Ionis Pharmaceuticals Publishes Papers on the Analysis of an Integrated Safety Database and Mechanisms of Antisense Oligonucleotides

— Results Demonstrate No Class Generic Effects of 2’MOE ASOs on Platelets

— Ionis Founder, CEO and Chairman, Stanley T. Crooke, Ph.D., M.D., and Recipient of the Lifetime Achievement Award from the Oligonucleotide Therapeutics Society Discusses the Mechanisms of Antisense Oligonucleotide Activity

In order to determine whether there is a class generic effect of 2’-O-methoxyethyl (2’MOE)-modified antisense oligonucleotides (ASOs) on platelet numbers and function, Ionis conducted an analysis of its integrated safety database (ISDB). The Ionis ISDB includes clinical data for 16 2’MOE ASOs evaluated in over 40 placebo-controlled and open-label clinical trials, including Phase 1, Phase 2 and Phase 3 studies. The results of this analysis were published in the peer-reviewed journal Nucleic Acid Therapeutics in a paper titled, “The Effects of 2’-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human Clinical Trials.”[i]

The Ionis ISDB contains laboratory test results from over 2,600 human subjects. This population includes approximately 1,000 subjects treated for 3 months or longer, with drug exposure up to 4.6 years, which equates to approximately 800 subject years. Subjects received doses of up to 624 mg/week.

The analysis of the ISDB demonstrates that there is no class generic effect of 2’MOE ASOs on platelet numbers and function. Findings of the analysis found no incidence of confirmed platelet levels of below 50 K/µL (Grade 3). Further, only seven of 2,638 subjects (0.3%) treated with 2’MOE ASOs experienced a confirmed post-baseline platelet count between 100 K/µL and 50 K/µL.

A sensitivity analysis that looked for slight to moderate effects on platelets found that only three of 16 2’MOE ASOs had a greater than 10% incidence of platelet decreases of more than 30% from baseline, suggesting that certain sequences may be associated with clinically insignificant platelet events. In addition, there was no evidence that 2’MOE ASOs alter platelet function as demonstrated by the lack of clinically relevant bleeding in the presence or absence of other drugs that are known to alter platelet function and number of platelets. Of particular note, in a Phase 2, open-label, randomized parallel-group study of IONIS-FXIRx in subjects undergoing total knee arthroplasty and fully anticoagulated, serious bleeding events among subjects treated with IONIS-FXIRx were substantially lower than subjects in the control group. Further, 2’MOE ASOs have been shown to have no class generic effect on liver, kidney, cardiac, central nervous system, muscle, or bone marrow function.

In the last year, Ionis reported cases of severe thrombocytopenia experienced with two 2’MOE ASOs currently being evaluated in Phase 3 clinical studies, volanesorsen and IONIS-TTRRx. Data from these ongoing, blinded Phase 3 studies were not included in this analysis. Based on the findings of this published analysis, it appears that the platelet events observed in the Phase 3 studies are unique. Preliminary evidence suggests that the mechanisms accounting for the severe platelet events in these diseases differ and are related to each of the diseases being studied.

In a second paper that was also published in Nucleic Acid Therapeutics titled “Molecular Mechanisms of Antisense Oligonucleotides,”[ii] Stanley T. Crooke, Ph.D., M.D., founder, CEO and chairman of the board of directors of Ionis Pharmaceuticals, provides insight into the mechanisms that result in the activities of ASOs, drawn from his extensive experience as a pioneer in the field. Published in conjunction with his Lifetime Achievement Award from the Oligonucleotide Therapeutics Society, in this paper, Dr. Crooke highlights the contributions he and his colleagues at Ionis have made in the understanding of antisense technology.

Dr. Crooke and his team have focused their work on the three main phases of antisense drug action: prehybridization, hybridization, and post-hybridization. Within this framework, Dr. Crooke describes the design of ASO therapeutics, how they can be targeted with a target RNA sequence, and the mechanisms by which ASO drugs are able to degrade, disable, or modify a target RNA to inhibit the expression of a specific gene.

Dr. Crooke’s work in advancing the science of antisense technology has allowed scientists at Ionis and in other organizations to more efficiently translate ASOs to therapeutics targeting a wide range of diseases. Ionis has three approved drugs and a pipeline of over three dozen antisense drugs that are potentially first-in-class and/or best-in-class therapeutics.


[i] Crooke, Stanley T., et al. “The Effects of 2’-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human Clinical Trials.” Nucleic Acid Therapeutics. Published online February 1, 2017.
[ii] Crooke, Stanley T. “Molecular Mechanisms of Antisense Oligonucleotides.” Nucleic Acid Therapeutics. Published online January 12, 2017.