Points of View Trends of Drug Discovery Modality in New Drugs Diversification/High Molecular Weight Trends and Evolving Small Molecular Drugs

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Yosuke Takahashi, Senior Researcher, National Institute of Biomedical Innovation Policy

Introduction

In the past few years, the terms "drug discovery modality" and "pharmaceutical modality" have become increasingly common in the field of pharmaceuticals. The term "modality" originally means "style" or "aspect," and in the field of medical devices, it has long been used to describe the type of equipment used, such as MRI (magnetic resonance imaging) and CT (computed tomography). In recent years, through research and development using various basic drug discovery technologies, not only small molecule drugs but also antibody drugs, nucleic acid drugs, gene therapy drugs, and various other molecules (medium to large molecules) have begun to be put to practical use as drugs. Under these circumstances, the term "drug discovery modality/pharmaceutical modality" has come to be used to describe a classification of methods and means of basic technologies for drug discovery for these drugs. In this paper, the term "modality" will be used without any specific reference.

In the recent worldwide pandemic of novel coronavirus infection (COVID-19), various pharmaceutical companies and research institutes around the world are conducting research and development of innovative therapeutic drugs and vaccines using the latest science and technology with the aim of ending the disease. AstraZeneca/Oxford University and Johnson & Johnson have developed vaccines using viral vectors, while Novavac has developed vaccines using recombinant proteins. The mRNA vaccines developed by Pfizer/Biontec and Moderna have attracted much attention, including the fact that they have been commercialized in an extremely short period of time, as they utilize a novel modality that has never been commercialized in other pharmaceutical products. Unlike conventional vaccines, these vaccines can be said to be novel modalities developed based on new drug discovery platform technology, and are examples of how the importance of drug discovery platform technology has been reaffirmed.

Against this backdrop, the Cabinet approved the "Strategy for Strengthening Vaccine Development and Production Systems " ^{1) in} June 2021. In this document, the Cabinet discussed how to organize and resolve issues related to the current situation in which domestic research and development of novel coronavirus vaccines is lagging behind that of Western countries, and confirmed the need to further promote the research and development of new modalities. In other words, it was pointed out that it is important to promote research and development utilizing new modalities such as cancer vaccines, gene therapy, and nucleic acid medicine, to foster and maintain a variety of modalities, and to establish a system that enables rapid development of drugs and vaccines by converting these technologies in case of emergencies.

In the field of pharmaceuticals other than vaccines and other infectious diseases, the global trend in recent years has been the development of pharmaceuticals using new modalities such as antibody drugs, nucleic acid drugs, gene therapeutic drugs, and cell ^therapy2). This is thought to reflect the fact that new modalities have been discovered as molecules that can act on drug targets that were difficult to target with conventional small molecule drugs, and are now being utilized as actual drugs.

The "Pharmaceutical Industry Vision 2021" issued by the Ministry of Health, Labour and Welfare on September 13, ²⁰²¹³⁾ states that the Japanese pharmaceutical industry should maintain and strengthen its drug discovery capabilities to meet unmet medical needs, including those for infectious diseases, and continue to provide a stable supply of all types of pharmaceuticals, including innovative drugs, to the public, The vision is described as a vision to be attained. It also states that one of the elements to realize this vision is the importance of research and development of increasingly diverse and complex modalities.

In this article, we will review the trends in approved drugs from the viewpoint of modality, and consider the future prospects for small molecule drugs, which are a conventional modality.

Modality Trends in Newly Approved Drugs

The modality classification of NMEs is based on the technology classification in EvaluatePharma. The NME modality classification was based on the technology classification in ^{EvaluatePharma4)}, and the dates extracted from the FDA Approval Date and Japan Approval Date (indication) were used to analyze the annual changes in the number of approved items. Note that COVID-19 vaccine, which has been attracting attention in recent years, is preferentially classified as a vaccine, and is not classified as a recombinant protein or gene therapy.

Figure 1 shows the number of approved products by modality in the U.S. since 2000, and Figure 2 shows the share of approved products by modality for that year. Figures 3 and 4 show the approval status in Japan.

The number of approved products in the U.S. was around 30 in the 2000s, but has been gradually increasing since then, and in recent years the number of approved products has been around 50-60 per year. This confirms that small molecule drugs are still the main modality. In the research paper by Keyi, it is reported that the percentage of low-molecular-weight drugs is on a declining trend in the pharmaceutical sales value ^index2). 2 ⁾ One of the reasons for the gap between the number of approved drugs and the amount of sales is considered to be the increase in the number of blockbusters in the biotech drug market.

The next modality after small molecule drugs was recombinant proteins in the early 2000s, but the number of approved antibody drugs has gradually increased since then, and antibody drugs have grown to become the second largest modality after small molecule drugs since around 2015. The number of approved new modalities such as nucleic acid drugs, gene therapy, and gene-cell therapy has been on the rise, with 2, 0, and 0 items approved by 2015, respectively, but 9, 2, and 5 items approved since 2016, respectively, confirming the diversification of modalities.

In Japan, small molecule drugs accounted for around 80% of the total in the early 2000s, a large figure compared to the United States. The main reason for the difference between Japan and the U.S. is due to the small number of recombinant proteins approved in Japan, and it can be seen from this data that there was a 3-5 year drug lag in ^{biopharmaceuticals6)}. In the last five years, the share of modality in both Japan and the U.S. has been almost the same, with small molecule drugs accounting for around 60%, followed by antibody drugs.

Trends in Mode of Action by Modality

The reason behind the progress in research for practical application of new modalities such as recombinant proteins and antibody drugs, whereas small molecule drugs have traditionally been the mainstay of pharmaceuticals, is that they have expanded the targets of drug discovery, which were difficult to approach with conventional small molecule drugs (see Fig. 5). However, there are uncertainties in the development of new modalities as pharmaceuticals (especially in terms of safety, quality control, and regulation), and biopharmaceuticals including new modalities have issues such as high manufacturing costs. In addition, biopharmaceuticals, including novel modalities, are subject to high manufacturing costs and other challenges. In this paper, we investigate whether there are any cases or indications that novel modalities that have recently been commercialized could be replaced by drugs based on smaller molecules, such as small molecule drugs, which have a proven track record as pharmaceuticals.

First, using Pharmaprojects, we investigated the MoA (Mechanism of Action) of approved drugs in the following four modalities that have been put into practical use relatively frequently: (1) antibody drugs, (2) recombinant protein and peptide drugs, (3) nucleic acid drugs, and (4) gene therapy. The MoAs were limited to those drugs approved in one of the countries listed in this database, and those developed (including those under development) in at least one of the countries (1) and (2) were limited to those developed in Japan or the United States. For (1) to (2), the MoA ranking of the approved products is shown in Tables 1 to 4. For (1) and (2), the number of drugs excluding biosimilars was also examined, as there are many drugs that fall under biosimilars.

Antibody drugs

More than 100 new antibody drugs have now been ^{approved7), 8) ,} among which the top MoAs are Tumour necrosis factoralpha antagonist, Vascular endothelial growthfactor receptor antagonist, CD20 antagonist, and ErbB-2 antagonist (Table 1), the majority of these were biosimilars. These are all MoAs for which first-in-class drugs were approved around 2000, and it is thought that multiple biosimilars have emerged due to their high medical necessity and importance. Excluding biosimilars, the most common NME is PD-1 antagonist, with a total of 10 products. Of these, only four are approved in either Japan or the United States, while the other six are approved only in China. However, all six are either under regulatory review or in clinical trials in the U.S., so it is expected that many more PD-1 inhibitors will be launched in the future. In addition, there are a total of five bispecific antibodies that have the ability to bind to multiple antigens, although they do not appear in the table because they differ individually as MoAs, and many antibody-drug conjugates (ADCs) in which functional molecules (mainly low molecular weight compounds) are attached. There are many ADCs (Antibody-drug conjugate: ADC) that bind functional molecules (mainly small molecule compounds), and there are several examples of ADCs that bind cell-killing compounds or radioactive substances.

Recombinant protein/peptide drugs

The history of biopharmaceuticals in this category is long, and since the 1980s, several drugs have been approved in MoAs, including insulin agonists, growth hormone receptor agonists, erythropoietin receptor agonists, and interferon agonists. As shown in Table 2, these drugs have in common the characteristic of being bioactive proteins that act like agonists. When the mechanism of a disease is elucidated and it becomes clear that the disease is caused by a quantitative deficiency of a bioactive substance, it is very logical that the MoA should be supplemented with the protein in question. Immunostimulant has the largest number of NMEs, and this is an example of a vaccine using an antigen produced as a recombinant protein, which has been put to practical use as a vaccine for hepatitis B and influenza. The next most common NME is Factor VIII stimulant, which is approved for the treatment of hemophilia A.

Also unique in this category are the large number of drugs that have been modified from natural bioactive substances in various ways, and these modifications have been made ahead of other modalities. Some have improved functionality compared to the natural form by modifying the amino acid sequence, some have added functional molecules such as PEG, and some have been created based on a part of antibody drugs (especially antigen binding sites), and so on. Modalities that are considered to be on the borderline of antibody drugs and those that combine recombinant proteins with antibody drugs have also emerged, and the modality is becoming more diversified.

Nucleic acid drugs

The number of nucleic acid drugs approved so far totals 14 (Table 3). Nucleic acid drugs with MoAs include Eteplirsen, which was approved by the FDA in 2016. This MoA is based on the exon-skipping action of antisense nucleic acids on target genes, which is achieved by increasing the expression level of a functional gene and thus replenishing the missing protein expression level (in this case, Dystrophin protein expression level), and is highly specific to and affinity for the target pre This is an example of drug discovery that makes good use of the characteristics of nucleic acid drugs, which have high specificity and affinity for the target pre-mRNA. Transthyretin inhibitor is a therapeutic drug for amyloid neuropathy caused by mutant transthyretin, and suppresses the production of mutant proteins that cause the disease. What these MoAs have in common is that nucleic acid medicine was the first modality to be commercialized for this MoA. The target was considered difficult to approach with conventional small molecule drugs, so nucleic acid drugs were selected as the most suitable modality and were successful in this case.

Gene Therapy

In this survey, gene therapy is broadly defined as a therapy in which viral vectors, plasmid vectors, or mRNAs are directly administered in vivo to express a target gene ^.9) However, as shown in Table 4, the number of practical applications of gene therapy is not large. However, as shown in Table 4, not many of them have been put into practical use. For those, there are multiple examples utilizing different types of modalities, including mRNA vaccines and viral vector vaccines. Although not shown here, there are also several items in the development stage, and this strategy of utilizing gene therapy will be the mainstream in the development of vaccines not only for COVID-19 but also for other emerging infectious diseases in the future.

Other than the COVID-19 vaccine, there are no other products on the market with a common MoA at this time. As seen in Zorgensma (SMN-1stimulant) and Luxturna (RPE65 stimulant, Phase 3 stage in Japan), which have already established a certain level of market, those targeting rare diseases caused by congenital single gene abnormalities have been launched. Perhaps due to the success of these drugs, there are several MoAs in the development pipeline at the Phase 3 stage, and the gene therapy modality is expected to expand further in the future.

Investigation of competition among modalities in the same MoA

Looking at the MoA trends for each of the four modalities investigated in this study, there are examples of multiple modalities being applied to the same MoA. In order to investigate such cases in detail, we conducted a search on PharmaProjects for the status of approved drugs and products in development (presence of other modalities, development stage, etc.) for all MoAs listed in Tables 1 through 4, and examined the status of competition among modalities. Due to space limitations, two cases of particular interest are introduced below.

Example in Calcitonin gene-related peptide inhibitor (CGRPinhibitor)

There are four NMEs (galcanezumab, eptinezumab, fremanezumab, and erenumab) as calcitonin gene-related peptide inhibitors in antibody drugs. These include those that suppress signaling by neutralizing CGRP itself and those that suppress signaling by binding to the CGRP receptor. As of September 2021, there are a total of five small molecule drugs with this MoA other than antibody drugs that have reached the clinical stage or later (as of September 2021), and rimegepant sulfate, ubrogepant, and atogepant have been approved in the United States, where development is in progress, while zavegepant hydrochloride is in Phase 3. None of these small molecule drugs has been approved in Japan (Table 5).

The history of research and development of drugs with this MoA is long, and in 1999, a clinical trial of Olcegepant, a small molecule drug, was conducted, showing its ability to abort migraine ^attacks10). 10) However, the drug was administered intravenously in clinical trials, and it is the author's guess that the pharmacokinetic characteristics resulting from its large molecular weight (approximately 870) may have prevented the choice of oral administration. Although the development of this drug was eventually halted, several orally-administrable small-molecule drugs were subsequently discovered and are undergoing research and development. However, these compounds also had safety issues in common, such as hepatotoxicity, and research and development was ^suspended11). Subsequently, research and development targeting CGRP with antibody drugs was initiated, and since the approval of erenumab in 2018, a total of four antibody drugs have been approved by 2020. These antibody drugs are used prophylactically for migraine, taking advantage of their safety and long half-life based on the high target selectivity of antibody drugs, and their usage is characterized by subcutaneous or intravenous administration once a month or once every three months. Although antibody drugs have taken the lead in practical application, research and development of small molecule drugs is also underway, and ubrogepant, which overcame the aforementioned issues, was approved for the first time as a small molecule drug in 2019 (none of the small molecule drugs have been approved in Japan). This is an orally administrable drug that takes advantage of the characteristics of small molecule drugs and can be used as an abortive treatment for acute migraine attacks. Rimegepant sulfate, the second small molecule drug to be approved, can be used either as an abortive or prophylactic agent, and can be used with the same indications as antibody drugs.

CGRP inhibitors have only recently been introduced to the market, and it is still unclear how they will be positioned in the treatment and prevention of migraine in the future. While the drugs have relatively similar profiles in the same modality, the profiles of drugs in different modalities, such as antibody drugs and small molecules, are very different. It is expected that the value of drugs will be judged comprehensively, not only in terms of efficacy and safety, but also in terms of differences in dosage and drug cost, and that medical needs will be met in the migraine area by taking advantage of the characteristics of each modality.

Case study in SMA therapeutics

Spinal muscular atrophy (SMA: spinal muscular atrophy) is a neuromuscular disease of autosomal recessive inheritance caused by a deficiency or deletion of the survival motor neuron (SMN) protein. The disease is associated with progressive muscle atrophy and respiratory failure shortly after birth, leading to early death in severe cases. In recent years, three innovative new drugs have been launched for this disease, which have brought gospel to patients. Although the mechanisms of action of these three drugs are strictly different, they share the common feature of supplementing SMN protein function.

Spinraza intramedullary injection ("Spinraza") is classified as a nucleic acid drug and has therapeutic effects for SMA by enhancing SMN2 gene expression and replenishing SMN protein ^function12) and was approved in Japan in 2017. Spinraza is administered intrathecally via lumbar puncture and is administered at 2, 4, and 9 weeks after the initial dose for infantile spinal muscular atrophy and at 4-month intervals thereafter. Based on the data provided by the Central Social Insurance Medical Council (hereafter referred to as "Chuikyo") at the time of the NHI drug price listing, the annual drug cost is calculated by dividing the market size by the number of patients, which is approximately 28.7 million yen (the price at normal administration after the loading dose is completed).

Zorgensma intravenous infusion ("Zorgensma") is a drug classified as a gene therapy, which carries the SMN1 gene in an AAV vector and, like Spinraza, has a therapeutic effect on SMA by replacing the SMN protein ^function13). Zorgensma was approved in Japan in 2020 as an intravenously administered systemic drug. The NHI drug price for Zorgensma was calculated based on the Comparable Drugs Method I with Spinraza as the comparator, to which the Pioneer Review Designation System Addition and the Usefulness Addition I were added, resulting in a price of 167,077,222 yen. However, this is a drug with a long-lasting effect after only one administration.

And in 2021, a small molecule drug called Ebrisdi Dry Syrup ("Ebrisdi") was approved in Japan for the treatment of SMA. Ebrisdi is designed to treat SMA by increasing SMN protein through a mechanism of action called SMN2 splicing ^{modification14)}. This is a noteworthy case of a MoA similar to the novel modality being achieved in a small molecule drug. Ebrisdi can be administered orally and is given once daily as a dry syrup. Based on the data provided by the Chuikyo at the time of NHI drug price listing, the annual drug cost is estimated to be approximately 24.5 million yen, similar to Spinraza.

The three drugs recently approved for the treatment of SMA are based on different modalities, and their usefulness has been confirmed in clinical trials. Each of the three drugs has its own characteristics, such as differences in dosage based on differences in modality and differences in drug cost. In the future, data on efficacy and safety will be accumulated and updated, and various characteristics other than efficacy and safety will be taken into consideration to contribute to medical care, such as meeting unmet needs. As shown in this case, the practical application of multiple innovative drugs with different characteristics is a very favorable situation from the patient's point of view. In addition, trials are underway to verify the effects of combining and switching between these drugs, and the results of these trials are highly ^{anticipated15), 16)}. It is the mission of pharmaceutical companies to create distinctive new drugs by making full use of various modalities and to provide patients with choices.

Summary and Future Outlook

As mentioned above, research and development of each modality has advanced in recent years, and the number of combinations of multiple modalities and those that fall somewhere in between has begun to increase, making it difficult to draw clear boundaries between modalities. As modalities become more diverse and even polymeric, it is becoming possible to add a variety of functions to pharmaceuticals. However, amidst this trend, the presence of small- and medium-molecule ^drugs17) is also increasing; as seen in the area of SMA therapeutics, replacing the function of biopharmaceuticals with smaller molecules may become a trend in future drug discovery research. In general, small molecule drugs have high oral absorption as one of their characteristics, and may be convenient to administer, although this depends on the disease and the symptoms of each patient. In addition, in general, small molecule drugs are said to be less expensive to manufacture than ^{biopharmaceuticals18)}, which may be beneficial in terms of healthcare economics. The drug discovery targets that were inaccessible with conventional small molecule drugs may also benefit from the development of science and technology (elucidation of disease mechanisms, utilization of AI and in silico technology, expansion of experimental and evaluation systems such as iPS cell and genome editing technology, practical application of ultra-high-throughput screening, improvement in the performance of analytical instruments such as cryo-electron microscopes, and the development of new drugs that can be used in the field of drug discovery). and other analytical instruments, the development of new technologies based on small molecule drugs such as Protein degrader, and advances in formulation technologies), it has become possible to obtain seeds with promising profiles for pharmaceuticals. In recent years, however, relatively large low-molecular-weight drugs with molecular weights approaching 1,000 (classified as low-molecular-weight drugs according to Evaluate's definition) have been introduced into the market, and these drugs are now called mid-molecular-weight drugs. However, in recent years, relatively large small molecule drugs with molecular weights approaching 1,000 (classified as small molecule drugs by Evaluate's definition, but sometimes referred to as mid-molecule drugs) have become common. This situation is discussed in detail in Policy Research Paper 72 (Toobe), which we refer the reader to for further ^details19).

Biopharmaceuticals are evolving as a new modality through molecular diversification and complexity, and are expected to play a very important role in future pharmaceuticals. What is important for pharmaceuticals is not only efficacy and safety, but also the value of the drug itself, including convenience of administration and price, and what modality is used is not a major issue. In the future, it would be desirable to create multiple drugs with unique features based on various modalities to meet diversifying needs, so that patients themselves can select the drug with the highest value for them.

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