Browsing by Author "Kelly, J."
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- Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathyPublication . Coelho, T.; Maia, L.; Martins-Silva, A.; Cruz, M.; Planté-Bordeneuve, V.; Suhr, O.; Conceição, I.; Schmidt, H.; Trigo, P.; Kelly, J.; Labaudinière, R.; Chan, J.; Packman, J.; Grogan, D.Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.
- Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin AmyloidosisPublication . Coelho, T.; Merlini, G.; Bulawa, C.; Fleming, J.; Judge, D.; Kelly, J.; Maurer, M.; Planté-Bordeneuve, V.; Labaudinière, R.; Mundayat, R.; Riley, S.; Lombardo, I.; Huertas, P.Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis.
- Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific SignaturesPublication . Kurian, S.; Novais, M.; Whisenant, T.; Gelbart, T.; Buxbaum, J.; Kelly, J.; Coelho, T.; Salomon, D.BACKGROUND: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. METHODS AND FINDINGS: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. CONCLUSIONS: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy.
- Predictive model of response to tafamidis in hereditary ATTR polyneuropathyPublication . Monteiro, C.; Mesgazardeh, J.; Anselmo, J.; Fernandes, J.; Novais, M.; Rodrigues, C.; Brighty, G.; Powers, D.; Powers, E.; Coelho, T.; Kelly, J.BACKGROUNDThe hereditary transthyretin (TTR) amyloidoses are a group of diseases for which several disease-modifying treatments are now available. Long-term effectiveness of these therapies is not yet fully known. Moreover, the existence of alternative therapies has resulted in an urgent need to identify patient characteristics that predict response to each therapy.METHODSWe carried out a retrospective cohort study of 210 patients with hereditary TTR amyloidosis treated with the kinetic stabilizer tafamidis (20 mg qd). These patients were followed for a period of 18-66 months, after which they were classified by an expert as responders, partial responders, or nonresponders. Correlations between baseline demographic and clinical characteristics, as well as plasma biomarkers and response to therapy, were investigated.RESULTS34% of patients exhibited an almost complete arrest of disease progression (classified by an expert as responders); 36% had a partial to complete arrest in progression of some but not all disease components (partial responders); whereas the remaining 30% continued progressing despite therapy (nonresponders). We determined that disease severity, sex, and native TTR concentration at the outset of treatment were the most relevant predictors of response to tafamidis. Plasma tafamidis concentration after 12 months of therapy was also a predictor of response for male patients. Using these variables, we built a model to predict responsiveness to tafamidis.CONCLUSIONOur study indicates long-term effectiveness for tafamidis, a kinetic stabilizer approved for the treatment of hereditary TTR amyloidosis. Moreover, we created a predictive model that can be potentially used in the clinical setting to inform patients and clinicians in their therapeutic decisions.
- Transancestral mapping and genetic load in systemic lupus erythematosusPublication . Langefeld, C.; Ainsworth, H.; Cunninghame Graham, D.; Kelly, J.; Comeau, M.; Marion, M.; Howard, T.; Ramos, P.; Croker, J.; Morris, D.; Sandling, J.; Almlöf, J.; Acevedo-Vásquez, E.; Alarcón, G.; Babini, A.; Baca, V.; Bengtsson, A.; Berbotto, G.; Bijl, M.; Brown, E.; Brunner, H.; Cardiel, M.; Catoggio, L.; Cervera, R.; Cucho-Venegas, J.; Dahlqvist, S.; D'Alfonso, S.; Da Silva, B.; de la Rúa Figueroa, I.; Doria, A.; Edberg, J.; Endreffy, E.; Esquivel-Valerio, J.; Fortin, P.; Freedman, B.; Frostegård, J.; García, M.; de la Torre, I.; Gilkeson, G.; Gladman, D.; Gunnarsson, I.; Guthridge, J.; Huggins, J.; James, J.; Kallenberg, C.; Kamen, D.; Karp, D.; Kaufman, K.; Kottyan, L.; Kovács, L.; Laustrup, H.; Lauwerys, B.; Li, Q.; Maradiaga-Ceceña, M.; Martín, J.; McCune, J.; McWilliams, D.; Merrill, J.; Miranda, P.; Moctezuma, J.; Nath, S.; Niewold, T.; Orozco, L.; Ortego-Centeno, N.; Petri, M.; Pineau, C.; Pons-Estel, B.; Pope, J.; Raj, P.; Ramsey-Goldman, R.; Reveille, J.; Russell, L.; Sabio, J.; Aguilar-Salinas, C.; Scherbarth, H.; Scorza, R.; Seldin, M.; Sjöwall, C.; Svenungsson, E.; Thompson, S.; Toloza, S.; Truedsson, L.; Tusié-Luna, T.; Vasconcelos, C.; Vilá, L.; Wallace, D.; Weisman, M.; Wither, J.; Bhangale, T.; Oksenberg, J.; Rioux, J.; Gregersen, P.; Syvänen, A.; Rönnblom, L.; Criswell, L.; Jacob, C.; Sivils, K.; Tsao, B.; Schanberg, L.; Behrens, T.; Silverman, E.; Alarcón-Riquelme, M.; Kimberly, R.; Harley, J.; Wakeland, E.; Graham, R.; Gaffney, P.; Vyse, T.Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.