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Silence Starts Phase Ib/IIa Trial of Cancer Drug as It Looks to Balance Pipeline


Silence Therapeutics this week announced that it has begun dosing patients in a phase Ib/IIa clinical trial of its cancer treatment Atu027 in combination with chemotherapy after having identified the drug’s maximum tolerated dose in a phase I study last year.

Also this week, Silence reported its 2012 financial results, posting a sharp increase in its operating loss due to a roughly £20.1 million ($30.2 million) impairment charge. Meanwhile, the company continues to weigh its options for its other pipeline programs in order to lower its dependence on Atu027.

Atu027 is a blunt-ended siRNA that is formulated with the company’s proprietary AtuPlex lipid-based delivery technology and targets the protein kinase PKN-3, which is associated with cellular morphology and locomotion in endothelial and cancer cells.

The drug has essentially been Silence’s sole product candidate for years, but it wasn’t until mid-2009 that it advanced into phase I testing. In 2012, Silence released data from that study showing that Atu027 was safe and well-tolerated in patients with advanced or metastatic solid tumors at a maximum tolerated dose of .336 mg/kg (GSN 6/7/2012).

In light of those data, Silence has recently begun dosing patients in the first portion of a phase Ib/IIa study that will examine Atu027 in combination with the chemotherapeutic agent gemcitabine in patients with locally advanced or metastatic pancreatic cancer.

The phase Ib portion of the study will examine the drug cocktail’s safety in three patients with non-pancreatic cancer who have failed conventional treatments. Atu027 will be administered twice a week for four weeks and gemcitabine will be given once a week for three weeks.

If no toxicity is observed, the phase IIa arm of the trial will begin with pancreatic cancer patients receiving the two drugs once a week for three consecutive weeks, with no treatment on the fourth week. This dosing schedule will continue in consecutive 28-day cycles until toxicity or disease progression occurs.

The phase IIa arm will also examine a second dosing regimen of gemcitabine once a week and Atu027 twice a week for four weeks, followed by a 28-day gemcitabine monotherapy cycle. Treatment will continue in consecutive 28-day cycles until unacceptable toxicity or disease progression is observed.

The 30-patient study is expected to wrap up in early 2015.

Despite the encouraging data available on Atu027, Ali Mortazavi, Silence’s director of corporate strategy, said in the company’s 2012 financial report that the drug remains a risky proposition.

“Atu027 could help cancer patients at risk from developing metastasis thereby slowing progression of disease and improve[ing] survival,” he wrote. However, demonstrating such benefits will require sizable clinical trials using progression-free survival or overall survival as endpoints.

“At this time, the early indicators of efficacy that are normally available to drugs with tumor-killing properties are not available to Atu027, given its mechanism of action,” he added. As a result, Silence considers the drug a “high-risk, but high-reward opportunity,” and is looking to “balance the pipeline accordingly.”

This includes not only exploring additional oncology indications for Atu027, including head and neck cancer and breast cancer, but also moving forward with candidates in other disease areas.

These include Atu111 for the treatment of acute lung injury/acute respiratory distress syndrome and Atu044 for hypercholesterolemia.

The first drug uses the company’s endothelium-targeting DACC system to deliver siRNAs against angiopoietin-2, a ligand of Tie-2 signaling that is elevated in patients who develop ALI/ARDS. Last year Silence reported preclinical data showing that treatment in combination with antibiotics could increase the survival of mice infected with pneumonia (GSN 9/13/2012).

Atu044, meanwhile, employs Silence’s DBTC delivery system, which targets liver cells, to carry siRNAs against apolipoprotein B. In mouse studies, a single dose of the drug has been shown to lower its target by 80 percent, according to the company.

Silence also has a number of earlier-stage drugs including Atu134, which uses the DACC technology to deliver siRNAs targeting CD31 as a treatment for lung cancer; Atu047, which uses DBTC to deliver siRNAs against factor VII for the prevention of blood coagulation/thrombosis; and Atu614, which comprises DBTC-formulated siRNAs against the Fas death receptor to treat acute liver injury.

2012 Financials

For the 12-month period ended Dec. 31, 2012, Silence’s operating loss swelled to £26.3 million ($39.8 million) from a year-ago loss of £5.8 million, driven by a £20.1 million charge related to the impairment of goodwill associated with the closure of the company’s US operations, the write down of intangible assets, and accounts payable.

Revenues for the year were about £160,000, down from £530,000. Meanwhile, research and development spending remained flat at £3.4 million, while administrative costs were essentially unchanged at £2.6 million.

At the end of 2012, Silence had cash totaling £8.9 million, which includes £10.3 million netted during the year through private stock placements and open offers. In April this year, the company raised an additional £19 million, before expenses, in an equity placement.