The Pharmaceutical Industry at a Glance Development Status of Pharmaceuticals for Unmet Medical Needs
Status of Drug Development for Unmet Medical Needs

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Shinji Tsubakihara, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

SUMMARY

Based on the results of the "Medical Needs Survey on 60 Diseases" conducted by the Japan Health Sciences Foundation, we analyzed the development status of pharmaceutical companies in response to unmet medical needs. The results of the survey of development items for 60 diseases as of the end of June 2023 by 20 domestic and foreign companies showed that (1) the number of development items for diseases in "Quadrant 1", where both medical satisfaction and drug contribution are 50% or more, decreased from the previous survey, while the number of development items in "Quadrant 3", where both medical satisfaction and drug contribution are less than 50%, increased. (2) The number of development items and the number of NME components increased from the previous survey. The number of development items for diseases in "Quadrant 3" varied widely among diseases, and there were some diseases with zero development items, including those from the previous survey. Although the expansion of new drug development can make a significant contribution to solving unmet needs of patients, there is a large bias in the number of new drugs developed among diseases, and solving this bias should be an issue for new drug development in the future.

1. Introduction

Based on the results of a survey on medical needs conducted by the Human Science Foundation (hereinafter referred to as "HS Foundation" ⁾¹⁾, the Pharmaceutical Industry Policy Institute compiles data on new drug approvals and development pipelines and continuously analyzes the status of pharmaceutical companies' efforts to address unmet medical needs2)3 ⁾. ²⁾³⁾.

In the previous issue of the Policy Research Institute ^News4), based on the 6th HS Foundation survey reported in 2019, we reported on the status of new drug approvals through 2022 for the 60 diseases covered by the survey, as well as the results of our analysis of the approval status trends by category for drugs for malignant tumors, which had particularly high approval numbers, report the results of a survey of the development pipeline for 60 diseases as of the end of June 2023. In addition, we report on our survey of the status of the development pipeline of drugs for diseases for which the HS Foundation survey showed low unmet medical needs, both domestically and internationally.

Survey Methodology

As in the 2022 survey of development items, the survey covered domestic development items (Phase I to Filed) from 20 domestic and foreign pharmaceutical companies.

The main source of information was the domestic development pipeline ^{information5)} disclosed on each company's website as of the end of June 2023. As reference information, we used the JapanRegistry of Clinical Trials "Clinical Research Submission and Release System" ^website6), "Tomorrow's New Drugs (produced by Technomic) ⁷⁾, and the "Release of Clinical Trial Information" ^website8) of the Pharmaceuticals and Medical Devices Agency website. In addition, Citeline's " ^{PharmaprojectsⓇ "site9)} was used for the modality survey and the survey of development items in Europe and the United States. Compounds whose molecular weight was unknown on this site and indicated as "Chemical, synthetic" or "Chemical, synthetic, biologic" were not identified by modality. The "Evaluate ^{PharmaⓇ"site10)} was used to investigate the year of establishment and company classification of overseas development companies.

The number of development products per disease for each of the 60 diseases was plotted and graphed on the axes of physician treatment satisfaction and drug contribution obtained from the 6th HS Foundation survey in 2019.

Results

(1) Number of products and ingredients developed for 60 diseases

As of the end of June 2023, there were 337 products and 207 ingredients in development for 60 diseases. Of these, 227 (67.4%) were new molecular entities (NMEs) and 154 (74.3%) were new molecular entities (NMEs), all of which were additional indications to already marketed drugs. By domestic and foreign ^investment5), 161 (47.8%) and 88 (42.5%) of the products were from domestic companies, while 176 (52.2%) and 119 (57.5%) were from foreign companies.

Figure 1 plots diseases along the treatment satisfaction (horizontal axis) and drug contribution (vertical axis) for 60 diseases selected in the 6th HS Foundation survey reported in 2019 as "serious diseases," "diseases that significantly impair quality of life," "diseases with a large number of patients," "diseases with high social impact," etc., with values and circle sizes The number of development items as of the end of June 2023 is indicated by the number and the size of the circle.

Looking at the number of development items related to 60 diseases by quadrant, the highest percentage of development items for diseases included in the "first quadrant" (37 diseases, 254 items (75.4%)), where both treatment satisfaction and drug contribution are 50% or higher. In the "second quadrant," where medical satisfaction is less than 50% and drug contribution is more than 50%, 16 items (4.7%) were developed for 6 diseases, 30 items (8.9%) were developed for 7 diseases in the "fourth quadrant," where medical satisfaction is more than 50% and drug contribution is less than 50%, and 37 items (11.0%) were developed for 10 diseases in the "third quadrant," where both medical satisfaction and drug contribution were less than 50%. The number of products developed in each quadrant was 37 (11.0%) for 10 diseases.

(2) Number of items under development and percentage of each quadrant

The number and percentage of products developed in each quadrant were analyzed by comparing the number and percentage of products developed in the two previous surveys in 2020 and ²⁰²²²⁾ with those in the current survey (Table 1). The overall number of items increased by 7 items from the previous survey, from 284 to 330 to 337. In the first quadrant, the number of items decreased by 4 from the previous survey, from 226 (79.6%) to 258 (78.2%) to 254 (75.4%), and the percentage decreased by about 3%. There were no significant changes in these quadrants: quadrant 2 went from 13 (4.6%) to 14 (4.2%) to 16 (4.7%), and quadrant 4 went from 25 (8.8%) to 30 (9.1%) to 30 items (8.9%). In contrast, in the third quadrant, where both treatment satisfaction and drug contribution were less than 50%, there was an increase of 9 items from the previous survey, from 20 (7.0%) to 28 (8.5%) to 37 (11.0%). These indicate that the increase in the number of items in the third quadrant mainly contributed to the overall increase in the number of items developed.

(3) Trends in the number of items under development by disease area

The 60 diseases included 10 malignant neoplastic diseases, which accounted for 192 items or 57.0% of the total number of items developed, the largest number of items developed in this disease area. The breakdown of the number of items was 58 for "lung cancer," 32 for "breast cancer," 18 for "malignant lymphoma," 17 for "liver cancer," 16 for "prostate cancer," 16 for "leukemia," 12 for "colon cancer," 15 for "stomach cancer," and 1 for "cervical cancer" in the first quadrant, and 7 for "pancreatic cancer" in the third quadrant. The number of "pancreatic cancer" in the third quadrant was 7.

As in the 2022 survey, the number of products developed for malignant neoplastic diseases and their ratio to the total number of products developed were evaluated over time. In addition, the number and percentage of NME items were analyzed by dividing the developed items in this survey into malignant tumor items and non-malignant tumor disease items. The number and percentage of malignant tumor items were 143 out of 284 (50.4%) in the 2020 survey, 183 out of 330 (55.5%) ²⁾ in the 2022 survey, and 192 out of 337 (57.0%) in this survey, an increase of 9 items from the previous survey (Figure 2 left). Of these 192 items, 122 (63.5%) were NMEs. There were 145 items other than malignant tumors, of which 105 (72.4%) were NMEs (Figure 2, right).

(4) NME modality analysis

The development items in this study were divided into malignant neoplastic disease and NME other than malignant neoplastic disease, and the breakdown of modalities was analyzed for each development stage. The left graph in Figure 3 shows the number of modalities in each stage of 122 NMEs for malignant tumors, and the right graph shows the percentage of modalities. In Phase III, low-molecular-weight compounds accounted for more than half of the total, suggesting a trend toward an increase in "Antibody Drug Drugs" and "Antibody Drug Conjugate (ADC)" in the early stage. However, in many cases, the modality could not be identified in Phase I, and several companies did not disclose Phase I, so the details of the trend could not be clarified. Similarly, when the 105 NMEs for diseases other than malignant tumors were analyzed (Figure 4), there were many cases where the modality could not be identified in the early development stage, but it was expected that protein/peptide and nucleic acid drugs, in addition to antibodies, will increase in areas other than malignant tumors in the future, leading to further diversification in modalities.

The development status has been analyzed in terms of items, but since items are counted for each developed indication, when an ingredient is developed for multiple indications, the number of indications is calculated as the number of items. In Figure 5, NMEs are analyzed by component, and looking at the trends over time (left figure), the number of NMEs in this survey increased by 28 components from the previous survey, an increase of approximately 20%. Looking at the modality distribution (right figure), no major characteristics were observed in comparison with the analysis of items, but the average number of indications per component was 1.5 for low molecular weight compounds (62 components in 92 items) and 1.3 for antibody drugs (50 components in 64 items), while the average number of indications for ADCs was 3.6 (7 components in 25 items), which was 2 to 3 times higher than those for other modalities. ADC was 3.6 (25 products, 7 components), which was 2 to 3 times higher than other modalities.

(5) Development status of diseases in the third quadrant

Since there was an increase in the number of products developed in the third quadrant, where both medical satisfaction and drug contribution were less than 50%, we conducted a more in-depth analysis. Figure 6 shows the number of products developed for the 10 diseases in the third quadrant over time since the 2020 survey. Alzheimer's disease," for which there were originally many development items, increased from 9 to 11 to 14, while the number of development items for "pancreatic cancer" remained unchanged. In addition, the number of development items for designated intractable diseases such as "Multiple Sclerosis," "Systemic Scleroderma," and "ALS/Amyotrophic Lateral Sclerosis" is also on the increase, with 7 out of 10 diseases in the current survey having more development items than in the previous survey. However, there were no products developed for "fibromyalgia" and "sarcopenia" in the three surveys.

Next, we surveyed the status of development items for quadrant 3 diseases in the U.S. and Europe (Figure 7). The data included development items that were not yet developed in Japan but were in Phase II or under submission in the U.S. or Europe. In total, 269 products were under development in the U.S. and Europe, with a large number of Phase II products. Venture companies established less than 20 years ago accounted for 53.2% of the total, and were developing alone or with partner companies. Many of the products were for Alzheimer's disease and pancreatic cancer, with 70 and 96, respectively, 5 to 10 times the number of products in Japan. Fibromyalgia and sarcopenia were less common, but were being developed mainly by venture companies.

4. summary and discussion

The HS Foundation reported on the status of products under development in Japan as of the end of June 2023 for the 60 diseases covered by the survey on medical needs. 337 products were under development for the 60 diseases, an increase of 7 products from the previous survey.

Of the 60 diseases, the number of products developed for those in the first quadrant, where both treatment satisfaction and drug contribution are 50% or higher, accounted for 75% of the total, or 254 products for 37 diseases. However, the percentage of items in the first quadrant as a percentage of the total has decreased since the previous survey, while the number and percentage of items in the third quadrant, where both treatment satisfaction and drug contribution are below 50%, have both increased.

The number of items for the 10 malignant neoplastic diseases increased by 9 from the previous survey to 192. Of the 192 items, 122 were NMEs, and approximately 60% of the malignant tumor items were NMEs. In addition, when analyzing the modalities of products for malignant tumor diseases by development stage, it was not possible to clearly indicate the future transition of the modalities, but ADCs were developed in almost the same number as antibody drugs and small molecules in the Phase II stage. Therefore, it is highly likely that ADCs will become an important part of malignant tumor therapy in the near future.

The number of NME components for 60 diseases increased by approximately 20% from the previous survey, indicating an increase in domestic development of NMEs. Several of these clinical trials had been completed at the time of this survey. It was inferred that this was one of the reasons for the expansion of NME entries.

It is interesting to note that the number of items in quadrants 1, 2, and 4 remained almost the same as in the previous survey, while the number of items in quadrant 3 increased in this survey. We believe that this result is evidence that companies are actively working to resolve issues related to diseases with lower unmet medical needs. However, among the diseases with residual unmet medical needs, there are some diseases such as fibromyalgia and sarcopenia for which no treatment has been developed for a certain period of time. The results of the survey also revealed that there are many drugs for these diseases that have been developed in the U.S. and Europe but not yet developed in Japan. One of the reasons for this gap may be that more than half of these Western drugs were discovered by venture companies or other start-ups and are currently undergoing clinical trials, and clinical development in Japan was not planned by many of these start-ups from the outset. Naturally, there may be other factors as well, but it is assumed that a significant portion of these events may overlap with the so-called "drug lag/loss" factors.

It has been reported that there are a large number of patients in Quadrant 3 who are affected by diseases that were never or only marginally developed (Table 2), and it is assumed that many patients and their families have unmet needs that remain unmet. Finally, in order to give an understanding of the nature of these diseases, we will briefly describe their characteristics and the current status of their treatment, with sarcopenia, fibromyalgia, and vascular dementia as representative examples.

Sarcopenia was defined in 2010 as "a syndrome characterized by a progressive and generalized loss of muscle mass and strength, associated with physical dysfunction, reduced quality of life, and risk of death. ^12). The main pathophysiology is the decline in skeletal muscle mass and muscle strength or physical function (e.g., grip strength and walking speed) seen in old age. The major problem of this disease is that elderly patients with sarcopenia are prone to fall due to muscle weakness, and the fractures and trauma caused by falls lead to frailty and disuse syndrome. Osteoporosis and chronic kidney disease are likely to coexist, and the risk of death is increased in cancer patients and surgical patients. Basic treatment centers on exercise therapy and nutritional therapy, with a focus on essential amino acid intake. Nutritional intervention is recommended because it is expected to improve knee extensor strength, but the long-term effect of improvement is ^unknown13). In the coming super-aging society, it will be extremely important to develop treatments and therapeutic agents, in addition to preventive methods, to enable the elderly to maintain physical activity and independent living.

Fibromyalgia (fibromyalgia: FM) is a disease of unknown cause characterized by severe pain and intense stiffness of the connective tissues, especially the musculoskeletal system, throughout the body for a period of three months or longer. It is accompanied by a variety of symptoms such as severe fatigue, insomnia, headache and depressed mood. According to the Japan Rheumatism Foundation, the prevalence of the disease in Japan is approximately 1.7%, which is higher than the prevalence of rheumatoid arthritis (0.7%). The age of onset of the disease is considered to be in the latter half of the 40s, and in Japan, the male-to-female ratio is 1:4.8, with a higher frequency in women. Since pain is felt even in the absence of nociceptive stimuli, as with other chronic pain, it is thought to be caused by a weakening of the descending pain inhibitory system function, a lowering of the pain threshold due to central sensitization, and the presence of neuroinflammation in the brain due to activation of microglia in the ^brain12) as its cause, although there are many unknown factors. Currently available medications include pregabalin, a voltage-gated calcium channel α2δ ligand, and duloxetine, an SNRI, but tricyclic antidepressants, antiepileptic drugs, vaccinia virus-inoculated rabbit inflammatory skin extract, and weak opioid analgesics may also be used, although not indicated The reasons for the low satisfaction with FM treatment from physicians in the HS Foundation survey are that "some benefit is obtained, but not necessarily for everyone," and "few cases of pain disappear after existing treatments," suggesting that FM is a refractory condition ^.1) The results of a 2004 national epidemiologic survey showed that FM is a highly functional disorder, and that the number of patients with FM who had a functional outcome was high. ¹⁾ The results of a 2004 nationwide epidemiological survey showed that approximately half of FM patients had some impairment in functional prognosis, and that the quality of life and activitiesof daily living (ADL) of FM patients were significantly lower than those of normal ^subjects15). And chronic pain diseases such as FM are prone to presenteeism and absenteeism, resulting in a significant loss of labor ^{productivity16)}.

Vascular dementia (VaD) is a condition of dementia resulting from cerebrovascular diseases such as cerebral infarction or cerebral hemorrhage, and is thought to be caused by brain tissue damage in the area controlled by the infarcted blood vessel, increased internal pressure or direct brain tissue damage due to cerebral hemorrhage. Alzheimer's disease and cerebrovascular disease share common risk factors and can easily merge, and those with microinfarction or microhemorrhage may have cerebral amyloid angiopathy ^.)

In the HS Foundation survey, 29% of physicians said "treatment is not available" and 31% said "there is no effective drug", and "there are methods to prevent the onset of the disease, but there are no effective drugs". and "There are methods to prevent the onset of the disease, but no means to improve it at the time of onset," "Treatment effectiveness (is low)," and "No radical cure" were the opinions ^cited1). In order to restore the function of infarcted lesions and damaged tissues, academia is currently taking the lead in clinical trials using autologous bone marrow mesenchymal stem cell ^{administration18)} and basic research on tissue regeneration using neural stem cell transplantation established from induced pluripotent stem cells (iPS cells) and other induced pluripotent stem cells. In addition, clinical trials have been initiated for a low-molecular-weight ^compound19) that promotes recovery of damaged cholinergic nerves and synaptic remodeling in humans, and for a bone marrow mesenchymal stem cell inducer for regeneration of infarcted brain tissue. ²⁰⁾ Future trends in treatment and therapeutic drug development are attracting attention.

Conclusion

Drug development for diseases with low treatment satisfaction and drug contribution is expected to be extremely difficult. In the future, strong collaboration among industry, government, and academia will be extremely important in disease areas where it is difficult for pharmaceutical companies, venture companies, and academia to develop therapeutic drugs on their own. Rapid drug development is necessary not only to help patients, their families, and caregivers regain a healthy lifestyle as soon as possible, but also as an agile approach to social issues. To prevent the gap between Japan and Europe and the U.S. in solving unmet medical needs from widening, we hope that a system will be established in Japan in the near future to promote speedy drug discovery research and practical application through cooperation between industry, government, and academia.

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