Repository Corticotropin Versus Glucocorticoid for Nephrotic Syndrome: When Will We See the Evidence?

Despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for repository corticotropin (rACTH) injection (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. We test this assertion by investigating the quality and provenance of the evidence likely to emerge in the foreseeable future. We identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (ie, another form of immunosuppression). We conclude that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications.

Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort.

BACKGROUND: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. METHODS: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. RESULTS: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 µm/year) and GCIPL (-0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (-0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. CONCLUSION: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging.

Shutter-speed analysis of dynamic-contrast-agent (CA)-enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ(b)) and blood volume fraction (v(b); capillary density-volume product (ρ(†)V)) in a high-resolution (1)H2O MRI voxel (40 µL) or ROI. The equilibrium water extravasation rate constant, k(po) (τ(b)(-1)), averages 3.2 and 2.9 s(-1) in resting-state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k(po) differences are dominated by capillary water permeability (P(W)(†)), not size, differences. NWM and NGM voxel k(po) and v(b) values are independent. Quantitative analyses of concomitant population-averaged k(po), v(b) variations in normal and normal-appearing MS brain ROIs confirm P(W)(†) dominance. (B) P(W)(†) is dominated (>95%) by a trans(endothelial)cellular pathway, not the P(CA)(†) paracellular route. In MS lesions and GBM tumors, P(CA)(†) increases but P(W)(†) decreases. (C) k(po) tracks steady-state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k(po) correlates with literature MRSI ATP (positively) and Na(+) (negatively) tissue concentrations. This suggests that the P(W)(†) pathway is metabolically active. Excellent agreement of the relative NGM/NWM k(po)v(b) product ratio with the literature (31)PMRSI-MT CMR(oxphos) ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k(io)) is proportional to plasma membrane P-type ATPase turnover, likely due to active trans-membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form "gliovascular units." We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k(po), letting it report neurogliovascular unit Na(+),K(+)-ATPase activity. Cerebral k(po) maps represent metabolic (functional) neuroimages. The NGM 2.9 s(-1) k(po) means an equilibrium unidirectional water efflux of ~10(15) H2O molecules s(-1) per capillary (in 1 µL tissue): consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.

Japanese macaque encephalomyelitis: a spontaneous multiple sclerosis-like disease in a nonhuman primate.

OBJECTIVE: To describe Japanese macaque encephalomyelitis (JME), a spontaneous inflammatory demyelinating disease occurring in the Oregon National Primate Research Center's (ONPRC) colony of Japanese macaques (JMs, Macaca fuscata). METHODS: JMs with neurologic impairment were removed from the colony, evaluated, and treated with supportive care. Animals were humanely euthanized and their central nervous systems (CNSs) were examined. RESULTS: ONPRC's JM colony was established in 1965 and no cases of JME occurred until 1986. Since 1986, 57 JMs spontaneously developed a disease characterized clinically by paresis of 1 or more limbs, ataxia, or ocular motor paresis. Most animals were humanely euthanized during their initial episode. Three recovered, later relapsed, and were then euthanized. There was no gender predilection and the median age for disease was 4 years. Magnetic resonance imaging of 8 cases of JME revealed multiple gadolinium-enhancing T(1) -weighted hyperintensities in the white matter of the cerebral hemispheres, brainstem, cerebellum, and cervical spinal cord. The CNS of monkeys with JME contained multifocal plaque-like demyelinated lesions of varying ages, including acute and chronic, active demyelinating lesions with macrophages and lymphocytic periventricular infiltrates, and chronic, inactive demyelinated lesions. A previously undescribed gamma-herpesvirus was cultured from acute JME white matter lesions. Cases of JME continue to affect 1% to 3% of the ONPRC colony per year. INTERPRETATION: JME is a unique spontaneous disease in a nonhuman primate that has similarities with multiple sclerosis (MS) and is associated with a novel simian herpesvirus. Elucidating the pathogenesis of JME may shed new light on MS and other human demyelinating diseases.

Characteristics of Prescription Drug Use Among Individuals With Multiple Sclerosis in the US Medicare Population.

Background: Few studies have characterized the full spectrum of prescription drug use for individuals with multiple sclerosis (MS). The objective of this study was to describe patterns and expenditures for disease-modifying therapies (DMTs) and other prescription drugs among Medicare beneficiaries with MS. Methods: Using Medicare claims data in 2014, we identified a cohort of Medicare beneficiaries with 12 months of continuous eligibility and 3 or more MS-related inpatient, outpatient, or prescription claims. We quantified the number, type, and costs of prescribed DMTs and other medications for MS-related symptoms. Medication costs were calculated according to whether beneficiaries received additional subsidies, which eliminate most out-of-pocket costs. Results: Of 43,283 Medicare beneficiaries identified with MS, 70% were DMT users. Most used self-administered DMTs (67%), and 3% used natalizumab; 93% received a supportive care medication. Among the 82% of individuals without subsidies, the annual median total and out-of-pocket DMT costs were $56,794 (interquartile range [IQR], $44,837-$62,038) and $4566 (IQR, $849-$5270), respectively. The most commonly used supportive care drugs were antidepressants (62%), opioid analgesics (50%), antispasticity drugs (47%), and anticonvulsants (46%). Annual median total and out-of-pocket costs for these drugs were $15,134 (IQR, $6571-$19,620) and $255 (IQR, $56-$877), respectively. Conclusions: Most Medicare beneficiaries with MS using DMTs face considerable out-of-pocket costs. Beneficiaries also used a significant number of medications potentially used for MS-related symptoms, although total and out-of-pocket costs were modest.

Association Between Pharmacy Benefit Restrictions and Disease-Modifying Therapy Use in the Medicare Part D Program.

Background and Objectives: To determine the association between Medicare Part D plan disease-modifying therapy (DMT) restrictiveness and adherence and outcomes among people with multiple sclerosis (MS). Methods: We used Medicare claims data from 2010 to 2014 to identify individuals with a full year enrollment (Parts A, B, and D), an MS diagnosis, and 1 or more self-administered DMT prescription. Plans were considered restrictive if all available DMTs required a prior authorization or step therapy restriction; otherwise they were considered permissive. We compared DMT adherence, defined as a medication possession ratio ≥80%, MS-related emergency department or inpatient admissions, and outpatient visits by Part D plan restrictiveness. We used multivariate regression models to control for patient demographics and comorbidities. Results: There were 37,713 Medicare beneficiaries with MS who were enrolled in either restrictive (n = 29,901) or permissive (n = 7812) Part D plans during the study period. Patients enrolled in restrictive plans were older (60 vs 58 years; p < 0.001), more likely to live in the south (38% vs 23%; p < 0.001), eligible through disability (67% vs 60%; p < 0.001), and more likely to have several chronic comorbid conditions. Patients enrolled in restrictive plans were less likely to be adherent to their DMT (54% vs 57%; p < 0.001; adjusted odds ratio [aOR] 0.92, 95% confidence interval [CI] 0.88-0.98) and had a higher rate of MS-related outpatient visits (1.7 vs 1.4 per year; p < 0.001; aRR 1.27, 95% CI 1.23-1.31). Discussion: Medicare beneficiaries with MS enrolled in restrictive Part D plans were less adherent to their DMT and had higher rates of MS-related outpatient visits.

Moderators of Improvements in Fatigue Impact After a Self-management Intervention in Multiple Sclerosis: A Secondary Analysis of a Randomized Controlled Trial.

ABSTRACT: Fatigue is one of the most common and disabling symptoms of multiple sclerosis. A recent randomized controlled trial comparing a fatigue self-management program and a general multiple sclerosis education program found that both programs improved fatigue in participants with multiple sclerosis. Participants were randomized to a self-management program (fatigue: take control, n = 109) or a multiple sclerosis education program (multiple sclerosis: take control, n = 109). This secondary analysis of that trial used multilevel moderation analysis to examine moderators of treatment-related effects on fatigue (Modified Fatigue Impact Scale) from baseline through the 6-mo follow-up. The following potential treatment moderators were examined: age, sex, cohabitation/marital status, and baseline levels of self-efficacy, depression symptoms, and sleep quality. Cohabitation status (living with or without a spouse/partner) interacted with intervention group and time to predict fatigue impact (P = 0.04). Fatigue: take control participants who lived with a spouse/partner showed a marginal effect in greater rate of improvement in fatigue compared with those who lived alone (P = 0.08). However, rates of improvement in fatigue in multiple sclerosis: take control participants were similar in those living with or without a spouse/partner. These findings suggest that living with a spouse or partner may facilitate benefit from self-management interventions for multiple sclerosis-related fatigue. Future research should investigate the contribution of supportive others in self-management of fatigue in multiple sclerosis.

Characterization of the Clinical Evidence Supporting Repository Corticotropin Injection for FDA-Approved Indications: A Scoping Review.

IMPORTANCE: Repository corticotropin injection is an expensive medication that was approved in 1952 for the treatment of many inflammatory conditions. The clinical evidence supporting the use of repository corticotropin (hereinafter referred to as corticotropin) has been weak, perhaps because its approval predated the modern review standards of the US Food and Drug Administration (FDA). OBJECTIVE: To characterize the clinical evidence supporting the use of corticotropin for its FDA-approved indications. EVIDENCE REVIEW: Studies were identified via electronic searches of Ovid MEDLINE, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL) from database inception to May 12, 2021 (the MEDLINE search was updated on June 8, 2021). Bibliographies of retrieved articles were also reviewed through ClinicalTrials.gov, FDA documents, and the manufacturer's website. Search terms included HP Acthar, ACTH gel, repository corticotropin, and terms for specific diseases, such as multiple sclerosis, nephrotic syndrome, rheumatoid arthritis, and West syndrome (or spasms, infantile). The review included randomized clinical trials (RCTs), nonrandomized and single-arm clinical trials, and prospective cohort studies that compared corticotropin with an active comparator, placebo, or no treatment. Data were extracted by 1 reviewer and verified by a second. Disagreements were resolved through discussion. Studies were qualitatively synthesized by indication to summarize important design features and results. FINDINGS: Of 1059 records screened, 203 full-text articles were assessed for eligibility. A total of 41 studies involving 2235 participants met inclusion criteria; of those, 11 involved infantile spasms, 10 involved multiple sclerosis (MS), 11 involved rheumatological conditions, 7 involved nephrotic syndrome, 1 involved ocular conditions, and 1 involved sarcoidosis. Overall, 19 studies either included a single arm or exclusively compared different corticotropin dosing strategies. The evidence was most robust for the treatment of infantile spasms and MS. The largest number of studies comparing corticotropin with an active agent (n = 4) or placebo (n = 5) pertained to MS, with almost all studies finding that corticotropin performed better than placebo but no different than corticosteroids. For the treatment of infantile spasms, 8 controlled studies were identified (6 were randomized); of those, only 1 small RCT found corticotropin to be significantly superior to corticosteroids. Studies of patients with other conditions (n = 20) frequently lacked a control group (n = 12), were placebo-controlled (n = 5), or exclusively examined different corticotropin dosing strategies (n = 2). Placebo-controlled RCTs of rheumatoid arthritis, ankylosing spondylitis, optic neuritis, systemic lupus erythematosus, and nephrotic syndrome were generally small and did not consistently demonstrate that corticotropin was superior to placebo. Blinded RCTs showed a similar or greater number of adverse effects with corticotropin relative to corticosteroids. CONCLUSIONS AND RELEVANCE: In this scoping review, few RCTs supported the clinical benefit of corticotropin for most FDA-approved indications. Most RCTs found that corticotropin was not superior to corticosteroids for treating relapses of MS or infantile spasms.

Closing the Part D Coverage Gap and Out-of-Pocket Costs for Multiple Sclerosis Drugs.

OBJECTIVE: To determine whether closing the Part D coverage gap (donut hole) between 2010 and 2019 lowered patients' out-of-pocket costs for disease-modifying therapies (DMTs) for multiple sclerosis (MS). METHODS: Using nationwide Medicare Formulary and Drug Pricing Files, we analyzed Part D drug benefit design and DMT prices in 2010, 2016, and 2019. We calculated average monthly list prices for DMTs available in each year (4 DMTs in 2010, 11 DMTs in 2016, and 14 DMTs in 2019). We projected patients' annual out-of-pocket cost for each DMT alone under a standard Part D plan in that year. We estimated potential savings attributable to closing the coverage gap between 2010 and 2019 (beneficiaries' cost sharing dropped from 100% to 25%) under 3 scenarios: no increase in price, an inflation-indexed price increase (3% annually), and the observed price increase. RESULTS: Median monthly DMT prices rose from $2,804 to $5,987 to $7,009 over the years 2010, 2016, and 2019, respectively. Median projected annual out-of-pocket costs rose from $5,916 to $6,229 to $6,618. With unchanged or inflation-indexed DMT price changes, closing the coverage gap would have reduced annual out-of-pocket costs by $2,260 (38% reduction) and $1,744 (29% reduction), respectively. Despite having the lowest monthly price, generic glatiramer acetate had among the highest out-of-pocket costs ($6,731 to $6,939 a year) in 2019. CONCLUSIONS: Medicare Part D beneficiaries can pay thousands of dollars yearly out of pocket for DMTs. Closing the Part D coverage gap did not reduce out-of-pocket costs for patients because of simultaneous increases in DMT prices.

Gray matter blood-brain barrier water exchange dynamics are reduced in progressive multiple sclerosis.

BACKGROUND AND PURPOSE: To compare transcapillary wall water exchange, a putative marker of cerebral metabolic health, in brain T2 white matter (WM) lesions and normal appearing white and gray matter (NAWM and NAGM, respectively) in individuals with progressive multiple sclerosis (PMS) and healthy controls (HC). METHODS: Dynamic-contrast-enhanced 7T MRI data were obtained from 19 HC and 23 PMS participants. High-resolution pharmacokinetic parametric maps representing tissue microvascular and microstructural properties were created by shutter-speed (SS) paradigm modeling to obtain estimates of blood volume fraction (vb ), water molecule capillary efflux rate constant (kpo ), and the water capillary wall permeability surface area product (Pw S ≡ vb *kpo ). Linear regression models were used to investigate differences in (i) kpo and Pw S between groups in NAWM and NAGM, and (ii) between WM lesions and NAWM in PMS. RESULTS: High-resolution parametric maps were produced to visualize tissue classes and resolve individual WM lesions. Normal-appearing gray matter kpo and Pw S were significantly decreased in PMS compared to HC (p ≤ .01). Twenty-one T2 WM lesions were analyzed in 10 participants with PMS. kpo was significantly decreased in WM lesions compared to PMS NAWM (p < .0001). CONCLUSIONS: Transcapillary water exchange is reduced in PMS NAGM compared to HC and is further reduced in PMS WM lesions, suggesting pathologically impaired brain metabolism. kpo provides a sensitive measure of cerebral metabolic activity and/or coupling, and can be mapped at higher spatial resolution than conventional imaging techniques assessing metabolic activity.

MRI characteristics of Japanese macaque encephalomyelitis: Comparison to human diseases.

BACKGROUND AND PURPOSE: To describe MRI findings in Japanese macaque encephalomyelitis (JME) with emphasis on lesion characteristics, lesion evolution, normal-appearing brain tissue, and similarities to human demyelinating disease. METHODS: MRI data were obtained from 114 Japanese macaques, 30 presenting neurological signs of JME. All animals were screened for presence of T2 -weighted white matter signal hyperintensities; animals with behavioral signs of JME were additionally screened for contrast-enhancing lesions. Whole-brain quantitative T1 maps were collected, and histogram analysis was performed with regression across age to evaluate microstructural changes in normal appearing brain tissue in JME and neurologically normal animals. Quantitative estimates of blood-brain-barrier (BBB) permeability to gadolinium-based-contrast agent (GBCA) were obtained in acute, GBCA-enhancing lesions. Longitudinal imaging data were acquired for 15 JME animals. RESULTS: One hundred and seventy-three focal GBCA-enhancing lesions were identified in 30 animals demonstrating behavioral signs of neurological dysfunction. JME GBCA-enhancing lesions were typically focal and ovoid, demonstrating highest BBB GBCA permeability in the lesion core, similar to acute, focal multiple sclerosis lesions. New GBCA-enhancing lesions arose rapidly from normal-appearing tissue, and BBB permeability remained elevated for weeks. T1 values in normal-appearing tissue were significantly associated with age, but not with sex or disease. CONCLUSIONS: Intense, focal neuroinflammation is a key MRI finding in JME. Several features of JME compare directly to human inflammatory demyelinating diseases. Investigation of JME combined with the development and validation of noninvasive imaging biomarkers offers substantial potential to improve diagnostic specificity and contribute to the understanding of human demyelinating diseases.

Myelin-specific T cells in animals with Japanese macaque encephalomyelitis.

OBJECTIVE: To determine whether animals with Japanese macaque encephalomyelitis (JME), a spontaneous demyelinating disease similar to multiple sclerosis (MS), harbor myelin-specific T cells in their central nervous system (CNS) and periphery. METHODS: Mononuclear cells (MNCs) from CNS lesions, cervical lymph nodes (LNs) and peripheral blood of Japanese macaques (JMs) with JME, and cervical LN and blood MNCs from healthy controls or animals with non-JME conditions were analyzed for the presence of myelin-specific T cells and changes in interleukin 17 (IL-17) and interferon gamma (IFNγ) expression. RESULTS: Demyelinating JME lesions contained CD4+ T cells and CD8+ T cells specific to myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and/or proteolipid protein (PLP). CD8+ T-cell responses were absent in JME peripheral blood, and in age- and sex-matched controls. However, CD4+ Th1 and Th17 responses were detected in JME peripheral blood versus controls. Cervical LN MNCs from eight of nine JME animals had CD3+ T cells specific for MOG, MBP, and PLP that were not detected in controls. Mapping myelin epitopes revealed a heterogeneity in responses among JME animals. Comparison of myelin antigen sequences with those of JM rhadinovirus (JMRV), which is found in JME lesions, identified six viral open reading frames (ORFs) with similarities to myelin antigen sequences. Overlapping peptides to these JMRV ORFs did not induce IFNγ responses. INTERPRETATIONS: JME possesses an immune-mediated component that involves both CD4+ and CD8+ T cells specific for myelin antigens. JME may shed new light on inflammatory demyelinating disease pathogenesis linked to gamma-herpesvirus infection.

Pharmacokinetic study of lipoic acid in multiple sclerosis: comparing mice and human pharmacokinetic parameters.

Lipoic acid is a natural antioxidant available as an oral supplement from a number of different manufacturers. Lipoic acid administered subcutaneously is an effective therapy for murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. The aim of this study was to compare serum lipoic acid levels with oral dosing in patients with multiple sclerosis with serum levels in mice receiving subcutaneous doses of lipoic acid. We performed serum pharmacokinetic studies in patients with multiple sclerosis after a single oral dose of 1200 mg lipoic acid. Patients received one of the three different racemic formulations randomly: tablet (Formulation A) and capsules (Formulations B and C). Mice pharmacokinetic studies were performed with three different subcutaneous doses (20, 50 and 100 mg/kg racemic lipoic acid). The pharmacokinetic parameters included Maximum Serum Concentrations (C(max) in microg/ml) and area under the curve (0-infinity) (AUC ( 0-infinity) in microg*min/ml). We found mean C(max) and AUC (0-infinity) in patients with multiple sclerosis as follows: group A (N = 7) 3.8 +/- 2.6 and 443.1 +/- 283.9; group B (N = 8) 9.9 +/- 4.5 and 745.2 +/- 308.7 and group C (N = 8) 10.3 +/- 3.8 and 848.8 +/- 360.5, respectively. Mean C(max) and AUC (0-infinity) in the mice were: 100 mg/kg lipoic acid: 30.9 +/- 2.9 and 998 +/- 245; 50 mg/kg lipoic acid: 7.6 +/- 1.4 and 223 +/- 20; 20 mg/kg lipoic acid: 2.7 +/- 0.7 and 119 +/- 33. We conclude that patients taking 1200 mg of lipoic acid from two of the three oral formulations achieved serum C(max) and AUC levels comparable to that observed in mice receiving 50 mg/kg subcutaneous dose of lipoic acid, which is a highly therapeutic dose in experimental autoimmune encephalomyelitis. A dose of 1200 mg oral lipoic acid can achieve therapeutic serum levels in patients with multiple sclerosis.

Immunomodulatory therapies in neurologic critical care.

INTRODUCTION: Neurologic disorders with autoimmune dysregulation are commonly encountered in the critical care setting. Frequently encountered diseases include Guillain-Barré syndrome (GBS), myasthenia gravis, multiple sclerosis, acute demyelinating encephalomyelitis, and encephalitides. Immunomodulatory therapies, including high-dose corticosteroids, plasmapheresis, and intravenous immunoglobulins, are the cornerstone of the treatment of these diseases. Here we review the efficacy and side effects of immunomodulatory therapies commonly utilized in critically ill neurologic patients in the intensive care setting. METHODS: Search of Medline, Cochrane databases, and manual review of article bibliographies. RESULTS: The efficacy of high-dose corticosteroids, plasmapheresis, and intravenous immunoglobulins have been studied extensively in GBS, myasthenia gravis, and demyelinating disorders such as multiple sclerosis and acute demyelinating encephalomyelitis. For these diseases, however, the duration of treatment, dosing regimens, and choices among different therapeutic modalities remain controversial. For many of the other diseases (e.g., encephalitis and status epilepticus of autoimmune etiology) discussed in this review, evidence is limited to small case series. CONCLUSIONS: There is good evidence for the efficacy and tolerability of immunomodulatory therapies in GBS, myasthenia gravis, and acute central nervous system demyelination, though data to establish superiority of one therapeutic regimen over another remains lacking. For most other conditions, the data for immunomodulatory therapies are limited, and further research is required.

The effect of out-of-pocket costs on initiation of disease-modifying therapies among medicare beneficiaries with multiple sclerosis.

BACKGROUND: Medicare beneficiaries with multiple sclerosis (MS) often face high out-of-pocket (OOP) costs for disease-modifying therapies (DMTs). It is unclear how cost-sharing affects therapy initiation. OBJECTIVES: To estimate the effects of patient cost-sharing on initiation of a DMT among Medicare beneficiaries with a new diagnosis code for MS. METHODS: Using Medicare claims data from 2010 to 2014, we identified a cohort of individuals with at least one inpatient or two outpatient diagnostic claims for MS. We restricted this group to beneficiaries with continuous Part A, B, and D coverage in the year before and after their initial diagnosis. To estimate the effect of cost-sharing on time to self-administered DMT initiation, we compared beneficiaries with a Low-Income Subsidy (LIS), who are shielded from cost-sharing, to those without LIS using multivariate Cox Proportional Hazards models adjusting for potential demographic and health-related confounders. RESULTS: There were 39,661 Medicare beneficiaries who met inclusion criteria; 3827 had full LIS benefits throughout the study period. Beneficiaries were predominately White (36,447, 91.9%) and female (29,406, 74.1%). LIS recipients were generally younger (55 vs 67 years, p<0.001) and more likely to be enrolled through disability eligibility (79% vs 36%, p<0.001). In the year after their index diagnosis, 434 LIS recipients initiated DMT versus 1682 non-LIS (11% vs 5%; p<0.001). Among those who started a DMT, the average time to initiation was 115 days in those with LIS and 137 days for non-LIS (p<0.001). After adjustment for covariates, individuals with LIS benefits were significantly more likely to initiate a DMT in the year following their diagnosis (adjusted hazard ratio 1.4, 95% CI 1.25 to 1.57). The effect of OOP costs on initiation did not differ by demographic subgroups. CONCLUSIONS: Medicare beneficiaries with MS who are shielded from traditional cost-sharing are more likely to initiate a DMT in the year following receipt of their first diagnosis code. Future work should examine the effect of cost-related treatment delays on relapse rates and disability progression.

Effect of generic glatiramer acetate on spending and use of drugs for multiple sclerosis.

OBJECTIVE: To estimate changes in costs and utilization trends for disease-modifying therapies (DMTs) from 2011 to 2017 in the US Medicaid program. METHODS: Using quarterly Medicaid State Drug Utilization Data from 2011 to 2017, we summarize trends in spending, utilization, and costs per prescription for 15 multiple sclerosis (MS) DMTs including brand and generic versions of glatiramer acetate. We use interrupted time series regression to estimate the effect of market entry of generic glatiramer acetate on cost per prescription of other self-administered DMTs. RESULTS: Gross annual expenditures on MS DMTs increased from $453 million to $1.32 billion between 2011 and 2017 within the Medicaid program. Increased spending was primarily driven by increases in per prescription costs, which doubled during the study period. Although total utilization was stable, product specific utilization shifted from injectable to oral DMTs. However, throughout the study, the plurality of utilization was glatiramer acetate. The introduction of generic glatiramer acetate in Q2 of 2015 was associated with an immediate increase of $441 (95% confidence interval [CI] $184-$697; p < 0.001) in the cost per prescription of branded glatiramer acetate followed by a gradual $52 per prescription reduction (95% CI -$86 to -$18) over time. There were minimal changes in the costs for the other DMTs. CONCLUSIONS: Spending on MS DMTs in the Medicaid program have more than doubled over the last 7 years primarily as a function of higher costs per prescription. Introduction of a generic glatiramer acetate product in 2015 had nominal effects on overall price trajectories and utilization within the class.

Qualitative study on the price of drugs for multiple sclerosis: Gaming the system.

OBJECTIVE: To describe pricing decisions, justifications, and attitudes among current and former biotech industry executives for companies that manufacture multiple sclerosis disease-modifying therapies. METHODS: Four leaders in biotech who have been directly involved in multiple sclerosis disease-modifying therapy pricing or marketing volunteered to participate in 30-minute semistructured interviews conducted via telephone. An expert in qualitative methods moderated and analyzed the interviews alongside the principal investigator. Brief, preinterview online surveys were also administered to provide additional context and insight for discussion. Interviews were audio-recorded and professionally transcribed. RESULTS: Participants consistently stated that initial price decisions were dictated by the price of existing competitors in the market. Revenue maximization and corporate growth were drivers of price escalations in the absence of continued market penetration. Lower revenue predictions outside the United States also informed pricing strategies. The growing complexity and clout of drug distribution and supply channels were also cited as contributing factors. Although decisions to raise prices were motivated by the need to attract investment for future innovation, recouping drug-specific research and development costs as a justification was not strongly endorsed as having a significant influence on pricing decisions. CONCLUSIONS: Contrary to prevailing narratives that underscore drug development costs, findings from our interviews suggest that the existing price ecosystem, overall corporate growth, international pricing disparities, and supply chain-related distortions may play a more central role in drug pricing decision.

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging.

BACKGROUND AND PURPOSE: Transvascular water exchange plays a key role in the functional integrity of the blood-brain barrier (BBB). In white matter (WM), a variety of imaging modalities have demonstrated age-related changes in structure and metabolism, but the extent to which water exchange is altered remains unclear. Here, we investigated the cumulative effects of healthy aging on WM capillary water exchange. METHODS: A total of 38 healthy adults (aged 36-80 years) were studied using 7T dynamic contrast enhanced MRI. Blood volume fraction (vb ) and capillary water efflux rate constant (kpo ) were determined by fitting changes in the 1 H2 O longitudinal relaxation rate constant (R1 ) during contrast agent bolus passage to a two-compartment exchange model. WM volume was determined by morphometric analysis of structural images. RESULTS: R1 values and WM volume showed similar trajectories of age-related decline. Among all subjects, vb and kpo averaged 1.7 (±0.5) mL/100 g of tissue and 2.1 (±1.1) s-1 , respectively. While vb showed minimal changes over the 40-year-age span of participants, kpo declined 0.06 s-1 (ca. 3%) per year (r = -.66; P < .0005), from near 4 s-1 at age 30 to ca. 2 s-1 at age 70. The association remained significant after controlling for WM volume. CONCLUSIONS: Previous studies have shown that kpo tracks Na+ , K+ -ATPase activity-dependent water exchange at the BBB and likely reflects neurogliovascular unit (NGVU) coupled metabolic activity. The age-related decline in kpo observed here is consistent with compromised NGVU metabolism in older individuals and the dysregulated cellular bioenergetics that accompany normal brain aging.