N o n - i n v a s i v e therapeutic ultrasound, with its 18 distinct bio-effects on tissue, is now approved or under investigation to treat nearly 60 conditions ranging from neurological disorders to cancers, pain and even hypertension. Over these past two years, the field has experienced unparalleled progress, and recent research advances have brought us to the tipping point for the technology to transform from research to clinical use. The FDA recently approved two prostate devices, giving patients in the United States access to a therapy that has been available in several other countries for years.

The blood-brain barrier has been opened to deliver chemotherapy directly to the brain and demonstrate the potential of treating other diseases including Alzheimer’s. We are on the cusp of starting the first clinical trials to enhance cancer immunotherapy which could demonstrate a critical role for focused ultrasound in combination with promising immunotherapies to treat advanced cancer.

And the FDA is currently reviewing a focused ultrasound system for noninvasive, precise ablation of the brain to treat essential tremor. Once approved, this would open the door to treating Parkinson’s and other movement disorders, as well as psychiatric disorders and brain tumors. A technology once referred to as “medicine’s best kept secret” is poised to become a major therapeutic tool with the ability to impact the lives of countless individuals.

Expanding patient access and growing the U.S. market (for prostate)
Focused ultrasound has been used worldwide to treat more than 50,000 men with prostate cancer over the past 20 to 25 years. Yet despite approvals in Europe and elsewhere, men in the United States have had to travel overseas to access this less invasive and non-ionizing treatment. But men who want to avoid surgery and radiation now have a new option — the FDA recently approved two focused ultrasound systems (Sonablate from Sonacare and Ablatherm from EDAP) for prostate tissue ablation.

This is great news for patients who desire treatment that is less invasive and may offer fewer complications and quicker recovery than traditional methods. FDA approval of two new prostate systems is a huge step forward for the field in the U.S. Because of the potential for fewer complications and side effects, many prostate patients will pay out-of-pocket for focused ultrasound treatment. This helps to build momentum for clinical use as well as eventual widespread reimbursement and commercial success. Knowing that patient demand will be robust, urologists are investing in the technology — more than 10 practices have acquired Sonacare or EDAP’s systems in the past few months since FDA approval.

In addition to opening the market for prostate treatment, Sonacare and EDAP’s focused ultrasound systems also provide new diversity in focused ultrasound imaging approach. A key benefit of the technology is that it allows for real-time treatment monitoring. These new prostate systems are ultrasound-guided, with the imaging built into their systems, making them fairly mobile and cost-effective. Each system was designed specifically for treating the prostate, yet some hardware may serve as a platform for future devices and indications. The Sonablate system was approved through the
FDA’s de novo 510(k) process, which then allowed for EDAP to utilize the 510(k) pathway.

This could potentially enable a quicker and more streamlined regulatory pathway for future focused ultrasound devices. The other focused ultrasound system in the U.S. market, developed by Israeli company Insightec, is approved for the treatment of uterine fibroids and pain from bone metastases. This ExAblate system is magnetic resonance (MR)-guided, enabling MR thermometry for treatment monitoring.

This system serves as a platform for other uses being researched, like soft tissue tumor ablation. The different types of focused ultrasound systems give providers choices on what fits best into their practice or hospital system.

Beyond ablation — opening the blood brain barrier
Recent developments demonstrate focused ultrasound’s reach far beyond that of a simple tool for ablation. This past November, focused ultrasound was used for the first time to noninvasively open the blood-brain barrier (BBB), enabling more effective delivery of chemotherapy into a patient’s malignant brain tumor. A team at Sunnybrook Health Sciences Centre infused the chemotherapy agent doxorubicin, along with gas-filled microbubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the micro-bubbles to vibrate, loosening the tight junctions of the cells comprising the BBB and allowing delivery of the chemotherapy to the targeted tissues.

While this recent experience is a first-inhuman achievement, numerous pre-clinical studies over the past decade have demon strated the ability of focused ultrasound to safely and temporarily open the blood brain barrier with micro-bubbles. Research has shown that this approach may not only enable drug delivery, but might also stimulate the brain’s natural immune response.

For example, two separate laboratories using two different Alzheimer’s mouse models have demonstrated that focused ultrasound and micro-bubbles alone, through temporary opening of the BBB, appear to facilitate the brain’s clearance of beta amyloid, a key pathologic protein related to Alzheimer’s. The approach also demonstrated improved memory and cognitive function with no unwanted damage to brain tissue. While the results are preliminary, having two sites validate this approach is very promising. Based on these two pre-clinical studies, a pilot clinical trial using focused ultrasound to treat Alzheimer’s is being organized.

Safe, reliable and temporary opening of the BBB remains an unmet critical medical need for the treatment of a range of diseases. The current methods of getting through this barrier, either via direct brain injections or using mannitol, are far from ideal, and focused ultrasound may offer a better option. Furthermore, the ability of focused ultrasound to non-invasively induce various other effects in the brain, including precise ablation, immunomodulation and neuromodulation, offers potential future benefits to disorders beyond Alzheimer’s, -Parkinson’s, epilepsy, glioblastoma and possibly others — and has the potential to impact millions of patients worldwide.

Grisham book raises hope, increases awareness
For widespread clinical adoption of focused ultrasound to become a reality, there is a continuous need to raise awareness of this promising and multi-functional platform technology among important stakeholder groups including physicians, payers, hospital administrators and patients. In an effort to raise awareness on a wide scale, John Grisham has written a short book about focused ultrasound called The Tumor. It is a fictional account portraying the potential of focused ultrasound to impact the lives of many suffering from deadly or debilitating diseases such as brain tumors.

Grisham has been a Board member and steadfast supporter of the Focused Ultrasound Foundation for years. He decided to write this book to ignite widespread interest in the field and potentially drive donations to fund future research. The book is available through the Foundation (www. thetumor.org) and a free e-book on Amazon. More than 200,000 books have been ordered to date.

What’s ahead?
Before the end of 2016, the FDA should rule on focused ultrasound to treat essential tremor using a dedicated brain system. Promising results of a pilot trial of 15 patients, published in the New England Journal of Medicine, led to a larger multi-site pivotal trial. The FDA is currently reviewing the PMA submission of this pivotal trial. Approval will open the door to treatment of other movement disorders, as well as psychiatric disorders, using precise ablation of known targets in the brain. Clinical trials are ongoing in the U.S. for Parkinson’s tremor and dyskinesia, and are on the horizon for epilepsy, OCD, depression and dystonia.

With successful initiation of the first trial using focused ultrasound to non-invasively open the blood-brain barrier, and building on promising pre-clinical results in Alzheimer’s models, a pilot clinical trial for treatment of Alzheimer’s is being organized. Our hope is that this safety and feasibility trial will begin within the next year, and successful results could lead to follow-on trials investigating the efficacy of focused ultrasound with and without drugs to treat or slow the progression of Alzheimer’s.

Pre-clinical evidence is mounting, demonstrating that focused ultrasound can enhance the immune response to cancer and/or enhance the effects of promising cancer immunotherapies such as checkpoint inhibitors. In the near future, the first clinical trial testing focused ultrasound in combination with immunotherapy should begin. If successful, this could open the door to a promising new combination approach in the treatment of advanced cancer. Recent research advances and increasing awareness have pushed focused ultrasound to the tipping point, where it is primed to develop into a multipurpose therapeutic technology to improve outcomes for patients with a wide range of serious medical disorders.

About the author: Jessica L. Foley, Ph.D., is chief scientific officer of the Focused Ultrasound Foundation. Dr. Foley joined the Foundation in 2012 after completing a one-year AAAS Science and Technology Policy Fellowship at the National Science Foundation. Prior to that, she was the Neuro Projects Manager and Clinical Marketing Manager at InSightec, one of the pioneering focused ultrasound medical device manufacturers.