Pipeline

PF-'655 in Diabetic Macular Oedema (DME)

Market opportunity

Diabetic macular Oedema is the major cause of blindness in diabetic patients and is a common complication of diabetic retinopathy. DME affects up to 10% of all patients with diabetes with almost one million people affected globally. In the US alone, 75,000 new cases of DME are diagnosed annually. The market for DME treatments is expected to reach $2.6bn by 2016 (Source: Credit Suisse)

Current clinical studies

Quark has initiated a multicentre double blind Phase IIb trial in 264 patient comparing both single and monthly intravitreal injections of PF-'655 to monthly intravitreal injections of Lucentis (Roche/Novartis), the current standard of care in DME. The trial will also compare PF-‘655 in combination with Lucentis to Lucentis alone.

Earlier studies:

In March 2011, Quark announced results of a randomised controlled Phase II clinical trial designed to evaluated the safety and efficacy of PF-'655 in184 patient with DME. Following 12 months of treatment with PF-'655, a dose dependent improvement in visual acuity was observed with the best results achieved at the 3mg dose level. At this dose, the mean improvement from baseline on a visual acuity test was 5.8 letters for all patients enrolled in this dose group while in patients treated with laser photocoagulation control visual acuity improved by only 2.4 letters on average (p=0.08). Furthermore, in a separate secondary analysis of the 111 patients who completed the 12 month follow up visit, the mean improvement from baseline on a visual acuity test in the 3mg group was 9.1 letters while in patients treated with laser photocoagulation control visual acuity improved by only 3.2 letters on average (p<0.01).

PF-'655 in Age-related macular degeneration (AMD)

Market opportunity

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. AMD affects 1.7% of people in the US with 200,000 new cases diagnosed there each year. The market for AMD treatments is predicted to reach $2.9bn by 2016 (Source: Credit Suisse).

Current clinical studies

Quark and Pfizer recently completed a phase II trial in 152 with AMD. The trial compared intravitreal injection of Lucentis (Roche/Novartis), the current standard of care, alone, in combination with PF-'655, and sequentially with PF-'655 intravitreal injections. The results of this study have not been announced yet.

Earlier studies:

Quark completed a dose-escalation trial (phase I) with PF-'655 in 2010 (in doses up to 3mg). This study assessed the safety and tolerability of PF-‘655 for the patients enrolled over a 24-Month Period. No drug-related adverse events were observed. Anatomical changes in the retina and choroid were described 14 days after injection of PF-'655. Changes in the visual acuity ETDRS chart were determined 14 days after a single intravitreal injection of the siRNA. More than three quarter of the patients showed improved or stable vision 14 days after a single injection of the siRNA. Moreover, some of the patients (18 of the 27 patients enrolled) showed an improvement on a visual acuity test (mean improvement of 4 letters) after a single injection of the siRNA. While the study was designed to test for safety, and not to assess PF-‘655’s efficacy, these changes were presented as clinically meaningful.

QPI-1002

QPI-1002 is a synthetic, chemically modified siRNA molecule designed to inhibit the expression of p53, a gene involved in the stress-response causing programmed cell death (apoptosis). The p53 gene is involved in acute kidney injury in patients undergoing major cardiac surgery and in delayed kidney graft function. Quark used AtuRNAi® technology to develop QPI-1002. In August 2010, Quark granted an option to Novartis to obtain an exclusive worldwide license to develop and commercialise QPI-1002. Under the terms of Silence's agreement with Quark, Silence's milestone payments from this program could potentially exceed $82 million. Silence already received $2m in milestones.

QPI-1002 in Delayed Graft Function

Market opportunity

Delayed Graft Function is generally the result of ischemia-reperfusion injuries that can take place during the transplantation process. DGF is one of the most common postoperative complication in renal transplantation and affects 25-40% of the deceased donor renal transplant patients. DGF does not have any treatment, actually, and QPI-1002 has been granted Orphan designation for prophylaxis of DGF by the European Medicines Agency (EMA) and the US FDA. The treatment with QPI-1002 would target the population at risk in the 30,000 renal transplants conducted every year in the seven major markets, this figure could increase to 43,000 by 2015 in these markets (source: Datamonitor).

Current clinical studies

Quark is in the process of recruiting 326 patients in a multicentre double-blind phase II trial designed to determine if a single administration of QPI-1002 can prevent DGF in patients undergoing deceased donor kidney transplantation. This study will assess the incidence of delayed graft function and the rate of improvement in renal function over time and the need for renal replacement therapy following a single administration of QPI-1002 (10.0 mg/kg) in patients undergoing deceased donor kidney transplantation.

Earlier studies:

Quark completed a phase I trial where QPI-2002 was administered systemically via intravenous injection and no-dose limiting toxicities were observed. This study was composed of a dose escalation phase (0.5, 1.5, 5, and 10 mg/kg) in 4 cohorts of 10 patients with the main outcome measured being safety.

QPI-1002 in Acute Kidney Injury

Market opportunity

Acute Kidney Injury (AKI) is a devastating disease characterised by a rapid decline of kidney function that occurs in 5% of hospital admissions and up to 30% of admissions to intensive care units. The mortality rate following an onset of AKI is greater than 50%. Major cardiovascular surgeries are the main cause of AKI with up to 30% of cardiac surgery patients developing clinically relevant kidney injury. AKI is, actually, an unmet medical need. With 860 cases of cardiac surgery per million populations, annually, in North America, Australia, and Europe the need for such treatment is significant and is rising.

Current clinical studies

Quark will soon initiate dosing in a phase II clinical trial for Acute Kidney Injury using QPI-1002.

Earlier studies:

Quark completed in 2010 a multicentre phase I double-blind, dose escalation, pharmacokinetic and safety study with 16 patients split in 4 cohorts. The aim of this study was to assess the safety of QPI-1002 and to measure how long the drug stays in the blood stream after injection. This study confirmed the absence of dose-limiting toxicities for systemically administered QPI-1002 (intravenous injection).

Atu027 for the treatment of solid tumours, is Silence’ most advanced internal drug candidate. Moreover, Atu027 exclusively uses AtuPLEX®, Silence's most advanced proprietary delivery system. AtuPLEX® delivers an AtuRNAi® targeted against the patented target: PKN3 to the vascular endothelium.

Atu027 has shown anti-tumor activity and blockage of cancer cell dissemination suggesting a profound anti-metastatic effect of the drug. The blockage of these mechanisms by the removal of the regulatory action of PKN3 could be an essential tool to target tumour which are richly vascularized and prone to metastasise. Atu027, in combination with other currently marketed anti-cancer drugs, has demonstrated additive effects.

Market opportunity:

Several indications have characteristics that make them potential targets for Atu027, particularly: Pancreatic Adenocarcinoma, Ovarian Cancer, Soft Tissues Sarcoma, Melanoma, and Glioblastoma. These diseases represent areas of high unmet medical need with no satisfactory treatments for the patients affected. More than 400,000 persons are diagnosed every year with these afflictions and this figure is rising. Finally, these diseases are characterised by poor prognosis mainly due to the aggressive nature of the tumours and their ability to metastasise.

Current clinical studies:

Atu027 is being tested in a Phase I dose-escalation to assess its toxicity. To date 27 out of 33 patients with solid tumours have been enrolled without any drug-related side effects observed. Solid tumours represent a group of cancers that can form abnormal mass of tissue such as: carcinomas, lymphomas, or sarcomas and may be benign or malignant. From these patients, in advanced stage of their disease, eleven have been confirmed with stable disease. The interim data showing an excellent safety profile has been presented at ASCO (in June 2011). The final data from this study is expected to be released by mid-2012. After Phase-I-finalization, a Phase-Ib/IIa with selected chemotherapeutic regimens is planned in order to obtain important insights in the pharmacological activity of Atu027

Earlier studies:

The efficacy of Atu027 has been demonstrated in multiple cancer animal models with the corresponding studies being published in peer reviewed journals. Atu027 has been shown to knock-down protein and mRNA expression of PKN3 in these animal models, preventing the spread of breast cancer cells, for example. Moreover, combination with other currently available anti-cancer drugs has shown additive effects.

Atu111

Silence Therapeutics is currently evaluating the therapeutic value of using the DACC-siRNA delivery system for RNAi of an undisclosed target in the pulmonary vascular endothelium in acute lung injury (ALI). ALI is a devastating syndrome associated due to many inflammatory and mechanic insults leading to pulmonary edema and hypoxemia. Silence Therapeutics aims to use this therapeutic RNAi approach to ameliorate the severity of ALI for the management of severely ill patients. This is Silences most advanced drug development candidate outside oncology. Pre-clinical models using the DACC delivery system has shown sustained knockdown of up to three weeks in the lung endothelium.

Lung diseases (DACC programs)

Silence Therapeutics is currently evaluating the therapeutic value of using the DACC-siRNA delivery system for RNAi of an undisclosed target in the pulmonary vascular endothelium in specific lung disease. Pre-clinical models using the DACC delivery system has shown sustained knockdown of up to three weeks in the lung endothelium.

Liver diseases (DBTC programs)

Silence Therapeutics is currently evaluating the therapeutic value of using the DBTC-siRNA delivery system for RNAi of undisclosed targets in specific liver diseases. DBTC is a novel lipid-based formulation that functionally delivers siRNA to liver endothelial cells, hepatocytes and other liver cell types with high efficiency. Silence Therapeutics aims to use this therapeutic RNAi approach to address unmet medical needs in liver fibrosis, liver cancer and liver failure.