Enfermedades Neuromusculares.pósters

Eplontersen in Hereditary ATTR-polyneuropathy: Week 66 Final Analysis of the Phase 3 NEURO-TTRansform Study

2025-01-03T15:52:41Z

Eplontersen in Hereditary ATTR-polyneuropathy: Week 66 Final Analysis of the Phase 3 NEURO-TTRansform Study Khella, Sami; Marques, Wilson; Chao, Chi-Chao; Yesim Parman, Fatma; Franca, Marcondes C.; Guo, Yuh-Cherng; Ro, Long-Sun; Calandra, Cristian R.; Kowacs, Pedro A.; Berk, John L.; Piera Obici, Laura; Barroso, Fabio Adrián; Conceição, Isabel; Schneider, Eugene; Viney, Nicholas J.; Dyck, P. James B.; Waddington Cruz, Marcia; Coelho, Teresa Background ATTRv-PN is a rare, progressive, and debilitating disease caused by accumulation of amyloid fibrils composed of transthyretin (TTR) protein in multiple organ systems. Eplontersen, a ligand-conjugated antisense oligonucleotide that inhibits TTR protein synthesis, is being assessed in the NEURO-TTRansform study. Previously reported topline statistics established that the coprimary endpoints and key secondary endpoint were met at the prespecified Week 35 interim analysis. Eplontersen treatment resulted in significant reductions in serum TTR concentration and neuropathy impairment (modified Neuropathy Impairment Score +7 [mNIS+7]), and improved quality of life (Norfolk Quality of Life-Diabetic Neuropathy score [Norfolk QoL-DN]), compared with external placebo (from the NEURO-TTR study [NCT01737398]). Eplontersen treatment also demonstrated an acceptable safety and tolerability profile. Objective To evaluate the final efficacy and safety analysis of eplontersen at Week 66 in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, open-label NEURO-TTRansform study (NCT04136184). Design/Methods NEURO-TTRansform enrolled 168 adults with ATTRv-PN, defined by Coutinho Stage 1?2, a documented TTR sequence variant, and signs/symptoms consistent with polyneuropathy (Neuropathy Impairment Score ≥10 and ≤130). Patients were assigned 6:1 to eplontersen 45 mg subcutaneously every 4 weeks (n=144) or inotersen 300 mg once weekly (n=24) until the prespecified Week 35 interim analysis, after which all patients received eplontersen 45 mg subcutaneously every 4 weeks. All patients who received eplontersen were compared with an external placebo group from the NEURO-TTR study at Week 66. Coprimary efficacy assessments at Week 66 included serum TTR concentration, mNIS+7, and the Norfolk QoL-DN score. Safety and tolerability were also assessed. Results Full results from the efficacy and safety analysis at Week 66 and Week 35 will be presented. Conclusions Results from the final analysis at Week 66 will provide detailed longer-term data on the efficacy and safety of eplontersen in patients with Stage 1 or 2 ATTRv-PN.

Familial Amyloid Polyneuropathy: Impact of Biopsies and Mutations on Diagnostic Considerations (P3.4-033)

2023-02-09T00:48:30Z

Familial Amyloid Polyneuropathy: Impact of Biopsies and Mutations on Diagnostic Considerations (P3.4-033) Gibbons, Christopher; González-Duarte, Alejandra; Barroso, Fabio Adrián; Campagnolo, Marta; Rajan, Sharika; Freeman, Roy Objective: To characterize the symptoms, signs and skin biopsy neuropathological findings in a cohort of individuals with TTR Mutations. Background: Familial amyloid polyneuropathy is due to one of many mutations in the transthyretin(TTR) gene, resulting in a progressive fatal disease with sensory, motor and autonomic involvement. Design/Methods: Individuals with a variety of TTR mutations underwent detailed neurological examinations including the Neuropathy Impairment Score in the Lower Limb(NIS-LL), the Utah Early Neuropathy Score(UENS), Coutinho staging, autonomic testing, symptom scores (using the EuroQol, Brief Pain Symptom Inventory, and the orthostatic hypotension Questionnaire). All subjects had 3mm punch skin biopsies at the distal leg and distal thigh with analysis of amyloid burden by Congo Red, and neuropathy severity by staining with protein gene product 9.5. Results: A total of 88 subjects participated with the following TTR mutations: 43-Val30Met, 30-Ser50Arg, 6- Gly47Ala, 5- Ser52Pro, 2- F64L, 1- I73V and 1 with Y136H. Coutinho staging included 47 stage 0, 32 stage 1, 8 stage 2 and 1 stage 3. The diagnostic sensitivity for amyloid detection from a single skin biopsy was 72%, the diagnostic yield increased to 89% with 2 biopsies. Biopsies were positive for amyloid in 78% of individuals with no clinical evidence of neuropathy (NIS-LL scores of 0) and 94% for individuals with any evidence of neuropathy. Amyloid burden was inversely correlated with nerve density at the distal leg (R=0.59, P<0.01) and distal thigh(R=−0.53, P<0.01), and correlated with the NIS-LL (R=0.48, P<0.05), and UENS (R=0.49, P<0.05). Conclusions: Skin biopsy is a sensitive and specific pathological marker for tissue diagnosis of familial amyloid polyneuropathy across multiple mutations, even in individuals with no clinical evidence of disease. Amyloid burden correlates with neuropathy severity, both pathologically and by examination criteria; skin biopsies may prove informative for studies that seek to alter the natural history of the disease.

Long-Term Efficacy and Safety of Inotersen for Hereditary Transthyretin Amyloidosis: NEURO-TTR Open-Label Extension 2-Year Update (S27.008)

2025-01-06T16:34:34Z

Long-Term Efficacy and Safety of Inotersen for Hereditary Transthyretin Amyloidosis: NEURO-TTR Open-Label Extension 2-Year Update (S27.008) Brannagan, Thomas H.; Waddington Cruz, Marcia; Wang, Annabel K.; Polydefkis, Michael J.; Dyck, P. James B.; Khella, Sami; Planté-Bordeneuve, Violaine; Berk, John L.; Barroso, Fabio Adrián; Merlini, Giampaolo; Conceição, Isabel; Hughes, Steven G.; Kwoh, Jesse; Jung, Shiangtung W.; Guthrie, Spencer; Pollock, Michael; Benson, Merrill D.; Gertz, Morie; Coelho, Teresa Objective: To provide an update on the long-term efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production, in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy. Background: Patients with hATTR, a rare protein misfolding disorder, experience progressive and debilitating polyneuropathy. A randomized, controlled phase 3 trial (NEURO-TTR; NCT01737398) demonstrated efficacy and safety of inotersen treatment in patients with hATTR polyneuropathy (Benson 2018 NEJM). Design/Methods: Patients who completed NEURO-TTR were eligible to enroll in the ongoing open-label extension (OLE) study (NCT02175004). Assessments included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN), and adverse events. Results: Of 139 patients who completed NEURO-TTR, 135 (97.1%) enrolled in the OLE. As of 9/15/17, 134 patients had received ≥1 dose of inotersen. Patients were predominantly white (93.3%) and male (69.4%), and 88/134 (65.7%) had both polyneuropathy and cardiac involvement. At OLE baseline, 83/134 (61.9%) patients were ambulatory without assistance, 47/134 (35.1%) required walking aid(s), and 4/134 (3.0%) were unable to walk. Patients who initiated inotersen in the OLE demonstrated slowing of neurologic disease progression by mNIS+7 and Norfolk QoL-DN within 6 months, and patients who had received inotersen for 27 months (15 months in NEURO-TTR + 12 months in the OLE) continued to show benefit. Greater benefit in mNIS+7 and Norfolk QoL-DN was observed in patients treated earlier with inotersen. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure, and no new safety concerns have been identified. This presentation will be updated with data from 2 years of follow-up in the OLE. Conclusions: In the OLE, inotersen treatment slowed hATTR polyneuropathy progression, with greater stabilization observed in patients who initiated inotersen earlier. Disclosure: Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Ionis, Alnylam, and CSL Behring. Dr. Brannagan has received research support from Ionis, Alnyalm, Viromed, Catalyst, Pharnext, Novartis, Grifols. Dr. Waddington Cruz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc., Genzyme/Sanofi, and Pfizer. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. Dr. Polydefkis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis, Alnylam, Vertex, Chromocell. Dr. Polydefkis has received compensation for serving on the Board of Directors of Travel-Ionis and Pfizer. Dr. Polydefkis has received research support from Pfizer, Ionis, and Alnylam . Dr. Dyck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam and Ionis. Dr. Khella has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics and Alnylam Pharmaceuticals. Dr. Khella has received research support from Akcea Therapeutics. Dr. Plante-Bordeneuve has nothing to disclose. Dr. Berk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea, Alnylam. Dr. Barroso has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Barroso has received research support from Alnylam. Dr. Merlini has nothing to disclose. Dr. Conceicao has nothing to disclose. Dr. Hughes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals Inc. Dr. Kwoh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Jung, PhD has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Guthrie has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Pollock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Benson has nothing to disclose. Dr. Gertz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc., Alnylam Pharmaceuticals, and Prothena. Dr. Coelho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam and Biogen. Dr. Coelho has received research support from Pfizer, Ionis and Alnylam.

Association between neurological syndromes and Arbovirus in Buenos Aires - Relationship between Guillain Barre Syndrome, Encephalitis and Myelitis with Zika, Dengue and Chikungunya (P4.6-024)

2024-01-16T13:49:55Z

Association between neurological syndromes and Arbovirus in Buenos Aires - Relationship between Guillain Barre Syndrome, Encephalitis and Myelitis with Zika, Dengue and Chikungunya (P4.6-024) Kohler, Alejandro Alfredo; Farez, Mauricio Franco; Heck, Evelyn Sabrina; Barroso, Fabio Adrián; Bruno, Verónica Objective: Analyze the association between Guillain Barre Syndrome (GBS), Infectious Encephalitis (IE) and Transverse Myelitis (TM) with secondary infections to arboviruses in hospitalized patients of Buenos Aires city. Background: Arbovirus infections are currently considered a pandemic in Argentina. There was a significant increase in the incidence of these infections during the 2014–2016 period, compared to previous years. Viruses such as Zika (ZIKV), Dengue (DENV) and Chikungunya (CHIKV) have been associated with different neurological syndromes, mainly with GBS and to a lesser extent with IE and TM. Design/Methods: We conducted a prospective cohort study, including all adult patients diagnosed with GBS, IE and TM, attended at our institution from 1/1/17 to 12/31/17. Samples of serum and / or cerebrospinal fluid were obtained. ELISA test was performed to detect antibodies against ZIKV, DENV and CHIKV. Clinical-epidemiological variables and complementary methods of both groups were recorded. We compared the GBS incidence results obtained in 2017 with respect to those presented in the last 10 years of our institution. Results: We included 39 patients with diagnosis of GBS (n=17), IE (n=18) and TM (n=4). 2 cases of GBS presented positive serology for ZIKV and 2 cases of IE presented positivity for DENV. During the period from 2015–2017, there was an increase in the incidence of GBS cases compared to previous years. Conclusions: In the present cohort, the incidence of cases of GBS, IE and MTA associated with arbovirus infections was relatively low. However, the cases associated with arbovirus infections showed differential clinical characteristics. We believe that epidemiological surveillance of neurological syndromes associated with arbovirus infections is essential to understand the magnitude of the problem at a national and regional level.