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Updated: Apr 20, 2026
Using Lipid Nanoparticles for the Delivery of Chemically Modified mRNA into Mammalian Cells
Published on: June 10, 2022
First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid
Beate Schultheis1, Dirk Strumberg2, Ansgar Santel1
1Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Purpose:
Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions.
Patients And Methods:
Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST.
Results:
Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10.
Conclusion:
Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.
Insights
Atu027, a novel RNA interference therapy, demonstrated safety and tolerability in patients with advanced solid tumors. Disease stabilization was observed in 41% of patients, indicating therapeutic potential for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- RNA Therapeutics
Background:
- Atu027 is a liposomal RNA interference therapeutic utilizing short-interfering RNA (siRNA) to silence protein kinase N3 expression.
- Preclinical studies in mouse cancer models showed Atu027 inhibited tumor invasion and metastasis.
Purpose of the Study:
- To evaluate the safety, tolerability, and pharmacokinetics of Atu027 in a first-in-human study.
- To assess the therapeutic efficacy of Atu027 on primary tumors and metastatic lesions in patients with advanced solid tumors.
Main Methods:
- Thirty-four patients with advanced solid tumors received escalating doses of Atu027 via intravenous infusion over 28-day cycles.
- Tumor response was monitored using computed tomography/magnetic resonance imaging and assessed per RECIST criteria.
Main Results:
- Atu027 was well tolerated up to 0.336 mg/kg, with predominantly low-grade adverse events; no maximum tolerated dose was reached.
- Forty-one percent of patients achieved disease stabilization at the end of treatment, with some experiencing regression of metastases.
- Soluble Fms-like tyrosine kinase-1 (sFLT1) levels decreased in most patients at higher dose levels.
Conclusions:
- Atu027 is safe and tolerable in patients with advanced solid tumors, with significant disease stabilization observed.
- Further clinical trials are warranted, and sFLT1 is proposed as a potential biomarker for therapeutic response.
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01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
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