Silence Therapeutics ASCO 2012 Presentation


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Silence Therapeutics' presentation to ASCO 2012 - American Society of Clinical Oncology - given 01st - 05th June 2012. It reveals the latest results of Silence's RNAi therapeutic Atu027.

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Silence Therapeutics ASCO 2012 Presentation

  1. 1. ASCO 2012Presentation
  2. 2. Disclaimer The statements made in this presentation may contain certain forward-looking comments. Actual events or results may differ from the Company’s expectations. In addition to the matters described in the presentation, future actions by the European Agency for Evaluation of Medicinal Products, the U.S. Food and Drug Administration or equivalent regulatory authorities in other countries and results of pending or future clinical trials, as well as other risk factors outlined from time to time in the Company ’ s regulatory filings, may affect actual results achieved by the Company. The Alternative Investment Market (AIM) has not reviewed and does not accept responsibility for the adequacy or accuracy of this presentation.
  3. 3. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression inthe vascular endothelium Product Description Atu027 is an siRNA in a liposomal formulation, forming particles (siRNA-lipoplexes) which can be administered systemically. Atu027 is composed of four-components including a chemically synthesized double-stranded ribonucleotide (23-mer blunt-ended siRNA), a cationic lipid, a neutral helperlipid and PEGylated lipid, “lipoplexed” in isotonic sucrose carrier. Atu027 produced as sterile lyophilized concentrate for infusion solution RNAi mediated inhibition of PKN3 and becomes reconstituted by dilution with in non-human primates isotonic Xylitol solution for application in the clinic.Further reading: The liposomal complex (siRNA-lipoplex) is exclusively taken up by endothelial cells of fairly all vascular beds, delivering siRNAs functionally into the cytoplasm of these cells in vivo for(1) Aleku et al. 2008. Atu027, aliposomal small interfering RNA degradation of the cognate PKN3-mRNA by an RNA interference mode of action. Thisformulation targeting protein kinase pharmacodynamic effect was seen in monkeys at the dose of 0.3 mg/kg/q4d with a down-N3, inhibits cancer progression. regulation of PKN3 mRNA in lung homogenates1,2. No effects on pulmonary or cardiovascularCancer Res. 68 (23): 9788-9798. functions as well as central nervous function were observed. The non-clinical pharmacology was(2) Santel et al.2010. Atu027 prevents evaluated in nude mice, rats and Cynomolgus monkeys after repeated i.v. administration. Safetypulmonary metastasis in pharmacology studies were performed. The toxicology program comprised acute as well asexperimental and spontaneous mousemetastasis models. repeated dose toxicology studies in rats and non-human primates and included aClin Cancer Res. 16 (22): 5469-5480. pharmacokinetic and distribution assessment. Genotoxicity and immunogenicity were addressed.
  4. 4. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression inthe vascular endotheliumControl Rationale & Mechanism of Action PKN3 was found to be a novel downstream target of PI-3 kinase. Atu027 enables a systemic means for RNAi mediated suppression of PKN3 expression in the vascular endothelium of both tumor and tissue vasculatures1. This particular spatial suppression ofAtu027 PKN3 ensues for some anti-tumor activity but more profoundly robust inhibition of both lymphogenicas well as hematogenous metastasis. In particular, loss of PKN3 in vascular endothelial cells is likely to bloc intercellular barrier disruption as well as pro-inflammatory cell activation. This kind of pharmacological modulation of the endothelium makes blood vessels less susceptible for promoting successful cancer cell dissemination and outgrowth during metastasis, rather than blocking tumor growth in the classical anti-angiogenic manner of traditional anti-angiogenic drugs2. Therefore, Atu027 is destined for therapeutic support of any anti-neoplastic drug (e.g. chemotherapy) in a combination regimen by addressing the stromal compartment. In addition, it may act as single drug agent in an adjuvant setting for the prevention of metastasis. Atu027 offers the opportunity of therapeutic intervention for all metastatic cancers.
  5. 5. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression inthe vascular endothelium Clinical status Atu027 is currently being evaluated in a Phase-I trial in patients (first-in-man) with various advanced or metastatic solid tumors. The trial is assessing the safety and tolerability in a dose- escalating manner across ten dose levels, in order to determine a DLT and MTD. To date, Atu027 has been administered in 34 patients as single and repeated i.v. infusions. The trial is ongoing in the last (10th) dose-level and will be completed by mid-summer 2012. Study Phase Study title Design Description Atu027 Phase-I A prospective, open label, 1° Objective : DLT, MTD; PK single-centre, dose (plasma siRNA conc.), PD Dose-escalation finding phase I study with (biomarker), cytokine, NCT009385 10 dose levels Atu027 (an siRNA complement 74 formulation) in subjects Monotherapy with advanced solid 2° Clinical Response according cancer “Atu027-I-01” to RECIST
  6. 6. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression inthe vascular endothelium Safety Event Outcome The clinical safety, tolerability of the drug Serious 17 SAEs in 13 different patients and potential biomarkers reflecting Adverse All SAEs judged unrelated to Atu027 PD are being evaluated. As a Events Atu027 treatment secondary objective the clinical response (SAEs) is monitored according to RECIST criteria. According to the clinical trial • Fatigue grade G1 (6pts), protocol a dose-escalation over 11 levels • Hair loss G1 (2pts), was designed and to date dosing of • Sweating G1 (1pt), patients was completed up to dose level • Abdominal pain G2 (1pt). 10 (DL10). One dose limiting toxicity Adverse occurred at dose level 10 (increase of Events AEs (G3) not considered DLT: lipases, grade 3). Altogether, Atu027 was (AEs) - elevated Lipase (1pt, DL2) very well tolerated and safe up to the 10th - diarrhea (1pt, DL5) dose level. No premedication was needed in support of Atu027 treatment. The AE (G3) considered DLT: prospective/recommended MTD is at - elevated Lipase (1pt, DL10) 0.336 mg/kg. Sporadic observation of high Cytokines values scattered across different time points Atu027-related transient activation of the alternative Complement pathway of the complement system (C3a, Bb, sC5b-9)
  7. 7. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression inthe vascular endothelium Clinical Parameter Comments Atu027 was given to patients as a single 4h- No. Patients 34 infusion with subsequent follow-up for Breast (6), Pancreas CA (4), three weeks. Patients were subsequently CUP (3), Gynecologic treated twice weekly for additional four Cancers (Cervix&Ovarian, weeks. In case of SD, patients were treated 3), Colon CA (4), Rectum until PD. Dose escalation was associated Types of advanced (2), Melanoma (2), NET with assessment of toxicity, cancer (2), Sarcoma (2), Prostate pharmacokinetics (PK), and OncoMap CA (1), Liver & Cholangio biomarker analyses in plasma from treated (No. Pts) cellular cancer (1+1), patients (pts). Kidney (1), Esophageal (2) “Stable disease” response for three and six and Oropharyngeal after months after treatment was observed in 10 Squamous CA (1) and 3 pts, respectively. Two pts with Various chemo-therapies, neuroendocrine cancer had disease Previous treatments Hormone therapy , stabilization for 9 and 12 months. Partial Immune therapy, Antibody, before regression of pulmonary metastases was found in 1 pt. Another patient with breast Stable disease/ 11 pts (32%) at E.o.S./5 pts cancer had regression of liver metastases. Compassionate use
  8. 8. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression inthe vascular endothelium Pharmacokinetic & Pharmakodynamics Treatment with Atu027 at DL8 (0.18 mg siRNA/kg) reaches the plasma siRNA concentration reflecting the dose sufficient to trigger RNAi of PKN3 in Cynomolgus non-human primates. Robust reduction of soluble VEGF- R1 (sFLT-1) levels was observed in plasma samples from 8 out of 9 patients in DL6-9 after repeated Atu027 treatment. The levels of VEGF-R2 and VEGF-R1 were not changed upon Atu027 treatment. Therefore soluble VEGF-R1 might sFLT-1 ELISA with plasma from patients in DL6-9 serve as a biomarker.