Public Policy Should Foster Alzheimer’s Treatment Availability: Comment on the Draft US Medicare Decision to Limit Payment for Aducanumab (Aduhelm™) to Patients Participating in Clinical Trials

Aducanumab (AduhelmTM) was approved by the United States (US) Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease on June 7, 2021. Soon after, the approved labeling was adjusted to direct treatment to mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD dementia reflecting the severity of cognitive impairment among participants in the clinical trials that led to the approval (1, 2). Individuals over age 65 in the US are entitled to have the cost of prescription drugs partially paid by the Center for Medicare and Medicaid Services (CMS; “Medicare”) if they participate in an approved insurance plan. Most people pay a monthly fee for this benefit. When a new agent becomes available it may be subject to a National Coverage Determination (NCD) to ascertain if CMS will pay for the drug and under what circumstances. CMS covers drugs that are considered “reasonable and necessary” for the treatment of an illness. The covered treatment must be shown to meaningfully improve health outcomes. The NCD process can lead to approval of coverage, denial for coverage, or limited coverage (3). On January 11, 2022, Medicare Issued its draft NCD on Coverage with Evidence Development (CED) for aducanumab which limits coverage to patients participating in CMS-approved randomized controlled clinical trials supported by the US National Institutes of Health (NIH) (3). This decision, if sustained, would greatly limit and delay availability of aducanumab to patients who could benefit from treatment. This decision has many foreseeable adverse consequences. The draft proposal must be understood in the context of the available efficacy data and the process of accelerated approval. These are discussed here followed by a description of the CMS proposal to limit the coverage of aducanumab to participants in trials. The proposed CED is not in the best interest of patients with early AD or the field of AD treatment development. The current decision is a draft of the proposed CED and is subject to change until a final decision is rendered on April 11th, 2022. Public comment on the decision is invited until February 10, 2022, and there is an opportunity to modify this draft determination (https://www.cms.gov/ medicare-coverage-database/search.aspx)

Susans Career Dilemma At MGR, LLC

Professionals starting their first job after graduate school want to launch a successful career. Unfortunately, some of them soon find out that performing at a high level does not always guarantee rapid promotion or success in their organization. This is a story about Susan, a highly recruited attorney, who joined an established law firm in Washington, DC, and was slow to realize that managing her boss is a critical skill needed for her survival and prosperity. Carlos, her direct supervisor and advocate of a tough love approach to management, views the effective nurturance and mentoring of new employees as his means of entr into the ranks of senior partner. Carlos and Susan are on a collision course with a potential impact on both of their careers. Susan needed to decide at the end of the case what to do to strategically manage her career

A Practical Algorithm for Managing Alzheimer\u27s Disease: What, When, and Why?

Alzheimer\u27s disease (AD) is the most common form of dementia and its prevalence is increasing. Recent developments in AD management provide improved ways of supporting patients and their caregivers throughout the disease continuum. Managing cardiovascular risk factors, maintaining an active lifestyle (with regular physical, mental and social activity) and following a Mediterranean diet appear to reduce AD risk and may slow cognitive decline. Pharmacologic therapy for AD should be initiated upon diagnosis. All of the currently available cholinesterase inhibitors (ChEIs; donepezil, galantamine, and rivastigmine) are indicated for mild-to-moderate AD. Donepezil (10 and 23 mg/day) and rivastigmine transdermal patch (13.3 mg/24 h) are indicated for moderate-to-severe AD. Memantine, an N-methyl-d-aspartate receptor antagonist, is approved for moderate-to-severe AD. ChEIs have been shown to improve cognitive function, global clinical status and patients\u27 ability to perform activities of daily living. There is also evidence for reduction in emergence of behavioral symptoms with ChEI therapy. Treatment choice (e.g., oral vs. transdermal) should be based on patient or caregiver preference, ease of use, tolerability, and cost. Treatment should be individualized; patients can be switched from one ChEI to another if the initial agent is poorly tolerated or ineffective. Memantine may be introduced in moderate-to-severe disease stages. Clinicians will regularly monitor symptoms and behaviors, manage comorbidities, assess function, educate and help caregivers access information and support, evaluate patients\u27 fitness to drive or own firearms, and provide advice about the need for legal and financial planning. Review of caregiver well-being and prompt referral for support is vital

Constellation Ground Systems Launch Availability Analysis: Enhancing Highly Reliable Launch Systems Design

Success of the Constellation Program's lunar architecture requires successfully launching two vehicles, Ares I/Orion and Ares V/Altair, within a very limited time period. The reliability and maintainability of flight vehicles and ground systems must deliver a high probability of successfully launching the second vehicle in order to avoid wasting the on-orbit asset launched by the first vehicle. The Ground Operations Project determined which ground subsystems had the potential to affect the probability of the second launch and allocated quantitative availability requirements to these subsystems. The Ground Operations Project also developed a methodology to estimate subsystem reliability, availability, and maintainability to ensure that ground subsystems complied with allocated launch availability and maintainability requirements. The verification analysis developed quantitative estimates of subsystem availability based on design documentation, testing results, and other information. Where appropriate, actual performance history was used to calculate failure rates for legacy subsystems or comparative components that will support Constellation. The results of the verification analysis will be used to assess compliance with requirements and to highlight design or performance shortcomings for further decision making. This case study will discuss the subsystem requirements allocation process, describe the ground systems methodology for completing quantitative reliability, availability, and maintainability analysis, and present findings and observation based on analysis leading to the Ground Operations Project Preliminary Design Review milestone

Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch

INTRODUCTION: OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer’s disease (OPTIMA) was a randomized, double-blind comparison of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch in patients with mild-to-moderate Alzheimer’s disease who declined despite open-label treatment with 9.5 mg/24 h patch. Over 48 weeks of double-blind treatment, high-dose patch produced greater functional and cognitive benefits compared with 9.5 mg/24 h patch. METHODS: Using OPTIMA data, a post-hoc responder analysis was performed to firstly, compare the proportion of patients demonstrating improvement or absence of decline with 13.3 mg/24 h versus 9.5 mg/24 h patch; and secondly, identify predictors of improvement or absence of decline. ‘Improvers’ were patients who improved on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) by ≥4 points from baseline, and did not decline on the instrumental domain of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS-IADL). ‘Non-decliners’ were patients who did not decline on either scale. RESULTS: Overall, 265 patients randomized to 13.3 mg/24 h and 271 to 9.5 mg/24 h patch met the criteria for inclusion in the intention-to-treat population and were included in the analyses. Significantly more patients were ‘improvers’ with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Weeks 24 (44 (16.6%) versus 19 (7.0%); P < 0.001) and 48 (21 (7.9%) versus 10 (3.7%); P = 0.023). A significantly greater proportion of patients were ‘non-decliners’ with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Week 24 (71 (26.8%) versus 44 (16.2%); P = 0.002). At Week 48, there was a trend in favor of 13.3 mg/24 h patch. Functional and cognitive assessment scores at double-blind baseline did not consistently predict effects at Weeks 24 or 48. CONCLUSION: More patients with mild-to-moderate Alzheimer’s disease who are titrated to 13.3 mg/24 h rivastigmine patch at time of decline are ‘improvers’ or ‘non-decliners’ i.e. show responses on cognition and activities of daily living compared with patients remaining on 9.5 mg/24 h patch. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00506415; registered July 20, 2007. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-014-0088-8) contains supplementary material, which is available to authorized users

Further Analyses of the Safety of Verubecestat in the Phase 3 EPOCH Trial of Mild-To-Moderate Alzheimer’s Disease

Background: Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. Methods: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. Results: Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. Conclusions: Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors

Efficacy of Higher Dose 13.3 mg/24 h Rivastigmine Patch on Instrumental Activities of Daily Living in Patients with Mild-to-Moderate Alzheimer's Disease

Background: Stabilizing/reducing decline in the ability to perform activities of daily living (ADLs) is important in management of Alzheimer's disease (AD). Methods: Post hoc analysis of OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer's disease (OPTIMA), a double-blind trial comparing 13.3 and 9.5 mg/24 h rivastigmine patch in patients with AD demonstrating functional and cognitive decline with 9.5 mg/24 h patch. Efficacy on Alzheimer's disease Cooperative Study-instrumental ADL (ADCS-IADL) items, higher level function (HLF), and autonomy factors was assessed. Results: The ADCS-IADL, HLF, and autonomy factors favored 13.3 mg/24 h patch at all time points, reaching significance from weeks 16 to 48, 24 to 48, and 32 to 48, respectively. Higher dose patch demonstrated significantly greater efficacy on 10 of 17 ADCS-IADL items at 1 or more time points ( P < .05 vs 9.5 mg/24 h patch). More adverse events were observed with higher dose patch; study discontinuations were similar between the doses. Conclusions: Greater efficacy of 13.3 versus 9.5 mg/24 h patch on ADL, including autonomy and HLF factors, supports this additional dosing option to prolong patients' independence