The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.

Burden of illness and healthcare resource use in United States patients with sporadic inclusion body myositis.

INTRODUCTION: We analyzed the burden of illness of sporadic inclusion body myositis (sIBM) patients and the costs to the healthcare system. METHODS: A retrospective cohort analysis of 333 sIBM patients aged ≥ 50 years was performed using United States (U.S.) claims data. sIBM patients were matched in a 1:5 ratio to randomly selected individuals with ≥1 healthcare encounter within the year of index date. RESULTS: sIBM patients presented with higher rates of disease- and muscle-related conditions, such as myalgia, myositis, muscle weakness, dysphagia, pneumonia, and falls. Use of healthcare resources, including physical therapy, office visits, emergency room (ER) visits, and hospitalizations, was greater in sIBM patients. This was also reflected in significantly higher overall healthcare costs in the sIBM population driven mainly by more all-cause office visits, all-cause ER visits and hospitalizations. CONCLUSIONS: sIBM imposes a substantial burden on U.S. patients in terms of additional healthcare usage and associated costs. Muscle Nerve 56: 861-867, 2017.

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis.

BACKGROUND: Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. OBJECTIVE: The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. METHODS: This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon ß or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. RESULTS: Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). CONCLUSIONS: Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.

Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial.

BACKGROUND: The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs. METHODS: Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment. RESULTS: Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001). CONCLUSIONS: After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01216072 .

Compliance to fingolimod and other disease modifying treatments in multiple sclerosis patients, a retrospective cohort study.

BACKGROUND: Adherence to disease-modifying therapies (DMTs) results in the reduction of the number and severity of relapses and delays the progression of multiple sclerosis (MS). Patients with lower adherence rates experience more inpatient visits and higher MS-related medical costs. Fingolimod, the first oral DMT approved by the US Food and Drug Administration, may improve the access and compliance to MS treatment when compared to injectable DMTs. METHODS: This retrospective cohort study used pharmacy claims from Medco Health Solutions, Inc., of patients who initiated DMTs between October 2010 and February 2011. Initiation was defined as no prescription fills for the same DMT in the prior 12 months. Patients without a DMT prescription fill 12 months before the index date were considered naïve users. Compliance was measured via proportion of days covered (PDC) and medication possession ratio (MPR) for 12 months post-index. Discontinuation was defined as a ≥60-day gap of index DMT supply. Cox proportional hazard models compared time to discontinuation between cohorts. RESULTS: Of 1,891 MS patients (mean age: 45.7; female: 76.4%), 13.1% initiated fingolimod, 10.7% interferon beta-1b, 20.0% intramuscular interferon beta-1a, 18.8% subcutaneous interferon beta-1a, and 37.4% glatiramer acetate. Patients initiating fingolimod had highest average PDC and MPR in both experienced (fingolimod: mean PDC=0.83, 73.7% with PDC≥0.8; mean MPR=0.92, 90.5% with MPR≥0.8) and naïve DMT users (fingolimod: mean PDC=0.80, 66.7% with PDC≥0.8; mean MPR=0.90, 87.4% with MPR≥0.8). The proportion of patients discontinuing index DMT within 12 months was significantly lower for the fingolimod cohort (naïve: 31.3%; experienced: 25.7%). Adjusted results found that patients receiving self-injected DMTs discontinued significantly sooner than fingolimod users. This association was generally stronger in experienced DMT users. CONCLUSIONS: Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later than patients who initiated self-injected DMT.

Resource utilization, costs and treatment patterns of switching and discontinuing treatment of MS patients with high relapse activity.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease that affects mainly adults in the prime of their lives. However, few studies report the impact of high annual relapse rates on outcomes. The purpose of this study was to identify high relapse activity (HRA) in patients with MS, comparing differences in outcomes between patients with and without HRA. METHODS: A retrospective longitudinal study was conducted using the MarketScan® Commercial Claims and Encounters and Medicare Supplemental Database. Patients had to have at least one ICD-9 for MS (340.XX) in 2009 and one in 2008, be older than 18 years, and have continuous enrolment in the years 2009-2010. HRA was defined as having ≥2 relapses in 2009. Multivariate analyses compared all-cause and MS-specific emergency room (ER) visits, hospitalizations, and all-cause costs, excluding disease modifying therapy (DMT) costs, in 2010 between patients with and without HRA, controlling for baseline characteristics. A subgroup analysis using treatment exposure was also performed. RESULTS: 19,219 patients were included: 5.3% (n=1,017) had ≥2 relapses in 2009. Patients with HRA were more likely to have all-cause and MS-specific resource utilization than patients without HRA. Mean total all-cause non DMT costs were $12,057 higher for the HRA group. In the subgroup analysis, HRA treatment-naïve patients were more likely to start treatment, and HRA treatment-experienced patients were more likely to discontinue or switch index DMT (P<0.01). CONCLUSIONS: Patients with ≥2 relapses annually have higher resource utilization and costs. The difference in cost was over twice as large in treatment-naïve patients versus treatment-experienced patients. HRA was also associated with an increased likelihood of starting DMT treatment (treatment-naïve patients), and switching or discontinuing DMT therapy (treatment-experienced patients).

Antivascular endothelial growth factor agents for wet age-related macular degeneration: an IRIS registry analysis.

OBJECTIVE: To evaluate treatment patterns and outcomes of patients in the United States who received antivascular endothelial growth factor (anti-VEGF) agents for wet age-related macular degeneration (AMD). DESIGN: Retrospective study PARTICIPANTS: Patients with wet AMD. METHODS: Using the Intelligent Research in Sight Registry, we studied patients with wet AMD who received ≥1 anti-VEGF injection, who were ≥50 years old, and with ≥1.5 years of follow-up. Patients were grouped based on follow-up duration (in years): ≥1.5 (cohort 1), ≥2.5 (cohort 2), and ≥3.5 (cohort 3). RESULTS: Patient characteristics were similar between treatment groups. 36.8%, 34.5%, and 39.2% of ranibizumab, aflibercept, and all anti-VEGF eyes, respectively, had an injection interval <8 weeks in length at the end of year 1. Results were similar at year 2 and 3. In cohorts 1-3, visual acuity (VA) changes from baseline ranged from 0.3 to 0.7 (year 1), -1.3 to -1.7 (year 2), and -2.8 to -3.1 (year 3) Early Treatment Diabetic Retinopathy Study letters. By the end of year 3, 41%, 39%, and 42% of ranibizumab, aflibercept, and all anti-VEGF eyes, respectively, had discontinued treatment (no injection for >6 months). CONCLUSION: Approximately one-third of eyes had injection intervals <8 weeks in length at the end of year 1. VA was slightly better at the end of year 1 and declined after the first year despite treatment. By the end of year 3, more than one-third of eyes had discontinued treatment. Given the high treatment burden, wet AMD patients may benefit from more durable approaches that require less frequent dosing.

Comparison of patient characteristics and gout-related health-care resource utilization and costs in patients with frequent versus infrequent gouty arthritis attacks.

OBJECTIVE: To examine the association between frequent gouty arthritis and the presence of absolute/relative contraindications to gout therapies, and health-care expenditure associated with frequent gouty arthritis. METHODS: This retrospective study used administrative claims to identify patients with gouty arthritis between 1 July 2005 and 30 June 2010. Patients with ≥3 yearly gouty arthritis attacks (frequent gout) were matched 1:2 to patients with <3 yearly attacks (infrequent gout). Absolute and relative contraindications to gout medications were evaluated based on product labelling. Negative binomial regression and generalized linear models with logarithmic transformation were used for multivariate analysis of overall and gout-related health-care use and cost. RESULTS: Mean patient age was 58 years (n = 15 669) and 77% were men. Compared with patients with infrequent gout, those with frequent gout had higher rates of absolute/relative contraindications to NSAIDs (91.5% vs 78.7%, P < 0.0001), corticosteroids (96.4% vs 87.3%, P < 0.0001), allopurinol (51.0% vs 41.2%, P < 0.0001) and probenecid (13.4% vs 9.4%, P < 0.0001). Mean gout-related costs were $889 for frequent gout vs $210 for infrequent gout (P < 0.0001) and all-cause direct costs were $10 913 for frequent vs $10 685 for infrequent gout (P = ns). Mean all-cause outpatient visits among patients with comorbidities compared with those without were 25.8 vs 11.8 among frequent and 19.7 vs 9.0 among infrequent (both P < 0.001) groups. Gout-related costs were higher among frequent gout patients with comorbidities than those without comorbidities ($886 vs $513, P = 0.03). CONCLUSION: Patients with frequent gouty arthritis are likely to have absolute and/or relative contraindications to gout medications and higher gout-related treatment costs.

Safety Outcomes of Brolucizumab in Neovascular Age-Related Macular Degeneration: Results From the IRIS Registry and Komodo Healthcare Map.

IMPORTANCE: Limited data exist on the real-world safety outcomes of patients with neovascular age-related macular degeneration treated with brolucizumab (Beovu). OBJECTIVE: To determine the real-world incidence of intraocular inflammation (IOI), including retinal vasculitis (RV) and/or retinal vascular occlusion (RO), for patients with neovascular age-related macular degeneration who underwent brolucizumab treatment. Additionally, potential risk factors associated with these adverse events were evaluated. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients with neovascular age-related macular degeneration in the Intelligent Research in Sight (IRIS) Registry and Komodo Healthcare Map. Patients initiating and receiving 1 or more brolucizumab injections from October 8, 2019, to June 5, 2020, with up to 6 months of follow-up were included. INTERVENTION: Brolucizumab injections. MAIN OUTCOME AND MEASURES: Incidence of IOI (including RV) and/or RO and RV and/or RO and risk stratification for the identified risk factors. RESULTS: Of 10 654 and 11 161 included eyes (from the IRIS Registry and Komodo Health database, respectively), the median follow-up times were 97 and 95 days. Most eyes switched from another anti-vascular endothelial growth factor agent (9686 of 10 654 [90.9%] and 10 487 of 11 161 [94.0%], respectively), most commonly aflibercept (7160 of 9686 [73.9%] and 7156 of 10 487 [68.2%]), and most were from women (6105 of 10 654 [57.3%] and 6452 of 11 161 [57.8%]). The overall incidence of IOI and/or RO was 2.4% (255 of 10 654 eyes) and 2.4% (268 of 11 161 eyes) for the IRIS and Komodo groups, respectively, and RV and/or RO, 0.6% (59 of 10 654 eyes and 63 of 11 161 eyes), respectively. Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7% [95% CI, 6.0%-11.4%] and 10.6% [95% CI, 7.5%-13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets). There was an increased estimated incidence rate in women (2.9% [95% CI, 2.5%-3.3%] and 3.0% [95% CI, 2.6%-3.4%]) compared with men (1.3% [95% CI, 1.0%-1.7%] and 1.4% [95% CI, 1.0%-1.7%]), but this risk was not as large as that of a prior IOI and/or RO. Similar findings were observed for patients with RV and/or RO events. CONCLUSIONS AND RELEVANCE: The incidence rate of IOI and/or RO was approximately 2.4%. Patient eyes with IOI and/or RO in the 12 months prior to first brolucizumab injection had the highest observed risk rate for IOI and/or RO in the early months after the first brolucizumab treatment. However, given study limitations, the identified risk factors cannot be used as predictors of IOI and/or RO events, and causality with brolucizumab cannot be assessed.

Anti-VEGF Treatment Patterns in Patients With Wet Age-Related Macular Degeneration in Clinical Practice.

BACKGROUND AND OBJECTIVE: To characterize on-label anti-vascular endothelial growth factor (VEGF) treatment patterns in patients with wet age-related macular degeneration (AMD) in clinical practice in the U.S. PATIENTS AND METHODS: Retrospective cohort analysis using administrative claims data from the IQVIA Open Source Databases. Treatment-naïve patients in the U.S. who received one or more wet AMD-related anti-VEGF injection from July 1, 2013, to April 30, 2017, were included. The main outcome was the injection interval closest to Month 12. RESULTS: This study included 21,960 patients who initiated an anti-VEGF agent (ranibizumab, aflibercept, or bevacizumab): 5,489 initiated aflibercept and 4,253 initiated ranibizumab. Among ranibizumab, aflibercept, and all anti-VEGF eyes, 38.1% (n = 2,035), 33.5% (n = 3,262), and 40.0% (n = 12,505) of patient eyes had injection intervals of less than 8 weeks, respectively, at Month 12 with the mean (standard deviation) number of injections over 12 months being 8.0 (2.4), 7.6 (2.4), and 7.8 (2.5). CONCLUSION: A substantial proportion of patients receive injections more frequently than every 8 weeks within the first year of treatment. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:263-272.].

Brolucizumab vs aflibercept and ranibizumab for neovascular age-related macular degeneration: a cost-effectiveness analysis.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness worldwide and is the most common cause of blindness in developed countries. Despite antivascular endothelial growth factor (anti-VEGF) therapy demonstrating improvements in visual and anatomical outcomes, unmet needs remain. Brolucizumab-dbll (ie, brolucizumab), a VEGF inhibitor for treatment of neovascular (wet) AMD and recently approved by the FDA for its treatment of wet AMD, attempts to mitigate treatment burden through less frequent injections. OBJECTIVE: To assess the incremental cost-effectiveness of brolucizumab compared with aflibercept and ranibizumab, given similar costs per injection and the potential for longer dosing intervals based on phase 3 clinical trial data. METHODS: A Markov model was developed to model the treatment of wet AMD patients with brolucizumab vs aflibercept and vs ranibizumab over a lifetime time horizon (base case) and 5-year time horizon (scenario analysis). The Markov model consisted of 3 primary health states: on treatment, off treatment, and death. Markov substates (5 total) described visual acuity (VA) ranging from no vision impairment to blindness. These VA-based substates were defined by best-corrected visual acuity (BCVA) values measured using Early Treatment Diabetic Retinopathy Study letters. Fixed-dosing regimens for each therapy were included in the model: dosing every 4 weeks (q4w) for the first 3 months followed by dosing q8w/q12w for brolucizumab, dosing q4w for the first 3 months followed by dosing q8w for aflibercept, and q4w for ranibizumab. RESULTS: In the base case, brolucizumab was less costly than aflibercept ($63,614 vs $72,189), and brolucizumab generated 0.0079 more quality-adjusted life-years (QALYs) than aflibercept (4.580 vs 4.572). Lower total costs with brolucizumab were driven by reduced drug costs ($56,432 vs $64,057), reduced administration costs ($6,013 vs $6,825), and reduced monitoring costs ($1,168 vs $1,306). When evaluating the cost-effectiveness of brolucizumab over a 5-year time horizon, brolucizumab was less costly than aflibercept ($44,644 vs $50,772) and generated an additional 0.0049 QALYs (2.953 vs 2.948). Additionally, brolucizumab was less costly than ranibizumab ($63,614 vs $128,163) and generated 0.0078 more QALYs than ranibizumab (4.580 vs 4.572) in the base case. Lower total costs with brolucizumab were driven by reduced drug costs ($56,432 vs $114,516), reduced administration costs ($6,013 vs $11,541), and reduced monitoring costs ($1,168 vs $2,107). When evaluating the cost-effectiveness of brolucizumab over a 5-year time horizon, brolucizumab was less costly than ranibizumab ($44,644 vs $89,665), and brolucizumab generated an additional 0.0046 QALYs (2.953 vs 2.948). CONCLUSIONS: Brolucizumab can be cost saving and cost-effective compared with aflibercept and ranibizumab in the treatment of wet AMD. DISCLOSURES: Novartis Pharmaceuticals Corporation provided funding to Xcenda for the cost-effectiveness analysis and preparation of this manuscript. Carlton is an employee of Xcenda. Agashivala is employed by Novartis Pharmaceuticals Corporation; Yu was an employee of Novartis Pharmaceutical Corporation at the time of this study. Hassan reports personal fees from iOPEN, BVI/Visitrec, ArcticDx, Bayer, F. Hoffmann-La Roche Ltd, Broadspot, BMC, Katalyst Surgical, Alcon, Vitreq, Surgicube, personal Ocugenix, Regeneron, Allergan, Oculus Surgical, Novartis, Genentech, and Eyepoint, unrelated to this work. Wykoff reports personal fees from Corcept Therapeutics, DORC, EyePoint, Gyroscope, IVERIC Bio, Merck, Notal Vision, ONL Therapeutics, Oxurion, Palatin, PolyPhotonix, Takeda, Thea Open Innovation; grants from Aerie Pharmaceuticals, Aldeyra, Gemini Therapeutics, Graybug Vision, IONIS Pharmaceutical, LMRI, Mylan, Neurotech Pharmaceuticals, Outlook Pharmaceuticals, Samsung Bioepis, Senju, Taiwan Liposome Company, Xbrane BioPharma, Santen; and grants and personal fees from Adverum, Allergan, Apellis, Chengdu Kanghong Biotechnologies (KHB), Clearside Biomedical, Genentech, Kodiak Sciences, NGM Biopharmaceuticals, Novartis, Opthea, Recens Medical, Regenxbio, Roche, and Regeneron, unrelated to this work. This research was presented as a virtual poster at the AMCP 2020 Annual Meeting, April 2020.

Health care costs and comorbidities for patients with inclusion body myositis.

OBJECTIVE: This study identifies the health care costs and utilization, as well as comorbidities, in a Medicare population of inclusion body myositis (IBM) patients. METHODS: Medicare patients aged ≥65 years with a diagnosis claim for IBM were identified and matched to a cohort of non-IBM patients based on age, sex, race, calendar year and census region. Generalized linear models were used to estimate health care costs and utilization during the follow-up period. RESULTS: The prevalence of IBM in this population, aged ≥65 years, was 83.7 cases per 1 million patients. Mean 1 year costs for the IBM cohort (N = 361) were $44,838 compared to $10,182 for the matched non-IBM cohort (N = 1805), an excess of $34,656. IBM was significantly associated with multiple unsuspected comorbidities, including hypertension (66% vs. 22%), hyperlipidemia (47% vs. 18%) and myocardial infarction (13% vs. 2%) (all p < .0001). CONCLUSIONS: IBM patients utilize more health care resources and incur higher health care costs than patients without IBM. Furthermore, IBM patients were more likely to have multiple comorbidities, including cardiovascular risk factors and events, muscle and joint pain, and pulmonary complications compared to those without IBM. LIMITATIONS: The presence of a diagnosis code for a condition on a medical claim does not necessarily indicate the presence of the disease condition because the diagnosis code could be incorrectly entered in the database. Clinical and disease-specific parameters were not available in the claims data. Additionally, due to the observational study design, the analysis may be affected by unobserved differences between patients.

Relationship between symptom change, relapse activity and disability progression in multiple sclerosis.

BACKGROUND: Symptom changes may serve as a risk factor for relapse activity (RA) and disability progression (DP), which could facilitate multiple sclerosis (MS) treatment decisions. OBJECTIVE: To assess the relationship of symptom change with RA and DP. METHODS: We evaluated the relationship of symptom change with subsequent RA and DP using NARCOMS registry data reported over a five-year period. Symptom change was evaluated using both symptom worsening (SW) and average of Performance Scales (APS) scores. Disability progression was defined as a one-point or more increase in Patient-Determined Disease Steps (PDDS) score between two consecutive updates. Repeated measures logistic regression was used to investigate the relationship between symptom change and RA and DP. RESULTS: SW and APS were both significant predictors of subsequent RA and DP. Both SW and APS have a significant interaction with levels of disability (Mildly Impaired versus Highly Impaired) for the prediction of the subsequent RA or DP. For Mildly Impaired MS subjects, both SW and APS were significant predictors of both RA and DP. However, for Highly Impaired MS subjects, SW did not significantly predict future RA and neither SW nor APS predicted disability progression. CONCLUSION: Changes in self-reported overall symptomatology may precede and predict clinical relapse and future disability progression. The predictive power of symptom changes may only be present at lower levels of disability.

Impact of a switch to fingolimod on depressive symptoms in patients with relapsing multiple sclerosis: An analysis from the EPOC (Evaluate Patient OutComes) trial.

BACKGROUND: Depression is common in patients with multiple sclerosis (MS), may confound evaluation of therapeutic effectiveness and may be impacted by MS-specific treatments. OBJECTIVE: First, to assess the impact on depressive symptoms of a switch to fingolimod versus remaining on an injectable disease-modifying therapy (iDMT) in a post-hoc analysis of prospectively collected data from the EPOC study. Secondly, to investigate the underlying Beck Depression Inventory-II (BDI-II) factor structure in patients with MS, and estimate treatment differences using the resulting subscales. METHODS: EPOC was a 6-month, open-label study assessing patient-reported outcomes after switch from iDMT to oral fingolimod 0.5mg versus remaining on iDMT in 1053 patients with relapsing-remitting MS. RESULTS: At end of study (EOS), a greater proportion of patients on fingolimod versus iDMT no longer had BDI-II scores indicating depression (p<0.001). Fewer mildly and moderately symptomatic patients developed severe depressive symptoms, and fewer severely symptomatic patients continued to have scores indicating severe depression at EOS on fingolimod versus iDMT (p=0.027, p=0.038, p=0.030, respectively). Two BDI-II subscales were identified and labelled Somatic and Affective; fingolimod demonstrated more reduction on both subscales at EOS versus iDMTs (p<0.0001 and p=0.0001, respectively). CONCLUSION: A switch to fingolimod versus remaining on/switching to another iDMT was associated with an improvement in depressive symptoms in patients with relapsing-remitting MS.

Treatment selection and experience in multiple sclerosis: survey of neurologists.

BACKGROUND: Multiple sclerosis (MS) is a complex disease with many therapeutic options. Little is known about how neurologists select particular disease-modifying therapies (DMTs) for their patients. OBJECTIVE: To understand how neurologists make decisions regarding the prescription of DMTs for patients with MS, and to explore neurologists' experiences with individual DMTs. METHODS: From December 2012 to January 2013, members of a nationwide physician market research panel were sent an online study invitation with a link to a survey website. Eligible neurologists were included if they currently practice medicine in the United States, and if they treat ≥20 patients with MS. RESULTS: A total of 102 neurologists (n=63 general neurologists; n=39 MS specialists; 81.4% male) completed the survey. The mean (standard deviation) number of years in practice since completing medical training was 16.4 (8.6) years. Overall, the most commonly prescribed DMTs were subcutaneous interferon (IFN) ß-1a and glatiramer acetate; approximately 5.5% of patients were untreated. The most important attributes of DMT medication selection were (in order of importance) efficacy, safety, tolerability, patient preference, and convenience. The DMT with the highest neurologist-reported percentage of patients who were "Very/Extremely Satisfied" with their therapy was fingolimod (31.0%), followed by glatiramer acetate (13.9%; P=0.017). Compared with fingolimod (94.0%), significantly fewer (P<0.05) neurologists reported that "All/Most" of their patients were adherent to treatment with glatiramer acetate (78.0%), subcutaneous IFN ß-1a (84.0%), and IFN ß-1b (75.0%); no significant differences were observed with intramuscular IFN ß-1a (92.9%; P=0.75). Patients' calls to neurologists' offices were most commonly related to side effects for all self-injectable DMTs, whereas calls about fingolimod primarily involved insurance coverage issues. CONCLUSION: Our survey results showed that very few patients with MS did not received any DMT. Among the DMTs available at the time of the survey, neurologists reported that patients were most satisfied with, and adherent to, fingolimod, but these patients also faced more problems with insurance coverage when compared with those taking self-injectable DMTs.

Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study.

BACKGROUND: Approximately one-third of patients with multiple sclerosis (MS) are unresponsive to, or intolerant of, interferon (IFN) therapy, prompting a switch to other disease-modifying therapies. Clinical outcomes of switching therapy are unknown. This retrospective study assessed differences in relapse rates among patients with MS switching from IFN to fingolimod or glatiramer acetate (GA) in a real-world setting. METHODS: US administrative claims data from the PharMetrics Plus™ database were used to identify patients with MS who switched from IFN to fingolimod or GA between October 1, 2010 and March 31, 2012. Patients were matched 1∶1 using propensity scores within strata (number of pre-index relapses) on demographic (e.g. age and gender) and disease (e.g. timing of pre-index relapse, comorbidities and symptoms) characteristics. A claims-based algorithm was used to identify relapses while patients were persistent with therapy over 360 days post-switch. Differences in both the probability of experiencing a relapse and the annualized relapse rate (ARR) while persistent with therapy were assessed. RESULTS: The matched sample population contained 264 patients (n = 132 in each cohort). Before switching, 33.3% of patients in both cohorts had experienced at least one relapse. During the post-index persistence period, the proportion of patients with at least one relapse was lower in the fingolimod cohort (12.9%) than in the GA cohort (25.0%), and ARRs were lower with fingolimod (0.19) than with GA (0.51). Patients treated with fingolimod had a 59% lower probability of relapse (odds ratio, 0.41; 95% confidence interval [CI], 0.21-0.80; p = 0.0091) and 62% fewer relapses per year (rate ratio, 0.38; 95% CI, 0.21-0.68; p = 0.0013) compared with those treated with GA. CONCLUSIONS: In a real-world setting, patients with MS who switched from IFNs to fingolimod were significantly less likely to experience relapses than those who switched to GA.

Persistence with and adherence to fingolimod compared with other disease-modifying therapies for the treatment of multiple sclerosis: a retrospective US claims database analysis.

OBJECTIVE: Achieving therapeutic goals in multiple sclerosis (MS) requires strict adherence to treatment schedules. This retrospective study analyzed persistence with, and adherence to, fingolimod compared with injectable/infusible disease-modifying therapies (DMTs) in patients with MS. METHODS: Patients in the PharMetrics Plus™ US administrative claims database with at least one prescription for, or administration of, fingolimod, glatiramer acetate (GA), interferon (IFN), or natalizumab (index DMT) between October 1, 2010 and September 30, 2011 were included. Patients were naïve to index DMT (no claim in the previous 360 days) and had an MS diagnosis code within 360 days of the first index DMT prescription. Outcomes were persistence, risk of discontinuing index DMT (evaluated by a Cox proportional hazards model), adherence (measured using the medication possession ratio [MPR] and proportion of days covered [PDC] in patients with at least two index DMT prescriptions), and the risk of being non-adherent (MPR <80% and PDC <80%, assessed using a logistic regression model). RESULTS: The study included 3750 patients (fingolimod, n = 889; GA, n = 1233; any IFN, n = 1341; natalizumab, n = 287). Discontinuation rates (fingolimod, 27.9%; GA, 39.5%; IFN, 43.7%; natalizumab, 39.5%; all p < 0.001) and risk of discontinuation were significantly higher (hazard ratios vs fingolimod [95% confidence interval]: GA, 1.75 [1.49-2.07]; IFN, 2.01 [1.71-2.37]; natalizumab, 1.53 [1.22-1.91]) for patients receiving other DMTs compared with fingolimod. The risk of being non-adherent was also lower for patients in the fingolimod cohort than the other treatment cohorts, irrespective of whether non-adherence was defined as MPR <80% (p < 0.05 for all) or PDC <80% (p < 0.05 for GA and IFN). LIMITATIONS: As with all studies assessing real-world treatment patterns it is unclear if medications were used as prescribed. CONCLUSIONS: In a real-world setting, persistence with, and adherence to, oral fingolimod was higher than for injectable and infusible DMTs.

Patient perspectives on switching disease-modifying therapies in the NARCOMS registry.

INTRODUCTION: The evolving landscape of disease-modifying therapies (DMTs) for multiple sclerosis raises important questions about why patients change DMTs. Physicians and patients could benefit from a better understanding of the reasons for switching therapy. PURPOSE: To investigate the reasons patients switch DMTs and identify characteristics associated with the decision to switch. METHOD: The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry conducted a supplemental survey among registry participants responding to the 2011 update survey. The supplemental survey investigated reasons for switching DMT, origin of the discussion of DMT change, and which factors influenced the decision. Chi-square tests, Fisher's exact tests, and logistic regression were used for the analyses. RESULTS: Of the 691 eligible candidates, 308 responded and met the inclusion criteria (relapsing disease course, switched DMT after September 2010). The responders were 83.4% female, on average 52 years old, with a median (interquartile range) Patient-Determined Disease Steps score of 4 (2-5). The most recent prior therapy included first-line injectables (74.5%), infusions (18.1%), an oral DMT (3.4%), and other DMTs (4.0%). The discussion to switch DMT was initiated almost equally by physicians and participants. The primary reason for choosing the new DMT was based most frequently on physician's recommendation (24.5%) and patient perception of efficacy (13.7%). CONCLUSION: Participants frequently initiated the discussion regarding changing DMT, although physician recommendations regarding the specific therapy were still weighed highly. Long-term follow-up of these participants will provide valuable information on their disease trajectory, satisfaction with, and effectiveness of their new medication.

First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis.

BACKGROUND: In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. OBJECTIVE: We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072). METHODS: This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6h post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6h post-dose. RESULTS: A transient decrease in mean HR and blood pressure occurred within 6h of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. CONCLUSION: First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.

Implications of real-world adherence on cost-effectiveness analysis in multiple sclerosis.

OBJECTIVES: Adherence to medication is essential for optimal outcomes, especially for chronic diseases such as multiple sclerosis (MS). Studies in MS indicate that lower adherence is associated with an increased risk of relapse, hospitalization or emergency room (ER) visits, and higher medical costs. A previous investigation assessed the cost per relapse avoided for patients with MS receiving first-line disease modifying therapies (DMTs); however, the model assumed 100% adherence. METHODS: Because real-world utilization patterns influence the actual effectiveness of medications, this analysis assessed the impact of real-world adherence from a US commercial payer perspective, using updated costs. RESULTS: As was seen in the original study, in this revised model, fingolimod was associated with the lowest cost per relapse avoided ($90,566), followed by SC IFN ß-1b (Extavia: $127,024), SC IFN ß-1b (Betaseron: $137,492), SC IFN ß-1a ($144,016), glatiramer acetate ($160,314), and IM IFN ß-1a ($312,629). The model inputs that had the greatest impact on the results were adherence-adjusted relative relapse rate reduction (RRR) of fingolimod, the wholesale acquisition costs of fingolimod, and the average number of relapses in untreated patients with MS. LIMITATIONS: The estimates of DMT adherence are from a single claims database study of a large national pharmacy benefit manager that only measured adherence, not actual relapses, and the model does not incorporate manufacturer discounts and rebates, which are not publicly available. CONCLUSION: These results suggest that economic analyses of MS therapies should incorporate real-world adherence rates where available, rather than relying exclusively on trial-based efficacy estimates when considering the economic value of treatment alternatives, and that highly efficacious therapies with low adherence may yield real-world efficacy that is substantially lower than that observed in closely monitored clinical trials.