Abstract Details

Title Responsiveness of Neuropathy Symptom and Change (NSC) Score Components in Inotersen Treatment of Hereditary Transthyretin Amyloidosis Polyneuropathy

Topic General Neurology

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 4-060

Objective To report the impact of inotersen, a transthyretin-directed antisense oligonucleotide indicated for treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis, on neuropathy symptoms and change (NSC) scores in patients with hATTR amyloidosis as an exploratory outcome in a global, randomized, double-blind, placebo-controlled phase 3 study (NEURO-TTR, NCT01737398).

Background hATTR amyloidosis is a rare, progressive, fatal disease that manifests with a buildup of transthyretin (TTR) protein in major organ systems, resulting in organ failure. Inotersen demonstrated significant benefit in the NEURO-TTR co-primary end points: modified Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life–Diabetic Neuropathy questionnaire (Norfolk QoL-DN). The NSC score is a standardized measure of motor, sensory, and autonomic symptoms in generalized polyneuropathy useful for the conduct of clinical practice, epidemiology surveys, and therapeutic trials. The NSC is used to quantitate and assess the distribution and severity of muscle weakness, sensory symptoms, pain symptoms, and autonomic symptoms.

Design/Methods Adults with stage 1/2 hATTR amyloidosis were randomized (2:1) and received 300 mg weekly subcutaneous doses of inotersen or placebo for 15 months. The NSC score (total and individual domains) was assessed in tandem with the primary study end points at 9 and 15 months.

Results A total of 172 patients were evaluated. Compared with placebo, inotersen-treated patients experienced significant improvement in NSC total score from baseline to 9 months (least-square mean [LSM] difference, -3.28; 95% CI, -5.70 to -0.86; P = 0.008) and 15 months (LSM difference, -6.33; 95% CI, -9.12 to -3.55; P < 0.001). Compared with placebo, inotersen-treated patients also experienced improvements in NSC subdomains of muscle weakness, sensory, pain, and autonomic symptoms.

Conclusions Inotersen improved neuropathic symptoms in patients with hATTR amyloidosis. Results are consistent with previously reported benefits in neuropathy composite score (mNIS+7) and in patient-reported neuropathy quality of life (Norfolk QoL-DN).

Authors/Disclosures
P. James B. Dyck, MD, FAAN (Mayo Clinic) PRESENTER	Dr. Dyck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea/Ionis.
Teresa Coelho, MD (Unidate Clinica de Paramoloidose Hospital)	Dr. Coelho has nothing to disclose.
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.
Thomas Brannagan III, MD, FAAN (Columbia University)	Dr. Brannagan has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. 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 Intellia. 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 Astra Zenica. 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 Annexon. The institution of Dr. Brannagan has received research support from Alnylam. The institution of Dr. Brannagan has received research support from Abcuro. The institution of Dr. Brannagan has received research support from Ionis. The institution of Dr. Brannagan has received research support from Vertex. The institution of Dr. Brannagan has received research support from NMD Pharma.
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.
Chafic Y. Karam, MD (University of Pennsylvania)	Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alnylam. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Annexon. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nuvig. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Applied therapeutics. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astra Zeneca. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Intellia. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Takeda. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vertex.
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.
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.
John C. Kincaid, MD, FAAN (Indiana University)	Dr. Kincaid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for strongbridge pharmaceuticals. Dr. Kincaid has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for social security administrstion. The institution of Dr. Kincaid has received research support from Ionis Pharmaceuticals. Dr. Kincaid has received publishing royalties from a publication relating to health care. Dr. Kincaid has received personal compensation in the range of $500-$4,999 for serving as a medical expert for disability cases with social security administrstion. Dr. Kincaid has a non-compensated relationship as a I am the historian of the Board of Directors for this organization with AANEM that is relevant to AAN interests or activities.
Janice F. Wiesman, MD, FAAN	No disclosure on file
William J. Litchy, MD, FAAN	Dr. Litchy has nothing to disclose.
Michelle L. Mauermann, MD, FAAN (Mayo Clinic)	The institution of Dr. Mauermann has received research support from Intellia. Dr. Mauermann has received publishing royalties from a publication relating to health care.
Elizabeth Ackermann, PhD (ISIS PHARMACEUTICALS, INC)	No disclosure on file
Brenda F. Baker	No disclosure on file
	No disclosure on file
Spencer Guthrie	No disclosure on file
	No disclosure on file
Peter J. Dyck, MD, FAAN (Mayo Clinic)	Dr. Dyck has nothing to disclose.

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