Denis Keohane

Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy

Abstract Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. Trial Registration: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.

Comparative Efficacy and Safety of Selective Serotonin Reuptake Inhibitors and Serotonin‐Norepinephrine Reuptake Inhibitors in Older Adults: A Network Meta‐Analysis

To establish the comparative efficacy and safety of selective serotonin reuptake inhibitors and serotonin‐norepinephrine reuptake inhibitors in older adults using the network meta‐analysis approach.

Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial

Abstract Background: Tafamidis, a non-NSAID highly specific transthyretin stabilizer, delayed neurologic disease progression as measured by Neuropathy Impairment Score–Lower Limbs (NIS-LL) in an 18-month, double-blind, placebo-controlled randomized trial in 128 patients with early-stage transthyretin V30M familial amyloid polyneuropathy (ATTRV30M-FAP). The current post hoc analyses aimed to further evaluate the effects of tafamidis in delaying ATTRV30M-FAP progression in this trial. Methods: Pre-specified, repeated-measures analysis of change from baseline in NIS-LL in this trial (ClinicalTrials.gov NCT00409175) was repeated with addition of baseline as covariate and multiple imputation analysis for missing data by treatment group. Change in NIS-LL plus three small-fiber nerve tests (NIS-LL + Σ3) and NIS-LL plus seven nerve tests (NIS-LL + Σ7) were assessed without baseline as covariate. Treatment outcomes over the NIS-LL, Σ3, Σ7, modified body mass index and Norfolk Quality of Life–Diabetic Neuropathy Total Quality of Life Score were also examined using multivariate analysis techniques. Results: Neuropathy progression based on NIS-LL change from baseline to Month 18 remained significantly reduced for tafamidis versus placebo in the baseline-adjusted and multiple imputation analyses. NIS-LL + Σ3 and NIS-LL + Σ7 captured significant treatment group differences. Multivariate analyses provided strong statistical evidence for a superior tafamidis treatment effect. Conclusions: These supportive analyses confirm that tafamidis delays neurologic progression in early-stage ATTRV30M-FAP. Trial registration number: NCT00409175.

Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy

To better characterize the effects of tafamidis in non‐Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12‐month, open‐label study of non‐Val30Met versus Val30Met patients at month 12 from the 18‐month, double‐blind, placebo‐controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity.

Potential Clinical and Economic Impact of Switching Branded Medications to Generics

Switching branded to generic medications has become a common cost-containment measure. Although this is an important objective for health care systems worldwide, the impact of this practice on patient outcomes needs to be carefully considered. We reviewed the literature summarizing the potential clinical and economic consequences of switching from branded to generic medications on patient outcomes. A literature search of peer-reviewed articles published 2003–2013 using key words of “generic switching” or “substitution” was conducted using PubMed, OvidSP, and ScienceDirect. Of 30 articles identified and reviewed, most were related to the diseases of the central nervous system, especially epilepsy. Based on our review, potential impacts of switching fell into 3 broad categories: patient attitudes and adherence, clinical and safety outcomes, and cost and resource utilization. Although in many cases generics may represent an appropriate alternative to branded products, this may not always be the case. Specifically, several studies suggested that switching may negatively impact medication adherence, whereas other studies found that generic switching was associated with poorer clinical outcomes and more adverse events. In some instances, switching accomplished cost savings but did so at increased total cost of care because of increased physician visits or hospitalizations. Although in many cases generics may represent an appropriate alternative, mandatory generic switching may lead to unintended consequences, especially in certain therapeutic areas. Although further study is warranted, based on our review, it may be medically justifiable for physicians and patients to retain the right to request the branded product in certain cases.

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, severe, and irreversible, adult‐onset, hereditary disorder caused by autosomal‐dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR‐FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease‐modifying treatment options for a wider spectrum of patients with TTR‐FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation‐specific predictive genetic testing in first‐degree relatives of index patients diagnosed with TTR‐FAP and the structured clinical follow‐up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353–360, 2016

Positive real-world effectiveness of tafamidis for delaying disease progression in transthyretin familial amyloid polyneuropathy

Background Tafamidis (Vyndaqel) was approved by the EMA in 2011 and is emerging as the standard of care for transthyretin familial amyloid polyneuropathy (TTR-FAP) in clinical settings. Efficacy was demonstrated in the clinical trials, yet little is known about its real-world effectiveness. A global disease registry, the Transthyretin Amyloidosis Outcomes Survey (THAOS), collects data on both treated and untreated patients from real-world settings. Ethics committee approval was obtained prior to patient enrolment.

Tafamidis reduces disease progression in patients with transthyretin familial amyloid polyneuropathy: supportive post-hoc analyses of a pivotal trial

Background Safety and efficacy of once-daily 20 mg tafamidis, a transthyretin (TTR) stabilizer, was evaluated in an 18-month, multicentre, randomized, double-blind, placebo-controlled study in 128 patients with early symptomatic V30M TTR familial amyloid polyneuropathy (TTR-FAP). In the intent-to-treat population, a responder analysis for Neuropathy Impairment Score-Lower Limb (NIS-LL) (co-primary with Norfolk Quality of Life-Diabetic Neuropathy) favoured tafamidis (P=0.07). A pre-specified, key secondary analysis of change from baseline to Month 18 in NIS-LL continuous scores was significant (P=0.04). Placebo-corrected point estimates for 5 pre-specified and validated measures of disease progression also favoured tafamidis and were directionally consistent. Additional post-hoc analyses supporting tafamidis for delaying progression of TTR-FAP are reported here.

Early intervention with tafamidis provides long-term benefit in delaying neurological progression in patients with transthyretin familial amyloid polyneuropathy

Background Tafamidis is a transthyretin (TTR) stabilizer approved to delay neurological progression associated with stage 1 TTR familial amyloid polyneuropathy (FAP). A placebocontrolled, randomized 18-month registration trial allowed for continued evaluation of patients receiving tafamidis (20 mg oral once-daily) through an ongoing open label extension study. The effectiveness of tafamidis for delaying long-term neurological progression relative to baseline levels of neuropathy impairment at the start of treatment has not been reported previously.