TY - JOUR
T1 - 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
AU - Coelho, Teresa
AU - Ando, Yukio
AU - Benson, Merrill D.
AU - Berk, John L.
AU - Waddington-Cruz, Márcia
AU - Dyck, Peter J.
AU - Gillmore, Julian D.
AU - Khella, Sami L.
AU - Litchy, William J.
AU - Obici, Laura
AU - Monteiro, Cecilia
AU - Tai, Li Jung
AU - Viney, Nicholas J.
AU - Buchele, Gustavo
AU - Brambatti, Michela
AU - Jung, Shiangtung W.
AU - St. L. O’Dea, Louis
AU - Tsimikas, Sotirios
AU - Schneider, Eugene
AU - Geary, Richard S.
AU - Monia, Brett P.
AU - Gertz, Morie
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021
Y1 - 2021
N2 - Introduction: 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. Trial Registration: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
AB - Introduction: 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. Trial Registration: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
KW - AKCEA-TTR-L
KW - Antisense oligonucleotide
KW - Clinical trial design
KW - Hereditary transthyretin-mediated amyloid polyneuropathy
KW - Phase 3 clinical trial
UR - http://www.scopus.com/inward/record.url?scp=85101909788&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101909788&partnerID=8YFLogxK
U2 - 10.1007/s40120-021-00235-6
DO - 10.1007/s40120-021-00235-6
M3 - Article
AN - SCOPUS:85101909788
JO - Neurology and Therapy
JF - Neurology and Therapy
SN - 2193-8253
ER -