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Silence Puts Sepsis Program on Backburner as it Advances Cancer Drug

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NEW YORK (GenomeWeb) – Silence Therapeutics this month disclosed that it was ending its work with investigational sepsis drug Atu112 amid disappointing results in preclinical testing. However, given positive data around the drug's target, the British company is continuing to evaluate whether Atu112 can be resurrected using a different delivery technology, according to a company official.

Meanwhile, Silence said its other programs are proceeding apace including its flagship cancer treatment Atu027, which recently entered Phase IIa testing for pancreatic cancer and is on track to move into a Phase Ia study in head and neck squamous cell carcinoma by the end of the year.

Atu112 comprises siRNAs against angiopoietin-2, a ligand of Tie-2 signaling and the same target as Silence's lung injury treatment Atu111. However, Atu112 is formulated with the company's vascular endothelium-targeting AtuPlex delivery technology, while Atu111 uses the firm's so-called DACC delivery technology, which is designed to carry RNAi molecules specifically to pulmonary endothelial cells.

Thus far, angiopoietin-2 has proven to be a promising target in sepsis. In August, Silence and collaborators published data in Critical Care Medicine showing that intravenously administered siRNAs against AGPT2 could reduce the severity of sepsis-related illness and improve survival in mice. Treated animals exhibited reduced pulmonary interleukin-6 transcription, intercellular adhesion molecule expression, neutrophil infiltration, and vascular leakage. Further, manifestations of sepsis were attenuated in distant organs, and the severity of illness was ameliorated.

But it seems that Silence was unable to obtain similar results with Atu112, and in an announcement of its half-year 2014 results released this month, the company said that "preclinical research into the potential of [the drug] in sepsis … has now ceased."

In an email to Gene Silencing News, Silence CEO Ali Mortazavi stated that "we are not giving up all hope" on the drug and indicated that the company is still interested in sepsis as an indication, as well as Atu112 as a potential treatment for the condition, but only if delivery issues can be overcome.

Despite the encouraging Critical Care Medicine study, Silence's primary focus for Atu111 remains in acute lung injury, with preclinical testing in the indication continuing.

As for Atu027, Silence said that the Phase IIa trial recently completed enrollment with 24 patients with locally advanced or metastatic pancreatic adenocarcinoma at clinics throughout Germany. The study is designed to evaluate the drug's safety and pharmacokinetics when used in combination with the standard of care, gemcitabine.

Specifically, the trial is testing two different treatment regimens. One involves a 28-day cycle of Atu027 and gemcitabine once weekly for three consecutive weeks, with no treatment during week four. The second is testing a 28-day cycle of gemcitabine once weekly and Atu027 twice weekly, followed by a 28-day cycle of gemcitabine alone. In both cases, the treatment is continued in 28-day cycles until unacceptable toxicity or disease progression is observed.

Follow-up analysis of these patients is expected in mid-2015, Silence said. Patient enrollment in the Phase Ia study in head and neck cancer is slated to begin before the end of this year.

Silence also said that it is currently evaluating a number of discovery-stage compounds as potential pipeline candidates, an effort bolstered by the establishment of a dedicated unit recently within its 40-person research and development facility in Berlin.

First-half financials

During the first six months of 2014, Silence reported an 86 percent rise in its research and development spending to £3.9 million ($6.3 million) from £2.1 million in the same period a year earlier.

General and administrative costs rose to £1.8 million from £400,000, in part due to rent for a newer London office and hirer salary costs linked to an increase in headcount.

Silence's loss for the six-month period ended June 30 was £5.6 million, up from £3.4 million in the six-month period the year before.

At the end of the first-half of 2014, Silence had cash and cash equivalents totaling £21.3 million, a figure that reflects a successful £11.4 million placement of shares in April.

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