatePharma has a three-level hierarchy of indications for drugs and products in development: Indication level 1 (20 disease areas), level 2 (98 disease categories), and level 3 (946 indications), and in this report, levels 1 through 3 are classified as "major classification," &quot In this report, levels 1 to 3 are defined as "major classification," "intermediate classification," and "minor classification," respectively.

When a component is developed in multiple disease areas, each is counted in duplicate in the hierarchy to be analyzed. For example, in the case of a major category analysis, if an ingredient is developed in the "oncology" and "immunology" fields, it is counted as 1 for each. However, even if a drug has multiple indications in the medium categories of "solid tumors" and "hematologic cancers," or in the small categories of "lung cancer" and "colorectal cancer," they are not counted together.

2) Modality classification

The modality classification in this study corresponds to the EvoluatePharma ^{classification3)}.

(3) Number of active ingredients (items) covered

The development stages and the number of active ingredients (products) covered in this survey are shown in Table 1. In this survey, the P1 to application stages are collectively referred to as the "development stage.

3 Results

3.1 Disease indications of developed products by modality (major classification)

Figure 1 shows a breakdown of the development products in Table 1 by indication, and Figure 2 shows a breakdown by modality. Overall, the largest number of products were developed in the oncology field, and this was also the case for individual modalities.

In particular, antibody drugs and gene cell therapy are being developed in the oncology field for more than 60% of the products under development. Gene cell therapies, such as CAR-T cell therapy and T cell receptor (TCR) therapy, are the main products in development targeting cancer. In addition, oncolytic viruses are 100% indicated in oncology due to their characteristics.

In gene therapy, the percentage of active ingredients developed in oncology is less than 20% of all gene therapies, which is low compared to other modalities, and the number of "other" (mainly including lysosomal diseases; see Appendix 1) and "sensory organs" developments is high. Targeting specific genes and genetic diseases is thought to be driving development in a wide range of disease areas.

3.2 Disease indications for approved small molecule and antibody drugs (broad category)

Since many small molecule and antibody drugs have been launched, we surveyed the indications of approved (approved and launched) products in these two modalities (Figure 3).

For small molecule drugs, the percentage of approved drugs in the infectious disease and cardiovascular (circulatory organ) fields is high. Among already approved antibody drugs, the percentage of products with cancer indications was slightly lower at 44.9% than that of products under development (Figure 2, 63.1%), with higher percentages for "immunology" and "musculoskeletal" indications.

3.3 Modality Breakdown of Developed Products by Disease Area (Large Category)

The next section shows a breakdown of the modality classification of products under development by disease area. In addition to the top three disease areas (oncology, neurology, and infectious diseases), the cardiovascular, musculoskeletal, and sensory organ disease areas are shown with the highest percentages of nucleic acid drugs, cell therapy, and gene therapy as new modalities, respectively. (See Figure 4 and Appendix 1 for other disease areas.)

In the oncology area, small molecule drugs account for roughly half of the total, and the proportion of biopharmaceuticals such as antibody drugs and gene cell therapies is higher than in other areas. In the neurology area, the percentage of small molecule drugs is high, partly due to their superiority in terms of drug delivery to the central nervous system. In the cardiovascular area, nucleic acid drugs account for a higher percentage than in other areas, but their disease targets and mechanisms of action differ from those of other modalities (discussed below in section 3.4). It was confirmed that the share of each individual modality being developed differs depending on the indication disease area, such as musculoskeletal area for cell therapy in terms of tissue regeneration, etc., and sensory organ area for gene therapy, where local administration is possible.

3.4 Disease areas of developed products by modality (medium classification, small classification)

Medium

All modalities have a large proportion of components with indications in the oncology area, and the breakdown of these components (in the middle category) is shown in Figure 5. Small molecule drugs, antibody drugs, nucleic acid drugs, gene therapy, and tumor-soluble viruses account for a large proportion of solid tumors, while gene-cell therapy accounts for a large proportion of hematologic cancers. Cellular therapies are generally comparable. For disease areas other than oncology (medium classification), data are presented in Appendix 2.

Sub-category

Table 2 shows the indications with the largest number of products developed for each modality (subcategories) for "oncology" and "non-oncology.

In the oncology field, many of the products developed for breast cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, and acute myeloid leukemia are those for which individual disease names can be confirmed, while those for nucleic acid drugs, tumor-soluble viruses, and cell therapy are those for melanoma, head and neck cancer, and other diseases different from those of small molecule drugs and antibody drugs.

Among diseases other than oncology, those common to both low-molecular-weight and antibody drugs include COVID-19, neurological diseases such as Parkinson's disease and Alzheimer's disease, and, for antibody drugs, autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. As for COVID-19, many drug repositionings from already approved drugs are included.

The most common nucleic acid drug is "dyslipidemia," which is an RNA interference (RNAi) or antisense nucleic acid targeting specific genes related to lipid metabolism (ApoC3, ANGPTL3, ^{PCSK96, etc.} ), although the target molecules are different from those of small molecule drugs, Although the target molecules are different from those of small molecule drugs, they generally have much in common with antibody drugs (Table 3). Other liver-related diseases, such as hepatitis B, are also seen at the top of the list, which may be due to the drug delivery ^properties7) of nucleic acid drugs (antisense nucleic acids), which can easily reach the liver. In gene therapy, ophthalmology-related diseases are the most common targets for gene therapy, because local administration reduces drug delivery and the risk of systemic side effects, and the dosage is smaller than that for systemic administration, making it a suitable target for gene therapy. In cell therapy, there are many COVID-19 products in development, but they do not target the coronavirus itself, but rather focus on the utilization of mesenchymal stem cells (MSCs), which are expected to have immunosuppressive effects against cytokine storms (Table 4).

4 Summary and Discussion

This paper surveys the pipeline currently under development, focusing on drug discovery modalities and indications.

In addition to the large number of unmet medical needs, the reasons for this are thought to include the wide range of indications, such as solid tumors and hematologic cancers, the greater room for additional indications from marketed products compared to other disease areas, and the discovery of new target molecules.

Looking at the current pharmaceutical market as a whole, the percentage of biopharmaceuticals, including antibody drugs, is increasing, but the modalities of the development pipeline differ depending on the disease area. The utilization ratio of novel modalities is high in areas such as intractable cancer, genetic diseases, and tissue regeneration, where there are high unmet needs that are difficult to approach using conventional modalities such as small molecule drugs and antibody drugs. There are also many products under development for COVID-19, for example, 26 out of 286 (9.1%) for cell therapy and 62 out of 1,033 (6.0%) for antibody ^drugs8). Thus, it can be seen that the novel coronavirus pandemic has had a significant impact on drug development.

In the case of small molecule and antibody drugs, we also surveyed the indication disease areas of already approved drugs. The percentage of oncology indications for already approved drugs was lower than that for drugs under development, and the percentage of infectious disease indications was higher for low-molecular-weight drugs.

The change in the indication disease areas of marketed and developed products can be attributed to multiple factors, such as changes in unmet medical needs due to the launch of new therapeutic agents, depletion of drug targets in certain therapeutic areas, and business predictability issues in the area of antimicrobial ^agents9. On the other hand, it can be imagined that there are many technological issues that have not yet been solved in new modalities, and the development and manufacturing costs per patient tend to be high, thus limiting the number of diseases that can be targeted. We hope that these issues will be resolved in the future, and that the indications for each modality will be expanded to new areas.

Conclusion

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