The Association of Retinal Disease with Vision Impairment and Functional Status in Medicare Patients.

Background: The association of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO) with functional status in the general Medicare population are not well established. Objectives: This study examined patient-reported survey data linked with Medicare claims to describe the burden of these vision-threatening retinal diseases (VTRDs) among Medicare beneficiaries. Methods: Medicare Current Beneficiary Survey data linked with Medicare Fee-for-Service claims data from 2006 to 2018 were used in a nationally representative retrospective pooled cross-sectional population-based comparison study. Outcomes between community-dwelling beneficiaries with nAMD (n = 1228), DME (n = 101), or RVO (n = 251) were compared with community-dwelling beneficiaries without any VTRDs (n = 104 088), controlling for baseline demographic and clinical differences. Beneficiaries with a diagnosis of nAMD, DME, or RVO during the data year were included; those with other VTRDs were excluded. Outcomes included vision function and loss, overall functioning as assessed by difficulties with activities of daily living (ADLs) and instrumental ADLs (iADLs), anxiety/depression, falls, and fractures. Results: In patient cohorts with nAMD, DME, and RVO, approximately one-third (34.2%-38.3%) reported "a little trouble seeing" (vs 28.3% for controls), and 26%, 17%, and 9%, respectively, reported "a lot of trouble seeing/blindness" (vs 5% of controls). Difficulty walking and doing heavy housework were the most reported ADLs and iADLs, respectively. Compared with those without VTRDs, beneficiaries with nAMD had higher odds of diagnosed vision loss (odds ratio [OR], 5.39; 95% confidence interval, 4.06-7.16; P < .001) and difficulties with iADLs (odds ratio, 1.41; 95% confidence interval, 1.11-1.80; P = .005); no differences were observed for DME or RVO vs control. After adjusting for age, sex, race/ethnicity, poverty status, comorbidities, and other relevant covariates, nAMD, DME, and RVO were not significantly associated with anxiety/depression, falls, or fractures. Discussion: Patients with nAMD or DME were more likely to report severe visual impairment than those without VTRDs, although only those with nAMD were more likely to be diagnosed with vision loss. Conclusions: Patients with nAMD continue to experience more vision impairment and worse functional status compared with a similar population of Medicare beneficiaries despite availability of therapies like antivascular endothelial growth factor to treat retinal disease.

Healthcare resource utilization in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD): a real-world data analysis.

RATIONALE: There is a lack of real-world characterization of healthcare costs and associated cost drivers in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (PH-COPD). OBJECTIVES: To examine (1) excess healthcare resource utilization (HCRU) and associated costs in patients with PH-COPD compared to COPD patients without PH; and (2) patient characteristics that are associated with higher healthcare costs in patients with PH-COPD. METHODS: This study analyzed data from the IQVIA PharMetrics® Plus database (OCT2014-MAY2020). Patients with PH-COPD were identified by a claims-based algorithm based on PH diagnosis (ICD-10-CM: I27.0, I27.2, I27.20, I27.21, I27.23) after COPD diagnosis. Patients aged ≥40 years and with data available ≥12 months before (baseline) and ≥6 months after (follow-up) the first observed PH diagnosis were included. Patients with other non-asthma chronic pulmonary diseases, PH associated with other causes, cancer, left-sided heart failure (HF), PH before the first observed COPD diagnosis, or right-sided/unspecified HF during baseline were excluded. Patients in the PH-COPD cohort were matched 1:1 to COPD patients without PH based on propensity scores derived from baseline patient characteristics. Annualized all-cause and COPD/PH-related (indicated by a primary diagnosis of COPD or PH) HCRU and costs during follow-up were compared between the matched cohorts. Baseline patient characteristics associated with higher total costs were examined in a generalized linear model in the PH-COPD cohort. RESULTS: A total of 2,224 patients with PH-COPD were identified and matched to COPD patients without PH. Patients with PH-COPD had higher all-cause HCRU and annual healthcare costs ($51,435 vs. $18,412, p<0.001) than matched COPD patients without PH. Among patients with PH-COPD, costs were primarily driven by hospitalizations (57%), while COPD/PH-related costs accounted for 13% of all-cause costs. Having a higher comorbidity burden and a prior history of COPD exacerbation were major risk factors for higher total all-cause costs among patients with PH-COPD. CONCLUSIONS: Treatment strategies focusing on preventing hospitalizations and managing comorbidities may help reduce the burden of PH-COPD.

Real-world costs of obesity-related complications over eight years: a US retrospective cohort study in 28,500 individuals.

BACKGROUND: Obesity-related complications (ORCs) are associated with high costs for healthcare systems. We assessed the relationship between comorbidity burden, represented by both number and type of 14 specific ORCs, and total healthcare costs over time in people with obesity in the USA. METHODS: Adults (≥ 18 years old) identified from linked electronic medical records and administrative claims databases, with a body mass index measurement of 30-< 70 kg/m2 between 1 January 2007 and 31 March 2012 (earliest measurement: index date), and with continuous enrolment for ≥ 1 year pre index (baseline year) and ≥ 8 years post index, were included. Individuals were grouped by type and number of ORCs during the pre-index baseline year. The primary outcome was annual total adjusted direct per-person healthcare costs. RESULTS: Of 28,583 included individuals, 12,686 had no ORCs, 7242 had one ORC, 4180 had two ORCs and 4475 had three or more ORCs in the baseline year. Annual adjusted direct healthcare costs increased with the number of ORCs and over the 8-year follow-up. Outpatient costs were the greatest contributor to baseline annual direct costs, irrespective of the number of ORCs. For specific ORCs, costs generally increased gradually over the follow-up; the largest percentage increases from year 1 to year 8 were observed for chronic kidney disease (+ 78.8%) and type 2 diabetes (+ 47.8%). CONCLUSIONS: In a US real-world setting, the number of ORCs appears to be a cost driver in people with obesity, from the time of initial obesity classification and for at least the following 8 years.

Characteristics and current standard of care among veterans with major depressive disorder in the United States: A real-world data analysis.

BACKGROUND: This study examined MDD treatment regimens received during the first observed and treated major depressive episode (MDE) among US veterans. METHODS: This retrospective study, conducted using the Veterans Health Administration (VHA) database, supplemented with Medicare Part A/B/D data, included adults with ≥1 MDD diagnosis (index date) between 10/1/2015-2/28/2017 and ≥1 line of therapy (LOT) within the first observed complete MDE. Patient baseline (6-month pre-index) characteristics and up to six LOTs received during the first observed and treated MDE were assessed. RESULTS: Of 40,240 veterans with MDD identified (mean age: 50.9 years, 83.9% male, 63.4% White, 88.6% non-Hispanic), hypertension (27.5%), hyperlipidemia (20.8%), and post-traumatic stress disorder (17.5%) were the most common baseline comorbidities. During the first observed and treated MDE, patients received a mean of 1.6 ± 1.0 LOTs, with 14.6% of patients receiving ≥3 LOTs. SSRI-monotherapy was the most commonly observed regimen in the first six LOTs, followed by SNRI-monotherapy in LOT 1 and antidepressants augmented by anticonvulsants in the remaining five LOTs. The antidepressant class of the previous LOT was commonly used in the subsequent LOT. SSRI-SSRI-SSRI was the most common LOT1-to-LOT3 sequencing pattern among patients receiving ≥3 LOTs. LIMITATIONS: The study findings are limited to data in the VHA database and may not be generalizable to the non-veteran US population. CONCLUSIONS: During the first observed and treated MDE, SSRI-monotherapy was the most common therapy in the first six LOTs. Cycling within SSRI class was the leading sequencing pattern of the first three LOTs among veterans who received ≥3 LOTs.

Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism.

X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disease in which increased very long chain fatty acids (VLCFAs) in the central nervous system (CNS) cause demyelination and axonopathy, leading to neurological deficits. Sobetirome, a potent thyroid hormone agonist, has been shown to lower VLCFAs in the periphery and CNS. In this study, two pharmacological strategies for enhancing the effects of sobetirome were tested in Abcd1 KO mice, a murine model with the same inborn error of metabolism as X-ALD patients. First, a sobetirome prodrug (Sob-AM2) with increased CNS penetration lowered CNS VLCFAs more potently than sobetirome and was better tolerated with reduced peripheral exposure. Second, co-administration of thyroid hormone with sobetirome enhanced VLCFA lowering in the periphery but did not produce greater lowering in the CNS. These data support the conclusion that CNS VLCFA lowering in Abcd1 knockout mice is limited by a mechanistic threshold related to slow lipid turnover.

Myelin repair stimulated by CNS-selective thyroid hormone action.

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.

Structure-Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs.

Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N-methyl (4), N-ethyl (5), N-fluoroethyl (15), and N-cyclopropyl (18) substantially favor selective CNS distribution of the parent drug in mice. Additionally, lead compounds exhibit moderate to good rates of hydrolysis at FAAH in vitro suggesting both enzymatic and physicochemical properties are important parameters for optimization. Both 4 and 15 were orally bioavailable while retaining appreciable CNS parent drug delivery following an oral dose. The pharmacokinetic parameters of 4 over 24 h postdose (i.v. and p.o.) were determined.

Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy.

The blood-brain barrier (BBB) can be a substantial impediment to achieving therapeutic levels of drugs in the CNS. Certain chemical functionality such as the carboxylic acid is a general liability for BBB permeability preventing significant CNS distribution of a drug from a systemic dose. Here, we report a strategy for CNS-selective distribution of the carboxylic acid containing thyromimetic sobetirome using prodrugs targeted to fatty-acid amide hydrolase (FAAH), which is expressed in the brain. Two amide prodrugs of sobetirome were shown to be efficient substrates of FAAH with Vmax/KM values comparable to the natural endocannabinoid FAAH substrate anandamide. In mice, a systemic dose of sobetirome prodrug leads to a substantial ∼60-fold increase in brain distribution (Kp) of sobetirome compared to an equimolar systemic dose of the parent drug. The increased delivery of sobetirome to the brain from the prodrug was diminished by both pharmacological inhibition and genetic deletion of FAAH in vivo. The increased brain exposure of sobetirome arising from the prodrug corresponds to ∼30-fold increased potency in brain target engagement compared to the parent drug. These results suggest that FAAH-targeted prodrugs can considerably increase drug exposure to the CNS with a concomitant decrease in systemic drug levels generating a desirable distribution profile for CNS acting drugs.

Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration.

Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.

Increasing Thyromimetic Potency through Halogen Substitution.

Sobetirome is one of the most studied thyroid hormone receptorâ€…ß (TRß)-selective thyromimetics in the field due to its excellent selectivity and potency. A small structural change-replacing the 3,5-dimethyl groups of sobetirome with either chlorine or bromine-produces significantly more potent compounds, both in vitro and in vivo. These halogenated compounds induce transactivation of a TRß-mediated cell-based reporter with an EC50 value comparable to that of T3, access the central nervous system (CNS) at levels similar to their parent, and activate an endogenous TR-regulated gene in the brain with an EC50 value roughly five-fold lower than that of sobetirome. Previous studies suggest that this apparent increase in affinity can be explained by halogen bonding between the ligand and a backbone carbonyl group in the receptor. This makes the new analogues potential candidates for treating CNS disorders that may respond favorably to thyroid-hormone-stimulated pathways.