Israeli firm InSightec, which is partly owned by General Electric Co., is nearing a milestone. At the time of this writing, a counter on the privately held company’s website read 9,587. These are the number of women, to date, who have had their uterine fibroids, painful non-cancerous growths in the uterus, burned away by the manufacturer’s MR-guided High Intensity Focused Ultrasound system, known as ExAblate. Well before the year is out, InSightec’s global patient base should pass 10,000.

Whether or not champagne corks pop at the company’s Tirat Carmel headquarters when that happens, research is underway for new applications for the technology, from treating cancer to neurological disorders. InSightec’s rival, Philips Healthcare, is also amassing evidence for its own MR-guided HIFU system, the Sonalleve. Although the system is not available yet in the United States, Philips is running a pivotal trial on the treatment of uterine fibroid with the device, which it hopes to wrap up by spring of 2016, according to the clinicaltrials.gov page documenting it.

Although ultrasound (and not MR)-guided HIFU treatments for cancer, particularly prostate cancer, have attracted some controversy, researchers are pushing for new studies. This spring, a new journal formed to publish results from HIFU therapies, the Journal of Therapeutic Ultrasound, backed by the Focused Ultrasound Foundation, a society whose board includes a rather surprising mix of names from outside medicine, from former “junk bond king” Michael Milken to best-selling author John Grisham.

It’s not just HIFU that’s attracting attention. Researchers are looking at another ultrasound technique to turn sound waves into an incision-less scalpel, allowing, in effect, a kind of surgery without breaking the skin.

“It’s a platform and a modality that I believe is going to be around for a long time, and along with HIFU, a lead modality for noninvasive surgery,” says Tom Davison, CEO of the startup HistoSonics that’s working on the technology. But whether MR-HIFU, or HistoSonics’ product, gain their lead status will depend greatly on the results of a range of clinical studies going on now or slated for the near future.

Uterine fibroids

HIFU works by using ultrasound transducers to concentrate acoustic energy on a target to raise its temperature, much like how a magnifying glass can focus the sun’s rays to scorch grass or hapless bugs. As its name suggests, MR-HIFU uses real-time MR imaging to help doctors guide HIFU procedures.

MR-HIFU treatments of uterine fibroids take about three hours, and work by heating the fibroid to about 65 degrees centigrade, according to Thomas Andreae, with Philips’ MRC Therapy Business Development unit in Helsinki, Finland. “That’s enough to ablate the tissue, but it’s not overheating or putting the patient at too much risk,” he says.

This use is by far the most common application for the technology in the U.S. In fact, so far, InSightec’s ExAblate has only two clinical uses approved by the U.S. Food and Drug Administration (Philips has none): treating uterine fibroids (approved in 2004) and zapping painful bone metastases which don’t respond to medication (approved last October). But the bread-and-butter of the systems is still uterine fibroids, and likely will be for the next few years. InSightec, which in addition to GE is owned by Elbit Imaging and Meditech Advisors, says its ExAblate treats about 1,200 women a year globally.

“It’s still a small fraction of the potential market,” Eyal Zadicario, vice president of R&D at InSightec, tells DOTmed News.

To strengthen the case for the technology and potentially capture more of that market, InSightec, along with Philips, announced in May the launching of a new treatment registry, RELIEF, to record both clinical and economic data on MR-HIFU fibroid treatments. The goal is to collect data on 1,000 patients, Zadicario says.

For its part, Philips is working to get its MR-HIFU system, the Sonalleve, on the U.S. market soon. The company is still running a phase 3 trial for the FDA, which is recruiting patients at nine sites worldwide, eight of which are in North America. The product has been available in Europe since early 2010, and it’s also for sale in Canada, Korea and a few others countries. About 50 units have been installed globally.

According to Philips, uterine fibroids were a good early candidate for technological, clinical and financial reasons. “(Fibroids are) sitting there in the pelvis and they don’t move and they’re fairly big, and you have a good acoustic window,” says Andreae.


Neurology

But while a good early candidate, for MR-HIFU, uterine fibroids are just the beginning. Currently, InSightec has its transducers pointed next to a neurological disorder: essential tremor.

Essential tremor is a neurodegenerative disease characterized by an unpleasant rhythmic shaking of the hands or other limbs. Zadicario says it’s the most common movement tremor worldwide. About 10 million people suffer from it in the United States, making it nearly eight times more prevalent than Parkinson’s disease, according to the International Essential Tremor Foundation.

Sadly, about 30 percent of cases don’t respond to medication, Zadicario says. For them, the treatment of choice is usually deep brain stimulation, where a pacemaker-type device is surgically implanted, and which sends brief jolts to the brain to control tremors. But Zadicario believes there’s a market for a surgery-free alternative.

“There is a very significant interest from the essential tremor patient society for non-invasive treatment,” he says.

Enter ExAblate Neuro, the brain-treatment version of InSightec’s MR-HIFU device. In late April, InSightec and University of Virginia researchers, led by Dr. Jeffery Elias, presented results of a phase I feasibly study using the device to treat essential tremor at the American Association of Neurological Surgeons annual event in New Orleans. In the trial, researchers used the ExAblate Neuro to zap tissue in the thalamus, particularly around the Vim nucleus, which is implicated in the tremors.

Elias and colleagues said after the therapy, the 15 patients in the trial experienced an average 67 percent decrease in symptoms, according to a Richmond Times-Dispatch write-up.

“We reduced the amount of tremor in the dominant hand fairly substantially,” Elias told the paper. “That led to a very significant improvement in quality of life.”

So far, though, the data are only preliminary. As part of the full FDA application process, Zadicario says they’ll launch a multi-center pivotal study with around 70 patients at five sites in the U.S., and up to eight worldwide. Overall, Zadicario expects a three-year commercialization process.

But non-Americans already have access to the treatment. The ExAblate Neuro was approved for sale in the European Union on December 27 in Europe, with two sites in Switzerland offering treatment now, Zadicario says.

Breast cancer

One potential application of MR-HIFU, and one of possibly the greatest interest both to the vendors and to clinicians, is cancer treatment. Both InSightec and Philips have clinical trials underway investigating how their devices fare against a variety of cancers. Last year, Philips says it launched a feasibility pilot trial on breast cancer treatments with 10 patients. For the trial, the company says they built a dedicated version of the Sonalleve to accommodate the anatomy of the breast.

In the fibroid-blasting Sonalleve, a half-sphere-shaped transducer array squats beneath the imaging table. By contrast, for the breast system, Philips says it built a ring structure that lets the transducers fit around the breast, so ultrasound energy can come from multiple directions to build the focus in the tumor. This set-up reduces the risk of burning the skin, Philips’ Andreae says. By maximizing the amount of skin surface exposed, each bit of skin heats up less.

“Non-target tissue only rises a few centigrade above body temperature,” he says. “At maximum, a mild skin reddening (appears) and not more than that.”

For the first trial, Philips is looking at large tumors, which will be removed and dissected after the treatment to see how successful the ablation was.

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