ClearPoint in the News
September 26th, 2022
Clinical Laserthermia Systems (CLS) AB receives 510(k) clearance for the ClearPoint Prism™ Neuro Laser Therapy System. ClearPoint Neuro has exclusive global rights to commercialize the CLS magnetic resonance (MR) guided laser interstitial thermal therapy (MRgLITT) system for neuro applications.
ClearPoint Neuro Inc. said Clinical Laserthermia Systems AB (CLS), snared a 510(k) from the FDA for a laser interstitial therapy system that will be marketed in the U.S. as part of the ClearPoint Prism Neuro system. This product package adds to a growing ClearPoint footprint in the neurological disorders space, adding to an inventory that already consists of targeted drug delivery and deep brain stimulation systems.
Solana Beach, Calif.-based ClearPoint Neuro, which until roughly two years ago went by the name of MRI Interventions, nudged its way into the limelight in this end of the neurosurgery space nearly a decade ago when it reported on developments associated with the first iteration of its namesake system. The company had won a 510(k) for the system three years earlier, but was carefully expanding its market with eight centers in the U.S. and two in Europe at that point in time.
David Franco, general manager of ClearPoint’s laser business operations, told BioWorld, that the current operating configuration includes the laser system by Lund, Sweden-based CLS and thermometry by Pessac, France-based Image Guided Therapy SA, in addition to ClearPoint’s surgical management system, which includes a dedicated laptop computer, a console and surgical instruments. Franco confirmed that the 510(k)for the CLS component is agnostic for tissue type and location, but that it generally calls for necrotizing and coagulating soft tissue through interstitial irradiation or thermal therapy under MRI guidance.
This system will typically be used for brain cancers and other intracranial tumors, but Franco said epilepsy is one potential addition to the indication for use for the ClearPoint. The big advantage in this class of surgical interventions is that these systems typically require the creation of a surgical access point of only 3-4 millimeters in many instances, whereas craniotomy was required in times gone by for epilepsy treatments.
This configuration allows the surgeon to conduct the procedure within the MRI torus without breaking the sterile barrier even though the gantry must slide out and back in from time to time. Among the other companies working in this space are Monteris Medical Inc., and Medtronic plc (for its Visualase unit), but Franco said ClearPoint has a compelling story to tell customers. For one, the system’s fiberglass tip does not heat up like the polymerase tips used by the competition, which eases workflow concerns on the part of hospital administrators and neurosurgeons alike.
The second competitive advantage is that ClearPoint can offer all a neurosurgeon’s needs from just one vendor, something Franco said was on the wish list for many clinicians and hospital administrators. Beyond that, this combination of products allows the surgeon to confirm the trajectory of the laser insertion device while the patient is inside the MRI and before the need to commit to placing the catheter. "The Thermoguide software loaded into the ClearPoint navigation platform is highly accurate for voxel size and refresh rates as well", Franco said, adding that the company has 2,000 cases in evidence to back the company’s claims about the ClearPoint platform.
Franco said the ClearPoint Prism™ moniker will be used across the globe, adding that the company’s next geographic play is the European Union. Pursuant to a CE mark, the company has obtained regulatory approval for a clinical study that teams the company up with Lund University in Lund, Sweden, but after that, ClearPoint will be “looking opportunistically” at nations in Asia and South America.
From early on, there were other projects in other spaces that ClearPoint management saw as attractive, but the novel technology behind the ClearPoint platform, which was invented via a collaboration between company scientists and their counterparts at Johns Hopkins, seemed to suggest the neurosurgery space was the best application. “That was understood early on and became the focus shortly after the company was founded", Franco said, adding that this focus was solidified with the name change.
The company’s share prices have oscillated quite a bit since February of 2021, when they reached roughly $29, but share prices (NASDAQ: CLPT) are struggling to stay above $10 in late afternoon Sept. 26 trading.Franco said CEO Joseph Burnett is clear about the operational plan. “Our company continues to grow on multiple levels,” Franco said, such as revenues and case volumes. Franco said a number of factors that are affecting med-tech share prices generally are plaguing ClearPoint as well, but he added, “If you look at our stock compared to comparable baskets of stocks, we’re actually doing quite well.”
Franco said ClearPoint has a strong cash position, and thanks to this latest approval and other sources of good news, “we’re going to continue to see share price growth".
ClearPoint Neuro in July 2021 entered into an agreement with none other than Blackrock Neurotech to develop an automated surgical solution for implanting BCIs into patients with neurological disorders — including from paralysis, ALS, blindness and hearing loss.
Solana Beach, Calif.–based ClearPoint Neuro at the time that the partnership aims to leverage its platform and software with Blackrock Neurotech’s Utah Array to deliver a clinical solution for surgeons that is more streamlined and effective than other BCI implantation surgeries performed to date.
Earlier this year, ClearPoint announced a collaboration with Durham, North Carolina–based Higgs Boson Health to bring to market a patient-facing digital application based on the ManageMySurgery platform. The application will specialize in drug delivery to the brain and spine, as well as BCI technology.
August 11th, 2022
The Maestro Brain Model reportedly provides automated identification, quantification and labeling of brain structures on magnetic resonance imaging (MRI).
Offering the promise of more efficient reporting of findings from magnetic resonance imaging (MRI) of the brain, the Maestro Brain Model has garnered 510(k) clearance from the Food and Drug Administration (FDA), according to the software’s manufacturer ClearPoint Neuro.
Combining deformable surfaces with active shape models and machine learning, the Maestro Brain Model can provide neuroradiologists with automated labeling as well as shape and volumetric quantification of brain structures on MRI scans.
ClearPoint Neuro said the anatomical segment analysis tool emerged from research examining volumetric and shape abnormalities caused by mild traumatic brain injuries. Noting cross-validation of the technology with more than 1,000 MRI scans, the company noted the Maestro Brain Model offers accurate and highly reproducible results.
The company says future applications of the Maestro Brain Model may facilitate targeted treatment of brain injuries.
“Our plan is to quantify drug delivery using intraoperative imaging and simulate patient-specific infusions in targeted brain regions,” explained Lyubomir Zagorchev, a vice-president of Clinical Science and Applications at ClearPoint Neuro. “The unique shape representation in (the Maestro Brain Model) will provide reproducible lead placement for deep brain stimulation and micro electrode recording. Surface meshes of segmented anatomical regions will define safety zones and optimal trajectories for patient-specific laser ablations.”
June 10th, 2022
A pioneering surgical technique treats a tough form of epilepsy while also giving a rare close-up of the insula, a structure crucial to consciousness and treacherous to access.
Camille LaRock’s seizures looked nothing like the ones people see in movies. She stayed fully conscious and could move well enough to play soccer in the midst of a seizure. The only outside sign was a twitch in her eye, a slight droop in her face, and an uncontrollable moan emanating from her lips. The seizures began in middle school, and disrupted her life throughout her teens, sometimes multiple times a day. She was on so much anti-seizure medication at one point that she had to lean against the wall to walk between classes. And yet, even with all that medication, the seizures didn’t stop.
“I felt like I wasn’t really living,” the 19-year-old says. With nothing to lose, she signed up for an experimental surgery at the hands if Eyiyemisi Damisah, a neurosurgeon at the Yale School of Medicine. When LaRock was 17, Damisah robotically reached into her brain to remove a tiny sliver of the insula, an area not commonly seen or accessed.
Exploring the Insula
The insula is “like an island,” Damisah says. It helps maintain homeostasis, arousal, and consciousness while hidden beneath critical layers of cortex that orchestrate our big life experiences—memory, language, movement, decision-making. From the body, blood vessels course into the brain, getting smaller, but denser, the deeper they go. For a neurosurgeon entering someone’s brain, damaging the tiny vessels surrounding the insula would be catastrophic. The insula is “kind of a treacherous region actually to sample,” says Damisah, among the first to forge ahead.
The procedure has two steps. First, while a patient is awake, Damisah robotically places electrodes deep inside the brain. Partly she’s waiting for a seizure to occur naturally so she can watch how it moves through the patient’s brain. But being able to access this area of the brain while a person is alive and awake is so novel in itself that the electrodes also help her learn more about what the elusive insula actually does.
Damisah says many of her patients’ seizures make them feel crazy—their bodies suddenly get hot, they experience untethered distressing emotions, or in LaRock’s case a low moan turned into a full-blown scream as she got older. “The insula, the way I look at it, is like a compact brain itself,” she says. “All the functions you have in the big cortex, you actually have a lot of those in the insula.” So unusual seizure symptoms may actually be a sign of epilepsy originating inside the insula. After the electrode diagnosis and placement are complete, the patient will return for the second surgery, during which they’re unconscious, and Damisah removes a small sample of the insula as a seizure-busting method.
She believes this tricky little structure to be the origin of many kinds of seizures that spread throughout the brain and remain unresponsive to other surgeries and medications. So far, post-surgery, LaRock has been seizure free.
February 21st, 2022
TVN24 interview with Polish Neurosurgeon Dr. Mirosław Ząbek - how ClearPoint technology enables partner uniQure to administer potential one-time gene-therapy approach for the treatment of Huntington's Disease in their EU open-label Phase Ib/II clinical trial of AMT-130.
August 19th, 2022
Final electrode location (right side) from the intraoperative MRI images taken during the procedure.
On June 28, 2022, functional neurosurgeon Michael C. Park, MD, PhD, performed the first deep brain stimulation (DBS) procedure in Minnesota that used the MRI-guided ClearPoint™ Neuro system. He was treating an epilepsy patient and found that the technology provided distinct advantages.
Using DBS to treat intractable epilepsy was approved by the FDA in 2018. The procedure delivers electrical stimulation to the anterior nucleus of the thalamus (ANT), a small brain structure involved in the spread of an initially localized seizure. “The ANT really can’t be mapped using electrophysiology to determine where you are when placing the electrodes,” said Park. “It’s a very small area in the brain – less than a centimeter in diameter.”
Prior to using ClearPoint Neuro, these procedures could be tricky, according to Park (pictured here). “You would have to look at an image, pick a target, and place the electrode,” he explained. Unlike DBS procedures to treat movement disorders, the patient cannot be awake to help the neurosurgeon understand if the electrodes are positioned accurately. “If an epilepsy patient is awake during surgery, you might trigger a seizure,” said Park.
Pre-op, intra-op, and post-op CT scans and fluoroscopic X-ray images are also required during the typical DBS procedure for epilepsy. “That kind of imaging gives you indirect confirmation of where you are,” said Park. “The procedure takes a long time and is complicated to navigate, and in the end, you really don’t know where your electrode is with any degree of confidence.”
Making it more precise
With the ClearPoint Neuro system, Park used IMRIS intraoperative MRI, another advanced technology available to neurosurgery at University of Minnesota Medical Center, which makes the process much more precise and eventually, will reduce time in the OR. He can also use the ClearPoint Neuro system to plan his approach. “You can put in a cannula or a sheath to get to the target, insert a slender probe known as a stylet, which shows up on the MRI, confirm that’s where you want to go, and then place the electrode,” said Park. “You know where you are in real-time with no guessing. That’s ClearPoint Neuro’s advantage. It’s very accurate with little room for error relative to being off target.”
Department Head Clark C. Chen, MD, PhD, was using the ClearPoint Neuro system for brain tumor surgeries and recommended its use to Park. To learn how to use the system, Park went to Mayo Jacksonville in Florida to observe neurosurgeon Sanjeet Grewal, MD, who uses ClearPoint Neuro with intraoperative MRI on a regular basis.
Excited by the possibilities
As more people with epilepsy turn to DBS to manage their symptoms, Park is excited about the possibilities that ClearPoint Neuro gives him to improve patient outcomes. He and his surgical team have completed two surgeries using the technology and both patients are doing well. Additional procedures are being planned.
“Based on the first two cases, I really like the precision, accuracy, and real-time feedback from the intraoperative MRI,” said Park. “The technology isn’t too difficult to learn how to use, either. And as we become more proficient, I believe it will help us cut down surgery time.”
March 14th, 2022
Joshua P. Aronson, MD, a neurosurgeon at Dartmouth-Hitchcock Medical Center (DHMC), is pictured here during the procedure to implant a neurostimulator device targeting four areas of the brain into Jessica Sargent, an epilepsy patient.
January 19th, 2021
Leveraging real-time MRI guidance for intracranial gene therapy administration potentially improves efficacy and outcomes.
While pharmaceutical companies spend billions of dollars developing groundbreaking gene therapies and drugs to address complex diseases of the central nervous system (CNS) (1), the method of delivery is often relegated to an afterthought. With interest and investment in this area continuing to grow at a rapid rate, it is increasingly important to maximize the therapeutic efficacy of both the drug and the delivery method.
Neurodegenerative disorders and brain cancers are two of the most devastating human diseases, and the world’s aging population continues to increase the frequency of these disorders, making rapid and successful drug development more important than ever. Yet, CNS drug development faces extraordinary hurdles and typically takes much longer than non-CNS therapies. Gene therapy clinical trials for CNS diseases are particularly challenging and protracted due to complexities of the brain, potential side effects, the need for direct and often targeted infusion, and delivery complications. Ultimately, the impact of these life changing CNS drugs is being diminished by the “physics of infusion”. Improved delivery methods must be considered and adopted early in the drug development process, or we risk negating their potential therapeutic benefits (2).
The following discusses the current limitations of traditional drug delivery into the brain, reviews recent advancements and benefits of real time interventional MRI (iMRI)-guided gene therapies, describes some ongoing clinical trials, and provides advice for pharmaceutical companies on how to proceed with intracranial therapies and delivery.
Current limitations of CNS drug delivery
It is well known that local delivery of therapeutic agents into the central nervous system offers advantages, including circumventing the blood-brain barrier, the potential for minimizing systemic toxicity, and the ability to achieve higher concentrations of agents at the target site (3). Intracranial delivery has been performed using traditional neurosurgical techniques and tools, including stereotactic frames and standard cannulas or catheters.
These methods lack the ability to confirm accurate catheter placement. Another major challenge has been the inability to visualize the drug delivery in real-time—thus making it impossible to evaluate the accuracy and coverage of drug delivery within target stuctures (4).
This traditional delivery method has become known as “blind” infusion; surgeons would infuse the prescribed amount of the drug to the target area but could not ascertain whether the drug covered the target as intended. In addition, traditional blind delivery with a simple hand injection using a syringe does not allow for infusing at a consistent flow rate, making measurement of delivery rates inaccurate and variable across procedures (4).
Gene therapy trials using traditional intracranial delivery methods began almost 15 years ago, but early results showed limited initial success (4). For example, the PRECISE trial, a large-scale Phase III trial delivering interleukin 13 (IL13)-pseudomonas exotoxin for recurrent glioblastoma, failed to show clinical benefit of survival. Post hoc analysis of the trial patients revealed that less than half of the implanted catheters were in the optimal position—in fact, only 68% of catheters were positioned in accordance with the specified protocol. Additionally, the investigators described “a fundamental lack of infusion distribution physics” as a major reason for efficacy failures. In the years since, similar outcomes have been noted in other trials (3).
Traditional surgical image guidance in the operating room is not real time, but rather dependent on co-registration to a previously-acquired MRI. In addition to the errors that co-registration can introduce with regards to device placement, conventional neuro-navigation platforms offer no means of visualizing infusions in real-time. Without live image guidance, a surgeon has no way to ensure accurate catheter placement and monitor the pattern of distribution of the infusions within the intended target (3).
Initially, surgeons believed that an infusion cannula could be placed into the center of a brain target and the injected fluid would behave in a predictable fashion, similar to an injection of fluid into a beaker of homogenous gelatinous material. The assumption was that the infusion would grow as a uniform spherical ball, increasing in size proportional to an increase in infusion volume. Surgeons now know this is not the case. For example, infusions in the putamen can result in spread of infusate outside the putamen along perivascular spaces, reflux along the inserted cannula, and, to a lesser extent, leakage into the vacated catheter tract upon its removal. Utilizing real-time imaging has enabled surgeons to observe these delivery complications and test new techniques and devices to optimize results.
The advent of real time iMRI-guided infusion has enabled larger volumes of delivered therapeutics and tactics, such as varying infusion rates and adjusting cannula depth/position to maximize coverage of the target area—and to minimize the degree of vector spread away from the intended target. This has significant implications for the success of clinical trials, as evidence suggests that adequate coverage of the target area may have a dramatic impact on patient outcomes (3).
For pharmaceutical and biologics companies, the inability to predict, visualize, and confirm infusate coverage of target regions has proven to be a major hurdle in clinical development—and a cause for therapeutic inefficacy. Without intraoperative monitoring, it has not been possible to determine how differences in surgical approaches, cannula designs, vector volumes, and dosing affect coverage within the brain (4).
One platform that allows for iMRI-guided catheter placement and real-time visualization of delivery of therapeutic agent is ClearPoint NeuroNavigation, developed by US-based medical device company, ClearPoint Neuro, which is currently enabling a range of clinical trials involving neuro-oncology, neurodegenerative disorders, rare genetic disorders, and movement disorders. It is an integrated hardware and software platform that communicates with the MRI scanner console to provide high-resolution imaging for trajectory planning, entry point selection, device placement, and infusion monitoring. The navigation system has been used in conjunction with the ClearPoint Neuro SmartFlow Cannula for precise dosage of drugs or gene therapies in approved clinical trials.
The introduction of iMRI-guided drug delivery uncovered many injection challenges associated with targeted infusion within the brain. Based upon the diffusion behaviors and characteristics observed during early iMRI monitoring in non-human primates, many protocols have now adopted a technique of either progressive advancement from proximal to distal for the duration of infusion, or a “pull-back” method for cell delivery where the first deposit is delivered to the most distal region. This technique of administering multiple infusions along the trajectory path was found to increase the surgeon’s ability to achieve infusions that cover the putamen or other target area as uniformly as possible, with the added benefit of providing the ability to move the cannula tip away from problematic perivascular spaces. In addition, innovations in cannula design have resulted in more reliable, efficient, and increased distribution of agents. Because image-guided systems provide real-time visualization of the infusion, they allow for intraoperative troubleshooting and real time modification to key infusion parameters, such as flow rate, positioning of the catheter, or terminating the infusion when the desired coverage has been attained (3).
This latter advancement is particularly noteworthy as it introduces the potential for specific patient dosing, a game-changing capability in treating CNS disorders or brain cancer. Historically, physicians have strictly followed a standardized trial protocol that specifies uniform infusion parameters across all patients, including the dose (volume) of therapeutic delivered. Evidence suggests that many early trials administered dosages that were insufficient to achieve desired clinical outcomes. iMRI-guided surgery offers the possibility of using much higher volumes, and adjusting the volume to focus on patient specific coverage, rather than a pre-determined amount. This concept of patient specific dosing is new and exciting in its potential to improve clinical outcomes—and it is currently being applied right now in an ongoing Parkinson’s Disease (PD) trial.
Finally, these technological advancements afford an improved level of safety. iMRI provides surgeons with a significantly higher degree of confidence that the cannula is following a safe trajectory and being placed in the desired target location. This is particularly important when targeting deep structures, where safe corridors through the brain can be only 2–3 millimeters wide.
Ongoing clinical trials of iMRI-guided drug delivery
At the University of California San Francisco, Paul Larson, MD, a professor and the vice-chair of Neurological Surgery at the university, is involved in three active human clinical programs utilizing iMRI-guided gene therapy delivery. The first is an amino acid decarboxylase program (AADC), which is an enzyme replacement gene therapy strategy for PD that uses adeno associated virus (AAV) to deliver a gene for AADC. The program, sponsored by Neurocrine Biosciences and Voyager Therapeutics, is now a Phase II multi-center study. The Phase I results indicate that, as coverage of the putamen improved, there was a significant increase in PET activity and a concurrent decrease in PD medications (5).
The second is a Phase Ib investigation sponsored by Brain Neurotherapy Bio to evaluate the safety and potential clinical effect of AAV2-GDNF delivered to the putamen in subjects with earlier stage PD. Growth factors are an exciting approach as they have the potential to be a disease-modifying therapy.
The third is the world’s first intracranial gene therapy study for Huntington’s Disease (HD). Sponsored by uniQure Biopharma, it is a Phase I/II study of AMT-130 delivered to the striatum of patients with early manifest HD and is designed to establish safety and proof-of-concept. The gene product is designed to interrupt production of the aberrant Huntington protein.
Beyond these studies, iMRI-guided delivery is being used in many other ongoing or planned Phase I and Phase II clinical trials for indications, including glioblastoma, PD, Huntington’s Disease, Amyotrophic Lateral Sclerosis (ALS), and pediatric indications, including AADC deficiency, Freidreich’s Ataxia, Angelman Syndrome, and Sanfillippo Syndrome. iMRI-guided delivery with the SmartFlow cannula is already cleared for Cytarabine injection into the ventricles to treat leukemia and non-Hodgkin's lymphoma, and numerous other programs are in development involving gene therapy, cell transplants, and other therapeutics.
Although it may be premature to assign hard savings to iMRI-guided drug delivery, there are significant potential benefits from such an approach. Given the tremendous R&D costs to develop a gene therapy as well as the cost of a single dose and the infusion procedure, any increase in the likelihood of a successful procedure would translate into considerable savings for the healthcare industry at large—as well as accelerating adoption of pharmaceutical gene therapies. The potential for iMRI guidance to ensure safe and accurate placement of the catheter, administer patient-specific dosages, minimize leakage, and optimize coverage addresses many of the challenges faced by early gene therapy trials. When considering the costs of past negative phase two trials, the business case for leveraging iMRI is apparent.
Advice for pharma
The advantages of real-time MRI-guided gene therapy delivery are clear. However, one challenge for pharma companies is the number of neurosurgery centers that have implemented iMRI at their facilities. The ClearPoint NeuroNavigation system is currently installed in more than 60 of the leading neurosurgical centers across the United States, and is expanding into Europe. While the number of institutions adopting iMRI is growing, there is a need for more pharmaceutical companies and neurosurgeons to embrace this improved delivery method for intracranial therapeutics. To do otherwise is to potentially jeopardize billions of dollars in R&D investments, put study participants in harm’s way with little chance to show benefit, and run the risk of obviating cures for life-threatening diseases.
1. J.P. Fuhr, “The Possibility of Encouraging Innovation and Competition by Erwin A. Blackstone.” www.semanticscholar.org (2015).
2. X. Dong, Theranostics 8 (6) 1481–1493 (2018).
3. S.J. Han, et al., Expert Rev Neurother. 16 (6) 635–639 (2016).
4. R.M. Richardson, et al., J Neurol Neurosurg Psychiatry91, 1210–1218 (2020).
5. C.W. Christine, et al., Ann Neurol. 85 (5) 704–714 (2019).
About the author
Paul S. Larson*, MD, email@example.com, is professor and vice-chair of Neurological Surgery at the University of California San Francisco, chief of Neurosurgery at the San Francisco Veterans Affairs Medical Center, and surgical director of the Parkinson’s Disease Research, Education and Clinical Center.
*To whom all correspondence should be addressed.