Assessing the economics of biologic and small molecule therapies for the treatment of moderate to severe ulcerative colitis in Japan: a cost per responder analysis of upadacitinib.

AIM: Patients with moderately to severely active ulcerative colitis have an increasing number of advanced therapy options including several biologics and Janus kinase inhibitors. Though data on efficacy and safety of these advanced therapies are available, less is known about the potential economic implications of their utilization in Japan. We evaluated the relative value of these advanced therapies in Japan using a locally developed cost per responder model. METHODS: A model was developed using relevant clinical endpoints and treatment costs to calculate cost per responder of all advanced therapies used for moderately to severely active ulcerative colitis treatment in Japan. Cost per responder was assessed in biologic-naïve and biologic-exposed populations, respectively. The model incorporated induction and maintenance therapy pathways as patients progressed through based on efficacy rates (clinical response, clinical remission and endoscopic improvement). Total costs for induction and maintenance included: drug acquisition, drug administration and serious adverse event management (as necessary) for responders, with additional rescue treatment cost only for non-responders. RESULTS: Upadacitinib showed lower cost per clinical response and cost per clinical remission across both biologic-naïve and biologic-exposed populations with only one exemption in cost per clinical remission in biologic-naïve population. In addition, upadacitinib demonstrated lower cost per endoscopic improvement in both populations. Janus kinase inhibitors outperformed with lower cost per responder than other mediations across all outcomes and patient populations with the exception of tofacitinib for clinical remission in biologic-exposed UC population. LIMITATIONS: Comparative data used in this analysis have been derived from network meta-analysis, not from direct comparison. CONCLUSIONS: The results of this cost per responder analysis suggest upadacitinib is a cost-effective option for the first- and second-line treatment of moderately to severely active ulcerative colitis in Japan.

Healthcare resource utilisation and economic burden of patients with adequate and inadequate responses to biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis in Japan.

OBJECTIVE: To compare healthcare resource utilisation (HCRU) and direct costs between responders vs non-responders to advanced therapies for rheumatoid arthritis (RA). METHODS: Patients initiating ≥1 advanced therapy (Oct 2018-Sept 2019) with ≥1 RA claim (6-month pre-index period), ≥2 RA claims (any period), and ≥12 months follow-up were identified from the Medical Data Vision claims database. HCRU and all-cause and RA-related costs (direct medical, emergency department [ED], laboratory, and pharmacy) were compared between responders vs non-responders. Adjusted incidence rate ratios (IRRs) for HCRU or cost were calculated via multivariable analyses. RESULTS: Among 2,446 patients (non-responders [n=1,817]; responders [n=629]), non-responders had significantly longer hospitalisation days (IRR: 1.8 [95% CI: 1.2-2.6]), and significantly more ED visits (2.5 [1.5-4.2]) and prescriptions (1.1 [1.1-1.2]). Mean all-cause hospital/outpatient medical costs were significantly higher for non-responders (1.4 [1.3-1.6], ¥530,895 vs ¥357,009 [$;3,992 vs $;2,684] for responders; ¥173,886 [$;1,307] difference); RA-related medical costs showed a similar trend (¥351,306 vs ¥253,030 [$;2,641 vs $1,902]; ¥98,276 [$;739] difference). No differences between responders and non-responders were observed in mean all-cause and RA-related pharmacy costs. CONCLUSIONS: Non-responders to advanced therapies had greater HCRU and all-cause/RA-related direct costs as compared with responders, suggesting a need for more effective RA therapies to reduce the economic burden associated with non-response.

Number needed to treat and cost per responder of Janus kinase inhibitors approved for the treatment of moderate-to-severe rheumatoid arthritis in Japan.

OBJECTIVE: This study evaluated the effectiveness and cost-effectiveness of baricitinib, tofacitinib, and upadacitinib regimens, compared to conventional synthetic disease-modifying antirheumatic drug (csDMARD) alone, among Japanese patients with moderate-to-severe rheumatoid arthritis (RA) inadequately responsive to csDMARD, measured in terms of number needed to treat (NNT) and cost per responder (CPR). METHODS: Efficacy data were derived from two recent network meta-analyses among global and Japanese population. The cost perspective was that of the Japanese Health Service. Both NNT and CPR were based on disease activity score for 28 joints with C-reactive protein (DAS28-CRP) remission and American College of Rheumatology (ACR) 20/50/70 at 12 and 24 weeks. RESULTS: Over 12 weeks, the median NNT and the median CPR to achieve DAS28-CRP remission were 4.3 and JPY 1,799,696 [USD 16,361], respectively, for upadacitinib 15 mg + csDMARD. The equivalent results were 6.0 and JPY 2,691,684 [USD 24,470] for baricitinib 4 mg + csDMARD and 5.6 and JPY 2,507,152 [USD 22,792] for tofacitinib 5 mg + csDMARD. Similar rankings were observed at 24 weeks and for other outcomes. CONCLUSIONS: Upadacitinib 15 mg was associated with the lowest NNT and CPR among the three Janus kinase inhibitors used in treatment regimens for Japanese patients with moderate-to-severe RA inadequately responsive to csDMARD.

An economic evaluation of risankizumab versus other biologic treatments of moderate to severe plaque psoriasis in Japan.

OBJECTIVE: To evaluate the cost-effectiveness of risankizumab versus other biologic treatments (adalimumab, infliximab, ustekinumab, secukinumab, brodalumab, ixekizumab, and guselkumab) of moderate-to-severe psoriasis in Japan. METHODS: A Markov cohort-level model was constructed to estimate quality-adjusted life years (QALYs) and costs for each treatment over a lifetime horizon. The model simulated patients' transition through one line of active biologic therapy followed by best supportive care and death. Transition probabilities were informed by network meta-analyses of Psoriasis Activity and Severity Index responses and adverse event-related discontinuation in clinical trials, as well as published real-world evidence and national mortality rates. Costs were evaluated from the health system, societal, and patient out-of-pocket perspectives. RESULTS: Risankizumab was expected to provide 0.30-0.89 additional QALYs versus comparator biologics. Under the health system perspective, incremental cost-effectiveness ratios (ICERs) of risankizumab ranged from ¥2,545,812/QALY versus ustekinumab to ¥6,077,134/QALY versus adalimumab. Societal ICERs were lower, ranging from ¥921,770/QALY to ¥4,350,879/QALY. From the patient perspective, risankizumab was estimated to be cost-saving versus four comparators and was associated with ICERs of <¥500,000/QALY versus the remaining comparators. CONCLUSION: Risankizumab was associated with higher QALYs and, based on typical willingness-to-pay benchmarks (¥5-6.7 million/QALY), considered cost-effective versus other biologics for the treatment of psoriasis in Japan.

Cost-Effectiveness Analysis of Etanercept 25 mg Maintenance Therapy After Treatment With Etanercept 50 mg for Moderate Rheumatoid Arthritis in the PRESERVE Trial in Japan.

OBJECTIVES: To use Markov modeling to estimate the cost-effectiveness of treatment with etanercept 25 mg once weekly plus methotrexate (MTX) in Japanese patients with rheumatoid arthritis who had achieved remission or low disease activity with etanercept 50 mg once weekly plus MTX. METHODS: Effectiveness data were estimated based on results from a clinical trial (PRESERVE) in patients with rheumatoid arthritis who had achieved remission or low disease activity and who were then randomized to receive etanercept 25 mg plus MTX or placebo plus MTX. A Markov model was established and included flare rates of 21% and 62% in the etanercept 25 mg and placebo groups, respectively. EQ-5D was calculated using an ordinary least-squares model that included the health assessment questionnaire disability index and pain visual analog scale. Worsening of the health assessment questionnaire score over 1 year was estimated to be 0.047 for patients with flare, and when associated with radiographic progression it was estimated to increase by 0.006 and 0.025 in the etanercept 25 mg and placebo groups, respectively. A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness for a 10-year time span. RESULTS: Compared with the placebo group, the quality-adjusted life-years for the etanercept 25 mg group was increased by 0.841. The incremental cost-effectiveness ratio was ¥6 173 772. CONCLUSION: These results suggest that maintenance treatment with etanercept 25 mg is cost-effective.

A Cost-Effectiveness Analysis of Glecaprevir/Pibrentasvir Versus Existing Direct-Acting Antivirals to Treat Chronic Hepatitis C in Japan.

INTRODUCTION: The objective of the study was to evaluate the cost-effectiveness of glecaprevir/pibrentasvir versus other direct-acting antivirals (DAAs) for treating chronic hepatitis C virus (HCV) infections in Japan. METHODS: We developed a health state transition model to capture the natural history of HCV. A cost-effectiveness analysis of DAAs from the perspective of a public healthcare payer in Japan with a lifetime horizon over annual cycles was performed. Treatment attributes, baseline demographics, transition probabilities, health-state utilities, and costs data were extracted from publications. Costs and outcomes were discounted at 2% per annum. In the base case we focused on genotype 1 (GT1) treatment-naïve patients without cirrhosis. The scenario analysis examined a pan-genotype treatment in GT1-3 (i.e., portfolio), treatment-naïve, and treatment-experienced patients. The portfolio cost-effectiveness of DAAs was derived by calculating a weighted average of patient segments defined by treatment history, cirrhosis status, and genotype. RESULTS: The base case results indicated that glecaprevir/pibrentasvir was dominant (i.e., generating higher quality-adjusted life years [QALYs] and lower lifetime costs) compared to all other DAAs. The predicted lifetime risk of hepatocellular carcinoma was 3.66% for glecaprevir/pibrentasvir and sofosbuvir/ledipasvir, 4.99% for elbasvir/grazoprevir, and 5.27% for daclatasvir/asunaprevir/beclabuvir. In scenario analysis the glecaprevir/pibrentasvir (GLE/PIB) portfolio dominated the sofosbuvir (SOF)-based portfolio (namely sofosbuvir/ledipasvir in GT1-2 and sofosbuvir + ribavirin in GT3). The base case probabilistic sensitivity analysis (PSA) showed that glecaprevir/pibrentasvir was cost-effective in 93.4% of the simulations for a willingness-to-pay/QALY range of Japanese yen (JPY) 1.6-20 million. The PSA for the portfolio scenario indicated that the GLE/PIB portfolio was cost-effective in 100% of simulations until the willingness-to-pay/QALY reached JPY 5.2 million; this proportion decreased to 69.4% at a willingness-to-pay/QALY of JPY 20 million. Results were also robust in deterministic sensitivity analyses. CONCLUSION: In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio.

Patient preference for biologic treatments of psoriasis in Japan.

Psoriasis is a chronic autoimmune disease affecting skin which may also manifest in nails and joints. Several biologic treatments have been approved in Japan for psoriasis. Each biologic has a different profile for efficacy and safety, including different dosing regimens and co-payment considerations which may complicate treatment decisions made by patients and physicians during short consultations. Elucidating patient preference is expected to contribute to shared decision-making between patients and physicians to optimize treatment satisfaction and outcomes. However, the number of studies investigating this in Japan is very limited. The study used a discrete choice experiment methodology to elicit patient preferences for hypothetical options in an experimental framework. Participants were asked to choose their preferred treatment option from two hypothetical choices, defined by different levels of six attributes (i.e. early onset of efficacy, long-term efficacy, sustained efficacy after drug withdrawal, dosing convenience, co-payment and risk of serious infection). The survey included 16 treatment choice scenarios and was completed by 395 participants. Across all participants, the attribute regarded as most important was sustained efficacy after drug withdrawal, followed by dosing convenience, co-payment, long-term efficacy, early onset of efficacy and risk of serious infection. The study found that patients prefer treatments which have durable efficacy and lower treatment burden characterized as fewer injection frequency and lower co-payment. These results may be helpful to understand patient preference for biologic treatments used for psoriasis in Japan and contribute to shared decision-making between patients and physicians to improve patient satisfaction and treatment outcomes.

Assessment of Instructions on Protection Against Food Contaminated with Radiocesium in Japan in 2011.

The Japan Ministry of Health, Labour and Welfare (MHLW) has published instructions for radiological protection against food after the Fukushima Daiichi nuclear power plant accident in 2011. Following the instructions, the export and consumption of food items identified as being contaminated were restricted for a certain period. We assessed the validity of the imposed restriction periods for two representative vegetables (spinach and cabbage) grown in Fukushima Prefecture from two perspectives: effectiveness for reducing dietary dose and economic efficiency. To assess effectiveness, we estimated the restriction period required to maintain consumers' dose below the guidance dose levels. To assess economic efficiency, we estimated the restriction period that maximizes the net benefit to taxpayers. All estimated restriction periods were shorter than the actual restriction periods imposed on spinach and cabbage from Fukushima in 2011, which indicates that the food restriction effectively maintained consumers' dietary dose below the guidance dose level, but in an economically inefficient manner. We also evaluated the response of the restriction period to the sample size for each weekly food safety test and the instructions for when to remove the restriction. Stringent MHLW instructions seemed to sufficiently reduce consumers' health risk even when the sample size for the weekly food safety test was small, but tended to increase the economic cost to taxpayers.

The association between osteoporosis and patient outcomes in Japan.

Objective To quantify the burden of osteoporosis and examine the interplay between osteoporosis and various comorbidities as it relates to patient outcomes. Methods Data from the 2011 Japan National Health and Wellness Survey (NHWS; n = 30 000), an internet health survey fielded to a nationally representative sample of the Japanese population were used. Only women between the ages of 50-90 years were included in the analyses (n = 6950). Results Compared with matched controls (n = 404), patients with osteoporosis (n = 404) had lower MCS scores (48.94 vs 51.63), PCS scores (45.57 vs 49.12) (all p < 0.05). The presence of osteoporosis was associated with worse patient outcomes among those with hypertension, high cholesterol, and insomnia, among other conditions. Conclusions The results suggest a significant quality-of-life and economic burden for patients with osteoporosis in Japan. Moreover, in a complex co-morbid environment, the presence of osteoporosis contributes more to patient outcomes than other chronic conditions.

A framework for analysis of abortive colony size distributions using a model of branching processes in irradiated normal human fibroblasts.

BACKGROUND: Clonogenicity gives important information about the cellular reproductive potential following ionizing irradiation, but an abortive colony that fails to continue to grow remains poorly characterized. It was recently reported that the fraction of abortive colonies increases with increasing dose. Thus, we set out to investigate the production kinetics of abortive colonies using a model of branching processes. METHODOLOGY/PRINCIPAL FINDINGS: We firstly plotted the experimentally determined colony size distribution of abortive colonies in irradiated normal human fibroblasts, and found the linear relationship on the log-linear or log-log plot. By applying the simple model of branching processes to the linear relationship, we found the persistent reproductive cell death (RCD) over several generations following irradiation. To verify the estimated probability of RCD, abortive colony size distribution (≤ 15 cells) and the surviving fraction were simulated by the Monte Carlo computational approach for colony expansion. Parameters estimated from the log-log fit demonstrated the good performance in both simulations than those from the log-linear fit. Radiation-induced RCD, i.e. excess probability, lasted over 16 generations and mainly consisted of two components in the early (<3 generations) and late phases. Intriguingly, the survival curve was sensitive to the excess probability over 5 generations, whereas abortive colony size distribution was robust against it. These results suggest that, whereas short-term RCD is critical to the abortive colony size distribution, long-lasting RCD is important for the dose response of the surviving fraction. CONCLUSIONS/SIGNIFICANCE: Our present model provides a single framework for understanding the behavior of primary cell colonies in culture following irradiation.