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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 Polyneuropathy

2021-06Journal article Open access
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dc.contributor.authorCoelho, Teresa
dc.contributor.authorAndo, Yukio
dc.contributor.authorBenson, Merrill D.
dc.contributor.authorBerk, John L.
dc.contributor.authorWaddington-Cruz, Márcia
dc.contributor.authorDyck, Peter J.
dc.contributor.authorGillmore, Julian D.
dc.contributor.authorKhella, Sami L.
dc.contributor.authorLitchy, William J.
dc.contributor.authorObici, Laura
dc.contributor.authorMonteiro, Cecilia
dc.contributor.authorTai, Li-Jung
dc.contributor.authorViney, Nicholas J.
dc.contributor.authorBuchele, Gustavo
dc.contributor.authorBrambatti, Michela
dc.contributor.authorJung, Shiangtung W.
dc.contributor.authorSt. L. O’Dea, Louis
dc.contributor.authorTsimikas, Sotirios
dc.contributor.authorSchneider, Eugene
dc.contributor.authorGeary, Richard S.
dc.contributor.authorMonia, Brett P.
dc.contributor.authorGertz, Morie
dc.date.accessioned2023-11-14T10:53:05Z
dc.date.available2023-11-14T10:53:05Z
dc.date.issued2021-06
dc.descriptionTrial registration: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10)pt_PT
dc.description.abstractIntroduction: 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.pt_PT
dc.description.sponsorshipThis study and Rapid Service Publication Fee is supported by Ionis Pharmaceuticals, Inc. (Carlsbad, CA, USA) and Akcea Therapeutics (Boston, MA, USA)pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCoelho T, Ando Y, Benson MD, et al. 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 Polyneuropathy. Neurol Ther. 2021;10(1):375-389. doi:10.1007/s40120-021-00235-6pt_PT
dc.identifier.doi10.1007/s40120-021-00235-6pt_PT
dc.identifier.issn2193-6536
dc.identifier.issn2193-8253
dc.identifier.urihttp://hdl.handle.net/10400.16/2882
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s40120-021-00235-6pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectAKCEA-TTR-Lrxpt_PT
dc.subjectAntisense oligonucleotidept_PT
dc.subjectClinical trial designpt_PT
dc.subjectHereditary transthyretin-mediated amyloid polyneuropathypt_PT
dc.subjectPhase 3 clinical trialpt_PT
dc.titleDesign and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceNew Zealandpt_PT
oaire.citation.endPage389pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage375pt_PT
oaire.citation.titleNeurology and Therapypt_PT
oaire.citation.volume10pt_PT
person.familyNameCoelho
person.givenNameTeresa
person.identifier.ciencia-idC71E-3343-F445
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationca69c0a3-d48a-4b92-bbf7-c17288d609b7
relation.isAuthorOfPublication.latestForDiscoveryca69c0a3-d48a-4b92-bbf7-c17288d609b7

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