Examining Real-World Adherence to Nusinersen for the Treatment of Spinal Muscular Atrophy Using Two Large US Data Sources.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare neuromuscular disease characterized by progressive muscular atrophy and weakness. Nusinersen was the first treatment approved for SMA. Per the US label, the nusinersen administration schedule consists of three loading doses at 14-day intervals, a fourth loading dose 30 days later, and maintenance doses every 4 months thereafter. Using two large US databases, we evaluated real-world adherence to nusinersen with its unique dosing schedule among generalizable populations of patients with SMA. METHODS: Patients with SMA treated with nusinersen, likely to have complete information on date of treatment initiation, were identified in the Optum® de-identified electronic health records (EHR) database (7/2017-9/2019), and in the Merative™ MarketScan® Research Databases from commercial (1/2017-6/2020) and Medicaid claims (1/2017-12/2019). Baseline demographics, number of nusinersen administrations on time, and distribution of inter-dose intervals were summarized. RESULTS: Totals of 67 and 291 patients were identified in the EHR and claims databases, respectively. Most nusinersen doses were received on time (93.9% EHR, 80.5% claims). Adherence was higher during the maintenance phase (90.6%) than the loading phase (71.1%) in the claims analysis, in contrast with the EHR analysis (95.5% and 92.6%, respectively), suggesting that not all loading doses of nusinersen may be accurately captured in claims. Inter-dose intervals captured in both databases aligned with the expected dosing schedule. CONCLUSION: Most nusinersen doses were received on time, consistent with the recommended schedule. Our findings also highlight the importance of careful methodological approaches when using real-world administrative databases for evaluation of nusinersen treatment patterns.

Adherence to medicines in the real world is important for patients with chronic disease to see long-term benefits of treatment. This study shows the importance and challenges of measuring adherence using real-world administrative data sources. This is especially important for drugs given through lumbar puncture with unique dosing schedules, such as nusinersen for the treatment of spinal muscular atrophy. In this study, most patients with spinal muscular atrophy received their nusinersen doses on time.

Comparative All-Cause Mortality Among a Large Population of Patients with Spinal Muscular Atrophy Versus Matched Controls.

INTRODUCTION: There is little information about survival of spinal muscular atrophy (SMA) patients into adulthood, in particular from population-based samples. We estimated and compared age-specific, all-cause mortality rates in patients with SMA and matched controls in a large, retrospective cohort study using electronic health records (EHRs) from the pre-treatment era. METHODS: The US Optum® de-identified EHR database contains EHRs for ~ 104 million persons (study period: January 1, 2007-December 22, 2016). SMA cases were identified by one or more International Classification of Diseases, Ninth/Tenth Edition codes for SMA. Controls with no SMA diagnosis code were matched 10:1 to SMA cases based on birth year, gender, and first diagnostic code date. For both groups, ≥ 1 month of observation and (if deceased) a valid date of death were required for inclusion. Age-specific mortality rates per person-year (PY) and hazard ratios were calculated. RESULTS: Five thousand one hundred seventy-nine SMA cases and 51,152 controls were analyzed. The overall hazard ratio comparing cases with controls was 1.76 (95% CI 1.63-1.90). In patients with SMA type III diagnostic codes only, the all-age mortality rate was 1059/100,000 PYs in cases and 603/100,000 PYs in controls. In older age groups (13-20, 21-30, 31-40, 41-50, 51-60, and > 60 years), age-specific mortality rates for cases consistently exceeded those of controls. Limitations of this study included the inability to confirm the SMA diagnosis or SMA type by genetic or clinical confirmation. CONCLUSION: Patients with SMA of all ages, including adults and type III patients, had a higher all-cause mortality rate as compared to age-matched controls during the pre-treatment era.

The incidence of hydrocephalus among patients with and without spinal muscular atrophy (SMA): Results from a US electronic health records study.

BACKGROUND: The incidence of hydrocephalus in the spinal muscular atrophy (SMA) population relative to the general population is currently unknown. Since the approval of nusinersen, an intrathecally administered drug for SMA, a small number of hydrocephalus cases among nusinersen users have been reported. Currently, the incidence of hydrocephalus in untreated SMA patients is not available, thereby making it difficult to determine if hydrocephalus is a side effect of nusinersen or part of SMA's natural history. This retrospective, matched cohort study used electronic health records (EHRs) to estimate and compare the incidence of hydrocephalus in both SMA patients and matched non-SMA controls in the time period prior to the approval of nusinersen. METHODS: The U.S. Optum® de-identified EHR database contains records for approximately 100 million persons. The current study period spanned January 1, 2007-December 22, 2016. Patients with SMA were identified by one or more International Classification of Diseases (ICD)-9 and/or ICD-10 codes for SMA appearing as primary, admission, or discharge diagnoses, without a pregnancy diagnostic code in the 1-year time before and after the first occurrence of SMA. The first occurrence of SMA defined the index date and non-SMA controls were matched to cases. Incident cases of hydrocephalus were identified with one or more ICD-9 and/or ICD-10 code for any type of hydrocephalus following the index date. Hydrocephalus incidence rates per person-months and the incidence rate ratio comparing SMA cases with non-SMA controls were calculated. RESULTS: There were 5354 SMA cases and an equal number of matched non-SMA controls. Incident hydrocephalus events were identified in 42 SMA cases and 9 non-SMA controls. Hydrocephalus incidence rates per 100,000 person-months were 15.5 (95% CI: 11.2-20.9) among SMA cases and 3.3 (95% CI: 1.5-6.3) among non-SMA controls. The incidence rate ratio was 4.7 (95% CI: 2.4-10.2). CONCLUSIONS: Based on this retrospective analysis utilizing US EHR data, SMA patients had an approximately fourfold increased risk of hydrocephalus compared with non-SMA controls in the era preceding nusinersen treatment. This study may assist in properly evaluating adverse events in nusinersen-treated SMA patients.

[Synthesis and 5-HT reuptake inhibition activity of biarylbenzamidine derivatives].

A series of biarylbenzamidine analogs were synthesized and tested for their biological activities of inhibiting the reuptake of 5-HT. All of them were new compounds, and their structures were confirmed by 1H NMR and HRMS. Preliminary in vitro pharmacological tests showed that all target compounds exhibited 5-HT reuptake inhibition activity. Among the tested compounds, 5i, 4a and 5m exhibited potent inhibitory activity against 5-HT reuptake in vitro. It is a chance to find a better precursor of SSRIs (selective serotonin reuptake inhibitors) for further optimization of compounds.