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. For more information, please go to www.silence-therapeutics.com or www.twitter.com/rnaihub

1. ASCO 2012
Presentation

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. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the 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, a
liposomal small interfering RNA
degradation of the cognate PKN3-mRNA by an RNA interference mode of action. This
formulation 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 cardiovascular
Cancer 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. Safety
pulmonary metastasis in pharmacology studies were performed. The toxicology program comprised acute as well as
experimental and spontaneous mouse
metastasis models. repeated dose toxicology studies in rats and non-human primates and included a
Clin Cancer Res. 16 (22): 5469-5480. pharmacokinetic and distribution assessment. Genotoxicity and immunogenicity were addressed.

4. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Control 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 of
Atu027
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. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the 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. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the 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. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the 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. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the 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.