BMS-844421 / Ionis, BMS - LARVOL DELTA

Cellular immune changes during severe antisense oligonucleotide-associated thrombocytopenia in a nonhuman primate model. (PubMed, J Immunol) - "In this pilot study, we used a mass cytometry-based intracellular cytokine staining assay, to evaluate the immune-phenotypic and functional changes in cryopreserved PBMCs, collected over 8 time points of ASO therapy (ISIS 405879) from 12 Cambodian and 12 Mauritian monkeys (9 treated and 3 controls)...Immune populations also changed over the course of this treatment, wherein IL-17- and GM-CSF-producing T cells and IgM-producing B cells increased markedly in Mauritians. Identification of these differentially abundant immune cell subsets in treatment sensitive NHPs could help decipher potential immune mechanisms contributing to severe TCP observed during administration of specific ASO sequences in humans."

Journal • Preclinical • Hematological Disorders • Thrombocytopenia • CD4 • CD8 • CSF2 • IFNG • IL17A

Complement C3d/C4d Deposition on Platelets Correlates with 2'-O-Methoxyethyl Antisense Oligonucleotide-Induced Thrombocytopenia in Monkeys. (PubMed, Nucleic Acid Ther) - "In addition, increases in total serum IgM, anti-PLT IgM, and anti-PLT factor 4 IgM levels were observed in monkeys from both sources but were more evident in the Mauritian-sourced monkeys. These data suggest an enhanced innate immune cell activation to ISIS 405879, leading to increased PLT destruction through complement fixation on the PLTs or PLT crossreacting polyclonal antibody production."

Journal • Hematological Disorders • Thrombocytopenia

[VIRTUAL] An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans (AHA 2020) - "A monkey tolerability study of the PCSK9 ASO further supports oral feasibility with all tested doses (28-56 mg/day) significantly reducing LDL-C already after 7 days of daily oral dosing. Based on available animal and human data, and an assumption of 5% oral bioavailability in humans, a daily dose of 15 mg ([10, 20], 90% CI) in man is predicted to reduce PCSK9 in plasma by 80% at steady-state. This supports the development of the compound for subcutaneous and oral administration to treat dyslipidemia."

Dyslipidemia • Metabolic Disorders • MALAT1

Aegerion Pharmaceuticals: We are bullish on the lomitapide story (SeekingAlpha) - FDA's EMDAC to hold an advisory panel to review lomitapide along with Kynamro in Sep or Oct 2012; Aegerion has a PDUFA date of Dec 29, 2012; The decision by the EU is expected in H1 2013; Lomitapide has a clear edge due to its efficacy, oral-dose formulation & superior safety/tolerability profile; AMG145 & REGN727 are being developed by Amgen & Regeneron /Sanofi, respectively; Two antisense drug candidates targeting PCSK9 mRNA, ALN-PCS01 & BMS-PCSK9Rx, are developed by Alnylam & Isis in collaboration with BMS, respectively

Anticipated FDA decision • Anticipated PDUFA date • EMDAC review • Dyslipidemia