-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3634 Transmembrane Protease, Serine 6 (TMPRSS6) Antisense Oligonucleotide (IONIS-TMPRSS6-LRX) Reduces Plasma Iron Levels of Healthy Volunteers in a Phase 1 Clinical Study

Program: Oral and Poster Abstracts
Session: 112. Thalassemia and Globin Gene Regulation: Poster III
Hematology Disease Topics & Pathways:
Monday, December 3, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Michael McCaleb, PhD1*, Jason Lickliter, MBBS, PhD2*, Andrew Dibble, PhD3*, Eugene Schneider, MD4*, Mariam Aghajan5*, Shuling Guo5*, Steve Hughes, MD, MBA6*, Richard S Geary, PhD7* and Brett P. Monia, PhD5

1Ionis Pharmacueticals, Carlsbad, CA
2Nucleus Network, Melbourne, AUS
3Ionis Pharmaceuticals, Carlsbad, CA
4Ionis Pharmacueticals, CARLSBAD, CA
5Ionis Pharmaceuticals, Inc., Carlsbad, CA
6Ionis Pharmaceuticals, Carlsbad
7Clinical Development, Ionis Pharmaceuticals, Carlsbad

Iron overload is the major cause of morbidity and mortality in beta-thalassemia patients. The low levels of beta-globin and ineffective erythropoiesis in these patients result in the suppression of hepcidin. The inappropriately low levels of hepcidin trigger an increased absorption of dietary iron and increased iron release from storage, causing iron overload. Expression of hepcidin, which is predominately produced in the liver, is negatively regulated by the transmembrane protease, serine 6 (TMPRSS6). Mouse and human genetic data indicated that lowering TMPRSS6 expression could up-regulate hepcidin and ameliorate many of the disease symptoms associated with beta-thalassemia. Previously we identified a highly specific and potent antisense oligonucleotide (ASO) targeting either the murine (Guo et al. J Clin Invest. 2013; 123(4):1531-41) or the human (Aghajan et al, Blood 2016; 128:1013) TMPRSS6 mRNA. Downregulation of TMPRSS6 with ASO treatment resulted in dose-dependent hepcidin upregulation, leading to dramatic reductions in serum iron and transferrin saturation in animal models This in turn ameliorated the anemia and iron overload phenotypes in a mouse model of beta-thalassemia (th3/+ mice), which recapitulates beta-thalassemia intermedia in humans.

Herein, we are reporting the initial clinical safety and pharmacodynamics of IONIS-TMPRSS6-LRX. This GalNAc-conjugated, TMPRSS6 ASO was evaluated in a placebo-controlled, double-blind, randomized, single-center Phase 1 clinical study enrolling healthy volunteers. During an 8-week period, placebo or IONIS-TMPRSS6-LRX was administered subcutaneously four times (Weeks 1, 4, 6 and 8) at doses of 20, 40 or 60 mg. At doses of 20 and 40 mg, mean (±SEM) levels of serum iron were reduced 34±10% and 49±7% on week 10 (The 60 mg treatment cohort is ongoing). Consistent with the reduction of plasma iron, the mean (+/-SEM) percent transferrin saturation was reduced from baseline levels of 28±3% and 30±1% to 14±2% and 13±2%, for 20 and 40 mg groups, respectively, at Week 10. Furthermore, plasma hepcidin levels were increased from 2.1±0.6 and 2.5±0.6 nM to 2.7±0.6 and 6.7±0.9 nM, respectively. During this time period, there were small reductions in Hgb (-9±2%), reticulocyte Hgb (-13±2%) at the 40 mg dose. There were no serious adverse events in the study and the treatment-emergent adverse events were generally mild. In summary, IONIS-TMPRSS6-LRX, a novel antisense oligonucleotide targeting TMPRSS6, effectively reduces plasma iron levels and has the potential as a therapeutic for patients with beta-thalassemia and related disorders. The safety profile of IONIS-TMPRSS6-LRX supports further development.

Disclosures: McCaleb: Ionis Pharmaceuticals, INC: Employment, Equity Ownership. Lickliter: Nucleus Network: Employment. Dibble: Ionis Pharmaceuticals, INC: Employment. Schneider: Ionis Pharmaceuticals, INC: Employment, Other: shareholders. Aghajan: Ionis Pharmaceuticals, Inc: Employment. Guo: Ionis Pharmaceuticals, Inc: Employment. Hughes: Ionis Pharmaceuticals, INC: Employment, Other: shareholders. Geary: Ionis Pharmaceuticals, INC: Employment, Other: shareholders. Monia: Ionis Pharmaceuticals, Inc: Employment, Other: Intellectual property rights.

*signifies non-member of ASH