Underlying Immune Disorder May Predispose Some Transthyretin Amyloidosis Subjects to Inotersen-Mediated Thrombocytopenia.

Abstract

Inotersen, a 2'-O-methoxyethyl (2'-MOE) phosphorothioate antisense oligonucleotide, reduced disease progression and improved quality of life in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in the NEURO-TTR and NEURO-TTR open-label extension (OLE) trials. However, 300 mg/week inotersen treatment was associated with platelet count reductions in several patients. Mean platelet counts in patients in the NEURO-TTR-inotersen group remained ≥140 × 109/L in 50% and ≥100 × 109/L in 80% of the subjects. However, grade 4 thrombocytopenia (<25 × 109/L) occurred in three subjects in NEURO-TTR trial, and one of these suffered a fatal intracranial hemorrhage. The two others were treated successfully with corticosteroids and discontinuation of inotersen. Investigations in a subset of subjects in NEURO-TTR (n = 17 placebo; n = 31 inotersen) and OLE (n = 33) trials ruled out direct myelotoxicity, consumptive coagulopathy, and heparin-induced thrombocytopenia. Antiplatelet immunoglobulin G (IgG) antibodies were detected at baseline in 5 of 31 (16%) inotersen-treated subjects in NEURO-TTR, 4 of whom eventually developed grade 1 or 2 thrombocytopenia while on the drug. In addition, 24 subjects in the same group developed treatment-emergent antiplatelet IgG antibodies, of which 2 developed grade 2, and 3 developed grade 4 thrombocytopenia. Antiplatelet IgG antibodies in two of the three grade 4 thrombocytopenia subjects targeted GPIIb/IIIa. Plasma cytokines previously implicated in immune dysregulation, such as interleukin (IL)-23 and a proliferation-inducing ligand (APRIL) were often above the normal range at baseline. Collectively, these findings suggest an underlying immunologic dysregulation predisposing some individuals to immune-mediated thrombocytopenia during inotersen treatment.

• Authors: PadmaKumar Narayanan, Brian R Curtis, Lijiang Shen, Eugene Schneider, Joseph A Tami, Suzanne Paz, Sebastien A Burel, Li-Jung Tai, Todd Machemer, T Jesse Kwoh, Shuting Xia, Sanford J Shattil, Joseph L Witztum, Jeffery A Engelhardt, Scott P Henry, Brett P Monia, Steven G Hughes
• Journal: Nucleic acid therapeutics (Nucleic Acid Ther) Vol. 30 Issue 2 Pg. 94-103 (04 2020) ISSN: 2159-3345 [Electronic] United States
• PMID: 32043907 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin G
• Oligodeoxyribonucleotides, Antisense
• Oligonucleotides
• Oligonucleotides, Antisense
• Inotersen

Topics

• Adult
• Aged
• Amyloid Neuropathies, Familial (drug therapy, genetics, immunology, pathology)
• Female
• Genetic Predisposition to Disease
• Humans
• Immune System Diseases (chemically induced, immunology, pathology)
• Immunoglobulin G
• Intracranial Hemorrhages (chemically induced, immunology, pathology)
• Male
• Middle Aged
• Oligodeoxyribonucleotides, Antisense (administration & dosage)
• Oligonucleotides (administration & dosage, adverse effects)
• Oligonucleotides, Antisense (administration & dosage, adverse effects)
• Quality of Life
• Thrombocytopenia (blood, chemically induced, immunology, pathology)