Important New Drug Development Research from Ionis Pharmaceuticals
As presented at SOT annual meeting, Baltimore MD
A wide array of drugs has adverse effects on platelet numbers and function making assays of in vivo platelet function so important in drug development. Platelets serve a critical role in hemostasis. Platelet (PLT) homeostasis is normally tightly regulated with PLT production in the bone marrow balanced with PLT removal or sequestration in the spleen and liver. But altering PLT mediated homeostasis has grave consequences. Too few and bleeding results. Activated and deadly thrombi can result in stroke, heart attack, and lung embolism.
A very important class of drugs, Anti-Sense Oligonucleotides or ASO are showing enormous potential in treating a variety of diseases from cancers to neurodegenerative diseases to inflammatory diseases. These drugs also have demonstrated moderate effects on PLT homeostasis. Understanding how (mechanism of action or MOA) a drug effects platelets can provide important insights into a drug’s safety and just as important how adverse effects can be mitigated or eliminated for patients.
To get the bottom of this issue Dr. PK Narayanan (Ionis Pharmaceuticals) and his team embarked on a detailed analysis of the drug ISIS 104838 and it’s MOA in vivo in Cynomolgus monkeys. The results were reported last week at the annual meeting of the Society of Toxicology (PK Narayanan, et al. P565). BioLaurus’ team led by Dr. Mario Bourdon conducted the in life study and performed the in vivo gamma-camera imaging of Indium-111 labeled PLT sequestration in Cynomolgus monkeys. Both dynamic imaging and static imaging at 24 hours provided details of PLT fate in the first minutes of PLT distribution through the body as well as the overall sequestration pattern and levels. This data correlated with a pattern of innate immune activation in the test subjects.
It is now clear that ISIS 104838 induces an IgM anti-PF4 and anti-PLT IgM/IgG response. While more research is needed to confirm it appears that individuals vary in their response to ISIS 104838 and therefore the severity of thrombocytopenia they may experience.