Tominerson (Roche), formerly known as IONIS-HTT

 and RG6042, made history in May 2019 when results from a phase 1/2a trial published in the New England Journal of Medicine demonstrated that the investigational antisense oligonucleotide was the first therapeutic to successfully target and reduce levels of mutant huntingtin protein in patients with Huntington disease (HD).

That trial, which enrolled 46 patients with early HD, showed dose-dependent reductions of mutant huntingtin protein in the cerebrospinal fluid, with the greatest reductions recorded in the 2 highest-dose groups (90 mg, 42% reduction; 120 mg, 38% reduction). Although nearly all patients experienced mild to moderate adverse events (AEs), investigators reported no serious AEs in patients who received the study drug.

“[Tominersen] is the first therapy in development designed to target the underlying cause of the disease by limiting production and lowering the levels of the specific toxic protein that breaks down the nerve cells in the brain, which may affect a person’s everyday functions, such as mobility and thinking,” Scott Schobel, MD, MSc, associate group medical director and clinical science leader for the IONIS/Roche HTT Rx program at Roche/Genentech in Switzerland, told 

Results from the early-phase trial increased confidence as Roche moved to launch the phase 3 GENERATION HD1 trial (NCT03761849), a pivotal study in which investigators hope to demonstrate the drug’s ability to slow or stop HD progression (

120 mg every 2 months, tominersen 120 mg every 4 months (with placebo during alternating procedures), or placebo every 2 months over a 101-week treatment period. Although the original trial design called for once-monthly dosing, investigators made adjustments after a review of 9-month data from the 15-month open-label exten-sion of the phase 1/2a study (NCT03342053), which suggested that more frequent dosing was not associated with a clinical benefit.

“While it is not yet appropriate to draw conclusions about clinical efficacy or longer-term safety, we are pleased that there are now data to support these study design changes and the explora-tion of less frequent dosing. We believe this will make study partic-ipation less demanding for patients, families, and health care providers,” Schobel said.

The global trial will include more than 900 participants aged 25 to 65 years with manifest HD, defined as a diagnostic confidence level score of 4 as well as an Independence Scale score >70. Patients excluded from the trial include those with any serious medical condition or vital sign abnormality, those who are currently pregnant or breastfeeding, and those who plan to become pregnant during the study.

Primary outcome measures of the study include a change from baseline to week 101 in the Composite Unified Huntington’s Disease Rating Scale, as well as the change from baseline to week 101 in Total Functional Capacity Score. Other secondary outcome measures include a change from baseline in Total Motor Score, Symbol Digit Modalities Test, Stroop Word Reading Test, Clinical Global Impression, Severity Scale.

Although GENERATION HD1 is expected to conclude in the third quarter of 2022, an ongoing open-label extension trial (NCT03842969) will help further tease out the therapy’s long-term impact. Patients eligible to enroll in the open-label study will receive tominersen 120 mg once every 8 weeks or once every 16 weeks via intrathecal injection. The study will assess primary outcomes such as percentage of participants with AEs and change from baseline in behavioral findings, as assessed by the Columbia-Suicide Severity Rating Scale. Additionally, investigators will use the Montreal Cognitive Assessment to assess changes from baseline in cognition.

Launched in April 2019, the extension study has an estimated completion date of August 2023.

“While early clinical trial findings are encouraging, we still have a lot to learn about the benefits and risks of [tominersen], which can only formally be shown in a longer, controlled clinical study,” Schobel concluded.

1. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al; &#8239;Phase 1—2a IONIS-HTTRx Study Site Teams. Targeting huntingtin expression in patients with Huntington’s disease [erratum in N Engl J Med.&#8239;2019;381(14):1398. doi: 10.1056/NEJMx190024]. N Engl J Med. 2019;380(24):2307-2316. doi: 10.1056/NEJMoa1900907 

2. Nguyen M-L. Update on the phase III GENERATION HD1 study. Huntington’s Disease Society of America website. hdsa.org/wp-content/uploads/2019/10/Roche-Genentech-global-HD-community-letter-October-2019.pdf. Published October 14, 2019. Accessed February 25, 2020. 

Articles

Clinical Trial in Progress

The drug successfully demonstrated an ability to reduce mutant huntingtin protein, but the clinical benefits of that effect are yet to be determined.

Antisense Therapy Tominersen Holds Promise in Huntington Disease

Therapies for patients with Parkinson disease (PD) have long focused on the symptomatic management of this neurodegenerative movement disorder, namely by compensating for the loss of dopamine in the brain.

 Loss of dopaminergic neurons in the substantia nigra pars compacta, a hallmark of PD, is promoted by the pathologic accumulation of aggregated α-synuclein protein, resulting in the disease’s characteristic motor symptoms: rigidity, tremor, and slowed movement. Accumulation of α-synuclein alsoaffects other neuronal systems, accounting for the nonmotor symptoms often observed in patients with PD, such as autonomic dysfunction, anxiety, depression, and sleep disorders.

Although the immediate cause of PD pathology—toxic aggregation of α-synuclein and the resultant neuronal death&mdash;is clear, many questions remain about the underlying mechanisms that drive this process. Kam et al provided new insights into those mechanisms in a 2018 article detailing the roles of poly—(adenosine diphosphate [ADP]-ribose) (PAR) and PAR polymerase (PARP), specifically the PARP-1 isoform, which functions as a DNA damage repair protein.

As a family of enzymes that catalyze ADP-ribosylation, or the transfer of ADP-ribose to protein substrates, PARPs are well known for their role in DNA repair. However, they also play roles in several cellular processes, including cell death. The PARP family includes at least 18 members. PARP-1, the best characterized, helps regulate cellular homeostasis and preserve genomic stability.

 Most cellular substrates of PARP are nuclear proteins involved in nucleic acid metabolism, modulation of chromatin structure, DNA synthesis, and DNA repair.

 In the presence of mild DNA damage, PARP-1 displays up to 500-fold—increased activity and uses oxidized nicotinamide adenine dinucleotide to synthe-size PAR polymers, which it adds to proteins as part of the DNA base-excision repair process.

 In cases of more significant DNA damage, PARP-1 becomes hyperactivated and produces long-chained, branched PAR polymers. The ensuing series of events, including large-scale DNA fragmentation and chromatin condensation, culminates in cell death.

This type of cell death, known as parthanatos, is a unique process, distinct from apoptosis and necrosis. Parthanatos is the result of rapid activation of PARP-1, which leads to accumulation of PAR polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor.

 In their study, Kam et al found that a synthetic form of aggregated α-synuclein activated nitric oxide synthase, resulting in DNA damage, activation of PARP-1, and ultimately cell death via parthanatos (FIGURE).

Research demonstrating increased PARP activity in the presence of DNA-damaging treatments, especially some chemotherapeutic agents and radiation, elucidated the role of PARPs in DNA repair. In fact, chemotherapy resistance in tumor cells has been tied to the upregulation of DNA repair mechanisms. These observations led to the development of PARP inhibitors, which have been used to treat various types of cancer, including tumors exhibiting chemo-therapy resistance, upregulated PARP activity, or reliance on PARP-mediated DNA repair because of defects in genes such as BRCA.

Kam et al employed PARP inhibitors in their study and used α-synuclein preformed fibrils (PFFs), an aggregated form of recombinant α-synuclein generated in vitro that is structurally similar to the endogenous form observed in PD, to better understand the drivers of α-synuclein aggregation and, in turn, cell injury and death in PD.

After adding α-synuclein PFF to cultured cortical neurons, the investigators used a specific and sensitive anti-PAR monoclonal antibody to measure PAR levels. The results revealed that PFF administration led to PARP activation, which peaked between 3 and 7 days and remained elevated for up to 14 days. Additionally, PAR elevation was accompa-nied by neuronal death. Kam et al then treated cultured neurons with 3 PARP inhibitors, ABT-888 (veliparib), AG-014699 (rucaparib), and BMN 673 (talazoparib); the latter 2 are currently FDA approved for the treatment of BRCA-mutated breast cancer.

 As a result, α-synuclein PFF-mediated PARP activation and cell death were prevented. Notably, the PARP inhibitors also reduced phosphorylation and aggregation of α-synuclein, processes associated with α-synucleinopathy pathology.

In addition, deletion or knockout of PARP-1 prevented α-synuclein PFF-mediated PARP activation and, in turn, parthanatos. Notably, the investigators reported that treatment with a broad-spectrum caspase inhibitor partially reduced PFF toxicity; however, use of necroptosis and autophagy inhibitors had no impact. Further investigation demonstrated that knockout of PARP-1 reduced the trans-mission of toxic α-synuclein between neurons; such transmission is observed both experimentally (with PFF) and in patients with PD, in which it contributes to the pathogenesis of the disease.

 In vivo assays involving PFF injection into mouse brains produced results consistent with the in vitro data. Furthermore, PFF injection caused neuro-degeneration; the number of dopaminergic neurons in the mouse brain was reduced by 50% at 6 months post treatment, an effect miti-gated by PARP inhibitor administration or prevented by PARP-1 knockout. Finally, the investigators generated a PAR-modified form of α-synuclein PFF by coincubating recombinant α-synuclein and PAR. This PAR-modified PFF proved particularly toxic, with accelerated α-synuclein fibril formation in biochemical assays, enhanced α-synuclein aggregation in cultured neurons, and an accelerated disease course in injected mouse brains compared with unmodi-fied PFF. In what Kam et al described as a “feed-forward loop,” PAR addition was found to enhance the neurotoxicity and cellular transmission of α-synuclein both in vitro and in vivo.

 When examining human cohorts, the investigators found increased levels of PAR in the cerebrospinal fluid and brains of patients with PD, further suggesting a role of PARP activation in the pathogenesis of this disease.

“Strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of DA [dopaminergic] neurons in PD and related α-synucleinopathies,” the authors concluded, adding that PAR levels in cerebrospinal fluid may be particularly useful as biomarkers of therapeutic benefit in the development of disease-modifying therapies for PD and other neurodegenerative diseases.

1. Dickson DW. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med.2012;2(8). doi: 10.1101/cshperspect.a009258 

2. Charvin D, Medori R, Hauser RA, Rascol O. Therapeutic strategies for Parkinson disease: beyond dopami-nergic drugs [erratum in Nat Rev Drug Discov.2018;17(11):844. doi: 10.1038/nrd.2018.184]. Nat Rev Drug Discov. 2018;17(11):804-822. doi: 10.1038/nrd.2018.136

3. Kam TI, Mao X, Park H, et al. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease. Science. 2018;362(6414). doi: 10.1126/science.aat8407

4. Morales J, Li L, Fattah FJ, et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr. 2014;24(1):15-28. doi: 10.1615/critreveukaryotgeneexpr.2013006875

5. Fatokun AA, Dawson VL, Dawson TM. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol. 2014;171(8):2000-2016. doi: 10.1111/bph.12416

6. Berger NA, Besson VC, Boulares AH, et al. Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases. Br J Pharmacol. 2018;175(2):192-222. doi: 10.1111/bph.13748

7. Mweempwa A, Wilson MK. Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology. Cancer Drug Resist. 2019;2:608-617. doi: 10.20517/cdr.2019.50.

NeuroPathways

Examining the underlying roles of poly adenosine diphosphate-ribose (PARP) play in the neurodegeneration of Parkinson disease. 

PARP Pathway May Hold Promise for Parkinson Disease Treatment

Over the past 18 months, the arsenal of treatment options for migraine and other headache disorders has multiplied, providing hope for the scores of patients who previously had inadequate control over their disease. Now exploration of novel pathways has opened the door to the development of therapies that act on the biological anchors of migraine and, as some specialists have put it, have begun to blur the lines between acute and preventive treatment.

Amaal J. Starling, MD, an assistant professor of neurology in the divisions of Concussion and Headache Medicine at Mayo Clinic in Scottsdale, Arizona, has witnessed the impact of these new developments first hand. In a conversation with NeurologyLive®, she recalled that she has a queue of patients awaiting the arrival of several therapies in development and another line of patients already reaping the benefits of available treatments.

Starling shared her experiences with these new devices, therapies, and developments and provided insight into what she is looking forward to seeing in the migraine armamentarium.

What has it meant for you to have so many new therapeutic modalities available in your toolkit?

Since May 2018, when the FDA approved the first calcitonin gene-related peptide (CGRP) monoclonal antibody for prevention, we’ve been able to help so many more patients, and even before that, when we started getting FDA clearance on the multiple neuromodulation devices, we were able to address migraine disease for individuals who have found other medications ineffective. [We have also been able to help] patients who have poorly tolerated other preventive and acute treatment options, even if they found them to be effective but were unable to tolerate them because of adverse effects.

In addition to exploring new mechanisms that may be underlying different migraine pathways, having access to devices and oral treatment options that are blurring the lines between acute and preventive treatment is really exciting. It’s confusing [to tell] patients, “OK, this is what we use for prevention. And this is what we use for as-needed.” With some of the neuromodulation devices, I like that we can use 1 device for both acute and preventive treatment. I believe that is the direction that these CGRP antagonists will also follow. The gepants, not in the immediate future but in the next couple of years, may obtain FDA approval for prevention as well as acute treatment, so those may be medications that we can recommend as needed. If [patients] need to use it daily in the beginning, that’s OK. It’ll work from a preventive perspective. And it’ll also work as needed.

Have any particular therapies stood out as particularly promising?

The first 3 FDA-approved CGRP monoclonal antibodies have been wonderfully useful in our headache practice. Mayo Clinic Scottsdale is a tertiary headache clinic, and the realist in me didn’t expect that the medications would work as well in our very medically complicated and very refractory population as they did in clinical trials. But we’ve had excellent results that mimic those of the clinical trials; regardless of which monoclonal antibody [we use], about 50% of patients will be responders, and that’s what we’ve seen even in our very complicated patient population.

We’ve also had great tolerability with all those monoclonal antibodies. It’s been beautiful to see that, to really change the lives of some of these patients, especially the ones who were super-responders and had a greater than 75% remission of their migraine attacks. That was awesome. I’m also excited about the recent FDA approval of eptinezumab, which is the first CGRP monoclonal antibody infusion, especially given the reported data about onset of efficacy. We are currently working on the logistics of using this infusion therapy for our patients in clinic, but I am hoping to initiate this treatment modality very soon.

The recent FDA approval of lasmiditan is going to be very helpful because it will help us address that patient population who has not responded to triptans. Thirty percent to 40% of patients who receive triptan medications do not get a good response, whether the reason is inefficacy or poor tolerability. I hope this will be an option for them and for the patient population who cannot use triptan medications because of a history of heart attack or stroke or significant peripheral cardiovascular or cerebrovascular disease. Also, ubrogepant received FDA approval for acute treatment in December 2019, and we have just started prescribing it to patients. It is too early to tell whether its efficacy is similar to what has been published in clinical trials, but patients do seem to be tolerating it without adverse effects. It’ll be interesting to see whether ubrogepant, which is a CGRP small molecule receptor antagonist, is effective in the setting of CGRP monoclonal antibodies to either the ligand or the receptor. These are unanswered questions, but we have been prescribing to those particular patients, so we should have some clinical observations soon.

As for the neuromodulation devices, we’ve already been using Cefaly, sTMS mini, and gammaCore. Usually, when we do use the neuromodulation devices, we use them in combination with either injectables or oral medications. Some patients would rather not use any type of medication, whether it be injectable or oral, and for them, we use solely neuromodulation.

The lovely thing about the neuromodulation devices is that they come with very few contraindications. In fact, some of the devices, such as the sTMS mini, have recently received label extensions to include the adolescent population, and some case reports have already been published on the sTMS mini in pregnant patients. So these are options we can use in our patients who are medically vulnerable for several reasons. The FDA [also recently cleared] the remote electrical stimulation patch to be used on the arm. It seems to be another effective as-needed treatment option for patients either in addition to their regimen or by itself.

Outside of CGRP, what ongoing developments have caught your attention?

It’s really important for not just headache specialists but also general neurologists and primary care providers, as well as patients, to understand that this is just the beginning. That’s really important because I’ve had patients who have come to me [saying,] “CGRP monoclonal antibodies and antagonists—that’s the last resort. If those things fail me, then there’s nothing else that’s going to ever work for me.” That is not true. This is just the beginning of the development of more disease-specific, mechanism-based targeted treatment options.

[Clinicians should know that] clinical trials involving other novel targets are ongoing. One of them is the pituitary adenylate cyclase-activating polypeptide, or PACAP, which is going to be another arena in which we may have monoclonal antibodies as well as poten-tially small molecule antagonists that will target that pathway. That’s important because of the heterogeneity, from a genetic perspective, of the patient population with migraine. It’s going to require that we have multiple mechanisms that we’re targeting with our different treatment options. And the CGRP pathway is one of them. The PACAP pathway is going to be another one, and [investigators will continue to identify] multiple other pathways.

Much research is currently looking at different types of neuro-peptides and hormones that would affect the origination [point] of that spontaneous migraine attack. We’ve seen imaging studies that demonstrate that the hypothalamus lights up first in a spontaneous migraine attack, and we do not have novel targets for the hypothalamus yet. Those are things that we need to continue to develop. As we learn more about spontaneous migraine attack, we’re going to be able to identify those windows of opportunity and those novel drug targets, and now we have the technology. Once we identify them, we can create not just a small molecule antagonist for it but also a mono-clonal antibody.

We’re not anywhere near the end. We’re not even in the middle. We’re just at the beginning. And I expect that over the next 10 to 20 years, we’re going to have so many more therapeutic options for our patient population.

What would you consider to be the biggest challenge remaining in this space?

Two things come to mind. One is going to be individualized medicine. I dream about the day when, based on clinical characteristics or other types of biomarkers—such as a blood biomarker or an imaging biomarker or some sort of physiology study biomarker&mdash;I will be able to identify which patient is going to respond to which medication. Right now, it is a little trial and error, but we’re working toward it.

The American Registry for Migraine Research, which the American Migraine Foundation sponsors, is something that will help with that. It’s collecting large amounts of clinical data and imaging data, as well as blood biomarker and genetic data, from large populations of patients who are visiting different headache clinics. Once we have all those data, we’ll be able to do artificial intelligence work, looking at big data, mining, and figuring out those predictive markers that will help us determine which medication needs to go to which patient. From a scientific level, I think that that’s the next big hurdle that we really need to approach from a clinical and, really, public health perspective.

However, the biggest barrier is still the stigma of migraine—not just within the lay public but also within the patient population themselves. We need to continue to work on the internalized stigma that results from the external stigma that patients have experienced their entire lives, as well as the stigma of patients with migraine that exists within the health care provider arena, among primary care providers and general neurologists. From a public perspective, we need patients to see a headache specialist or a neurologist. Study results still show that even among people with chronic migraine, 50% aren’t even presenting to a physician about their symptoms because they think it’s just a headache and something they just have to deal with. And that’s just not true. We have options available for them once they see the physician. They need to get the right diagnosis rather than just being told that they have tension-type headaches or stress headaches and that they need to just relax more, get a massage, or drink more water. After that, we need to make sure that our health care providers can not only properly diagnose but also apply the standard-of-care treatment options and refer to a headache specialist when appropriate. On that level, we need many more available head-ache specialists. There are 47 million people in the United States with migraine disease, and it’s simply unacceptable that there are only 564 board-certified headache specialists nationally.

Clinical Insights

The assistant professor of Neurology, Concussion and Headache Medicine divisions, Mayo Clinic, Scottsdale, Arizona discussed the evolving migraine treatment landscape and how they have been incorporated into her practice. 

The Evolving Landscape of Migraine Treatment

Andres M. Lozano, MD, PhD, FRCSC, FRSC, FCAHS

An estimated 40 to 50 million individuals worldwide are living with Alzheimer disease (AD) and other dementias.

 Characterized by progressive memory impairment and deterioration in quality of life, the disease is expected to pose a significant public health burden in the coming decade. With the isolation and characteriza-tion of the amyloid plaque core protein,

 investigators have focused their search on therapeutics that can combat and clear the plaques. Unfortunately, most of the investigational agents have not demonstrated clear efficacy in reversing the progression or cognitive symp-toms of the disease.

 Neuromodulation techniques, however, may provide a promising treatment avenue, with the goal of modifying nerve activity via pharmaceutical or electrical stimulus.

Deep brain stimulation (DBS) is a well-established surgical neuromodulation technique that has been used in the treatment of Parkinson disease (PD),

 It also has potential uses in obesity,11 eating disorders,12 depression,

DBS is an invasive procedure administered under local anaesthesia. Physicians make a small opening in the skull through which they insert an electrode. Digital brain mapping technologies deter-mine the precise locations for stimulation, and an implanted pulse generator (magnet) attached to the electrode can then regulate the timing and strength of stimulatory signals. According to estimates, over 160,000 patients around the world have undergone a DBS implant.

Patients with seizures who have received DBS have demonstrated improvement in memory,

and results of several studies have shown a potential improvement in visual memory in patients with epilepsy undergoing DBS.

 In rodent studies, DBS improved spatial memory and reversed the negative memory effects of scopolamine.

 In addition, in preclinical studies in both animal models and humans, DBS has demonstrated neuroprotective effects.

 Encouraged by these findings, practitioners are now exploring DBS in the treatment of AD. “With DBS, we believe that we are able to adjust the activity of brain circuits that are malfunctioning,” Andres M. Lozano, MD, PhD, FRCSC, FRSC, FCAHS, Dan Family Chair in Neurosurgery at the University of Toronto in Ontario, Canada, told NeurologyLive®. “In the case of Alzheimer disease, this could apply to circuits involved in memory and cognitive function.”

The Memory Circuit in ADResearch indicates that the cognitive impairment associated with AD results from widespread neuronal network dysfunction in the brain.

 The Papez circuit (or medial limbic circuit) involving the hippocampus, the fornix, the mammillary bodies, the anterior thalamic nuclei, and the posterior cingulate region26 is implicated in episodic memory and is therefore a viable candidate for study in AD.

The potential role of DBS in AD was a serendipitous discovery. Lozano’s team was exploring the use of DBS in the treatment of obesity, when hippocampal stimulation—particularly of the fornix&mdash;resulted in unexpected memory retrieval.

 Stimulation of these memory circuits in rats stimulated neurogenesis in the hippocampus.

 Subsequently, forniceal DBS resulted in the expression of neurotrophic factors and markers of synaptic plasticity involved in memory processing.

The ADvance phase 1 study (NCT01608061) of DBS in AD included 6 patients with mild to moderate AD.

 DBS of the fornix improved cognitive function and increased cerebral glucose metabolism and hippocampal volume. Although DBS was generally well tolerated, 2 of the 6 patients did report worse prognoses after the surgery.

Following 1 year of DBS, the patients presented with increased cerebral glucose metabolism and neural connectivity, in contrast with the decline associated with AD.

 Furthermore, fornix DBS appears to slow down the hippocampal atrophy associated with AD.

Phase 2 of the ADvance study, comprising 42 patients with mild AD, found an increase in cerebral glucose metabolism, which became nonsignificant at 12 months. In addition, investigators observed no significant improvement in cognitive outcomes. The long-term safety profile of fornix DBS was similar to that observed in the treatment of movement disorders.33 Four patients required addi52tional surgery for infection34 and the repositioning and drainage of chronic subdural hematoma.

An interesting finding of the ADvance study was the heterogeneity in cognitive decline between patients ≥65 and <65 years. Patients ≥65 years displayed an average reduction of 4.1 points in cognitive deterioration, as assessed via the AD Assessment Scale—Cognitive Subscale. Furthermore, cerebral glucose metabolism increased by 14% to 20% after 12 months of DBS in those patients; the cohort of patients <65 years uniformly exhibited declined glucose metabolism.

 “However, none of the 42 patients displayed any permanent neurological adverse effects from DBS,” Lozano said.

A 2-year follow-up study that sought to examine the long-term safety of fornix DBS also demonstrated no serious adverse effects of treatment. Younger patients manifested a rapid cognitive decline irrespective of treatment. However, older patients (>65 years) receiving active stimulation deteriorated less compared with their nonstimulated counterparts.

The cause of this heterogeneity is not fully clear. “Younger patients with Alzheimer disease may have a very malignant, severe form of Alzheimer that deteriorates very rapidly with or without DBS, whereas the older patients have a less malignant course that responds to DBS,” Lozano speculated. Another possible explanation could be that the autosomal dominant mutations that characterize early-onset AD might render the patients with an aggressive prognosis that is not alleviated with DBS.

 “Based on these findings, we have now decided to only operate on older patients because their illness is not progressing that rapidly,” Lozano said.

The phase 2b/3 trial is a 12-month, sham-controlled, double-blind study examining the safety and efficacy of fornix DBS in patients with mild AD. “We have just begun enrolling,” Lozano told NeurologyLive®. This study will be the largest trial of DBS in North America and Europe, exceeding previous trials of DBS for depression and epilepsy. The investigators intend to examine DBS efficacy and safety for up to 3 years after stimulation.

Other research points to another brain target for DBS: the nucleus basalis of Meynert (NBM). Although PD is generally characterized as a motor syndrome resulting from nigrostriatal dopaminergic denervation, recent studies have begun to explore nonmotor features such as cholinergic denervation. Evidence indicates that NBM, the source of cholinergic innervation in the cerebral cortex, may atrophy in PD, leading to protein aggregation and cognitive impairment.

Subsequently, DBS stimulation of the NBM in a 77-year-old patient with PD dementia improved apraxia.

 Interestingly, in a 71-year-old man suffering from PD dementia syndrome, DBS of the NBM markedly improved cognitive function. The patient reported improvement in attention, concentration, alertness, and drive, all of which resulted in improved quality of life.

 These findings formed the rationale for evaluating NBM DBS as a therapeutic strategy for AD.

Jens Kuhn, MD, of the University of Cologne in Germany, has pioneered the use of NBM DBS in the treatment of AD. Results of a phase 1, double-blind, sham-controlled study showed a reduction in cognitive decline in 4 of 6 patients. In contrast with results of fornix DBS, younger patients (<65 years old) with mild AD benefited more from NBM DBS. Furthermore, imaging studies revealed that patients with AD with less atrophy benefited more from the surgery.

 However, a limitation of the study is that for ethical reasons, all the patients also continued acetylcholinesterase inhibitor therapy. Therefore, the effect of DBS on the cholinergic system may have been disguised.

The pathology of AD has evolved past the singular view of amyloid plaque aggregation. The disease is characterized by multiple neuro-pathological changes that are thought to interfere with the function of memory networks. Many studies have demonstrated that dysfunction of synapses in the hippocampus precedes amyloid plaque aggregation and neuronal cell death.

 Furthermore, level of cognitive impairment appears to directly correlate with synaptic loss.

 The hippocampus also demonstrates a proportional decrease in glucose metabolism and gray matter volume with AD-related atrophy.

DBS is believed to regulate abnormal circuitry by generating action potentials, releasing neurotransmitters, and modulating sodium channels. In rodents, DBS also stimulates hippocampal neurogenesis.

 However, the precise mechanism of cognitive improvement triggered by DBS remains unknown.

The proposed etiology of the effect of DBS on AD may include an increase in cerebral glucose metabolism, stimulating hippocampal acetylcholine release, increasing nerve growth factor, increasing neuronal and synaptic activity, regulating neural oscillations, or resetting of theta activity.

 In rodents, DBS has been found to reduce deposition of amyloid plaques via lysosomal pathways.

DBS-stimulated reduction in synaptic and neuronal loss also led to an increase in hippocampal volume, but the neuroprotective mechanism is not fully understood.

Despite the effects of DBS in animal studies, clinical studies have not replicated the pronounced clinical effects. A possible expla-nation for this discrepancy could be the complex, interconnected nature of neural networks that regulate cognition. Subsequently, in patients with AD, fornix DBS induced visuospatial function that was preserved for 3 years despite a rapid decline in cognitive function.

Notably, animals and pharmacological models of AD may not accu-rately represent the pathophysiology of AD in humans.

Clinical doses of AD DBS have so far been guided by similar treat-ments of movement disorders. Therefore, the optimal dose remains unknown. However, the current ADvance II study (NCT03622905) will examine the difference between high and low frequencies of DBS.

 Other modifiable parameters that investigators should evaluate include pulse frequency, width, and voltage of the signal.

Another factor to consider is the effect of continuous versus acute stimulation. Continuous stimulation could lead to depletion of neurotransmitters and synaptic exhaustion. Therefore, a need exists for optimal stimulation strategies that regulate memory circuits without exhausting them.

Experts are debating the ethics of conducting DBS research from many perspectives, especially as AD is a progressive disease associated with cognitive decline, which raises many questions about obtaining consent. Research fellow and ethicist Merlin Bittlinger, MA, of the Berlin Institute of Health, told NeurologyLive® that “DBS for geriatric patients with severe Alzheimer disease is a no-go. Severe AD is characterized by dementia, which hampers autonomous-in-formed consent. Without autonomous-informed consent, participation in research that implies more than minimal risk is unethical and would cross the red line.”

Consequently, current DBS AD studies do not include patients with severe AD. Furthermore, Lozano said that because “patients with mild AD could become cognitively impaired or are already cognitively impaired, we insist on having double consent where both the patients and their families must consent. In this way, if the patient loses the ability to consent because of a decline in the illness, then the family can continue to give consent on their behalf.”

Bittlinger also insisted that from an ethical standpoint, the progres-sive nature of AD and the lifelong follow-up required of DBS necessitates a more robust proof of research rationale. “Animal experiments must be well designed and demonstrate that findings are relevant for translating the intervention to humans. They must allow an informed decision on whether or not the risk of serious unintended effects is unlikely to outweigh any potential clinical benefit.”

DBS studies in humans have also been limited by the period of follow-up. To date, the longest follow-up included only 7 patients for 2 years.

Investigators may identify more adverse events from larger cohorts with longer stimulation periods. “We know from previous research

 on DBS for PD that psychological adverse events are likely to be detected as soon as the number of patients receiving DBS for AD increases into the hundreds or thousands, compared to the limited number of patients who have undergone DBS so far,” Bittlinger said. “However, irreversible psychological effects are not the most pressing ethical problem. Most psychological effects will likely be manageable by adjusting stimulation parameters.”

Noninvasive brain stimulation (NIBS) is a new tool being examined for regulating the function of neuronal networks. Repetitive tran-scranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been shown to induce long-lasting neurological changes. Several studies in patients with AD have demon-strated a beneficial effect on cognitive function.

 Like DBS, NIBS also shows better efficacy in patients with mild and moderate AD compared with a severe prognosis.

The adverse effect profile of NIBS appears favorable. Effects associated with rTMS and tDCS have included neck pain, headaches, tinnitus, itching, mild psychiatric effects, and flashes of light.

NIBS remains in the preliminary stages of exploration, with its mechanisms not yet fully understood. Additionally, in rodents, chronic stimulation in the trough has been associated with long-term depression. Therefore, future studies in the field should include a determination of optimal doses and patterns of dose delivery.

Clinical studies examining the use of NIBS in AD have produced heterogeneous results, partially because of varied stimulation protocols. A need exists for larger, randomized clinical trials that could establish the safety and efficacy profile of NIBS.

In the past decade, the development of novel stimulation technologies has opened many exciting avenues for the treatment of neurological disorders. A potential future treatment strategy could include stimulation of multiple target sites in the brain that engage in cognitive function. Such a synergistic stimulation could exceed the efficiency of lone target stimulation. However, practitioners must also exercise caution in deriving overarching interpretations from these preliminary studies. Efforts should also focus on elucidating the etiology of neuropathological changes induced by DBS and NIBS. Despite their promise, neuromodulation technologies still have a long way to go before practi-tioners can widely apply them.

Features

Will ethical considerations and lack of consent stand in the way of thoroughly exploring the potential of this nondrug therapy?

Neuromodulation Holds Promise in Alzheimer Disease

Treatment of multiple sclerosis (MS) has reached a new milestone, in which discontinuation of therapy for some patients may be possible. This is a unique therapeutic situation, a crossroads of the benefits of long-term treatment with disease-modifying therapies (DMTs) in preventing progression of disability and a point when the disease course naturally wanes. In theory, if patients with MS can maintain function long enough, they will outlive the active period of the disease and no longer need therapy.

Since their introduction in the 1990s, DMTs have demonstrated significant efficacy in reducing the incidence of relapses and the appearance of new T2 lesions indicative of disease activity in MS, as well as the capacity to slow progression of disability.

 Perhaps one of the most significant clinical realizations recently is that DMTs are most effective in slowing progression of MS when they are initiated in the disease’s earliest preclinical stages, at the first sign of clinically isolated syndrome.

 Results of research have shown that aggressive treatment at the time of the first attack with drugs such as interferon beta, glatiramer acetate, and terifluno-mide can delay conversion to clinically definite MS and lead to a milder course of disease that preserves patient function longer.

The notion of being able to “retire” from a costly, long-term therapy associated with adverse effects and the risk of life-threatening infections holds great appeal to many patients who have for decades faced the effects of MS and its treatments. “It’s all rooted in the idea that the window of opportunity for most effectively treating MS is early on in the disease,” Robert Bermel, MD, director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic in Ohio, told NeurologyLive®. “Additionally, there’s been some research showing that not only are the DMTs less effective the older people are, but the disease is less active the older people are.” Taken together, he said, these factors suggest that continued lifelong therapy may not be necessary or even bene-ficial, but determining which patients will remain disease free after discontinuation has been a major obstacle to implementing a general plan for stopping MS treatment.

As the efficacy of DMTs has allowed patients to achieve and main-tain very low levels of disease activity, the question of whether these benefits would continue even with cessation of drug therapy has become increasingly relevant. According to Tanuja Chitnis, MD, an MS neurologist at Brigham and Women’s Hospital and Massachusetts General Hospital, and professor of neurology at Harvard Medical School, both in Boston, Massachusetts, “We’re entering an era where we have more patients who have been on DMTs long term and have been doing well, so we have a unique situation now.” Unfortunately, previous studies of interruption of DMTs focused on patients with ongoing disease activity who were nonadherent or who could not tolerate their therapies at earlier disease stages. Data on the outcomes after deliberate, medically endorsed discontinuation of DMTs in patients with stable disease are still largely lacking.

Bermel and his colleagues at Cleveland Clinic have been increasingly introducing patients who have been on long-term therapy to the concept of discontinuation. “We do believe that at some point, it’s appropriate to consider discontinuing DMT. We usually require that the person [has] been stable for 5 years or more, with no relapses and no new MRI [magnetic resonance imaging] activity,” he said. 

Chitnis, who is also the director of the Partners Pediatric MS Center at Massachusetts General Hospital for Children in Boston, takes a more conservative approach—at least for now. “There were some early studies, including ours,

 that suggested that there might be some patients for whom it might be safe to discontinue treatments,” she told NeurologyLive®, “but I think we are finding now in our further work, as we and others are looking into our cohorts of patients who have discontinued, that some patients continue to have disease activity. So I think we need to have better indicators, such as maybe biomarkers or biological mechanisms, to identify who might be safely discontinued.”

Early treatment with DMTs significantly modifies the natural course of MS. Tobin and Weinshenker

 noted “prolonged periods of disease quiescence during long term treatment of patients with clinically isolated syndrome,” suggesting the opportunity for discontinuing DMTs in these patients. However, the risks of relapse and accumulating disability associated with premature discontinuation of therapy were too high to ignore.

 This illuminated the second challenge, that if patients might indeed no longer need therapy for active MS, at what age could they safely discontinue treatment without reactivating disease?

The answer is not yet apparent. Chitnis was coauthor of a 2019 study by Yano et al

 that found a similar clinical course after 2 years among patients with relapsing-remitting MS who discontinued treatment compared with those who remained on therapy. This pattern was consistent across measures of clinical relapse, MRI event, disability progression, and disease activity, although the results varied by age at the time of discontinuation. “Older subjects (age >45) had a better disease course after discontinuation in terms of risk of MRI event and disease activity, while younger subjects (age ≤45) were more likely to experience disease activity after treat-ment cessation,”

 the authors reported. Likewise, Kister et al

 found that although relapse rates were equivalent between patients with MS (age >18) who discontinued first-line DMTs and with those who continued, time to disability progression was shorter following discontinuation.

Although these studies did not look specifically at outcomes in older patients who discontinued treatment, they did suggest that cessation at a late stage of MS was less likely to result in relapse or renewed activity on MRI. Supporting this, a 2019 investigation by Hua et al

 found that stopping DMTs in patients with MS over age 60 had only a minimal effect on outcomes, yet quality of life (QoL) was reduced. Studies suggest that older patients make better candidates for cessation because they have a more stable course of disease, whereas younger patients are more likely to discontinue therapy on their own.

 Bermel observed that as a result, the strategy of discontinuing DMTs after a certain age is becoming more common. 

"We do believe that at some point, it's appropriate to consider discontinuing DMT. We usually require that the person [has] been stable for 5 years or more, with no relapses and no new MRI activity," Bermel said.

Bermel and Chitnis both observe similar guidelines for discon-tinuation as those outlined by Tobin and Weinshenker,

 who determined, “It may be reasonable to stop immunomodulatory medications in patients who have experienced a progressive disease course for 5 years or longer, particularly those who are over the age of 60 years, if there are no accumulating T2 lesions or gadolinium enhancing lesions on MRI brain or spinal cord after a period of observation of several years. Earlier discontinuation, particularly in patients with active disease, may lead to increased disease activity, especially in patients treated with natalizumab. Clinical and MRI monitoring for recurrent disease activity is warranted in those discontinuing treatment.”

Continuation of immunomodulating therapy in older patients is associated with increased risk of infection and a higher susceptibility to malignancy, as well as a greater potential for drug inter-actions.

 Because it is now common for patients to have been on DMTs for decades, concerns are growing over the adverse effects of these powerful drugs. Adverse events range from non—life-threatening events such as flulike symptoms and local injection site reactions to dangerous infections like progressive multifocal leuko-encephalopathy associated with several DMTs.

"The primary risk to discontinuing is that the patient would have a relapse that would otherwise have been prevented, but we think we can minimize that risk by selecting patients who have been stable for 5 or more years and also who are above age 60, when the immune system becomes more senescent and they are less prone to disease activity,” Bermel said. “The other reason to consider stopping DMTs is [adverse] effects. Interferon is one of the medica-tions that may be worsening spasticity or depression that can make the patient’s quality of life worse, and in that setting, we definitely want to think about at least switching, if not stopping, DMTs.”

Chitnis agreed with the idea of switching therapies. Deciding not to discontinue does not necessarily mean that patients continue on the same therapy, she said. “I think there’s also the concept with older age of immunosenescence, and patients may not need to be on a stronger DMT, as there’s a lesser likelihood of relapse or developing new lesions, which presents an opportunity to either discontinue or step down to a milder therapy,” she said. “That is something I am increasingly considering doing. As patients who are on very high-efficacy treatments are nearing 50 or 60, I start to have the conversation about paring down to something that is milder. Although there are fewer relapses in older age, we know that patients do progress, and there might be benefits to a different profile of DMTs.”

As their base of patients with MS on aggressive drug therapies grows older, clinicians have been weighing the idea of discontinuing DMTs without reaching any definitive conclusions. Chitnis reserved judgment on whether DMT discontinuation is warranted. “I rarely discontinue patients,” she said, noting that they some-times bring up the idea of discontinuing because they might have seen an article on the topic. She will also discuss it with patients over 60, by letting them know this is something being studied and considered. “There are some I will discontinue, if I think based on the literature that they might be a good candidate, especially if they are having difficulty with their disease-modifying treatment, but usually at an older age above 60, at about 70,” she added.

Currently, no protocol exists for how or when to discontinue DMTs. The decision comes down to patient preference and clinical judgment. And although most patients are likely to look forward to not having to take medication (especially by injection) for the rest of their lives, Bermel has had some patients who prefer to remain on treatment, even in the absence of disease activity on MRI. “People who are stable on medication sometimes attribute that to being on the medication, and they’re not comfortable making a change. They feel protected and choose to stay on to avoid risk of relapse,” he said. “The only time we truly object to that is if the patient is having infectious complications or [adverse] effects of the drug, where I feel they would benefit by going off. But if the patient is tolerating it well, it’s perfectly fine for them to continue.”

Bermel reported that Cleveland Clinic has been successfully discontinuing DMTs in older patients in routine clinical practice for at least the past 5 years. “Discontinuation is not for everyone,” he said, “and it’s not across the board but in patients who have been very stable for 5 years or more, and where we consider the risk of the disease activity returning is low, we certainly consider it and may suggest that people discontinue after the age of 60.”

As the treatment of multiple sclerosis continues to evolve and improve, the proposition of lifetime therapy has come under scrutiny.

The Great Debate: Can Older Patients With MS Discontinue Therapy?

Rare neurological disorders are at the forefront of research now more than ever, with several novel therapies recently coming to market to address symptoms or the root cause of the diseases themselves. Tuberous sclerosis complex (TSC) may soon have its day in the spotlight, as health care providers and patients alike await next steps on a supplemental new drug application submitted to the FDA for Epidiolex (cannabidiol [CBD]; GW Pharmaceuticals). Nobody is closer to that process than Elizabeth A. Thiele, MD, PhD, who led the phase 3 clinical trial examining the safety and efficacy of the purified CBD in patients with the genetic disorder. For more than 15 years, Thiele has served as the director of the Carol and James Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital (MGH), one of the only centers of its kind that serve both children and adults with TSC.

With a multidisciplinary team, Thiele, who is also director of the Pediatric Epilepsy Program at MGH and a professor of neurology at Harvard Medical School, has worked tirelessly to address the whole-body issues that accompany TSC and bring awareness to what is often a misdiagnosed disease.

“As a neurologist, if I take a step back and look at lung involvement [and] look at kidney involvement, what can that help me understand about brain involvement?” Thiele told NeurologyLive®in an interview, in which she reflected on the evolution of the understanding of the disease and what that means for future treatment.

Q: How would you describe the current environment of TSC treatment?

What’s been really exciting in the world of tuberous sclerosis (TS) over the past 15 years is the emergence of mTOR inhibitors as possible treatment for some of the manifestations. They’re being used inconsistently, as no standard approach exists on how to use mTOR inhibitors. But given that we have them for patients with either significant renal involvement or women with LAM [lymph-angioleiomyomatosis] or children who have SEGAs [subependymal giant cell astrocytomas], I think they serve a really important role, and they created a lot of enthusiasm in the world of TS just to have specific FDA approvals for that. There is also a lot of enthusiasm in the TSC patient community over the TS CBD data about whether this would be an effective treatment, and I was pretty excited by the trial results. I think even aside from the trial, it’s going to be a very effective treatment for a lot of people with TS. There’s also some interest in whether CBD modulates mTOR, and some preclinical data show that it can. I don’t know whether that’s clinically significant, but we just submitted a paper that looked at all the patients who were in the expanded-access program for CBD over the years, and we did not see the same clinical effect that we see with the mTOR inhibitors—meaning tumor shrinkage, etcetera, but that’s a very small N, so that’s still unclear. People are starting to take a step back and say, “That’s great. We know what the mTOR inhibitors do. They shrink the tumors, but they don’t make them go away.” Patients have to stay on them long term or for life, and I think a lot of physicians are now considering the mTOR inhibitors as more of a [temporary solution], as patients need to be on them until a more definitive treatment becomes available.

Q: Do any particular therapies in the pipeline look promising to you? 

A couple of companies are looking at the possibility of gene therapy. Here at MGH, Xandra Breakefield, PhD, has been thinking about gene therapy and has both TSC1 and TSC2 in adenoviral vectors. The other drug I’m following closely is fenfluramine. Zogenix is doing a basket trial now that’s going to include TS, and I’m very enthusiastic about that because I don’t understand the difference in efficacy between the Dravet trial and the Lennox-Gastaut trial for fenfluramine. But there’s no reason to think that by mechanism of action, fenfluramine should be good specifically for Dravet but not good for other epilepsy syndromes, so I’m excited to see what happens with fenfluramine in TS.

I know that in the TS patient community, a lot of enthusiasm exists regarding Epidiolex and CBD in general. The difference between the TSC trial and the other Epidiolex trials was that the doses were higher, so instead of 10 and 20 mg/kg, it was 25 and 50 mg/kg. From the TSC trial, if you could compare it directly with the other trials for efficacy, we learned there was no dose response curve going up to 50 mg/kg, meaning it didn’t appear as if the 50-mg/kg dose was much more effective than the 20- or 25-mg/kg dose, so that’s important clinical information. What the trial really gave us was a type of safe passage, so to speak, because when any medication comes out, especially in pediatrics, I think we always push the dosing up as tolerated to see whether we get better efficacy at higher doses, especially because many of our medications have come out with very little pediatric data. What I think the TSC trial showed us for Epidiolex, in addition to demonstrating that it’s effective in treating seizures associated with TS, was that even up to doses of 50 mg/kg, the tolerability was still really good. You didn’t see the adverse effects and serious adverse effects skyrocket at those higher doses, and I think that’s important information for physicians who are going to clinically use this in both TSC and other epilepsies.

Q: What challenges have you faced with incorporating or switching your patients to CBD therapy?

What’s different about CBD is that the patient community, I think, is still more educated than the medical community. I think that’s changing, and I think GW has done a good job of trying to educate physicians about not only their product but also cannabinoids and the chemicals in cannabis. I’ve had very few patients over the years come in and tell me more about a medication than I know. Some families read up and know every possible adverse effect of clobazam or know the whole history of drug development or can draw me the chemical structure, but that’s unusual, whereas many patients are kind of aware of cannabinoids, THC, etc. I think interest still exists in the possible “entourage effect,” and we still get questions about whether having some THC or THC acid in addition to CBD provides particular benefits for some patients.

We’ve been lucky in Massachusetts so far that many payers have been reimbursing off-label use—that is, for patients with TSC who don’t have Lennox-Gastaut, but I’m pretty sure I do still have some patients who are taking the different artisanal products. In that case, I would have the same conversation with them that I have with our patients with Dravet and Lennox-Gastaut, looking at pros and cons of their product versus Epidiolex. Most of my patients with epilepsy transitioned to Epidiolex in large part because of cost. I do have a couple of patients who were doing really well on Charlotte’s Web, and the family could afford to keep them on that. So why rock the boat? If they’re seizure free, why would you risk transition? It’s something that may not be as effective for them.

"There's no reason to think by mechanism of action, fenfluramine should be good specifically for Dravet [syndrome] but not good for other epilepsy syndromes, so I'm excited to see what happens with fenfluramine in TS."

Q: What other treatment needs still exist? 

Even though it looks as if Epidiolex is effective, and results of the EXIST-3 trial [NCT01713946] of everolimus—even though I’m not that impressed with mTOR inhibitors in epilepsy for TS&mdash;were positive, very few patients were seizure free. That continues to be the goal especially because of the relationship with cognitive impairment and autism. The other thing that’s changed in epilepsy and TSC is the use of stereo electroencephalogram. Many programs are now are doing that to approach surgical management of a patient with TS, and many practitioners feel that that is much more effective at localizing the epileptic focus and zone than traditional methods of invasive monitoring. When I started [treating] TS 20 years ago, most experts thought that patients with TS weren’t good surgical candidates because they had more than 1 lesion and they often had more than 1 seizure type. That’s kind of gone the other way now as practitioners realize that if you have a child with TS who hasn’t responded to a couple of medications, you should really consider a surgical option.

Q: Can you describe the behavioral and cognitive comorbidities that affect this population? 

I think one of the biggest areas of increased clinical awareness in the TS world over the past 15 years has been the recognition of how incredibly prevalent and significant the neurobehavioral aspects of TS are. And now there’s an acronym, TAND, or “TSC-associated neuropsychiatric disorder,” to emphasize that. Almost all patients living with TSC probably experience some aspects of TAND. When we looked at our patient population retrospectively, about two-thirds had a formal psychiatric diagnosis, and about a third had 2 psychiatric diagnoses. So it’s very prominent. When the Tuberous Sclerosis Alliance polled its constituency a couple of years ago on what were the important things about TS that mattered on a daily basis, the neurobehavioral stuff was at the top with seizures. So I think there’s more research going on now, which is good because honestly, this hadn’t really been characterized. If you talk to families living with TSC, most of them had never been asked about mental health issues, and most people we meet have never received a diagnosis or been treated. In particular, anxiety is really prominent and very common in TS. It predates the [TS] diagnosis, and it’s more than just your typical anxiety; it’s an [obses-sive-compulsive disorder]—type of anxiety in which they get stuck worrying about particular things. Social anxiety is really common. We have some kids who can’t even go to school because the anxiety is so significant that they’re homeschooled. Patients with TS also replay interactions they’ve had with people. As part of the sleep disorder in TS, patients stay up at night replaying interactions that may have occurred that day or may be remote. The anxiety is distinct, and it’s very stereotyped, and we are trying to figure out on a research level, what about it across TSC1 and TSC2—across cognitive levels, across tumor burden&mdash;leads to that anxiety. Also, many children and adults who are more impaired with TS will have self-injurious behaviors, and we also have a collection of patients with TS who have savant syndrome. If we can characterize these things in TSC using it as a model, it may help us understand human memory and human behavior better.

Q: How do you address awareness and treatment of these comorbidities? 

Treatment of anxiety in TSC is similar to its treatment in the general population. No TSC-specific trials [have evaluated] the TAND features, though I think there’s a lot of interest in doing that. We have found over the years that selective serotonin reuptake inhibitors can be very effective. In fact, a medical student who is now a pediatric epileptologist at the University of California, Los Angeles, had worked with us and referred to Celexa as vitamin C because so many of our patients with TS were on it, and it can be profoundly effective even at low doses. In addition to the psychiatrists, we also have a dedicated neuropsychologist and a social worker for our TS group. Our social worker uses a lot of cognitive behavioral therapy, and we also are using other wellness approaches like meditation. But I don’t think that’s really specific to TS, as we and other practitioners are branching out and using those techniques in patients with epilepsy with these types of comorbidities. I think that the one thing that has evolved in TS with this recognition of TAND is the TAND checklist, which was developed several years ago with help from the Tuberous Sclerosis Alliance. The checklist assesses for TAND so it can be recognized, because in practitioners’ regular visits, they don’t have time to necessarily go through everything. Having that checklist makes it more concrete to health care providers that these issues are very significant for this patient population.

Q: What role do advocacy groups play for a rare disorder like TSC?

I think the advocacy groups are incredibly important for many reasons. For one, for patients living with one of these disorders, it gives them a home, it connects them with people who are following the same path, and that’s incredibly helpful for families. The other thing that the advocacy groups do—and this is true, as well, for the Dravet Syndrome Foundation and the LGS Foundation&mdash;is interface very well with the medical community. It builds a new team of medical professionals, scientists, patients, and families that all approach the same question: How do we better understand, treat, and cure this disorder? Being surrounded by people with the same thing is extremely powerful, and I find that for families, it’s an incredible support and advocacy force. The other thing that the advocacy groups do well, especially as these new treatments emerge, is help with infrastructure to identify participants for clinical trials. I think that that was true with the Dravet Syndrome Foundation with both the CBD and fenfluramine trials, as they educate their constituency about these potential treatments. The Tuberous Sclerosis Alliance has funded a huge amount of research, and now with their natural history database and their bio sample repository, I think they’ve become an incredible example for other advocacy groups. They are meeting the needs of their constituency, they are helping to identify care providers for people to turn to, and they are funding research. [More than that, they are] getting people together&mdash;both the experts in the field medically and people living with this&mdash;to say these are our research focuses and priorities to try to figure out this disease.

Clinical Viewpoint

Elizabeth Thiele, MD, PhD, answers a variety of questions on treating tuberous sclerosis, and the landscape of treatments available at this time. 

Treating Tuberous Sclerosis: A Time to Shine for a Rare Disease

The armamentarium of antiepileptic drugs has grown rapidly since 1990, more than doubling since the 1993 approval of felbamate for partial seizures with and without secondary generalization in adults.

 More recently, improvements in areas such as genetic sequencing have pushed the field of epilepsy care into a new domain, where the driving focus is no longer symptomatic treatment but proactive prevention and care designed with the individual patient in mind.

Some experts have argued that research in this field is poised to deliver the precision medicine model—particularly in the develop-ment and deployment of targeted therapeutics&mdash;because of gains in the understanding of genetics in epilepsy, the wide availability of in vitro and in vivo model systems and their translation into drug-screening platforms, and an established base of collaborative research organizations.

“We’re doing better in caring for patients with epilepsy, but we obviously still have gaps,” Anup D. Patel, MD, associate professor of clinical pedi-atrics and neurology at The Ohio State University and section chief of pediatric neurology at Nationwide Children’s Hospital in Columbus, told 

®. “Specifically, from a treatment standpoint, 30% of patients still remain unable to become seizure free.”

Daniel Lowenstein, MD, professor of neurology, executive vice chancellor, and provost at the University of California, San Francisco (UCSF), noted that this number has remained relatively unchanged over the past 50 years.

®, Lowenstein, who previously served as director of the UCSF Epilepsy Center and Epilepsy Research Laboratory, added that currently available drugs still carry with them limitations and drawbacks for patients whose seizures can be brought under control.

“There are certain syndromes where we know there is a selection or a portion of the [available] drugs that are more likely to be helpful and some that, in fact, can cause the epilepsy to get worse,” Lowenstein said. “But in most patients, doctors really are at best making an educated guess—and I’m being charitable when I use that phrase&mdash;in terms of picking which drug is most likely to work. We have to embark on this therapeutic odyssey of hoping that the first drug we choose is going to be the most effective. And when the patient has their seizures brought under control, they may have a certain amount of adverse effects.”

The ultimate goal of personalizing medicine for each patient requires that a number of pieces come together. The oncology community has already assembled several of them, with precision medicine allowing for more targeted and effective treatments for genetically driven cancers. Even with the broad phenotypic heterogeneity seen in epilepsy, the complexity of genotype-phenotype correlations, and the difficulties in translating the array of identified targets, investigators and clinicians are hard at work in identifying a path forward,

 led by advancements in genetics, artificial intelli-gence (AI), and other technology.

As investigators have identified more genes, advances in testing and next-generation sequencing have revolutionized the ability to provide genetics-based guidance in the laboratory and the clinic. In addition to providing answers to patients, genetic sequencing has opened the door for identifying potential protein targets. The best example of this may be in SCN1A-associated seizure disorders, which represent a spectrum of epilepsies that physicians can in part manage with a number of currently available pharmacologic agents, including clobazam, stiripentol, benzodiazepines, cannabidiol, topiramate, levetiracetam, valproic acid, and ethosuximide.

However, large gaps in treatment remain for patients with the more severe syndromes associated with the gene, namely Dravet syndrome and intractable generalized tonic-clonic seizures. A group of investigators including Ian Miller, MD, director of the Epilepsy and Neurophysiology Program at Nicklaus Children’s Hospital in Miami, Florida, presented a novel approach to adeno-associated viral (AAV ) vector—based gene therapy for SCN1A-positive epilepsy at the 2019 American Epilepsy Society Annual Meeting. The study, which used a mouse model of Dravet syndrome, showed that a γ-aminobutyric acid–selective AAV vector significantly reduced hyperthermic seizures, decreased the frequency and duration of electrographic seizures, and significantly reduced the risk for sudden unexpected death in epilepsy by 89% when administered to SCN1A-positive and -negative mice.

“Unlike the traditional model or the default mental picture that people have of taking an extra copy of SCN1A and putting it into the nucleus somewhere, the approach here is actually putting something into the nucleus, which, when translated, will increase transcription of SCN1A,” Miller told 

®. “It’s a very regulation-centric model rather than a copy number model. That approach brings down the size of the payload that’s needed to induce the effect. It makes it possible to deliver this well-characterized, relatively safe virus and makes it really exciting for patients.”

Other research has illustrated this paradigm in epilepsy, evidenced for example by the early-stage success of quinidine in the treatment of patients with KCNT1-positive epilepsy. One of 3 patients self-re-ported an 80% reduction in seizures, and another saw similar results accompanied by improved psychomotor development.

Significant advancements in genetics and the implementation of artificial intelligence have begun to carve a new, more personalized path for the diagnosis and treatment of seizure disorders.

April 2020