The Effects of 2′-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human Clinical Trials

Abstract

A thorough analysis of clinical trial data in the Ionis integrated safety database (ISDB) was performed to determine if there is a class effect on platelet numbers and function in subjects treated with 2′-O-methoxyethyl (2′MOE)-modified antisense oligonucleotides (ASOs). The Ionis ISDB includes over 2,600 human subjects treated with 16 different 2′MOE ASOs in placebo-controlled and open-label clinical trials over a range of doses up to 624 mg/week and treatment durations as long as 4.6 years. This analysis showed that there is no class generic effect on platelet numbers and no incidence of confirmed platelet levels below 50 K/μL in subjects treated with 2′MOE ASOs. Only 7 of 2,638 (0.3%) subjects treated with a 2′MOE ASO experienced a confirmed postbaseline (BSLN) platelet count between 100 and 50 K/μL. Three of sixteen 2′MOE ASOs had >10% incidence of platelet decreases >30% from BSLN, suggesting that certain sequences may associate with clinically insignificant platelet declines. Further to these results, we found no evidence that 2′MOE ASOs alter platelet function, as measured by the lack of clinically relevant bleeding in the presence or absence of other drugs that alter platelet function and/or number and by the results from trials conducted with the factor XI (FXI) ASO.

Assessing single-stranded oligonucleotide drug-induced effects in vitro reveals key risk factors for thrombocytopenia

“…It has been recently reported that 60% of the anti-PF4/heparin antibodies that induced platelet activation in the presence of heparin also caused platelet activation in the presence of nucleic acids [ 12 , 15 ] which suggests that only some aspects of ON-induced thrombocytopenia may be related to mechanisms leading to HIT and more research is required to delineate this effect. Of note, although the rare documented cases of ON-related thrombocytopenia in humans have generally had a late onset [ 9 ], other features such as dose-dependency and lack of documented thrombosis do not seem to match the HIT model.…”

“…Recently, cases of severe thrombocytopenia were reported in two phase 3 trials with 2’-O-methoxyethyl (2’-MOE)-modified phosphorothioate oligonucleotides, IONIS-TTR RX and volanesorsen. These findings triggered an investigation of a clinical safety database of over 2,600 subjects treated with 16 different MOE-ONs [ 9 ]. The analysis—which excluded data from oncology trials as well as the IONIS-TTR RX and volanesorsen trials—concluded that no generic class effect on platelet numbers could be observed and no platelet levels below 50 K/μl were seen in any of the investigated trials.…”

Evidence in focus: Nusinersen use in spinal muscular atrophy [RETIRED]

“…The FDA recommended that clinicians regularly monitor patients receiving nusinersen for coagulopathy, thrombocytopenia, and proteinuria. The incidence of clinically significant thrombocytopenia, platelet dysfunction, or nephrotoxicity across trials with similarly modified antisense oligonucleotides was very small, 11,14,15 but one patient treated with an antisense oligonucleotide (inotersen) in a study of individuals with familial amyloid polyneuropathy died due to thrombocytopenia-related intracranial hemorrhage. 16 Transient AEs related to intrathecal administration, including headache, vomiting, back pain, and post-LP syndrome, were reported in 40%-50% of patients.…”

The Effects of 2′-O-Methoxyethyl Oligonucleotides on Renal Function in Humans

“…A previous publication examined the general side effect profiles of 2′MOE ASOs in NHPs and human normal volunteer studies [ 7 ]. A second publication evaluated the effects of 2′MOE ASOs on number of platelets in completed clinical trials and those with unblinded locked data from analysis of primary end points [ 8 ].…”