Ultrasound and fury

Philips and RXi Pharmaceuticals look to fight disease by jointly researching innovative image-guided, RNAi-based therapy

Jeffrey Bouley
WORCESTER, Mass.—The problem with creating effective RNA interference (RNAi)-based therapeutics is finding ways to deliver them to their target while keeping them fully active. One of the solutions may be ultrasound. To that end, RXi Pharmaceuticals Corp. and Eindhoven, the Netherlands-based Royal Philips Electronics have entered into a joint research agreement to explore the benefits of combining proprietary technologies for the targeted delivery of experimental RNAi-based therapeutics.

As both companies note, compounds based on RNAi represent a promising new class of drugs for the targeted treatment of a number of complex diseases, including cancer and cardiovascular disease. The joint research program between Philips and RXi will attempt to overcome the RNAi delivery challenge by exploring, in preclinical studies, the possibility of using RXi's sd-rxRNA (self-delivering rxRNA) in conjunction with Philips' ultrasound technology to achieve the targeted delivery and monitoring of RNAi-based compounds in cells.

Although RXi spends a lot of its time on the sd-rxRNA program so that can engineer RNAi therapeutics to have small-molecule-like properties, the company's researchers and leaders know that they can't put all their eggs into that basket.

"The area we spend about two-thirds of our time on is the self-delivering RNAi system, so that we can have delivery system and payload in one package and have it work as effectively as a small molecule, with stability and minimal immunogenicity and other key characteristics," says Noah D. Beerman, president and CEO of RXi. "We're doing a very good job with that, but we do balance things, and the other third of our time is spent exploring other methods as well, alone or in partnership with other companies."

"It's been clear from the start that the pharmacokinetic properties of RNAi therapeutics are quite challenging," adds Dr. Dmitry Samarsky, vice president of technology development for RXi. "So, we've been making lists of companies and technologies that might help with the delivery problem for a long time. We've looked at Philips' technology before and it was very clear a few years ago that their methods stood out from many of the other technologies out there and it still does, and their very advanced equipment and expertise may be just what we need to help us achieve delivery of RNAi therapies to specific tissues."

As Beerman says, his company's RNAi molecules seem to be good at getting their job done once they are in close proximity to their target cells. The problem is often getting the RNAi molecules across the endothelial layer and close enough to the tissues and cells they need to reach, and Philips' ultrasound technology may overcome that.

Philips' image-guided ultrasound-mediated drug delivery platform offers researchers a potential approach to the delivery of various therapeutic molecules across blood vessel barriers and facilitating their uptake in cells—capitalizing on Philips' existing expertise in medical imaging technologies for diagnosis, therapy planning and minimally-invasive medical procedures.

"As part of Philips' holistic care cycle approach to patient care, we are constantly exploring novel concepts for the diagnosis, treatment and follow-up of diseases. Our decision to jointly research RNAi-based therapies with RXi is driven by our belief that patient care will ultimately benefit from the combination of novel drugs and advanced medical imaging technologies," says Henk van Houten, senior vice president of Philips Research and head of its healthcare research program. "The development of ultrasound techniques that could non-invasively trigger the delivery of new drug formats such as RNAi therapeutics at a targeted location opens up exciting possibilities for advancing personalized medicine."

Each company will contribute proprietary technologies, resources and expertise to test novel approaches for the targeted delivery of RXi's sd-rxRNA compounds in appropriate preclinical models using ultrasound-mediated drug delivery under image guidance. The preparation and research will be conducted at Philips' Life Tech research facilities at the High Tech Campus in Eindhoven, and at RXi's research and development facilities in Worcester.

The deal is very timely, given that it was nearly six months ago that Philips made a big push for its ultrasound-based, image-guided drug delivery technologies, when it announced that it would lead a major new European project to develop delivery technologies that would allow drugs to be delivered to disease sites via the patient's bloodstream and then activated by focused ultrasound pulses. Called the SonoDrugs project, the effort aims to maximize the therapeutic efficiency and minimize the side effects of drug treatments specifically for cancer and cardiovascular disease.

The SonoDrugs project involves 15 industrial partners, university medical centers and academic institutions throughout the European Union and will run for four years.
Philips notes that although powerful drugs are available to treat certain types of cancer and cardiovascular disease, they are mostly administered as intravenous or oral doses—posing the problem of very limited control over the distribution of those drugs. As a result, the therapeutic agents can circulate in the patient's bloodstream and interact with many different tissues and organs, both diseased and healthy.

The SonoDrugs project aims to address this challenge by developing drug delivery vehicles that can be tracked by ultrasound or magnetic resonance imaging and triggered by ultrasound to release the drugs at the desired location, theoretically increasing therapeutic efficiency and minimizing side effects, while also providing a means of tailoring the therapy to individual patients.

"New therapeutic options such as externally triggered local drug release at the specific site of disease hold the promise to significantly improve patient care," says Houten. "We realize that medical imaging technologies are only one of the enablers required to fulfill this promise. However, the wide-ranging expertise that has been brought together in the SonoDrugs project puts us in a strong position to ultimately deliver the benefits of image-guided drug delivery to patients and care providers."



RXi announces new focused therapeutic strategy for its next-generation RNAi technology

By Jeffrey Bouley

WORCESTER, Mass.—News of the Philips-RXi joint research in early June was followed mere days later by the announcement that RXi Pharmaceuticals Corp. would be pursuing a new focused RNAi therapeutic strategy.

"RNAi technology has so much promise and there are so many potential applications once the delivery problem is overcome," notes Noah D. Beerman, president and CEO of RXi. "So we can envision going to almost any target in the genome theoretically to fight disease. It is something that provides a kind of 'embarrassment of riches' issue. With 30 or so companies seriously playing in this space now, and more in the future, I'm sure, we need to make sure we are focused."

As such, the company has established a three-prong strategy. The first level is the "core focus" area, within which RXi will pursue potential candidates in select therapeutic areas with attractive market potential that it is prepared to take all the way to the clinic—alone if necessary. Right now, that involves two main areas: dermatology, in which RXi is pursuing a program in anti-scarring, and ophthalmology, in which RXi is moving forward with a program in retinal disorders, such as wet and dry age-related macular degeneration, diabetic retinopathy and diabetic macular edema.

The second level of the strategy, RXi will explore additional indications through preclinical development that are of "strategic interest" to the company and may provide partnership opportunities. Right now, in the area of neurology, RXi is exploring direct spinal cord delivery of sd-rxRNA. Also, in the area of oncology, RXi will be concentrating initially on liver metastases and hepatocellular carcinoma using systemic delivery of sd-rxRNA or rxRNA compounds in combination with delivery vehicles.

The third layer of the strategy would be "opportunistic pursuit" areas, where RXi will continue to evaluate multiple opportunities and is prepared to engage in more active therapeutic development in cases where a program is funded by a partner or where RXi attains promising initial results. Potential areas include hepatic disease (hepatitis C, for example), respiratory (including asthma and chronic obstructive pulmonary disease), oncology and others.
 

Jeffrey Bouley

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