I am Aviva Yabash, Professor of Neurosurgery and Chairman of the Department of Neurosurgery at the University of Nebraska Medical Center in Omaha. I'd like to extend my thanks to Fred Barker and the Scientific Program Committee of the AANS for the opportunity to give this presentation. My talk today is intended to provide an update on some of the clinical trials ongoing in stereotactic and functional neurosurgery. First, some reflections on an unprecedented 18 months in the history of humans on this planet. At UAMC, we have been faced with four distinct shutdowns or near shutdowns in our non-emergency surgical cases thanks to the COVID-19 pandemic. This, of course, has translated into a halting or slowing down of surgical volume that we perform for epilepsy, movement disorders, pain, spasticity, and the like. But we've also seen a significant impact on the pipeline of patients coming forward for the medical management of these entities, a pipeline from which the surgical candidates are derived. This has led to decreases in pipeline for our clinical trials in human subjects. And the extramural funding organizations, including NIH and industry, have been understanding that the truth is that human subjects research progress has been slowed in our institution. And in discussing with colleagues at other institutions and reading published literature and reading abstracts, the experience at other institutions has not been too dissimilar. As a consequence, there are a number of ongoing trials this year that are not quite ready to be discussed. For instance, the two laser ablation companies that are still going for specific labeling for the treatment of temporal lobe epilepsy have not released their data. And you'll see from my discussion that various other trials are running along as well. I will confine my comments here to specific clinical trials aimed at the treatment of Parkinson's disease, epilepsy, dementia, and tinnitus with background about these trials and where these trials currently stand. So Parkinson's disease, obviously a chronic progressive neurodegenerative disorder, affects about 1.5 million in the U.S., 10 million worldwide. It results from the progressive loss of dopamine-secreting neurons in the substantia nigra pars compacta, which then leads to a decrease in dopamine in the striatum, meaning the caudate of the containment, which then results in motor symptoms, the classic motor symptoms being tremors, rigidity, bradykinesia, postural instability, et cetera. Moral levodopa is always the first line of treatment, but there is no existing treatment, including DBS in conjunction with medications, that has been proven to reverse, slow or reverse the disease process. And over time, motor fluctuations ensue. So there are, have been over the years, a variety of gene therapy trials for Parkinson's disease. So Parkinson's disease is a multi-system disorder, but that classic triad of motor symptoms is due mostly to loss of dopaminergic neurons in the substantia nigra. And so the focal nature of this substantia nigra pathology has led to Parkinson's disease long being considered as an animal to gene therapy and to efforts that can restore neurotransmitter imbalance, enhance neuronal survival, or target genes directly linked to the disease. The table and the graph, this graphic over here, are from a recent review article in Nature of Neuroscience that describes the timeline of Marcia Mets and the attempts to treat Parkinson's disease through gene therapy, which is now at 13 years of trial and evolution. So in the lower right, you see the milestones of development of gene therapy tools, and in the upper right, a timeline of key clinical trials sponsored by the NIH for the treatment of Parkinson's disease. Now I should have just a couple of comments about dopamine synthesis. The dopamine synthesis pathway is regulated by three rate-limiting enzymes, GTP, cyclohydroxylase, tarosine hydroxylase, and aromatic amino acid dopamine decarboxylase, or AADC. AADC is the final enzymatic step in dopamine synthesis, and there have been a number of clinical trials with an adeno-associated environment vector and a payload of the AADC enzyme. And these have so far demonstrated safety, stable expression for up to four years, and modest improvements in symptoms. There have also been non-human primate trials, which have used real-time MRI guidance to deliver intraputaminal or intrastriatal injections of AAV2-AADC, which proved that it was safe and well-tolerated. This work laid the groundwork for a human clinical trial, which is 5192 in that graph. A table, which was a human clinical trial launched in 2017. I said it's been over a decade of effort in this arena. This is an abstract from neurology in 2009 about the safety and tolerability of intraputaminal AADC gene therapy in humans as an example. This is from a more recent review article, 2020, by Mark Richardson and colleagues, that shows the evolution in terms of study approach regarding the volume of infusion that could be expected from the various approaches in these trials. It's important to note that the current AAV2-AADC trial has roughly 54% coverage of the putamen from the infusions based now on intraoperative MRI images that are obtained progressively during the putaminal infusions. Obviously, an improvement in terms of the distribution of coverage of the putamen that has happened over time, and I'll talk more about how that's happened. These improvements in technology have been crucial for the ongoing optimization of these human trials. I mentioned before the duration of the disease, increasing doses of levodopa are required to maintain efficacy, but ultimately fail to maintain a significant clinical response. Patients get motor fluctuations, levodopa-induced dyskinesias. The explanation for this has been the AADC disappearing from the striatum. So the striatum is depleted of dopamine and this final step in the dopamine synthesis pathway. VYA-AADC is a gene therapy vector containing a gene encoding the AADC enzyme. And the notion leading into this trial was that a single intraputaminal injection of VYA-AADC could improve motor function and also decrease the requirements for dopaminergic medications and thereby decrease medication-induced side effects. Enter Voyager Therapeutics, a clinical stage gene therapy company focused on therapies for Parkinson's disease, ALS, etc. And they launched a Phase 1B trial for advanced Parkinson's disease using the techniques I described in an open-label trial that included 15 patients treated with a single administration of VYA-AADC. And the methods are described here. One of the problems has been traditionally reflux of the injection catheter as opposed to diffusion throughout the containment. So with the advent of intraoperative MRI and a different trajectory and an improved cannula, all of these issues have gotten better. This trial was aimed at safety and tolerability of the injections and tested distributions in the ascent doses, escalating doses of VYA-AADC. The subjects had an age of 58, Parkinson's disease for 10 years on average, and optimized on the medications, evaluated with the usual outcome rating scales. And as I mentioned, various aspects of the delivery have been optimized, including the advent of technology that allows us to reliably target within an intraoperative MRI, cannula design, which has improved targeting of the VYA-AADC specifically into containment and not back up the catheter, and a polar trajectory, which also has improved delivery and distribution. Concentration has been worked out and optimized, and the results were promising enough to lead to, in terms of percentage change from baseline and medication use, trouble with miscontact, trouble with miscommunications, etc., to lead to a subsequent trial called Restore-1. Restore-1 is a randomized placebo surgery-controlled double-blind Phase 2 trial of VYA-AADC-02, which is an identical vector to VYA-AADC-01, which is the one used in this trial, but made with updated manufacturing techniques. This trial is ongoing, enrolling patients with Parkinson's disease and refractory motor fluctuations. Now, this Phase 2 trial was on track to deliver a dose to its first patient in mid-2018, hit several bumps in the road, and is currently on hold. So, Restore-1, as I said, Phase 2 trial, assessing VYA-AADC intrapotaminal posterior injections, and in September, Voyager and its partner, Neurocrin, announced positive three-year efficacy and safety data in Parkinson's disease patients treated in this fashion, with a one-time dose of the investigational gene therapy. These patients were showing sustained improvement in motor function, including greater on-time without troubles and dyskinesia, reduction in PDRS Part 3 scores, reduction in the amount of medications required in these patients, but then it was placed on indefinite hold in December of 2020 because of the observation of MRI abnormalities in some of the Restore 1 study participants. So that's where we are at the present time. On to the treatment of epilepsy, I mentioned the SLATE trial earlier on, no data yet to report. This is follow-up data in RNS patients, post-market approval. RNS is used for treatment approved by the FDA for the treatment of epilepsy, 40% of patients with epilepsy are medication refractory, resection or ablation procedures intended for targeting the seizure onset zone result in the best likelihood of seizure freedom, but these treatments are not appropriate if the risk of neurological injury is too great and the possibility of benefit is too low. So neuromodulation is then the option, one of the options for this category of patients and has been demonstrated to be both safe and effective and in this category, this neuromodulation for epilepsy category, we include vagal nerve stimulation, deep brain stimulation, and RNS. I'm going to confine my comments to RNS and here you see the physician programmer and patient data management systems that provide a temporal display of electrocorticography data and allow the physician to view trends in detections, which is the surrogate procedures over selected periods of time. When combined with patients' reports of seizures, this information is used to assess the efficacy of treatment. So it's probably worth noting that RNS is really our first more or less closed loop device in neurologic diseases because it allows for both sensing and stimulation response to that sensing. So where does RNS fit into patient selection and treatment are a good question and it's worth pointing out that no prospective randomized controlled trial comparing the relative efficacy for seizure control has been carried out for these neuromodulatory devices, so no head-to-head comparison of VNS versus TDS versus RNS for the same patient population. Now, in 2018 at the American Epilepsy Society meeting, Erin and colleagues presented data on outcome from RNS in terms of seizure reduction and in 2020 further RNS post-approval study data was published and that data, these data included 230 of 256 patients in the initial trial participated. The early data, as I said, came out in 2018 and there is nine-year data as of September 2020, so a year ago, which showed continued decrease in seizure reduction. So 75% median percent seizure reduction in seizure frequency over the long term with a responder rate of 73% in nine years but with 35% of those patients having over 90% or equal to a 90% reduction, so ongoing efficacy from RNS. Interestingly, there's been work on the stored data that is uploaded from all of the patients whom RNS has implanted and these data are aimed at things like finding a more reliable assessment of patient outcome than detections. And so here is an article published by Barry and colleagues in 2021. You're looking in the top panel, A, at examples of a spectrogram, of spectrogram images of electrocorticography channels that are consistent with interectal, you know, non-seizure events, non-seizure detection. Bottom panel is seizure detection from electrocorticography channels. And these images, these spectrogram images are then used as input into convolutional neural network models and have been shown to be effective for training relatively accurate seizure classification models. Tools built using these models hold the potential to improve clinical outcomes by improving diagnostic assessments, so a sense of where the field is headed with the analysis of the data being captured. The problem with dementia is a clinical and socioeconomic problem of absolutely staggering proportions. Over 50 million people globally living with dementia. The numbers there downloaded from the Alzheimer's Organization in the U.S. and absolutely frightening. The rationale for deep brain stimulation in the fornix is that you're delivering stimulation to a node in the memory circuit, a circuit of tapes, and that forniceal lesions by nature result in memory deficits in humans. And there's a possibility that you could enhance CNS signal transmission by driving activity in other regions impacted by Alzheimer's disease. So these work of that nature led to, including case series, led to the ADVANCE-1 trial with forniceal stimulation in dementia. Forty-two subjects randomized, controlled phase two trial outcomes, the Alzheimer's disease assessment scale, and the clinical dementia rating scale. This led to this trial reported that DBS of the fornix was safe in patients with Alzheimer's disease associated with increased cerebral glucose metabolism and had the potential to slow cognitive decline in over 12 months of stimulation in patients greater than or at 65 years of age. Nothing significant from the standpoint of serious adverse events. Here are some of the events. One, findings, and you see in green and in red the difference in dementia rating scale scores for patients over 65 years or older versus patients under the age of 65. Patients under the age of 65 did worse with stimulation. Patients over the age of 65 did better compared to their baseline, where they were headed from a baseline standpoint. Graphic depiction of here on the left, patients under the age of 65 versus both 65 or older. You see that with the device on, stimulation on, these patients had a more rapid decline in terms of their integrated Alzheimer's disease rating scale than with the device off. That's DBS off. Here for patients 65 or older, this is DBS on in the dotted line and DBS off below. Kind of a watershed in terms of age. That led to the advanced two-pivotal trial exclusively for patients 65 years or older. This time, CSF biomarker used to confirm mild Alzheimer's dementia. Perspective randomized double-blind study design. 142 subjects have been consented out of 210. Actually, as of today, 48 subjects implanted and randomized. 20 sites in the U.S., Canada, and Germany with primary outcomes were being changed in baseline for over versus 12 months on the IADRS, the integrated Alzheimer's disease rating scale. Study design depicted there. Caudate stimulation for tinnitus. Tinnitus being an auditory disorder characterized by perception of internally generated phantom auditory sensations without a corresponding external stimulus arising from the body or from the external environment. Current treatment is there's auditory-based therapy and non-alertory-based strategies, including tinnitus retraining therapy, cognitive behavioral therapy, and attempting to mitigate symptoms. And it's not very effective in about 1 million patients who still nonetheless endure chronic continuous noises inside their head that are debilitating and interfere with activities of daily living. So why approach it with stimulation? Well, caudate strokes are known to result in long-term decreasing in the loudness of tinnitus. And here's one beautiful case report by the investigators involved in pushing this forward, Stephen Chung and Paul Larson. And you see the caudate infarct and tinnitus perception in this patient over time. Following that case report, that led to a pilot project involving six motor disorder patients with comorbid tinnitus and surprisingly positive results in five patients where the DDS lead traversed area LC. Of the caudate, tinnitus loudness in both ears was suppressed down to as low as 2 or below on a 0 to 10 tinnitus rating scale. Very exciting. A novel basal ganglia modulation approach to treating tinnitus. And this work led to an open-label efficacy and safety trial of caudate DDS for tinnitus, specifically tinnitus alone this time, not with motor disorders. So six patients in total, resting state epinephrine, all 5 to 13 months in DDS optimization, 24 weeks of caudate stim, primary outcome and secondary outcomes listed on the slide. And interestingly, clinical results were presented in 2019. Highly variable effect size, lengthy period of stimulation optimization in comparison to the trial that went into it, which was surprising and raises the question of whether tinnitus in isolation is different from a substrate standpoint than tinnitus combined with a movement disorder. But no safety concerns, 60% to 80% treatment response rate for significant benefit. And right now that work is ongoing that's aimed at refining the targeting based on functional imaging in anticipation of a phase 2 trial. So with all of these trials, I guess it's fair to say that you'll need to stay tuned. Thank you for your attention.

clinical trials

Parkinson's disease

gene therapy

epilepsy

Alzheimer's disease

tinnitus