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- Advances in the treatment of hereditary transthyretin amyloidosis: A reviewPublication . Gertz, M.; Mauermann, M.; Grogan, M.; Coelho, T.Introduction: Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR. Methods: A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR. Results: Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities. Conclusions: Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.
- Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosisPublication . González-Duarte, Alejandra; Berk, John L.; Quan, Dianna; Mauermann, Michelle L.; Schmidt, Hartmut H.; Polydefkis, Michael; Waddington-Cruz, Márcia; Ueda, Mitsuharu; Conceição, Isabel M.; Kristen, Arnt V.; Coelho, Teresa; Cauquil, Cécile A.; Tard, Céline; Merkel, Madeline; Aldinc, Emre; Chen, Jihong; Sweetser, Marianne T.; Wang, Jing Jing; Adams, DavidHereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.
- ATTR amyloidosis during the COVID-19 pandemic: insights from a global medical roundtablePublication . Brannagan, Thomas H.; Auer-Grumbach, Michaela; Berk, John L.; Briani, Chiara; Bril, Vera; Coelho, Teresa; Damy, Thibaud; Dispenzieri, Angela; Drachman, Brian M.; Fine, Nowell; Gaggin, Hanna K.; Gertz, Morie; Gillmore, Julian D.; Gonzalez, Esther; Hanna, Mazen; Hurwitz, David R.; Khella, Sami L.; Maurer, Mathew S.; Nativi-Nicolau, Jose; Olugemo, Kemi; Quintana, Luis F.; Rosen, Andrew M.; Schmidt, Hartmut H.; Shehata, Jacqueline; Waddington-Cruz, Marcia; Whelan, Carol; Ruberg, Frederick L.Background: The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient's preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis. Main body: ATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19. Conclusion: Patients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.
- Clinical 3-D Gait Assessment of Patients with Polyneuropathy Associated with Hereditary Transthyretin AmyloidosisPublication . Vilas-Boas, Maria do Carmo; Rocha, Ana Patrícia; Cardoso, Márcio Neves; Fernandes, José Maria; Coelho, Teresa; Cunha, João Paulo SilvaHereditary amyloidosis associated with transthyretin V30M (ATTRv V30M) is a rare and inherited multisystemic disease, with a variable presentation and a challenging diagnosis, follow-up and treatment. This condition entails a definitive and progressive motor impairment that compromises walking ability from near onset. The detection of the latter is key for the disease's diagnosis. The aim of this work is to perform quantitative 3-D gait analysis in ATTRv V30M patients, at different disease stages, and explore the potential of the obtained gait information for supporting early diagnosis and/or stage distinction during follow-up. Sixty-six subjects (25 healthy controls, 14 asymptomatic ATTRv V30M carriers, and 27 symptomatic patients) were included in this case-control study. All subjects were asked to walk back and forth for 2 min, in front of a Kinect v2 camera prepared for body motion tracking. We then used our own software to extract gait-related parameters from the camera's 3-D body data. For each parameter, the main subject groups and symptomatic patient subgroups were statistically compared. Most of the explored gait parameters can potentially be used to distinguish between the considered group pairs. Despite of statistically significant differences being found, most of them were undetected to the naked eye. Our Kinect camera-based system is easy to use in clinical settings and provides quantitative gait information that can be useful for supporting clinical assessment during ATTRv V30M onset detection and follow-up, as well as developing more objective and fine-grained rating scales to further support the clinical decisions.
- Corino de Andrade disease: mechanisms and impact on reproductionPublication . Lopes, R.; Coelho, T.; Barros, A.; Sousa, M.Familial amyloid polyneuropathy was first described by Corino de Andrade in 1952 in Northern Portugal. It is a fatal autosomal dominant neurodegenerative disorder characterized by a progression of neurologic symptoms, beginning early in the reproductive life. The Transthyretin gene mutation originates a mutated protein that precipitates in the connective tissue as amyloid deposits. This disease is presently named Transthyretin-related hereditary amyloidosis. We performed an extensive review on this disease based on searches in Medical databases and in paper references. In this review, we briefly summarize the epidemiology and the mechanisms involved on amyloid deposition; we detailed how to evaluate the mechanisms implicated on the development of the major signs and symptoms associated with reproductive dysfunction; and we discuss the mechanisms involved in secondary sexual dysfunction after psychological treatments. Treatment of the disease is directed towards relieving specific symptoms in association with liver transplant, and molecular and genetic therapeutics. Although the current clinical trials indicate symptoms relief, no data on the reproductive function was reported. Thus, preimplantation genetic diagnosis is presently the only available technique that eradicates the disease as it avoids the birth of new patients.
- Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid PolyneuropathyPublication . Coelho, Teresa; Ando, Yukio; Benson, Merrill D.; Berk, John L.; Waddington-Cruz, Márcia; Dyck, Peter J.; Gillmore, Julian D.; Khella, Sami L.; Litchy, William J.; Obici, Laura; Monteiro, Cecilia; Tai, Li-Jung; Viney, Nicholas J.; Buchele, Gustavo; Brambatti, Michela; Jung, Shiangtung W.; St. L. O’Dea, Louis; Tsimikas, Sotirios; Schneider, Eugene; Geary, Richard S.; Monia, Brett P.; Gertz, MorieIntroduction: AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. Methods/design: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire. Conclusion: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.
- Early data on long‐term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2‐year update from the open‐label extension of the NEURO‐TTR trialPublication . Brannagan, T. H.; Wang, A. K.; Coelho, T.; Waddington Cruz, M.; Polydefkis, M. J.; Dyck, P. J.; Plante‐Bordeneuve, V.; Berk, J. L.; Barroso, F.; Merlini, G.; Conceição, I.; Hughes, S. G.; Kwoh, J.; Jung, S. W.; Guthrie, S.; Pollock, M.; Benson, M. D.; Gertz, M.; Drachman, Brian; Gorevic, Peter; Heitner, Stephen; Scheinberg, Morton; Schmidt, Hartmut; Whelan, Carol; Adams, David; Campistol Plana, Josep Maria; Gamez, Josep; Gane, Edward; Kristen, Arnt; Obici, Laura; Salvi, Fabrizio; Souza Bulle Oliveira, Acary; Vita, GiuseppeBackground and purpose: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. Methods: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. Results: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. Conclusion: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.
- Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose studyPublication . Suhr, O.; Coelho, T.; Buades, J.; Pouget, J.; Conceicao, I.; Berk, J.; Schmidt, H.; Waddington-Cruz, M.; Campistol, J.; Bettencourt, B.; Vaishnaw, A.; Gollob, J.; Adams, D.BACKGROUND: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP).
- Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trialPublication . Adams, David; Tournev, Ivailo L.; Taylor, Mark S.; Coelho, Teresa; Planté-Bordeneuve, Violaine; Berk, John L.; González-Duarte, Alejandra; Gillmore, Julian D.; Low, Soon-Chai; Sekijima, Yoshiki; Obici, Laura; Chen, Chongshu; Badri, Prajakta; Arum, Seth M.; Vest, John; Polydefkis, MichaelBackground: The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. Methods: HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. Results: HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10-12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. Conclusions: Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile.
- Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 YearsPublication . Merlini, Giampaolo; Coelho, Teresa; Waddington Cruz, Márcia; Li, Huihua; Stewart, Michelle; Ebede, BenIntroduction: The effects of tafamidis on mortality in Val30Met and non-Val30Met patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN) were evaluated. Methods: The analyses were based on cumulative data from the Val30Met patients in the 18-month double-blind registration study and its 12-month open-label extension study, the non-Val30Met patients of the 12-month open-label study, and both patient groups in the ongoing 10-year extension study. Kaplan-Meier analyses of time to death from first treatment dose were performed. For the Val30Met group, two treatment groups were analyzed: those who received tafamidis in both the parent and extension studies (T-T) and those who received placebo in the parent study and switched to tafamidis in the extension studies (P-T). Results: Kaplan-Meier estimates (95% confidence interval [CI]) were available up to 9 years for the Val30Met group, at which time 85.9% (53.1-96.4) and 91.1% (77.9-96.6) of the patients in the T-T and P-T groups, respectively, were alive. For the non-Val30Met group, estimates were available up to 8 years from the first dose, and the percentage of patients alive was 75.9% (47.7-90.2). Conclusion: Long-term tafamidis treatment may confer survival benefit in patients with ATTR-PN.