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Introduction Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disorder caused by deletion/mutation of the survival motor neuron 1 gene, characterized by progressive loss of motor neurons, resulting in increasing muscular weakness, deteriorating motor function, and, in its most severe form, death before 2 years. Nusinersen, an antisense oligonucleotide that increases expression of the functional SMN protein, was approved for SMA by US and European regulatory agencies in 2016 and 2017, respectively. The indicated regimen requires intrathecal injections every 4 months, following the first four injections during the loading phase. Adherence is integral to treatment success. Adherence to nusinersen may pose particular challenges as most patients with SMA are young children who require complex multidisciplinary care (including ongoing intrathecal treatment administration and potential specialized anesthetic and surgical procedures) at specialized centers. However, real-world data on adherence to nusinersen are limited. Methods We conducted a retrospective claims database analysis from December 23, 2016, to November 20, 2019, to study nusinersen adherence and discontinuation/persistence in US patients with SMA types 1–3 who completed the loading phase, and to determine the impact of non-adherence or treatment discontinuation on SMA-related comorbidities, health care resource utilization (HCRU), and costs. Results We identified 23 patients with SMA type 1, 41 patients with SMA type 2, and 260 patients with SMA type 3 who had completed the loading phase. Deviations from the indicated nusinersen treatment schedule were frequent in real-world usage, with most patients receiving ≥1 dose outside the scheduled interval. Across SMA types, non-adherent patients were more likely to have had SMA-related comorbidities (e.g., feeding difficulties, dyspnea and respiratory anomalies, and muscle weakness) and greater HCRU. Persistence rates 12 months after treatment initiation for patients with SMA types 1, 2, and 3 were 55.2%, 42.4%, and 54.6%, respectively. Patients who discontinued nusinersen and those who did not had generally similar comorbidity profiles. Discontinuation was associated with greater health care costs across SMA types. Conclusion Our analysis of claims data indicated that discontinuation and non-adherence to nusinersen treatment were prevalent, and associated with greater frequency of comorbidities, greater HCRU, and increased costs for patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01938-w.

Objective Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. Methods In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naive indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. Results Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naive ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. Conclusions Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

The concept of a reference case, first proposed by the US Panel on Cost-Effectiveness in Health and Medicine, has been used to specify the required methodological features of economic evaluations of healthcare interventions. In the case of gene therapy, there is a difference of opinion on whether a specific methodological reference case is required. The aim of this article was to provide a more detailed analysis of the characteristics of gene therapy and the extent to which these characteristics warrant modifications to the methods suggested in general reference cases for economic evaluation. We argue that a completely new reference case is not required, but propose a tailored checklist that can be used by analysts and decision makers to determine which aspects of economic evaluation should be considered further, given the unique nature of gene therapy.

Introduction Infants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1. Methods Overall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of ≥ 4 points in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches. Results Among symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI) = 4.1–12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR) = 1.2, 95% CI 1.1–1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI 2.0–3.6) and RR was 1.6 (95% CI 1.4–1.9). For improvement in motor function, NNT was 3.5 (95% CI 2.6–5.3) and RR was 1.4 (95% CI 1.2–1.6). For milestone achievements, the NNTs were 1.4 (95% CI 1.1–1.9), 1.5 (95% CI 1.1–2.5), and 1.2 (95% CI 1.0–1.5); RRs 4.2 (95% CI 2.6–6.7), 7.8 (95% CI 3.6–17.0), and 11.2 (95% CI 5.1–24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach. Conclusion This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones. Funding AveXis.

Transformative cell and gene therapies have now launched worldwide, and many potentially curative cell and gene therapies are in development, offering the prospect of significant health gains for patients. Access to these therapies depend on decisions made by health technology assessment (HTA) and payer organizations. We sought to describe the emerging cell and gene therapies market access landscape by analyzing 17 US commercial payer medical policies, and HTA reports from five European countries and Canada. We found that some US health plans applied coverage restrictions more often than others (four plans applied restrictions in all decisions, while four plans applied restrictions in < 30% of decisions). The European and Canadian HTA bodies recommend access to fewer therapies than US health plans, reflecting a more stringent approach in the context of limited evidence and high scientific uncertainty that is commonly associated with these treatments. Our findings suggest that patient access to approved cell and gene therapies is restricted in all regions studied, though the nature of these restrictions differs between US health plans and the European/Canada HTA recommendations. Payers, HTA groups, pharmaceutical companies, and other stakeholders should collaborate to more clearly define the “uncertainties” and develop market access policies that balance benefits of early access with ongoing data collection to close evidence gaps over time.

Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective: To compare the manufacturer’s proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer’s model with long-term follow-up data and some key ICER assumptions. Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective: USA/Commercial payer Participants: Children aged

Background: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease. Objective: Characterize direct costs associated with SMA management. Data source: Truven Health Analytics MarketScan claims data (2012–2016). Patients: Eligible patients had ≥2 SMA-related medical claims ≥30 days apart. Patients were matched (1:1) to controls by birth year, gender, and geographic region. Patients were categorized as having infantile, child, or juvenile SMA based on diagnosis at age 50-fold higher compared with matched controls. Efforts are needed to reduce costs through improved standards of care.

BACKGROUND: Drug development for disease modifying agents in Alzheimer’s disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer’s. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder–vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer’s disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer’s prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include “digital independence.” CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

Objective: To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods: A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations: Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions: While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists. ispartof: J Mark Access Health Policy vol:8 issue:1 pages:1822666- ispartof: location:United States status: Published online

Background Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy. Methods Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function. Results All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently. Conclusions AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy. Trial registration ClinicalTrials.gov number, NCT02122952.

Background: In this retrospective claims analysis, real-world healthcare resource use (HRU) and costs among SMA type 1 (SMA1) patients were assessed. Methods: SMA1 patients were identified from Symphony Health’s Integrated Dataverse® (09/01/2016–08/31/2018). The study period spanned from the index date (date of first SMA1 diagnosis after nusinersen approval [12/23/2016]) until death/end of available data. HRU and costs per-patient-per-year (PPPY; 2018USD) were described during the study period for all patients and after treatment initiation for nusinersen-treated patients. Results: A total of 349 SMA1 patients (median age=1 year; 55.6% female) with median follow-up of 7.9 months were included. The proportion of patients receiving mechanical ventilation, nutritional support, and physical therapy/rehabilitation was 46.4%, 46.1%, and 22.6%. Patients had, on average, 59.4 days with medical visits/year (14.1 inpatient, 13.4 respiratory failure-related). The 45 nusinersen-treated patients had, on average, 56.6 days with medical visits/year (4.6 inpatient, 11.4 respiratory failure-related). Excluding nusinersen-related costs, mean healthcare costs PPPY were $137,627 (median: $43,167) for all patients and $92,618 ($29,425) for nusinersen-treated patients. Mean nusinersen-related costs were $191,909 ($144,487) per month for the first 3 months post-initiation and $36,882 ($16,132) per month thereafter. Conclusions: HRU and costs associated with SMA1 are substantial, even among patients treated with nusinersen.

Background Advanced therapy medicinal products (ATMPs) are innovative therapies likely associated with high prices. Payers need guidance to create a balance between ensuring patient access to breakthrough therapies and maintaining the financial sustainability of the healthcare system. Objective The aims of this study were to identify, define, classify and compare the approaches to funding high-cost medicines proposed in the literature, to analyze their appropriateness for ATMP funding and to suggest an optimal funding model for ATMPs. Results Forty-eight articles suggesting new funding models for innovative high-cost therapies were identified. The models were classified into 3 groups: financial agreement, health outcomes-based agreement and healthcoin. Financial agreement encompassed: discounts, rebates, price and volume caps, price-volume agreements, loans, cost-plus price, intellectual-based payment and fund-based payment. Health outcomes-based agreements were defined as agreements between manufacturers and payers based on drug performance, and were divided into performance-based payment and coverage with evidence development. Healthcoin described a new suggested tradeable currency used to assign monetary value to incremental outcomes. Conclusion With a large number of ATMPs in development, it is time for stakeholders to start thinking about new pathways and funding strategies for these innovative high-cost therapies. An “ATMP-specific fund” may constitute a reasonable solution to ensure rapid patient access to innovation without threatening the sustainability of the health care system.