ASCO 2012 Presentation

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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.

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 and becomes reconstituted by dilution with isotonic Xylitol solution for application in the clinic.

Further reading: (1) Aleku et al. 2008. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res. 68 (23): 9788-9798. (2) Santel et al.2010. Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models. Clin Cancer Res. 16 (22): 5469-5480.

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 degradation of the cognate PKN3-mRNA by an RNA interference mode of action. This pharmacodynamic effect was seen in monkeys at the dose of 0.3 mg/kg/q4d with a down-regulation of PKN3 mRNA in lung homogenates1,2. No effects on pulmonary or cardiovascular functions as well as central nervous function were observed. The non-clinical pharmacology was evaluated in nude mice, rats and Cynomolgus monkeys after repeated i.v. administration. Safety pharmacology studies were performed. The toxicology program comprised acute as well as repeated dose toxicology studies in rats and non-human primates and included a pharmacokinetic and distribution assessment. Genotoxicity and immunogenicity were addressed.

RNAi mediated inhibition of PKN3 in non-human primates

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

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 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.

Control

Atu027

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

Study Phase Study title Design Description

Atu027

NCT00938574

Phase-I

Dose-escalation

10 dose levels

Monotherapy

A prospective, open label,

single-centre, dose finding phase I study with

Atu027 (an siRNA formulation) in subjects

with advanced solid cancer “Atu027-I-01”

1° Objective : DLT, MTD; PK

(plasma siRNA conc.), PD (biomarker), cytokine,

complement

2° Clinical Response according to RECIST

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.

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

Safety The clinical safety, tolerability of the drug and potential biomarkers reflecting Atu027 PD are being evaluated. As a secondary objective the clinical response is monitored according to RECIST criteria. According to the clinical trial protocol a dose-escalation over 11 levels was designed and to date dosing of patients was completed up to dose level 10 (DL10). One dose limiting toxicity occurred at dose level 10 (increase of lipases, grade 3). Altogether, 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 MTD is at 0.336 mg/kg.

Event Outcome

Serious Adverse Events (SAEs)

17 SAEs in 13 different patients All SAEs judged unrelated to Atu027 treatment

Adverse Events (AEs)

• Fatigue grade G1 (6pts), • Hair loss G1 (2pts), • Sweating G1 (1pt), • Abdominal pain G2 (1pt). AEs (G3) not considered DLT: - elevated Lipase (1pt, DL2) - diarrhea (1pt, DL5) AE (G3) considered DLT: - elevated Lipase (1pt, DL10)

Cytokines Sporadic observation of high values scattered across different time points

Complement

Atu027-related transient activation of the alternative pathway of the complement system (C3a, Bb, sC5b-9)

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

Clinical Atu027 was given to patients as a single 4h-infusion with subsequent follow-up for three weeks. Patients were subsequently treated twice weekly for additional four weeks. In case of SD, patients were treated until PD. Dose escalation was associated with assessment of toxicity, pharmacokinetics (PK), and OncoMap biomarker analyses in plasma from treated patients (pts).

before

after

Parameter Comments

No. Patients 34

Types of advanced cancer

(No. Pts)

Breast (6), Pancreas CA (4), CUP (3), Gynecologic Cancers (Cervix&Ovarian, 3), Colon CA (4), Rectum (2), Melanoma (2), NET (2), Sarcoma (2), Prostate CA (1), Liver & Cholangio cellular cancer (1+1), Kidney (1), Esophageal (2) and Oropharyngeal Squamous CA (1)

Previous treatments Various chemo-therapies, Hormone therapy , Immune therapy, Antibody,

Stable disease/ Compassionate use 11 pts (32%) at E.o.S./5 pts

“Stable disease” response for three and six months after treatment was observed in 10 and 3 pts, respectively. Two pts with neuroendocrine cancer had disease stabilization for 9 and 12 months. Partial regression of pulmonary metastases was found in 1 pt. Another patient with breast cancer had regression of liver metastases.

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 serve as a biomarker.

sFLT-1 ELISA with plasma from patients in DL6-9