Date: 2016-04-05
Type of information: Results
phase: 1b-2a
Announcement: results
Company: Silence Therapeutics (UK)
Product: Atu027 and gemcitabine
Action
mechanism: RNAi. 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.
Disease: pancreatic cancer
Therapeutic area: Cancer - Oncology
Country: Germany
Trial
details: The purpose of the Atu027-I-02 study is to evaluate a new treatment strategy for advanced pancreatic cancer disease by combining the new investigational medicinal product Atu027 with the standard chemotherapeutic gemcitabine. This combination aims at enhancing gemcitabine´s anti-tumor activity with Atu027. The objectives of this clinical trial are to evaluate safety and activity of two Atu027 schedules in combination with standard gemcitabine treatment in patients with advanced or metastatic pancreatic adenocarcinoma. (NCT01808638)
Latest
news: * On April 5, 2016, Silence Therapeutics provides the final analysis of Atu027-I-02 Phase IIa study in pancreatic cancer. The primary objective of this trial was to assess safety and pharmacokinetics, and the secondary objective was to evaluate efficacy, including Progression Free Survival (PFS) and Overall Survival (OS). The presented results have been generated by an independent clinical research organisation. This study was open label in 23 patients with incurable pancreatic cancer (metastatic and locally advanced) and included two treatment arms with Atu027 in combination with the standard of care, gemcitabine. Treatment arm 1 delivered one dose per week for three weeks, followed by one week of no treatment, giving a total of 6 administrations in 8 weeks. Treatment arm 2 delivered 2 doses per week during 4 weeks, followed by 4 weeks of no treatment, a total of 8 administrations in 8 weeks. Validation of target gene: In the period between the announcement of the preliminary Phase IIa results and this statement, an independent research group based at the Kobe University validated the key role of our target gene, PKN3, in metastatic progression. These findings were published in a scientific reports article entitled * On June 1, 2015, Silence Therapeutics announced that following the draft interim analysis of its Atu027-I-02 Phase 2a trial in pancreatic cancer, as announced on 23 March 2015, the company has now completed a full interim analysis of the patient data. The study was open label in 23 patients with incurable pancreatic cancer and included two treatment arms. Both arms received the standard of care, gemcitabine, in combination with Atu027. No safety issues were detected for the combination of Atu027 with gemcitabine. Silence previously announced that a dose-dependent effect in Progression Free Survival (PFS) was observed between the two arms, for the whole patient safety population (both metastatic and locally advanced pancreatic cancer). Those exposed to the higher dose of Atu027 presented a longer median duration of PFS; 5.33 months compared to 1.81 months for those on the lower exposure regimen. One patient from each arm is still participating in the study and will continue to be monitored. In addition, a post-hoc analysis of those patients with metastatic cancer, a sub group of 19 patients within the two arms, revealed statistically significant differences in PFS between arms (p=0.0247). This analysis showed a median PFS period of 2.89 months for metastatic patients within treatment arm two, which received a 33% more total dose of Atu027 over an eight week period, while the metastatic patients within arm one saw a median PFS period of 1.61 months. * On May 14, 2015, Silence Therapeutics announced the positive results of the Atu027-I-02 trial have led the Board to review its strategic use of resources in cancer, including the design and initiation of the proposed head and neck * On July 16, 2014, Silence Therapeutics announced that the company has completed the recruitment of patients for its Phase 2a trial of Atu027 in pancreatic cancer. Silence has reached its enrolment target of 24 patients for its study, to be completed at clinics across Germany. The primary objective is to evaluate the safety and pharmacokinetics of Atu027 when used in combination with standard chemotherapy treatment, Gemcitabine, in subjects with locally advanced or metastatic pancreatic adenocarcinoma. Follow up analysis is expected in mid-2015. * On August 8, 2013, Silence Therapeutics announced that following the safety lead-in part of the study the company has commenced dosing the first patient in a Phase IIa part of the current Atu027-I-02 study. In this study, first-line patients with loco-regionally advanced or metastatic pancreatic cancer are given two different Atu027 treatments on top of the standard gemcitabine regime, the standard chemotherapy for these patients. This drug combination aims to attenuate further disease progression by combining the anti-neoplastic activity of gemcitabine with the anti-metastatic action of Atu027. * On June 18, 2013, Silence Therapeutics announced that the Data Safety Monitoring Board (DSMB) has unanimously recommended the continuation of the Phase Ib/IIa study of Atu027. The Phase Ib/IIa study uses Atu027 in combination with gemcitabine in patients with advanced pancreatic cancer qualifying for first-line-treatment. The recommendation was made after the DSMB reviewed results from the completed safety lead-in period in patients with refractory cancer disease supporting the tolerability of this combination. The timing of this recommendation is consistent with our expectations as disclosed in the 5 March 2013 business update. Silence will start recruiting patients with loco-regionally advanced or metastatic pancreatic cancer, the main part of the Phase Ib/IIa study. In this disease, the tumor micro-environment is implicated in fostering tumor growth, invasion and metastasis. The investigational drug combination aims to attenuate further disease progression by combining the anti-neoplastic activity of gemcitabine with the anti-metastatic action of Atu027. On March 5, 2013, Silence Therapeutics has announced that it has received formal approval from the German authorities (BfArM) for its phase 1b/2a combination trial into pancreatic cancer. The trial will test Silence's Atu027 anti-metastatic compound in combination with gemcitabine. It is expected that the 1b element of the trial will last for 3 months and the 2a element scheduled to begin in July 2013 and ending approximately in July 2014.
Arm 2 therefore received 33% more Atu027 during the same treatment period. The treatment period finished when the patients had progressive disease, but following discontinuation of Atu027 treatment, patients were followed up for up to another year. Following the cessation of treatment for the last patient, Silence presented an interim analysis last year, including the PFS for the two treatment arms.
Those exposed to the higher dose of Atu027 presented a longer median duration of PFS: 5.33 months compared to 1.81 months for those on the lower exposure regimen. A post-hoc analysis of those with only metastatic pancreatic cancer showed a median PFS of 1.61 for arm 1 vs. 2.89 months for arm 2 (p=0.0247).
The current analysis includes the OS data of the study. Subjects in the higher dosed arm of the study had a median OS of 7.79 months compared to 5.62 months for the lower dose (p=0.61), with 35% of patients being censored. For the metastatic group only, the median OS in the higher dosed group was 6.74 months vs. 3.29 (p=0.6) for the lower dose group, with 26% of patients being censored. There were no changes to the safety profile of the drug.
‘PKN3 is the major regulator of angiogenesis and tumor metastasis in mice’. The results described in the article using a knock-out model reproduce data generated in house at Silence when inhibiting endothelial PKN3 expression with Atu027 treatment.
cancer study. The company believes that the implication of higher and more frequent dosing warrants investigation
prior to a full Phase 2 study in pancreatic cancer patients. As a result, the head and neck cancer study, as originally designed, has been deferred to enable the Company to explore this dosing issue further. Once the dosing regimen has been optimised in pancreatic cancer, other metastatic cancers like head and neck can be addressed. At this stage the company will focus on achieving definitive success in pancreatic cancer, measured in terms of clear endpoints. A further statistical analysis of the pancreatic cancer study, which is expected to confirm the early indications of benefit of Atu027, will be made available in the Company’s AGM statement, which is due to be released on 1 June 2015.* On March 23, 2015, Silence Therapeutics provided a draft interim analysis of Atu027-I-02 Phase IIa study in
pancreatic cancer. The primary objective of this trial was to assess safety and pharmacokinetics, and the secondary objective was to evaluate efficacy, including Progression Free Survival (PFS). This study was open label in 23 patients with incurable pancreatic cancer and included two treatment arms with Atu027 in combination with the standard of care, gemcitabine. Treatment arm 1 delivered one dose per week for three weeks, followed by one week of no treatment, giving a total of 6 administrations in 8 weeks. Treatment arm 2 delivered 2 doses per week during 4 weeks, followed by 4 weeks of no treatment, a total of 8 administrations in 8 weeks. Arm 2 therefore received 33% more
Atu027 during the same treatment period. The presented results are preliminary but have been generated by an independent clinical research organisation.
Tolerability and platform validation: There was no difference in safety events leading to discontinuation between the two arms, with one subject withdrawing because of an adverse event in each arm. Atu027 was generally well tolerated. In addition, the study results are an important further validation of Silence’s two-component drug –a short interfering RNA (siRNA) and a delivery system. Over 400 patients have now been treated with the Company’s proprietary modified siRNA (AtuRNAi®), with excellent tolerability. In regards to delivery, this data gives further evidence of the favourable safety profile of Silence’s delivery platforms, which are the core components of the Company’s ‘multiple shots at goal’ strategy.
Progression free survival: A preliminary analysis of this open label study indicates that the subjects who were exposed to a 33% higher total dose of Atu027 had a longer duration of PFS (median of 5.33 months) than patients on the lower exposure regimen (median of 1.81 months). This suggests that in this study, a dose dependent effect was seen for Atu027.
* On November 18, 2014, Silence Therapeutics announced that study data on the first-in-human trial of the use of its Atu027 RNAi (RNA interference) technology in patients with advanced solid tumours has been pre-published online by the Journal of Clinical Oncology the peer reviewed journal and official publication of the American Society
of Clinical Oncology (ASCO). The study found that Atu027 was well tolerated and safe in patients with advanced solid tumours. Disease stabilisation was also achieved in 41% of patients for at least eight weeks after treatment.
The study was carried out alongside collaborators at theDepartment of Hematology and Oncology at the Marienhospital Herne, University of Bochum in Germany led by Dr Dirk Strumberg.
Silence Therapeutics will open additional centers in Germany, which is allowed under the current BfArM approval for human testing of Atu027. The University Hospital Freiburg will become active in the next few weeks. Further centers are being considered.
BfArM has also encouraged Silence, primarily due to the exceptional safety profile of ATU027 in phase 1, to apply for 1b/2a trials using Atu-027 as a combination therapy across a wide range of cancers. It indicated that these further trials could be run broadly in parallel with pancreatic cancer.
