Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors.

PURPOSE: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926). METHODS: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity. RESULTS: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: Cmax 217 µg/mL; Cmin 54.9 µg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 µg·day/mL; t1/2, 17.6 days. Best overall response was stable disease in two patients. CONCLUSION: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials. TRIAL REGISTRATION NUMBER: jRCT2080224926.

Analyzing Upward Deviation of Actual vs Predicted Drug Sales in Japan for a Reasonable Drug-Pricing Policy.

BACKGROUND: Predictions of drug sales play an important role in setting drug prices in Japan, where drug prices are highly regulated. One of 2 primary Japanese drug-pricing methodologies-the cost calculation method- refers extensively to the prediction of drug sales in establishing drug prices. Deviations from predicted sales can induce disproportionate drug prices and unexpected pharmaceutical expenditures. This study aimed to estimate the upward deviation of actual sales from predicted sales and to explore the predictors of such upward deviation. METHODS: Estimates of upward deviation in 2015 were produced for new molecular entities (NMEs) approved in 2006-2015. To identify the predictors associated with upward deviation through binary logistic regression analyses, sales within 3 years of launch and in the predicted year in which peak sales would be reached were used. RESULTS: Estimated upward deviation was more than 1220 billion yen in 2015 for the targeted drugs. Drugs priced by the cost calculation method or by obtaining additional indications were significantly more likely to show an upward deviation from predicted peak sales. CONCLUSIONS: There is substantial upward deviation between actual and predicted drug sales in Japan. So long as drug sales predictions are used in drug price calculations, a flexible repricing system is needed to buffer unexpected pharmaceutical expenditures.

A Comparative Study of the Market Configuration of the Japanese Pharmaceutical Market Using the Gini Coefficient and Herfindahl-Hirschman Index.

BACKGROUND: As of 2015, the Japanese pharmaceutical market was the world's third largest pharmaceutical market. Although previous studies have examined market differences in terms of market size and pricing policy, little is known about comparative market configurations. The present study provides a comparative analysis of pharmaceutical market configurations in Japan and five other markets. METHODS: Based on data for the 100 top-selling drugs in 2014 in Japan, the United States, the United Kingdom, France, Germany, and the global market, we explored differences in market configurations using the Herfindahl-Hirschman Index, Lorenz curves, and Gini coefficients. We also investigated market trends by analyzing changes in sales, sales volume, and price. RESULTS: The 100 top-selling drugs accounted for a lower share of the total market in Japan, France, and Germany as compared to the United States and the United Kingdom. The market deviation of the 100 top-selling drugs indicated by the Herfindahl-Hirschman Index and Gini coefficient was smallest in Japan. Sales of most of the top-100 drugs increased in all the countries studied; however, directional price changes differed by country and sales volume trend. CONCLUSION: Our findings showed that market deviations in Japan were relatively low compared with those in other developed countries, suggesting that some of the more beneficial drugs in other developed countries obtain relatively fewer benefits from the Japanese pharmaceutical market, and some less beneficial drugs obtained more benefits.

Analyzing Upward Deviation of Actual vs Predicted Drug Sales in Japan for a Reasonable Drug-Pricing Policy.

BACKGROUND: Predictions of drug sales play an important role in setting drug prices in Japan, where drug prices are highly regulated. One of 2 primary Japanese drug-pricing methodologies-the cost calculation method- refers extensively to the prediction of drug sales in establishing drug prices. Deviations from predicted sales can induce disproportionate drug prices and unexpected pharmaceutical expenditures. This study aimed to estimate the upward deviation of actual sales from predicted sales and to explore the predictors of such upward deviation. METHODS: Estimates of upward deviation in 2015 were produced for new molecular entities (NMEs) approved in 2006-2015. To identify the predictors associated with upward deviation through binary logistic regression analyses, sales within 3 years of launch and in the predicted year in which peak sales would be reached were used. RESULTS: Estimated upward deviation was more than 1220 billion yen in 2015 for the targeted drugs. Drugs priced by the cost calculation method or by obtaining additional indications were significantly more likely to show an upward deviation from predicted peak sales. CONCLUSION: There is substantial upward deviation between actual and predicted drug sales in Japan. So long as drug sales predictions are used in drug price calculations, a flexible repricing system is needed to buffer unexpected pharmaceutical expenditures.

Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.

BACKGROUND: The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. METHODS: The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. RESULTS: All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). CONCLUSIONS: Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

Anticancer Drug Prescription Patterns in Japan: Future Directions in Cancer Therapy.

BACKGROUND: Despite their benefits, the rapid development of new cancer treatments has been a significant driver of increasing health care expenditures in the face of limited health care budgets. In this study, we analyzed the prescribing trends for anticancer drugs from 2010 through 2016 in Japan and sought to identify unique trends that could provide a basis for future medical economic research aiming to develop more efficacious and cost-effective cancer therapies. METHODS: We used publicly available marketing data for anticancer drugs in Japan for 2010-2016. The drugs selected for this research were categorized according to the Anatomical Therapeutic Chemical Classification System. We investigated the overall anticancer drug market size, the number of anticancer drugs, the top 30 selling anticancer categories, sales and prescription volumes, and changes in sales and prescription volumes between 2010 and 2016 in the country. RESULTS: The anticancer agent market expanded each year from 2010 to 2016, with sales exceeding 1 trillion yen in 2015. The proportion of molecular targeted drugs (antineoplastic mAbs and protein kinase inhibitors) among the top 30 selling anticancer categories has continued to increase, and both the sales and prescription volumes of these drugs exceeded those of drugs in other categories, suggesting that these treatments play a dominant role in cancer pharmacotherapy. CONCLUSION: The availability and increasing use of innovative but more expensive targeted therapies were major drivers of increases in pharmaceutical expenditures for cancer treatment in Japan. Therefore, the effective use of genetic testing can mitigate these rising costs.

An Empirical Study of the Prescription Pattern of Drugs for Hematological Malignancies in Japan from 2010-2014.

The number of elderly patients with hematologic malignancies has been steadily increasing with the aging of society. However, little research has been conducted to evaluate the prescription status of drugs for such diseases in Japan. Therefore, the aims of this study were to identify the patient population currently being prescribed drugs for hematologic malignancies in Japan and the direction of drug development. To examine the prescription pattern of drugs for the treatment of hematological malignancies in Japan from 2010-2014, we used the IMS Japan Pharmaceutical Market database and the Japanese Society of Hematology Clinical Practice Guidelines, and for drug development status, we used ClinicalTrials.gov and the University Hospital Medical Information Network Clinical Trials Registry. We found a significant upward trend in prescriptions for molecular-targeted agents, which are typically prescribed over the long term, and a significant downward trend in chemotherapeutic agents, which are usually prescribed for the short term. We also found that recent drug development in hematological malignancies has focused on molecular-targeted agents. These results suggest that drug development should be directed toward anti-tumor agents in hematological malignancies that can help maintain and improve patients' QOL.

Comparative Analysis Between the Top-Selling Drugs in the Japanese Pharmaceutical Market and Those in the United States, the United Kingdom, France, and Germany.

BACKGROUND: Japan is currently the second largest pharmaceutical market in the world, and Japanese pharmaceutical companies are actively seeking to identify assets in other countries. An affluent population provides ample opportunity for pharmaceutical companies to develop within Japan; however, given its weak macroeconomic foundation, Japan is currently seeking to cut costs through the use of more generic drugs and lower prices. Nevertheless, no detailed empirical analyses regarding how Japanese companies can expand their global presence while ensuring domestic sales, or what opportunities lie ahead for global companies planning to enter the Japanese market, have been conducted. To our knowledge, this is the first study to provide statistical evidence regarding characteristics of the Japanese market. METHODS: The data set for this study was the most recent list of the 100 top-selling drugs globally and in Japan, the United States, the United Kingdom, France, and Germany. The data were obtained from the IMS Japan Pharmaceutical Market database. RESULTS: More cardiovascular and less central nervous system (CNS) and oncology drugs were ranked among the top 100 best-selling drugs in the Japanese market; however, the promotion of CNS and oncology drug development was evident, and competition from generic drugs was shown to have eroded, especially in therapeutic areas with no assured benefits in the global market, such as with cardiovascular drugs. CONCLUSIONS: These results suggest that the Japanese market will rival overseas markets in the near future. Pharmaceutical companies should seriously consider operating within Japan, whose market is currently transitioning to a global market.

Evaluating the Effectiveness of Repricing for Market Expansion in the Japanese Drug Pricing System.

BACKGROUND: In 1994, the "Repricing for Market Expansion" system (the repricing system) was introduced to the pharmaceutical market in Japan to improve the financial performance of the national health insurance system. In 2010, the "Reward Premiums for the Promotion of Innovative Drug Discovery and the Resolution of Off-Label Use Issue, Etc." system (the reward system) was introduced to promote the development of new drugs. This study evaluates the effectiveness of these systems from an empirical perspective. METHOD: The data set used in this study was created using publicly available information from the Ministry of Health, Labour and Welfare (MHLW) website and a market database maintained by IMS Japan Pharmaceutical Market Sales. RESULTS: Anticancer or immunomodulating drugs were the most frequently affected by the repricing system. The sales of similar drugs did not exceed double the sales forecast, and to begin with, the repricing system was not applied to these drugs, unintentionally reducing the profitability of pharmaceutical companies. In addition, we found that pharmaceutical expenditures have been steadily and significantly increasing, although this aspect is just one of the circumstances surrounding the Japanese pharmaceutical market. CONCLUSIONS: On the basis of these results, we propose that the current repricing system be replaced with one using a market mechanism that can evaluate the value of drugs from an economic perspective and help improving the financial performance of the national health insurance system. We also suggest that the number of generic medications on the market in Japan be increased to a ratio equivalent to those of the US and EU. We hope that the perspectives on Japan's unique drug pricing system obtained from this article are utilized by pharmaceutical companies in developing their businesses in Japan.

Impact of Premium Rewards for the Promotion of Innovative Drug Discovery on the Japanese Pharmaceutical Market: An Analysis by Therapeutic Area.

BACKGROUND: A new incentive program, "Premium Rewards for the Promotion of Innovative Drug Discovery and Resolution of Off-Label Use, etc," was introduced in Japan in 2010 and subsequently applied in 2010, 2012, and 2014. In our previous study, we reported statistical evidence regarding the attributes of drugs for which these premium rewards were used. We found that orphan drugs and drugs in certain therapeutic areas, including neuroscience, oncology, and immunology, were likely to receive rewards. However, that investigation was not conducted to clarify how the rewards system affects pharmaceutical sales or whether drugs that received rewards led to more profits for pharmaceutical companies. METHODS: The data set for this study was a list of the 500 top-selling pharmaceuticals in Japan from 2010 to 2014, which was obtained from the IMS Japan Pharmaceutical Market database. To clarify the effect of the rewards system on different therapeutic areas, total sales and quantity sold were compared between drugs that received rewards and those that did not. RESULTS: The rewards system positively affected drug sales in specific therapeutic areas, including those with Anatomical Therapeutic Chemical (ATC) classifications neuroscience (N) and oncology (L), as well as the quantity sold of neuroscience-related drugs. CONCLUSION: Our study suggests that this system has been working according to its original aim of promoting the development of innovative drugs in Japan.

Factors That Affect the Acquisition of Reward Premiums for Promotion of Innovative Drug Discovery in Japan.

BACKGROUND: A new reward premium system, "Reward Premiums for the Promotion of Innovative Drug Discovery and Resolution of Off-label Use Issue, etc," unique to Japan, was introduced in 2010 and was used in 2010, 2012, and 2014. If the new rewards system is applied to a drug, the company can recover costs early and reinvest in research and development of unapproved or innovative drugs. However, a detailed analysis of the drugs to which this new system was applied has not been conducted. In this study, a data analysis was performed to determine what factors were strongly associated with receiving a reward. METHODS: Domestic pharmaceuticals in the top 500 sales in September 2009, 2011, and 2013 were selected for this study. Multivariable or univariate logistic regression was performed. RESULTS: The following factors were significantly related to receiving a reward: a more recent launch, a global promotional company, and orphan drug designation. Cardiovascular drugs were less likely to receive rewards, whereas drugs acting on the central nervous system, anticancer agents, and immunomodulatory agents were significantly more likely to receive rewards. CONCLUSIONS: These findings suggest that orphan drugs and drugs with specific Anatomical Therapeutic Chemical (ATC) classifications such as N and L are likely to receive rewards. We can verify that this incentive program works well in Japan, launching truly innovative drugs that meet high medical needs.

A novel 2-decenoic acid thioester ameliorates corticosterone-induced depression- and anxiety-like behaviors and normalizes reduced hippocampal signal transduction in treated mice.

We characterized mice administered corticosterone (CORT) at a dose of 20 mg/kg for 3 weeks to determine their suitability as a model of mood disorders and found that the time immobilized in the tail suspension test was longer and the time spent in the open arms of the elevated plus-maze test was shorter than those of the vehicle-treated group, findings demonstrating that chronic CORT induced both depression-like and anxiety-like behaviors. Furthermore, the levels of phosphorylated extracellular signal-regulated kinase (pERK) 1/2 in the hippocampus and cerebral cortex were reduced in the CORT-treated group. Using this model, we investigated the protective effect of the ester, thioester, and amide compounds of 2-decenoic acid derivatives (termed compounds A, B, and C, respectively). The potency of the protective activity against the CORT-induced depression-like or anxiety-like behaviors and the reduction in pERK1/2 level were found to be in the following order: compound B > compound C > compound A. Therefore, we further investigated the therapeutic activity of only compound B, and its effect on depression-like behavior was observed after oral administration for 1 or 2 weeks, and its effect on anxiety-like behavior was observed after oral administration for 3 weeks. The ratios of phosphorylated ERK1/2, Akt, and cAMP-response element-binding protein to their respective nonphosphorylated forms were smaller in the CORT-treated group than in the vehicle-treated group; however, subsequent treatment with compound B at either 0.3 or 1.5 mg/kg significantly ameliorated this reduction. Compound B appeared to elicit intracellular signaling, similar to that elicited by brain-derived neurotrophic factor, and its mode of action was shown to be novel and different from that of fluvoxamine, a currently prescribed drug for mood disorders.