Browsing by Author "Obici, Laura"
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- 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 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.
- Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosisPublication . Coelho, Teresa; Yarlas, Aaron; Waddington-Cruz, Marcia; White, Michelle K.; Sikora Kessler, Asia; Lovley, Andrew; Pollock, Michael; Guthrie, Spencer; Ackermann, Elizabeth J.; Hughes, Steven G.; Karam, Chafic; Khella, Sami; Gertz, Morie; Merlini, Giampaolo; Obici, Laura; Schmidt, Hartmut H.; Polydefkis, Michael; Dyck, P. James B.; Brannagan III, Thomas H.; Conceição, Isabel; Benson, Merrill D.; Berk, John L.Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.
- A Narrative Review of the Role of Transthyretin in Health and DiseasePublication . Liz, Marcia Almeida; Coelho, Teresa; Bellotti, Vittorio; Fernandez-Arias, Maria Isabel; Mallaina, Pablo; Obici, LauraTransthyretin (TTR) is a tetrameric transport protein highly conserved through vertebrate evolution and synthesized in the liver, choroid plexus, and retinal pigment epithelium. TTR transports the thyroid hormone thyroxine and the retinol-binding protein (RBP) bound to retinol (vitamin A). Mutations in TTR are associated with inherited transthyretin amyloidosis (ATTRv), a progressive, debilitating disease that is ultimately fatal and is characterized by misfolding of TTR and aggregation as amyloid fibrils, predominantly leading to cardiomyopathy or polyneuropathy depending on the particular TTR mutation. Transthyretin amyloid cardiomyopathy can also occur as an age-related disease caused by misfolding of wild-type TTR. Apart from its transport role, little is known about possible additional physiological functions of TTR. Evidence from animal model systems in which TTR has been disrupted via gene knockout is adding to our cumulative understanding of TTR function. There is growing evidence that TTR may have a role in neuroprotection and promotion of neurite outgrowth in response to injury. Here, we review the literature describing potential roles of TTR in neurobiology and in the pathophysiology of diseases other than ATTR amyloidosis. A greater understanding of these processes may also contribute to further clarification of the pathology of ATTR and the effects of potential therapies for TTR-related conditions.
- Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosisPublication . Obici, Laura; Berk, John L; González-Duarte, Alejandra; Coelho, Teresa; Gillmore, Julian; Schmidt, Hartmut H-J; Schilling, Matthias; Yamashita, Taro; Labeyrie, Céline; Brannagan, Thomas H; Ajroud-Driss, Senda; Gorevic, Peter; Kristen, Arnt V; Franklin, Jaclyn; Chen, Jihong; Sweetser, Marianne T; Wang, Jing Jing; Adams, DavidIntroduction: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated.Methods: Patients received either patisiran 0.3 mg/kg (n = 148) or placebo (n = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL.Results: At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares [LS] mean difference: -21.1; p = 1.10 × 10-10; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2; p = 1.4 × 10-12), EuroQoL-visual analog scale (LS mean difference: 9.5; p=.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0; p = 4.07 × 10-16) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: -7.5; p=.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation.Conclusion: The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.