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Updated: Jun 6, 2026
Evaluation of Exon Inclusion Induced by Splice Switching Antisense Oligonucleotides in SMA Patient Fibroblasts
Published on: May 11, 2018
Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors
M Tanioka1, H Nokihara, N Yamamoto
1Division of Internal Medicine, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
Purpose:
LY2181308 is an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumor tissue. This phase I dose escalation study evaluated the tolerability, pharmacokinetics, and anticancer activity of LY2181308 in Japanese.
Methods:
Patients with solid tumors refractory to standard therapy received LY2181308 (400, 600, or 750 mg) as a 3-h intravenous infusion for 3 consecutive days and thereafter once a week.
Results:
LY2181308 was administered to 14 patients, aged 44-73 (median 60) years. Flu-like syndrome, prolonged prothrombin time-international normalized ratio (PT-INR), thrombocytopenia, and fatigue were common reversible grade 1/2 toxicities. The dose-limiting toxicity was reversible grade 3 elevation of ALT/AST/γ-GTP in 1 patient treated at the 750-mg dose. Pharmacokinetic analysis showed a long terminal half-life of 21 days and an extensive tissue distribution of LY2181308. In 12 evaluable patients, one patient had stable disease, while the remaining 11 patients had progressive disease.
Conclusions:
LY2181308 monotherapy is well tolerated up to 750 mg with a manageable toxicity, the pharmacokinetic profile warrants further evaluation of LY2181308 in combination with cytotoxic agents or radiotherapy.
Insights
LY2181308, an antisense oligonucleotide targeting survivin mRNA, showed manageable toxicity in Japanese patients with solid tumors. Further trials are recommended for combination therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Survivin is a key protein in tumor cell survival and proliferation.
- Antisense oligonucleotides offer a targeted approach to gene expression inhibition.
- LY2181308 is designed to inhibit survivin mRNA expression in tumor tissues.
Purpose of the Study:
- To assess the safety and tolerability of LY2181308 in Japanese patients.
- To determine the pharmacokinetic profile of LY2181308.
- To evaluate the preliminary anticancer activity of LY2181308.
Main Methods:
- Phase I dose-escalation study.
- Administered LY2181308 intravenously (400, 600, 750 mg) weekly.
- Enrolled 14 Japanese patients with refractory solid tumors.
Main Results:
- Common toxicities included flu-like syndrome and hematological changes.
- Dose-limiting toxicity was reversible grade 3 liver enzyme elevation at 750 mg.
- Pharmacokinetics revealed a long half-life (21 days) and wide distribution.
- One patient achieved stable disease; 11 showed progressive disease.
Conclusions:
- LY2181308 monotherapy up to 750 mg is well-tolerated with manageable toxicity.
- The pharmacokinetic profile supports further investigation.
- Combination therapy with cytotoxic agents or radiotherapy is warranted.
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