Abstract Details

Title Long-Term Efficacy and Safety of Inotersen for Hereditary Transthyretin Amyloidosis: NEURO-TTR Open-Label Extension 2-Year Update

Topic General Neurology

Presentation(s) S27 - General Neurology: Improving Neurologic Care and the Impact of Therapeutics (2:17 PM-2:28 PM)

Poster/Presentation
Number 008

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).

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.

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.

Authors/Disclosures
Thomas Brannagan III, MD, FAAN (Columbia University) PRESENTER	Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Grifols. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for CSL. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alnylam. The institution of Dr. Brannagan has received research support from Alnylam. The institution of Dr. Brannagan has received research support from Acceleron. The institution of Dr. Brannagan has received research support from Ionis. The institution of Dr. Brannagan has received research support from Pharnext.
Marcia Waddington Cruz, MD (Hospital Universitario)	Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astra Zeneca. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sobi. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ionis. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC. Dr. Waddington Cruz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NovoNordisk.
Annabel K. Wang, MD, FAAN (VA Long Beach Healthcare System)	Dr. Wang has nothing to disclose.
Michael J. Polydefkis, MD, FAAN (Johns Hopkins University School of Medicine)	Dr. Polydefkis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam Pharmaceuticals. Dr. Polydefkis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea. Dr. Polydefkis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex Pharmaceutical . Dr. Polydefkis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen-Idec. Dr. Polydefkis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer.
Peter J. Dyck, MD, FAAN (Mayo Clinic)	Dr. Dyck has nothing to disclose.
Sami L. Khella, MD, FAAN (Presbyterian Med Ctr/Dept of Neuro)	Dr. Khella has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Ionis. Dr. Khella has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ionis. Dr. Khella has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Khella has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Khella has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eidos.
Violaine Plante-Bordeneuve, MD (CHU Henri Mondor)	Dr. Plante-Bordeneuve has nothing to disclose.
John L. Berk	John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam Pharmaceuticals. John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals. John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astra Zeneca/IONIS. John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eidos/BridgBio. John L. Berk has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Intellia Therapeutics. John L. Berk has received research support from Alnylam . John L. Berk has received research support from Ionis. John L. Berk has received research support from Eidos/Bridgbio.
Fabio Adrian Barroso, MD	Fabio Adrian Barroso, MD has nothing to disclose.
	No disclosure on file
Isabel Conceicao (Hospital de Santa Maria)	Isabel Conceicao has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Isabel Conceicao has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sobi.
Steven G. Hughes	Steven G. Hughes has received personal compensation for serving as an employee of Avidity Biosciences. Steven G. Hughes has received personal compensation for serving as an employee of Arcturus Therapeutics. Steven G. Hughes has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Ionis Pharmaceuticals. Steven G. Hughes has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Arcturus Therapeutics. Steven G. Hughes has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Avidity Biosciences. Steven G. Hughes has stock in Arcturus Therapeutics. Steven G. Hughes has stock in Avidity Biosciences.
	No disclosure on file
	No disclosure on file
Spencer Guthrie	No disclosure on file
	No disclosure on file
Merrill Benson	No disclosure on file
	No disclosure on file
Teresa Coelho, MD (Unidate Clinica de Paramoloidose Hospital)	Dr. Coelho has nothing to disclose.

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