BioWorld International Correspondent

LONDON - SR Pharma plc is poised to be first to the clinic with a systemic RNAi therapeutic after establishing GMP manufacturing of a liposome formulation of its lead product, Atu027.

The London-based company will start preclinical toxicology studies of the product later this month and have discussions with the German regulator to define final steps before starting a trial in liver cancer in the first half of 2007.

Iain Ross, CEO, told BioWorld International, "Liposomal formulations are never simple, but we have brought together a really good team of people across several companies and cracked the limitations of RNAi - we can now deliver a GMP standard therapy systemically." Not only that, but the company's AtuPLEX technology also solves the problem of the limited half-life of naked siRNA, which should translate into lower doses, or fewer injections.

The principle of gene silencing using siRNA is well established, but the problem of delivering siRNA within the body to sites where offending genes are causing disease has been the barrier holding back the RNAi market.

Ross said SR Pharma's German subsidiary Atugen is on course to complete toxicology studies by the end of the year. Apart from paving the way for its own Phase I trial, that would open up the potential for licensing the AtuPLEX RNAi delivery platform.

"We could out-license the platform, or collaborate in terms of specific targets," Ross said. "We are in several discussions with big pharma on AtuPLEX, but they want to see the tox data first."

Ross said there is huge appetite for RNAi technology from pharmaceutical and biotech companies. "We even have other RNAi companies talking to us because they are interested in our delivery platform," he said.

Pharma companies have shown serious intent in the area already. Alnylam Pharmaceuticals, of Cambridge, Mass., signed a deal worth a potential $700 million with Novartis AG, of Basel, Switzerland, in September 2005; Sirna Therapeutics Inc., of San Francisco, has a deal of the same value with GlaxoSmithKline plc, of London, in respiratory diseases.

AtuPLEX both protects siRNA constructs from being degraded by nucleases and targets them to the required site in the body. SR Pharma is claiming another breakthrough with its formulation, which enables liposomal siRNA drugs to be lyophilized and stored at ambient temperatures. The resulting power is reconstituted with water with no additional preparation steps. That will extend the shelf life, simplify the distribution chain and make products easy to administer.

Although there are siRNA products in the clinic, they are in ophthalmic applications, such as Sirna's and Acuity Pharmaceuticals Inc.'s respective treatments for wet age-related macular degeneration, which are injected directly into the eye, or in pulmonary applications that use aerosol inhalation.

Alnylam published preclinical data on systemic delivery of siRNA in monkeys in Nature in March. The company subsequently announced a collaboration with Inex Pharmaceutical Corp., to use Inex's liposomal delivery platform and said it hoped to get an encapsulated product into the clinic in the next 18 to 24 months.

If SR Pharma stays on track, it should have two products in clinical trials by the end of 2007. The trials will take place in Charité University Hospital in Berlin. Atugen has been collaborating with the clinic for some time, and Ross said trials could be recruited quickly, with safety and delivery to the tumor as primary endpoints. "We would also hope to see some signs of efficacy, but obviously the patients in this trial are likely to be pretty ill."

The complexity of RNAi products is exemplified by the collaborations SR Pharma had to put in place to produce GMP standard material. Genzyme Corp. will manufacture the two main components of the delivery system, a cationic lipid AtuFECT and a fusogeneic lipid. Meanwhile, BioSpring GmbH, a German oligonucleotide manufacturer, will produce the siRNA molecules that are the main active ingredient. The Dutch company OctoPlus NV will then scale up GMP formulation of those components.

SR Pharma has done one deal on AtuPLEX, in which Introgen Therapeutics Inc., of Austin, Texas, took a £1.7 million (US$3.1 million) equity stake in SR Pharma in return for a license in August 2005. But, armed with the toxicology data, Ross is hoping for a bigger-ticket cash deal to demonstrate the value of the technology.

"We believe we have taken a big step up, but we are still getting beaten up in the [stock] market. Until we validate [the technology] in a deal with big pharma, the market won't appreciate our progress," he said.

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