The Pharmaceutical Industry at a Glance Development and Approval Status of Drugs for Unmet Medical Needs -Trends in 2022-.

Printable PDF

Akira Nakao, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

1. Introduction

The Pharmaceutical Industry Policy Institute (PIPI) continuously analyzes the status of pharmaceutical companies' efforts to address unmet medical needs by compiling data on new drug approvals and development pipelines based on the results of surveys on medical ^needs1) conducted by the Human Science Foundation (hereinafter referred to as "HS Foundation"). ^{2), 3)}.

In the previous Policy Research Institute News No. 61 (November 2020), based on the results of the FY2019 Treatment Satisfaction Survey, the number of development pipelines as of the end of August 2020 for 60 diseases was shown, and for the eight diseases newly added to the 60 diseases in the FY2019 survey, information on already approved drugs and the domestic development status of the selected five ^diseases4). This paper reports the number of development pipelines as of the end of May 2022 for the latest 60 diseases and the number of approved new drugs for 60 diseases for the three years from 2019 to 2021, based on the FY2019 treatment satisfaction survey. We would like to review the transition of its drug treatment, including its relevance to the number of new drug approvals, treatment satisfaction and drug contribution.

2) New Drug Development Status by Treatment Satisfaction Level

Figure 1 plots the diseases along the treatment ^{satisfaction5)} (horizontal axis) and drug ^{contribution6)} (vertical axis) in the 2019 HS Foundation survey, and shows the number of development ^items7) surveyed this time in terms of circle size and numerical values. The same 20 pharmaceutical ^companies8) as in the previous survey were included in the total number of development items (Phase I to Filed) in Japan as of the end of May ²⁰²²⁹⁾. The total number of development items was ³³⁰¹⁰⁾, of which 126 (38%) were new active ingredients ( ^NME11 ). Although the survey included the impact of some companies changing the stage of publication on their websites from Phase III or later to Phase II or later, the number of development items for 60 diseases increased by 46 compared to the previous survey, of which the number of NMEs increased by 4. The percentage of the number of products in development in the first quadrant, which indicates treatment satisfaction of 50% or more and drug contribution to treatment of 50%, was 78.2% (79.6% in the previous survey), indicating that this quadrant accounted for a large percentage of the products in development in this survey as in the previous survey, although it slightly decreased from the previous survey. The percentages of the number of developed products in the second and fourth quadrants remained almost unchanged from the previous survey at 4.2% and 9.1%, respectively (4.6% and 8.8%, respectively, in the previous survey). The percentage of products in the third quadrant, where both treatment satisfaction and drug contribution are less than 50%, was 8.5%, a slight increase of 1.5% from 7.0% in the previous survey, but the number of products in this quadrant increased from 20 to 28.

Of the 46 items that increased, 40 were related to oncology, and the ratio of the number of items developed for oncology to the 60 items developed in the previous survey, which was 50%, increased to 55% (183/330) (Figure 2, left). The percentage of NMEs in the number of oncology products developed decreased from 31% (44/143) in the previous survey to 27% (49/183). In other words, of the 40 products that increased, 5 are NMEs and 35 are additional indications (including some additional dosage and administration), suggesting that products developed for one specific cancer disease are being developed for other indications for the same cancer disease or for other cancer diseases (Figure 2, right).

As mentioned earlier, in this survey as well as in the previous survey, the percentage of products developed in the so-called Quadrant 1, which is the area where both treatment satisfaction and drug contribution are more than 50%, was 78.2%, accounting for a large percentage of the products developed. The number of products under development in this quadrant (78.2%) is quite large considering the fact that the proportion of diseases in the first quadrant is 61.7% (37/60) out of 60 diseases. As mentioned in the previous news, 10 of the 60 diseases are cancer diseases, and 9 cancer diseases other than pancreatic cancer are included in the first quadrant, "cancer" is a disease caused by genetic mutation, and there are various types of genetic mutation, and one disease called "XX cancer" is subdivided by various indications. The ratio of new drug development items in the first quadrant, which includes nine cancer diseases, is considered to be high because "cancer" is a disease caused by genetic mutation, and genetic mutation is subdivided into various types, and many therapeutic drugs are developed accordingly.

Even if the percentages indicating satisfaction with treatment and contribution to drug development both exceed 50, the breakdown of satisfaction and contribution is that "somewhat satisfied (contribution)" greatly exceeds "fully satisfied (contribution). Most of the remaining percentages that did not reach 100 were "unsatisfied" and "not contributing much," but some of them included responses such as "treatment is not working" and "there are no drugs that work. For example, for the nine cancer diseases in the first quadrant, the average percentage of "unsatisfactory" responses was 25.1% (11.7-42.1), the average percentage of "not well treated" was 6.2% (3.3-9.8), the average percentage of "not contributing much" was 16.5% (6.0-31.8), and the average percentage of "no effective medicine" was average of 2.4% (0.9-4.9) ^.12) This suggests that there is still a lot of room and demand for pharmaceuticals to contribute to the treatment of diseases, even if they are in the first quartile.

Looking at the number of products developed for each of the 60 diseases, the most common are lung cancer (53), breast cancer (34), malignant lymphoma (17), liver cancer (17), prostate cancer (16), and leukemia (15), followed by stomach cancer (11), CKD/chronic kidney disease (11), and Alzheimer's disease (11)" (numbers represent the number of products), indicating that the top development items are dominated by cancer diseases. The number of developed items for "lung cancer" has been the highest among the 60 diseases since the January 2014 survey (Policy Research Institute News No. 41 (March 2014)). ¹³⁾

3) Approval status of new drugs by level of treatment satisfaction 4) Lung cancer drug treatment

Figure 3 plots diseases along the treatment satisfaction (horizontal axis) and drug contribution (vertical axis) in the 2019 HS Foundation survey, and shows the number of new drugs approved in Japan in the last three years (2019-2021 ⁾¹⁴⁾ with indications for 60 diseases in terms of circle size and numerical value. The number of approved products during this period was 294, of which 133 (130 products) were for 60 ^diseases15). Of the 133 products, 54 (54 products) were approved by domestic companies and 79 (76 products) by foreign ^companies16).

Looking at the number of approved products related to 60 diseases by quadrant, the majority of the approved products, 85.7% (114/133), were in the first quadrant, where both treatment satisfaction and drug contribution were 50% or higher, as in the previous analysis of the number of products under development. In the 37 diseases in the first quadrant, 114 new drugs were approved, which was calculated to be 3 drugs per disease, or one drug per year.

On the other hand, the number of approved drugs for diseases in quadrants 2, 3, and 4 were 3.8% (5/133), 4.5% (6/133), and 6.0% (8/133), respectively. Nineteen products were approved for 23 diseases in these three quadrants, 15 of which had zero products approved in the past three years.

Looking at the number of approved items related to the 60 diseases by disease, the most common were malignant lymphoma (17), lung cancer (11), leukemia (8), CKD/chronic kidney disease (7), colorectal cancer (6), and breast cancer (6) (numbers represent number of items).

One of the first unique features of this survey of the number of approvals was that several new regenerative medicine products were included in the list of approved products related to 60 diseases: in 2015, ^{HeartSheetⓇ "} human (autologous) skeletal muscle-derived cell sheet" was approved with conditions and time limits for use in the treatment of heart failure, but However, no items related to 60 diseases were approved after that; between 2019 and 2021, nine new regenerative medicine products were approved, six of which (five products) were related to 60 diseases. Specifically, ^{KymriahⓇ "} Chisagen Recrule Ucell" for CAR-T cell therapy (leukemia and malignant lymphoma), ^{YescartaⓇ "} Axicabtagene Sylor Ucell" and ^{BreyanjiⓇ "} Lithocabtagene Malar Ucell" (both malignant lymphoma), and AllophycellⓇ "Allophycell" for human mesenchymal stem cell ^Ⓡ" Dalbadostrocel" (Crohn's disease) was approved, and ^{CollategeneⓇ "} Beperminogen perplasmid" (PAD/peripheral arterial disease) for gene therapy was approved with conditions and a time limit. All of these six products (five products) are therapeutic drugs for diseases located in the first quadrant and not in the other three quadrants, but the former four products were approved after being designated as "regenerative medicine products for rare diseases," and the latter Collategene was approved for the peripheral arterial disease "arteriosclerosis obliterans" as well as the The latter product, Collategene, was indicated for the improvement of ulcers in the peripheral arterial disease "arteriosclerosis obliterans" as well as the designated intractable disease "Buerger's disease".

In addition to conventional small molecule drugs and biopharmaceuticals such as antibody drugs and recombinant protein drugs, various modalities such as nucleic acid drugs and gene cell therapy have been added as options, and the addition of treatment methods for diseases that have been difficult to treat is expected to further increase treatment satisfaction and pharmaceutical contribution in the future. The second feature is the approval of cancer diseases.

The second feature is the large number of approved drugs for cancer. Figure 4 shows the percentage of new drugs approved since 2009 for the latest 60 diseases, divided into the three-year period 2009-2011, the three-year period 2014-2016, and the most recent three-year period 2019-2021 for cancer diseases (10 cancer diseases).

The number of approved drugs related to 60 diseases in each of the three-year periods 2009-2011, 2014-2016, and 2019-2021 was 110, 124, and 133, respectively, compared to 28, 45, and 62 new drug approvals for 10 cancer diseases, or a ratio of In the last three years, about half of the approved drugs for 60 diseases were for the 10 cancer diseases.

Changes in Lung Cancer Drug Therapy

The following is a review of the drug treatment of lung cancer, which had the largest number of items in the survey of products developed by 20 Japanese companies as of the end of May 2022, along with the changes in satisfaction with treatment (treatment satisfaction) and contribution of drugs to treatment (drug contribution) for the 60 diseases.

About Lung Cancer

Lung cancer is the third most common cancer among all cancers, after colorectal cancer and gastric cancer, with approximately 120,000 cases per year. The 5-year relative survival rate (2009-2011) is 34.9%, which is considerably lower than the 64.1% 5-year relative survival rate for all ^cancers17).

Treatment for lung cancer consists of surgery, radiation therapy, drug therapy, and palliative care, or a combination of these therapies. In the early stages, surgery is the mainstay of treatment, but as the stage progresses, drug therapy becomes the mainstay. Lung cancer is broadly classified into small cell lung cancer and non-small cell lung cancer, with non-small cell lung cancer accounting for about 85-90% of cases. Non-small cell lung cancer is further classified into "squamous cell carcinoma," "adenocarcinoma," and "large cell carcinoma" ^{18), 19)} (Figure 5).

Changes in Drug Treatment

Figure 6 shows treatment satisfaction and drug contribution for lung cancer and the number of new lung cancer drugs approved (new active ingredients + additional indications) by indication category. Although not limited to lung cancer, there are three paradigms of cancer drugs: cytotoxic anticancer drugs, molecular targeted drugs, and immune checkpoint ^{inhibitors20)}. By 1993, before the medical needs assessment was initiated, many cytotoxic anticancer agents had already been developed: platinum-based agents such as cisplatin were developed in the late 1980s, and combination chemotherapy with plant-derived chemotherapeutic agents developed in the 1990s and later was developed. While platinum-based chemotherapy remains the standard of care in lung cancer drug treatment today, it is also important to note the development of antiemetic agents and other supportive therapies to reduce the side effects associated with anticancer drug therapy.

Advances in science, technology, and molecular biology have clarified the mechanisms of cancer development, growth, and metastasis, and in 2002, gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was approved. Subsequently, gefitinib was found to be highly effective against tumors with mutations in the EGFR ^{gene21),22) and} the development of second- and third-generation EGFR-TKIs proceeded. In parallel, other molecularly targeted drugs were developed for other genetic mutations (ALK, ROS1, BRAF, MET, RET, and KRAS) (Table 1).

The PD-1 inhibitor antibody drug nivolumab, already approved in 2014 for the treatment of melanoma, was approved in 2015 for the treatment of non-small cell lung cancer. The PD-1 antibody pembrolizumab was subsequently approved in 2016, and the PD-L1 inhibitor antibodies atezolizumab and durvalumab were approved for non-small cell lung cancer in 2018.

The survey showed that treatment satisfaction and drug contribution for "lung cancer" were in the third quadrant of Figure 1 or Figure 3, with values for both treatment satisfaction and drug contribution below 20%, even though more than 20 drugs had been approved by the time of the 2005 survey. In the 2014 survey, treatment satisfaction was 37%, almost unchanged from the previous survey, but drug contribution increased to 73%, and in the early 2010s, with the advent of second- and third-generation EGFR-TKIs and the advent of molecular targeting agents other than EGFR, and immune checkpoint inhibitors since 2015, treatment satisfaction improved to 52% and drug contribution to 83% in the FY 2019 survey, finally reaching the first quadrant.

As mentioned earlier, although more than 20 drugs had been approved by the time of the 2005 survey, both treatment satisfaction and drug contribution were below 20%. We would like to examine in more detail the reasons for the increase in treatment satisfaction and drug contribution between the 2005 and 2010 surveys.

Increase in Treatment Satisfaction and Drug Contribution in FY2010

Following the discovery that gefitinib was effective in treating EGFR mutation-positive tumors, two randomized controlled trials conducted in Japan in patients with EGFR mutation-positive non-small cell lung cancer (gefitinib vs. chemotherapy: WJOG304523 ⁾ and NEJ00224 ⁾ showed that in both trials ²⁵⁾ showed an approximately 2-fold increase in progression-free survival (PFS) in the gefitinib-treated group.

Given that the PFS for the combination of platinum and chemotherapeutic agents, the standard of care for first-line treatment of advanced or recurrent non-small cell lung cancer established in the early 2000s, was approximately 6 months, the extension of PFS to approximately 10 months with a single molecularly targeted agent was considered to be a very significant ^impact26). In addition, the number of new drugs approved for non-small cell lung cancer between 2005 and 2009 was not large, consisting of the EGFR-TKI erlotinib, the angiogenesis inhibitor bevacizumab (in combination with other anti-cancer agents), and the folate metabolism antagonist pemetrexed, although the number of drugs approved for this indication was not large. ²⁷⁾ The results of clinical trials on gefitinib and the direct clinical experience of physicians who used gefitinib and erlotinib may have led to increased treatment satisfaction and drug contribution.

Changes in 5-year survival rate for lung cancer

Although there seemed to be a correlation between the development and approval of molecular-targeted drugs since the 2000s and the development and approval of immune checkpoint inhibitors since the mid-2010s and the increase in treatment satisfaction and drug contribution for lung cancer, how did the survival rate for lung cancer change? The following chart shows the 5-year relative survival rates for lung cancer according to the National Cancer Center by stage of ^{progression28)} (localized, regional, and distant) (Fig. 7). Although the survival rate declines as the disease spreads, the survival rate increases with each passing year in all three groups (Fig. 7 left). Although the survival rate in the stage of distant metastasis (equivalent to stage IV), in which drug therapy is considered to be the main treatment, is still in the single digit range, the improvement in survival after 2003 was greater than that before ^200229). It was ^reported30) that approximately 50% of adenocarcinomas (one of non-small cell lung cancers), which account for 50-60% of all lung cancers, have EGFR mutations, and it was thought that the advent of molecular targeted drugs called EGFR-TKI and their clinical efficacy may have contributed to the improved survival rate of lung cancer (Figure 7 right).

Future Prospects

The second and third paradigms, molecular-targeted agents and immune checkpoint inhibitors, are both indicated for non-small cell lung cancer; however, atezolizumab and durvalumab were approved for advanced small cell lung cancer in combination with chemotherapy beginning in 2019. In addition to combination therapies, a wide variety of other drugs are under development, including drug-antibody conjugates (ADCs), in which a cytotoxic anticancer drug is linked to an antibody by a linker, novel tyrosine kinase inhibitors, and novel antibody therapeutics, among the lung cancer drug mechanisms of action identified in this survey of development products. These drugs have been confirmed to be highly effective. It is hoped that the high efficacy of these drugs in development will lead to an increase in the lineup of drug treatments for lung cancer, which in turn will further improve treatment satisfaction and increase the "satisfaction" of all stakeholders, including patients.

Conclusion

According to the latest cancer statistics, the probability of being diagnosed with cancer in one's lifetime is 65.0% (1 in 2) for men and 50.2% (1 in 2) for women, and the probability of dying from cancer is 26.7% (1 in 4) for men and 17.9% (1 in 6) for ^women17).

It is hoped that the development and approval of new drugs in Japan will improve the mortality rate from cancer not only for the 60 cancer diseases but also for other cancer diseases, and that the continued development of new drugs for other unmet medical needs will increase the healthy life expectancy of people living in Japan. 2. New drugs by level of treatment satisfaction

Return to News List

TOP