Clinical Trials

Date: 2012-06-06

Type of information: Results

phase: 1

Announcement: results

Company: Silence Therapeutics (UK)

Product: Atu027

Action mechanism:

RNAi/RNA interference (RNAi) therapy. Atu027 is a RNAi therapeutic based on cationic lipoplexes containing chemically stabilized siRNAs, which targets PKN3 gene expression in the vascular endothelium. PKN3 acts as a downstream effector of PI3K-signaling pathway and is implicated in controlling cellular morphology and locomotion in endothelial and cancer cells. Preclinical data obtained in various cancer mouse models revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metastasis formation.


advanced solid tumours including neuroendocrine cancers and breast cancers

Therapeutic area: Cancer - Oncology


Trial details:

Silence’s open label, single-centre, dose-finding Phase I study of Atu027 in subjects with advanced solid cancer was designed to evaluate up to a total of 11 escalating doses of Atu027. The enrolment of patients in the last cohort in dose level 10 has been completed and last treatment is scheduled on 22nd of June 2012.

Latest news:

* On June 6, 2012, Silence Therapeutics has presented the latest data from its ongoing Phase I study of Atu027, alongside the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. At this meeting, Klaus Giese, Ph.D., Silence’s Chief Scientific Officer and the study’s principal investigator Dr. Dirk Strumberg, Professor of Medicine and Director of Department of Hematology and Medical Oncology at University of Bochum (Marienhospital Herne, Germany), gave an update and discussed the data from the Atu027 Phase I trial. Atu027 was very well tolerated and safe up to the 10th dose level. No premedication was needed in support of Atu027 treatment. The prospective recommended maximum tolerated dose is 0.336 mg/kg.
“Stable disease” response for three and six months after treatment was observed in 10 and 3 patients, respectively, of the 33 evaluable patients. Two patients with neuroendocrine cancer had disease stabilisation for 9 and 12 months. Partial regression of pulmonary metastases was found in another patient. A further patient with breast cancer showed regression of liver metastases.
Further evaluation showed that treatment with Atu027 at dose level 8 (0.18 mg siRNA/kg) achieved the same blood plasma siRNA concentration that in preclinical studies had been sufficient to trigger silencing of PKN3 expression. Therefore, the tested dose levels 8-10 can be considered effective and safe. These data are supported by the identification of a putative biomarker. Reduction of soluble VEGF-R1 (sFLT-1) levels was observed in plasma samples from 7 out of 9 patients in dose levels 6-9 after repeated Atu027 treatment. Interestingly, the levels of soluble VEGF-R2 and soluble VEGF-R3 were not changed upon Atu027 treatment. There is evidence that sVEGF-R1 function could be a direct downstream effector of PKN3 and as such serve as a readout for biological activity.
Silence also announces that it is in advanced discussions to raise between £4-5m from new and existing shareholders to secure the funding for the Company’s R&D and marketing through until 2014.
* On May 17, 2012, Silence Therapeutics, has announced that top line data from its ongoing Phase I trial of Atu027 show that of the 33 patients treated in the first 10 cohorts of the study, 10 patients experienced stable disease after three months.
Two patients with neuroendocrine cancers had disease stabilisation for nine and 12 months respectively, including partial regression of liver metastases in one patient. Another patient with breast cancer demonstrated regression of liver metastases.
Importantly, among various biomarkers tested, sVEGFR-1 plasma levels decreased significantly upon treatment further confirming a potential biological effect of Atu027.
* On June 6, 2011, Silence Therapeutics has announced interim results of its  ongoing open label, single-center, dose-finding Phase I trial with Atu027. Study results show Atu027 to be well tolerated with no observed dose-limited toxicities or evidence of cytokine activation. Favorable pharmacokinetic (PK) data showed dose-dependent increases in siRNA and lipid levels, suggesting no evidence of drug accumulation during repeat treatment. Additionally, the maximum tolerated dose for Atu027 has not been reached yet, further supporting the tolerability of the treatment and providing the opportunity to examine the possibility of enhanced efficacy at higher doses. Dose escalation and patient enrollment is continuing in the study with the goal of evaluating a total of 11 escalating doses of Atu027 in approximately 33 patients.
Silence expects to complete the ongoing open label, single-center, dose-finding Phase I trial in the second half of 2011.

Is general: Yes