In the 200 years since Parkinson disease was first defined as a medical condition, plenty of research has been done, but plenty of questions remain. The biggest one—How can it be stopped?&mdash;remains frustratingly unanswered. 

Even so, among the scientists and investigators who spend their days seeking a cure, there’s a growing sense that the turning point is just around the corner. 

“My impression is that there are more promising potential therapies now than in previous years, and that this is due to an accumulation of research over the past 10 to 20 years that has slowly brought us to the point that we are [at] today,” Rebecca Gilbert, MD, PhD, vice president and chief scientific officer at the American Parkinson Disease Association, told NeurologyLive™.

Therapies now under development have broader, higher aims than the therapies in drug developers’ pipelines several years ago, according to Brian Fiske, PhD, senior vice president of research programs at the Michael J. Fox Foundation for Parkinson’s Research. A decade or so ago, he said, drugs tended to focus on ameliorating the symptoms of Parkinson disease. Those drugs could have a major impact on quality of life but did not necessarily bring the field closer to a cure. 

“For us, what is probably most exciting is [that] we’re starting to see trials of drugs that are targeting biological and genetically defined mechanisms that have been linked to Parkinson,” Fiske said. In other words, the therapies in today’s pipeline are aiming for the disease’s fundamental causes. 

Scientists and pharmaceutical companies are focused not only on the causes but also more specifically on the disease, according to James Beck, PhD, chief scientific officer and senior vice president of the Parkinson’s Foundation. “Previous efforts to stop Parkinson really focused on issues central to Parkinson, but they were central to many other diseases, as well, like oxidative stress,” he said. “However, I feel the field is entering a time where experimental therapies are targeted to issues that are unique to Parkinson.” 

One of the biggest attempts to zero in on Parkinson disease involves looking more closely at genetics. “Personalized medicine is likely going to be an important aspect of the future of Parkinson research,” Beck said. 

That shift is good news for patients, because real-world cases have long suggested variability in the disease. “Some people have a lot of tremor; some have none,” Gilbert said. “Some have very severe nonmotor features; some have very few.” 

Work is underway to understand the different subtypes, their causes, and whether treatments will vary with subtypes. One variation that is already known involves genetics. About 10% of people with Parkinson disease have a genetic mutation that has been correlated to a much higher risk of developing the disease, Beck said. Several new drug candidates are aimed at tackling those mutations or limiting their effects. “The hope behind these drugs—and currently, it’s just hope&mdash;is that they might make a real difference for those with genetic forms of Parkinson and maybe, one day, for those with other forms, too,” he said. 

One target of gene-focused Parkinson research is the protein α-synuclein. The process of identifying the protein as an apparent genetic factor took many years and many scientists, according to Beck. “It all began with the work of Roger C. Duvoisin, MD, the [Parkinson’s] Foundation’s first fellow who first identified mutated forms of the protein as the cause of the first genetic forms of Parkinson in 1997,” he said, “to more recent work in 2008 by foundation researchers that discovered α-synuclein might underlie the progression of Parkinson.” 

The current scientific thinking suggests that the molecular cause of Parkinson disease is an abnormal buildup of α-synuclein, Gilbert explained. “Research suggests that the α-synuclein molecule can take on different structures and in certain structures can cause other α-synuclein molecules to clump together.” 

It is believed that in the small subset of patients with gene-associated Parkinson disease, a genetic variation causes their bodies to produce either too much α-synuclein or an altered form of the protein. 

A number of efforts are underway to combat those α-synuclein clumps, known as Lewy bodies. One is a vaccine, PD01A (Affitope; AFFiRiS), which is currently in phase 1b trials and is designed to target α-synuclein. In the phase 1a trial, the therapy proved safe and well tolerated. 

Another strategy against α-synuclein is being deployed with NPT200-11, a compound designed to bind to certain regions of α-synuclein to prevent toxicity. According to its developer, Neuropore Therapies, the therapy has been shown to prevent α-synuclein toxicity in the lab and in animal models.

The furthest along of the α-synuclein-targeting therapies is known as NPT088. In addition to α-synuclein, the therapy targets amyloid-ß and phosphorylated tau and thus is seen as a possible treatment for Alzheimer disease in addition to—or instead of&mdash;Parkinson disease. The therapy, which is delivered intravenously to the brain, has been shown in preclinical research to reduce levels of α-synuclein and improve motor function. Results from a phase 1b study are expected in 2019. 

Scientists are also working hard to better detect the buildup of α-synucein, Fiske said. “One of the really big pushes right now around α-synuclein…is being able to measure it in people and particularly being able to measure the accumulation in people with the disease— ideally, as early as possible,” he said. 

Additionally, a gene therapy that has shown positive results in a mulitdose phase 1b clinical trial is known as VY-AADC01. It uses adeno-associated viral vector serotype 2 (AAV2) to encode the AADC gene, which is involved in the conversion of levodopa to dopamine. Recently reported results showed an increase after 12 months in on-time without troublesome dyskinesia across all doses, varying from 14% to 32%, in 15 patients with Parkinson disease.

A mutation in the LRRK2 gene is believed to be a factor in just 1% to 2% of Parkinson cases. However, in certain ethnic populations, including Ashkenazi Jewish individuals and the North African Arab Berbers, the mutation is present in upward of 40% of Parkinson cases. 

In August 2018, Denali Therapeutics announced the results of a phase 1 trial for its LRRK2 inhibitor compound, DNL201.

 The results showed the drug to be safe and well tolerated. The company is planning a phase 1b study for the compound. 

Although the population of patients who currently expected to benefit from a drug candidate like DNL201 is relatively small, Gilbert said, the scientific community still has much to learn about the connection between genetic mutations and Parkinson disease. Other patients may have a different, yet-to-be-discovered mutation that could also affect the LRRK2 gene. “What this means is that a medication that affects LRRK2 biology may benefit more broadly than just for those who have the mutation,” she said. 

One other genetic avenue being explored relates to the enzyme glucocerebrosidase (GBA). It is believed that about 1 in 10 patients with Parkinson disease in the United States has a GBA gene mutation. Having the mutation does not meant that an individual will develop Parkinson disease—just a small percentage of patients with the mutation do. However, people with the mutation are more likely to be diagnosed compared with the general population. Results of a 2016 study showed that people with the mutation had a 217% higher risk of developing cognitive impairment.

One trait that makes the GBA gene interesting from a research perspective is the fact that the mutation is also linked to another serious condition—Gaucher disease. A rare but deadly lysosomal storage disorder affecting about 6000 people in the United States, it occurs when patients have 2 copies of the mutation; patients with Parkinson disease have just 1 altered copy. 

The link between the 2 conditions offers some hope that a treatment for one disease might lead to a treatment for the other. Lysosomal Therapeutics, Inc, is in the midst of a phase 1b trial for LTI-291, a drug candidate designed to treat GBA-associated Parkinson disease.

The parallels between Parkinson and other diseases also create new opportunities for speedy trials. A number of therapies already approved for other conditions are in phase 2 or 3 trials for the treatment of Parkinson disease. 

Among them is isradipine, which was approved for the treatment of high blood pressure but may also have a neuroprotective benefit in patients with Parkinson disease. The final results of a phase 3 study of isradipine for Parkinson disease are expected in the winter of 2019.

Another therapy, exenatide, which was approved more than a decade ago to treat type 2 diabetes, is being evaluated as a treatment to slow the progression of Parkinson disease. Phase 2 results published in 2017 were promising; however, the authors of the study noted that it is not yet clear whether the results were evidence that exenatide actually slowed the underlying progression of the disease or merely produced long-lasting alleviation of symptoms.

“The important thing to note is that if clinical trials do show that these medications work in Parkinson, they can be transitioned to use in Parkinson much more simply than a medication that is not yet approved,” Gilbert said, “since [adverse] effect profiles are already known, and they are already manufactured and available.” 

Of course, not all efforts at repurposing therapies pan out. Study results presented in October at the International Parkinson’s and Movement Disorder Society’s International Congress in Hong Kong showed that a nicotine patch did not slow progression of Parkinson disease.

 Investigators had hoped nicotine might have an effect because epidemiological research has suggested smokers face a significantly lower risk of developing the disease. 

Another exciting area of research that Gilbert noted relates to stem cell therapies. She said that investigators have long wondered if stem cells could be used to replace dopamine neurons, the loss of which is believed to be responsible for the motor symptoms of Parkinson disease. The intriguing theory met with a problem: “This is much easier said than done, and in the past, cell-based therapies tested in clinical trials caused unacceptable [adverse] effects such as uncontrollable dyskinesias,” she explained. 

Fortunately, stem cell research has grown by leaps and bounds, and now even adult stem cells can be reprogrammed to create stem cells. This raises hopes that dopamine neuron replacement could be on the horizon. A small trial is already underway in Japan. 

Still, Gilbert cautioned that the proliferation of stem cell research has also brought a proliferation of often dubious claims. A number of practitioners in the United States and abroad are already marketing stem cell treatments for disease, including Parkinson, often for large sums of money. “None of these treatments are currently FDA approved, and I urge anyone who is interested in stem cell treatment for Parkinson to hold off until he or she is able to join a properly structured clinical trial conducted at an academic medical center,” she said. 

The existing model to replace dopamine involves levodopa. Gilbert noted that the current methods of delivering the drug to the brain are problematic for many patients, leading to fluctuations in motor control throughout the day. “One strategy to try [to] prevent these fluctuations is changing how levodopa is given,” she said. “Many new strategies are under investigation, including a continuous infusion pump of levodopa into the subcutaneous tissue of the abdomen, similar to an insulin pump.” 

Gilbert also described work being done on a “rescue dose” that could be quickly delivered when a patient loses the ability to move. Acorda Therapeutics has an application before the FDA to market an inhaled form of levodopa; a decision is expected in late 2018 or early 2019. 

Although research in recent years has expanded beyond treating symptoms and focused increasingly on the underlying mechanisms, a number of therapies in the pipeline are specific to particular symptoms. Those advances are important, too, Beck said: “Therapies that address symptoms are important for helping people today and have been very important to improving the quality of life of people with Parkinson.” 

Among symptom-focused drugs in clinical trials is tropicamide, a solution used in ophthalmology procedures. A completed phase 2 study looked into whether it can alleviate sialorrhea in Parkinson disease. Meanwhile, a phase 2 study is investigating buspirone for the treatment of anxiety in patients with Parkinson disease. Although that therapy is approved for anxiety in the general population, there is some concern that it might have a negative impact on motor function in patients with Parkinson disease. Results are expected in March. 

Droxidopa was approved in 2014 to treat orthostatic dizziness, but a 2016 study showed that it can also reduce falls in patients with Parkinson disease.

More recently, data from a phase 2 trial of SYN-120, which blocks 2 serotonin receptors in the brain, proved inconclusive. Investigators want to know if the therapy can help improve cognition in patients with Parkinson disease. Although the trial data “trended in favor” of the drug versus placebo, the study’s primary end point was not achieved to a statistically significant degree, the drugmaker Acorda Therapeutics reported.10 The company is currently evaluating the data and next steps. 

Asked if the development of symptom-focused therapies might also help the larger effort to find a cure or prevention method, Beck said he hoped so but has not yet seen evidence of it: “Unfortunately, efforts to help symptoms have not resulted in any appreciable slowing of Parkinson.” 

Even as new therapies and formulations move through pharmaceutical pipelines, a number of major questions remain. For example, Beck said, the advancement in terms of gene therapies is hampered by this: “The community has a real problem—nobody really knows who has genetic forms of Parkinson.” 

The Parkinson’s Foundation is among the groups working to change that. Earlier this year, it launched a Genetic Initiative aimed at offering genetic testing and counseling to patients in order to gain a more robust understanding of the genetic data behind the disease.

 The Michael J. Fox Foundation also has an initiative, Fox Insight.

 The program is an online clinical study asking patients to self-report data about their Parkinson disease experiences. It also partnered with the genetic testing company 23andMe to study the genetics of patients with Parkinson disease. Thus far, more than 26,000 patients have contributed to the study. 

“It has really helped develop a better picture of what Parkinson’s is and the diversity of what Parkinson is,” Fiske said. Those data will help in clinical trial designs, but they could also have another impact— attracting more money into the fight to cure the disease.

Fiske said there is a good level of collaboration between his foundation, other Parkinson groups, and the National Institutes of Health. Government funding is also important, he said, but noted that funding levels can shift as political priorities shift, making it difficult to predict trends. 

As far as industry goes, the signs are positive. “We’ve seen a lot of increased commitment from companies,” he said. 

Drug companies look for things like clearly defined biology, clear unmet need, and clear patient need, Fiske said. As scientists gain ground investigating the mechanisms underlying Parkinson disease, it gets easier to get pharma involved. 

Gilbert also noted that some promising research doesn’t involve drugs at all. “There has been mounting evidence over the past number of years that physical activity is beneficial for the motor and nonmotor symptoms of Parkinson and possibly disease-modifying, as well,” she said. 

Unlike with drug candidates, she said, there are few adverse effects when it comes to exercise, which provides additional health benefits. The American Parkinson Disease Association recently launched an online training program for fitness professionals and a booklet about exercise for patients. 

As major studies continue to advance, it is not clear what the future of Parkinson disease care will look like, but there is plenty of enthusiasm. When asked which data he most looks forward to seeing in the coming months, Fiske had difficulty deciding but he said he is excited to see what comes from the studies looking into the genetic mechanisms. 

“We’re all, as a field, anxiously hopeful, awaiting positive results from those studies,” he said. If those studies produce the kind of data Fiske wants, investigators could be on the precipice of the turning point in the fight against Parkinson disease. 

“The holy grail, so to speak, of Parkinson treatment is a neuroprotective agent, or one that prevents, slows down, or cures Parkinson by changing the basic biology of the disease,” Gilbert said. 

1. Alpha-synuclein (ASYN). Neuropore Therapies website. neuropore.com/programs/alpha-synuclein.

2. Christine CW, Larson PS, Van Laar AD, et al. VY-AADC01 in Medically Refractory Parkinson’s Disease: Safety and Efficacy of a Phase 1b Dose-ranging Study 12 Months and Beyond. Presented at: 143rd American Neurological Association Annual Meeting; Atlanta, Georgia, October 21 to 23, 2018. Abstract M300. 

3. Denali Therapeutics announces positive clinical results from LRRK2 inhibitor program for Parkinson’s disease [press release] South San Francisco, CA: Denali Therapeutics Inc.; August 1, 2018. investors. denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-positive-clinical-results-lrrk2#ir-pages. Accessed October 18, 2018. 

4. Liu G, Boot B, Locascio JJ, et al; International Genetics of Parkinson Disease Progression (IGPP) Consortium. 

 neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. Ann Neurol. 2016;80(5):674-685. 

5. Clinical trials. Lysosomal Therapeutics website. lysosomaltx.com/patients. Accessed October 18, 2018. 

6. Simuni T, Halloway R, Oakes D, Biglan K, Lungu C. A phase 3 study of isradipine as a 

 agent in patients with early Parkinson’s disease (STEADY-PD III): baseline characteristics and study update [abstract P2.039]. Neurology. 2018;90(suppl 15; 

 P2.039). n.neurology.org/ content/90/15_Supplement/P2.039. 

7. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a 

, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664-1675. 

8. Dolhun R. Nicotine patch not beneficial in Parkinson’s. The Michael J. Fox Foundation for Parkinson’s Research website. michaeljfox.org/foundation/news-detail.php?nicotine-patch-not-beneficial-in-parkinson. Published October 8, 2018. Accessed October 18, 2018. 

9. Hauser RA, Heritier S, Rowse GJ, Hewitt LA, Isaacson SH. Droxidopa and reduced falls in a trial of Parkinson disease patients with neurogenic orthostatic hypotension. Clin Neuropharmacol. 2016;39(5):220-226.

10. Acorda provides financial and pipeline update for 

 2017 [press release]. Ardsley, NY: Acorda Therapeutics, Inc; February 15, 2018. ir.acorda.com/investors/investor-news/investor-news-details/2018/Acorda-Provides-Financial-and-Pipeline-Update-for-Fourth-Quarter-and- Year-End-2017/default.aspx. Accessed October 18, 2018. 

11. Parkinson’s Foundation announces new genetic initiative connecting Parkinson’s genetic data with clinical care [press release]. Miami, FL, and New York, NY: Parkinson’s Foundation; March 6, 2018. parkinson. org/about-us/Press-Room/Press-Releases/Parkinsons-Foundation-Announces-New-Genetic-Initiative- Connecting-Parkinsons-Genetic-Data-with-Clinical-Care. Accessed October 18, 2018. 

12. Fox Insight. The Michael J. Fox Foundation for Parkinson’s Research website. foxinsight.michaeljfox.org. Accessed October 18, 2018. 

Articles

Cover Story

Growing enthusiasm in the Parkinson disease research community largely centers on advances in understanding the genetic underpinnings of the disease.

Genetics Fuel Parkinson Pipeline Growth

The argument in favor of stroke telemedicine, or telestroke—the services in which neurologists offer remote treatment to patients who have had a stroke&mdash;has been growing. Many supporters of telestroke point to its ability to improve patient outcomes, although the implementation of these systems require overcoming a few obstacles. 

Nearly 800,000 people in the United States suffer a stroke each year, making it the fifth-leading cause of death. According to the American Stroke Association, someone in the United States has a stroke every 40 seconds, and someone dies of a stroke every 4 minutes.

An estimated 87% of strokes are acute ischemic strokes (AISs), in which timely use of a clot-dissolving drug is necessary to reduce morbidity and mortality. Eligibility for tissue plasminogen activator (tPA) requires administration within 3 to 4.5 hours after onset of stroke. Patients who receive tPA within 90 minutes are nearly 3 times as likely to have favorable outcomes 3 months post stroke compared with patients who did not receive tPA.

 However, only about 27% of patients with stroke arrive at a hospital within 3.5 hours.

Several factors may prevent timely treatment. Roughly one-third of Americans live an hour or more away from a primary stroke center.4 In addition, there are just 4 neurologists to 100,000 people in the United States.

 It has been estimated that, due to these barriers, just 3% to 6% of stroke patients receive tPA.

 Telemedicine technology allows emergency physicians to close the gap between stroke centers and neurologically underserved areas by allowing for interactive audio-visual evaluation and treatment of acute stroke.

“We’ve developed an innovative approach where we’ve taken a CT [computed tomography] scanner and have had the ability to put that into an ambulance,” M. Shazam Hussain, MD, director of the Cerebrovascular Center at Cleveland Clinic in Ohio, said in April 2018.

 “CT scanners have come into such a technology that they’re actually small enough to fit in an ambulance. We also now have the ability, virtually, to be able to beam into the vehicle using telemedicine. We’re saving, on average, about 40 minutes of time. That 40 minutes can really add up to a lot of impact for that patient.” 

In a 2009 study, Capampangan et al compared telephone with interactive audiovisual communication through telemedicine for remote emergency consultations in assessing neurologic deficits due to stroke.

 The investigators wanted to establish the efficacy of telemedicine in determining patient eligibility for thrombolytic therapy. Participants in the single randomized, blinded, prospective trial included consultant and resident neurologists, clinical epidemiologists, medical librarians, and clinical content experts in the fields of vascular neurology, emergency medicine, and telemedicine. Through a clinical scenario and structured questions, the participants declared decisions based on their devised search strategies, best evidence, critical appraisals, and summarizations of evidence. 

The investigators determined that correct stroke treatment decisions occurred more often in the telemedicine group (98%) versus the telephone-only group (82%). The former was more sensitive compared with the latter (100% vs 58%) and more specific by a measure of 98% to 92%. The telemedicine group also had higher positive predictive values (94% vs 76%) in determining thrombolysis eligibility. 

Evolving Technology for Precise Evaluation and Treatment 

A potential limitation of telestroke involves the lack of in-person physical examinations before consulting neurologists make critical treatment decisions. To look into that issue, Sinn et al conducted a retrospective study comparing patients who had received intravenous thrombolysis (IVT) through telestroke between January 2013 and October 2014 with patients who had IVT directly in-house in the same time period.

 The investigators sought to determine whether telestroke was associated with increased frequency of stroke mimics (SM). 

AIS was confirmed by radiological evidence or clinical evidence of symptoms persisting more than 24 hours, with other etiologies excluded. SM was defined as lacking radiological evidence of acute localized cerebral ischemia related to presenting symptoms and was further identified using 24-hour observation of post-IVT images and primary discharge diagnoses. Residual cases were reviewed by 2 vascular neurologists and 2 board-certified neurologists, who defined them as SM or as neuroimaging-negative cerebral ischemia. 

The group found that of the 195 patients in the telestroke group (mean age, 64.0) and the 88 in the in-house group (age, 64.3 ±15.5 years) who received IVT, good functional outcomes were 49% and 43%, respectively. In the telestroke group, 27.2% had SM compared with 14.8% of the in-house group. Among the key findings: Telestroke under the “drip and ship” paradigm—that is, administering tPA at a frontline hospital, following by immediate transportation to a stroke care facility&mdash;was associated with increased frequency of SM in patients who received IVT compared with those who were evaluated in-house and treated with IVT. The investigators acknowledged that their multistep method of identifying SM may have led to higher frequencies of identified SM than in similar studies which used at least 1 of 3 methods, or any of the 3 in combination that included radiological evidence, retrospective review, or alternative diagnoses at discharge. 

Centralized Care for Geographic Barriers 

Another major challenge to stroke assessment involves the geographic barriers that prevent patients from arriving at an appropriate center of care within the window of time for achieving a positive outcome. In a 2016 observational retrospective cohort study,

 Hubert et al found that decentralized thrombolysis service through telestroke in rural populations can achieve rates of door-to-needle time and tPA administration similar to those of a centralized system for an urban population. 

The investigators compared time delays of treatment initiation after onset between a centralized hospital and a decentralized hospital, expressed as onset-to-door time, door-to-needle time, and onset-to-treatment. They studied the time delay rates at centralized Helsinki University Central Hospital (HUCH), which for a time was the only hospital in the province of Uusimaa, Finland (2011-2013 mean population, 1.56 million), to provide thrombolysis for stroke. Although most residents were in Helsinki and its surrounding metropolitan area, the rest of the population lived in areas where driving to treatment could take up to 90 minutes. HUCH had a neurologist and resident on-site 24 hours a day, 7 days a week. Due to province-wide ambulance service, a stroke consultant could be contacted in transit by mobile phone to prepare for the patient’s arrival based on relevant details, medical history, and tPA eligibility. At the hospital, patient medical records and any prior imaging and lab test results could be analyzed, the patient was preregistered, and any necessary lab tests and imaging were ordered. 

With the aim of providing an update on the development of the telestroke web-based program at the Medical University of South Carolina (MUSC), Sami Al Kasab, MD, a clinical assistant professor of neurology in the Cerebrovascular Disease Division at the University of Iowa Carver College of Medicine in Iowa City, analyzed data on all patients evaluated through the MUSC Telestroke program from May 2008 through April 2014.12 With this technology, patients who had a stroke presenting with AIS at a rural hospital could receive expert evaluation and consultation within minutes. 

The investigators collected data on the numbers of patients transferred to MUSC, intravenous (IV) alteplase administrations, and mechanical thrombectomies performed on transferred patients, as well as the rate of symptomatic intracerebral hemorrhages (sICHs) and discharge location. Of the 7694 consults performed during the study period, 3795 (49.2%) of patients were diagnosed with AIS and 1324 were treated with IV alteplase. 

“Several measures were taken to improve door-to-needle time,” Al Kasab told NeurologyLive™. “Those include (a) hiring a coordinator who was in charge of providing constant education to the outside hospitals and immediate feedback on cases, (b) premixing tPA, (c) starting the consult while the patient is in the scanner, and (d) helping community hospitals obtain primary stroke center certification.” 

Over the course of the MUSC study, the number of participating sites increased from 6 to 19, whereas the percentage of transfers decreased from 36% to 14%—the telestroke program had evolved to include involve more sites throughout South Carolina. Additionally, this model allows for not only better outcomes but also opportunities for follow-up care. “In our experience, we found that implementing a teleneurology network where patients admitted for AIS workup are seen as a follow-up the next day by a neurologist to assure completion of workup and adjusting the plan based on the workup performed,” Al Kasab and colleagues wrote. 

Despite the advances in technology and the opportunities to overcome longstanding geographical barriers, telestroke programs have yet to be widely adopted by acute care hospitals.

Shea et al sought to identify the characteristics of 107 acute care hospitals associated with telestroke adoption in North Carolina, a state that has more rural counties (70) than urban (30).

 To identify variables relevant to telestroke adoption, this team of investigators used Consolidated Framework for Implementation Research constructs complemented by constructs identified in previous telemedicine studies.

 External and internal variables considered included the economic, political, and social context of an organization and the characteristics of the organization. The investigators had hypothesized that emergency department (ED) visits would be positively associated with telestroke adoption but found that this was not the case. 

Shea et al also considered financial factors. The study was, to the best of the authors’ knowledge, the first to analyze hospital financial variables in considering likelihood to adopt telestroke. They found that available resources (eg, Medicare reimbursement) may affect whether or not an acute care hospital allocates resources for the program and that hospitals located farther from telestroke hospitals are less likely to adopt the technology. Additionally, the authors noted that competitive pressure may run counter to the community’s need for telestroke service. 

“There are 2 key challenges to telestroke adoption among rural hospitals: access to knowledge and network selection,” study coauthor Kea Turner, PhD, MPH, MA, told NeurologyLive™. Turner is an assistant professor in the Department of Health Services Research, Management, and Policy in the University of Florida College of Public Health & Health Professions in Gainesville. 

“For example, some rural hospitals in our study were not part of a delivery system that offered telestroke or were geographically isolated from other hospitals participating in telestroke, which made it difficult to access information about telestroke networks, such as what services are offered [and] participation costs,” Turner said. “We also found that some rural hospitals, especially hospitals without a neurologist on staff, may find it difficult to assess which telestroke network offers the best advantage, such as high quality of care or technical assistance with implementation and performance measurement. 

“Therefore, it may be difficult for some hospitals to make an informed decision about which telestroke network to join,” she added. 

Shea et al identified acquisition of the necessary technology as another key barrier to telestroke adoption. One important finding that emerged during the study was that hospitals belonging to a network not operated by their integrated health care delivery system faced additional implementation challenges in comparison with hospitals in telestroke networks operated by their health care delivery system. Hospitals that were not part of a health care delivery system offering telestroke had to decide which technology (eg, telestroke robot) to purchase. For hospitals that were part of a delivery system offering telestroke services, the costs of the technology were covered. 

“Many hospital representatives we spoke with described how the technology adoption process was difficult because the hospital lacked familiarity with the different technologies or how to compare them,” Turner said. “Some representatives described that, after purchasing the telestroke technology, they gained a better understanding of which features were most useful and wished that they could go back and change their decision regarding which technology to purchase.” 

Additionally, Turner said, some hospitals purchased new technology after learning more about it through the implementation of telestroke—which she described as another key knowledge gap. “If a hospital has not participated in a telemedicine program before, it can be difficult to make decisions about which technology will be the easiest to use in practice and which features are most important for implementation,” she said. For example, if the robot being used is shared between the ED and intensive care unit, an easily moved one would be best. 

Commonality between electronic health record (EHR) systems could also pose financial and logistical obstacles to telestroke adoption. “Regarding EHRs specifically, challenges we heard about when hospitals have different EHRs included preimplementation issues around ensuring appropriate access—for example, credentialing and privileging, firewalls, and HIPAA [Health Insurance Portability and Accountability Act],” Christopher M. Shea, PhD, MA, MPA, an associate professor of health policy and management at the Gillings School of Global Public Health within the University of North Carolina (UNC) at Chapel Hill, told NeurologyLive™. 

Shea also serves as the faculty lead for the North Carolina Translational and Clinical Sciences (NC TraCS) Dissemination and Implementation Science Methods Unit and is a research fellow at The Cecil G. Sheps Center for Health Services Research at UNC Chapel Hill. He said that postimplementation of telestroke also proved difficult for some acute care centers and may constitute another potential logistical barrier. 

“Postimplementation challenges centered around auditing and performance measurement issues, which require access to and familiarity with the different EHRs among the network staff—e.g., the hub&mdash;so they can abstract charts to provide data back to spoke sites,” Shea said. “So, the postimplementation challenges make quality reporting and QI support more cumbersome.” 

One study participant suggested developing an accreditation system for telestroke programs so that hospitals could have information to help them compare telestroke networks when deciding which network to join. 

“We found that some rural hospitals did not have any resources or information about telestroke services and were trying to obtain information on their own, whereas other hospitals that were a part of a delivery system offering telestroke or were located near a hospital participating in telestroke were able to obtain information about telestroke from other participating hospitals,” Turner said. “For the hospitals that did not have any resources, representatives we spoke with expressed interest in participating in telestroke but felt that they did not know what services telestroke networks offered, how much participation cost, or that they did not have sufficient information to decide on which network to join.” 

The authors acknowledged that development of a profile of nonadopters of telestroke may require data from additional sources, such as existing telemedicine infrastructure—eg, internet capabilities&mdash;or a geographic/spatial analysis to reveal interrelationships between community and hospital characteristics. 

1. Impact of stroke (stroke statistics). American Heart Association/American Stroke Association website. 

/Impact-of-Stroke-Stroke-statistics_UCM_310728_Article.jsp. Updated June 6, 2016. Accessed October 2, 2018.

2. Lattimore SU, Chalela J, Davis L, et al; NINDS Suburban Hospital Stroke Center. Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy: the NINDS Suburban Hospital Stroke Center experience. 

3. Tong D, Reeves MJ, Hernandez AF, et al. Times from symptom onset to hospital arrival in the Get with the 

 Program 2002 to 2009: temporal trends and implications. 

4. Adeoye O, Albright KC, Carr BG, et al. Geographic access to acute stroke care in the United States. 

5. Freeman WD, Vatz KA, Griggs RC, Pedley T. The Workforce Task Force report: clinical implications for neurology. 

: connecting patients to quality treatment. American Heart Association website. heart.org/idc/groups/heart-public/@wcm/@adv/documents/downloadable/ucm_473486.pdf. Published March 2015. Accessed October 3, 2018.

7. Schwamm LM, Holloway RG, Amarenco P, et al; American Heart Association Stroke Council; Interdisciplinary Council on Peripheral Vascular Disease. A review of the evidence for the use of telemedicine within stroke systems of care: a scientific statement from the American Heart Association/American Stroke Association. 

8. Shazam Hussain, MD | stroke [video]. YouTube. youtube.com/watch?v=0KdyJrDNvq4. Published April 20, 2018. Accessed October 1, 2018.

9. Capampangan DJ, Wellik KE, Bobrow BJ, et al. Telemedicine versus telephone for remote emergency stroke consultations: a critically appraised topic.

10. Sinn DI, Al Kasab S, Banerjee C, Ozark S. Rate of stroke mimics over 

11. Hubert GJ, Meretoja A, Audebert HJ, et al. Stroke thrombolysis in a centralized and a decentralized system (Helsinki and Telemedical Project for Integrative Stroke Care Network). 

12. Al Kasab S Adams RJ, Debenham E, Jones DJ, Holmstedt CA. Medical University of South Carolina

: a telemedicine facilitated network for stroke treatment in South Carolina—a progress report. 

13. Martin AB, Probst JC, Shah K, Chen Z, Garr D. Differences in readiness between rural hospitals and primary care providers for telemedicine adoption and implementation: findings from a statewide telemedicine survey. 

14. Shea CM, Tabriz AA, Turner K, North S, Reiter KL. Telestroke adoption among community hospitals in North Carolina: a cross-sectional study. 

: 10.1016/j.jstrokecerebrovasdis.2018.04.032.

15. Stevenson L, Ball S, Haverhals LM, Aron DC, Lowery J. Evaluation of a national telemedicine initiative in the Veterans Health Administration: factors associated with successful implementation. 

Features

Although telestroke programs show more success in bringing stroke care to patients, lingering challenges have prevented widespread implementation.

Telestroke Offers Opportunities, But Challenges Persist

The past 5 years brought about monumental moments in the advancement of multiple sclerosis (MS) care. With the approval of ocrelizumab (Ocrevus; Genentech) in March 2017, the field not only welcomed the first treatment for primary progressive MS but also saw the number of available disease-modifying therapies rise to 15. 

Although this growing number of options puts MS ahead of the curve compared with other neurodegenerative diseases, yet another new frontier in treatment has crossed the sight line of many investigators: remyelination.

A staple of MS is its demyelinating nature, in which the immune system attacks either the protective myelin sheath that encases axons or the oligodendrocytes that produce this myelin. Normally, when axonal damage occurs, myelin self-repair is initiated, with oligodendrocyte progenitor cells (OPCs) engaging the demyelinated axons and differentiating into oligodendrocytes.

 But in MS, this natural process does not occur properly and fails in at least 1 of those 2 steps. To combat this, investigators have set their eyes on developing therapies that aid the process. 

“We have immunotherapeutic agents, immunomodulatory and targeted immunosuppressive agents that at least partially…and in some instances appear to almost fully, prevent new damage and new injury from happening,” Ari Green, MD, MCR, the medical director of the University of California, San Francisco (UCSF), Multiple Sclerosis Center and director of the UCSF Neurodiagnostics Center, told 

™. “And yet a substantial portion of people, despite that fact, still go on to develop some progressive disability.” 

Green, who has spent a large portion of his career studying the process of remyelination, pointed out that although neurologists treating MS are equipped with a large arsenal of options with which to prevent further damage, none of the therapies address the damage that exists at the time of initial presentation. “They might help calm the waters enough so that endogenous repair could at least partially take place, but we know endogenous repair is limited, and the goal with remyelinating therapeutics is developing agents that can actually enhance the capacity for endogenous repair,” he said. 

For nearly 2 decades, investigators have known that a unique population of cells—roughly 5% of the cells in the adult human central nervous system (CNS)&mdash;develop into oligodendrocytes, and that maintaining or restoring saltatory conduction (the proliferation of action potentials along myelinated axons) depends on the presence of normal myelin architecture. Because MS targets myelin, the question has become: How can that be restored, or how can oligodendrocytes be brought back? 

“The oligodendrocytes are evident; they’re found tiled throughout the brain, both in normal health and in disease,” Green said. “Those cells are there. How do we get them to do what they should otherwise be doing, which is, after demyelination happens, recovering and restoring that myelin? If we [take] an animal and we demyelinate the animal, either chemically or in a relatively targeted way [that] dissolves or damages myelin, or we induce an inflammatory response that targets myelin, you will see some remyelination occur in a period of just a few weeks.” 

Why this process does not occur in MS is not well understood. Even so, the ability to screen therapies that are capable of allowing—or forcing&mdash;OPCs to differentiate into oligodendrocytes is beginning to allow therapies to be developed. 

Right now, remyelination is the most exciting path for MS treatments, Darin Okuda, MD, the director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of Neuroinnovation, and deputy director of the Multiple Sclerosis Program and Clinical Center at the University of Texas Southwestern Medical Center in Dallas, told 

™. One therapy he has had his eye on is recombinant humanized-IgM 22 (rHIgM22), also known as antibody [22]. 

“That was really founded by Moses Rodriguez, MD, a clinician-scientist at the Mayo Clinic [in] Rochester, [Minnesota]. That compound is now being championed by Acorda Therapeutics, and it’s currently under study,” Okuda said. A phase 1 multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial is aiming to determine if a single dose of the treatment is safe and tolerable during relapse (NCT02398461). It is expected that, if applied immediately after relapse, remyelination strategies could result in not only full recovery but also prevention of long-term neurodegeneration and progressive disease course.3 That trial was expected to be completed in late 2017, though Acorda informed 

™ that it is “considering next steps for the program.” 

In a previous phase 1 trial of rHIgM22,4 the therapy, which was assessed in 72 adults with stable MS, was found to be well tolerated with no significant safety signals. There were no discontinuations due to treatment-emergent adverse events (AEs). All told, 86% (47 of 55) of participants treated with the therapy experienced a total of 186 treatment-emergent AEs compared with 95% (16 of 17) of those administered placebo, who experienced 54 treatment-emergent AEs. 

The authors noted that the most common AEs (frequency, >5%) in rHIgM22-treated individuals—that were not observed in placebo-treated patients&mdash;were MS relapse, fatigue, arthralgia, back pain, muscular weakness, pruritus, contusion, and flushing. 

“None of these AEs occurred in more than 7% of antibody-treated patients, so that an equivalent frequency for any of these events in the 17-person placebo group would have been represented by 1 individual or less,” Eisen et al wrote. “Most [treatment-emergent] AEs were mild or moderate in severity, and the occurrences of these events did not appear to be dose dependent.” 

Recently, research done in vitro suggested that despite rHIgM22’s incompletely defined molecular and cellular mechanisms of action, microglia may play a role in inducing remyelination.

 “[They do so by] phagocytosing rHIgM22-bound myelin debris, thereby potentially disinhibiting OPC differentiation in demyelinated lesions of MS patients and possibly mediating further paracrine sequelae favorable for remyelination,” Zorina et al wrote. 

Another antibody being studied for remyelination is opicinumab (BIIB033; Biogen), an anti-LINGO-1 antibody. In SYNERGY, a phase 2 trial of the therapy in patients with relapsing and progressive MS, it failed to meet its primary end point of improving disability, as measured by Expanded Disability Status Scale (EDSS) scores.

Despite this apparent lack of efficacy, those developing the therapy were not disheartened. Michael Ehlers, MD, PhD, the executive vice president of Research and Development at Biogen, said at the time of the data’s presentation that they “provide intriguing evidence that opicinumab, which has demonstrated remyelination properties in a previous phase 2 study, may have a treatment effect in certain patients.”

Gavin Giovannoni, MD, the chair of neurology at the Blizard Institute, part of Barts and The London School of Medicine and Dentistry in London, United Kingdom, said in a statement that upon analyzing the trials’ results, the investigators discovered the specific patients with relapsing MS that may be more responsive to opicinumab, which he noted “became a significant component” of the design for the phase 2 trial, AFFINITY. “We now have an exciting opportunity to apply a more precise biological approach when evaluating the potential of opicinumab as a therapy that may improve patients’ disability and lead to a better overall outcome,” Giovannoni said. 

Now actively recruiting, AFFINITY (NCT03222973) will assess the effect of 750-mg opicinumab compared with placebo on disability improvement over 72 weeks, with a target enrollment of 240 participants. The primary outcome will be the overall response score, a multicomponent score based on EDSS, the timed 25-foot walk test (T25W), the 9-hole peg test in the dominant hand, and the 9-hole peg test in the nondominant hand. 

Sarah Sheikh, MSc, BMBCh, MRCP, senior medical director at Biogen, said in an interview that those with “disease duration less or equal to 20 years and 2 MRI characteristics [lower baseline magnetization transfer ratios (MTRs) and diffusion tensor imaging—radial diffusivity values] in preexisting T2 lesions” were the 3 factors predictive of response opicinumab.

An additional route for remyelination involves high-dose biotin, otherwise known as vitamin B7. At the 2017 joint meetings of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Paris, France, data were presented on biotin (MD1003; MedDay), which revealed improvements in EDSS and T25W compared with placebo.

The most intriguing bit of data from the substudy

 of the phase 2b/3 trial suggested a pseudo-atrophy phenomenon that was likely related to remyelination for patients with progressive, nonclinically active MS. Douglas L. Arnold, MD, of the Montreal Neurological Institute and Hospital of McGill University Health Centre in Quebec, Canada, who presented the data, said, “The effects of MD1003 on volumetric with a decrease in virtual hypoxia. Results from MTR and DTI [diffusion tensor imaging] analyses suggest possible remyelination.” 

Of the 74 patients who were part of the substudy, 49 had received the therapy from the start and 25 received placebo during randomization, followed by MD1003 in the extension period. At 12 months, there was a 0.3% decrease in whole brain volume (WBV) in the MD1003 group versus a 0.1% increase in the placebo arm (

 = .046). For gray matter volume (GMV), there was a 0.6% decrease with MD1003 and no change in the placebo group (

 = .0435). Changes in WMV were not statistically significant, at —0.3% with MD1003 and 0.2% in the placebo group (

At month 24, there was a 0.5% decline in WBV in the MD1003 group and a decline of 0.6% in those initially treated with placebo who crossed over to the biotin group (P = .502). For GMV, there were declines of 0.5% and 0.8% in the initial MD1003 and placebo/MD1003 groups, respectively (P = .606). WMV declined by 0.4% and 0.5% in the MD1003 and placebo/MD1003 groups, respectively (P = .874). 

Since then, a phase 3 trial of the therapy has begun (NCT02936037), with a primary end point of EDSS and T25W and a target enrollment goal of 600 patients. It is estimated to complete in September 2019. 

“There is a lot of science that has gone on in Europe and a lot of talk about how biotin may actually help to facilitate mitochondrial behavior but may also play a role in self myelin repair,” Okuda told 

™. He explained that currently, doses of 300 mg—100 mg taken 3 times daily&mdash;can be acquired sans prescription online. “That dose is 30 times higher than the highest dose one could acquire from any drugstore,” he said. 

Due to their success in other facets of medicine, as well as the interest in using them for other neurodegenerative diseases, stem cells have become a topic of conversation in MS treatment. One population of cells of particular interest is mesenchymal stem cells (MSCs), which were originally noted in part because of their ability to generate major mesenchymal lineages. More recently, investigators realized that MSCs have pronounced immunomodulatory capacities. This led to the cells’ development as a therapeutic for a number of conditions, including demyelinating diseases of the nervous system.

This hypothesis—that MSCs could generate CNS cells&mdash;has been considered controversial and contested by some mouse-model research.

 However, several other groups have shown in animal models of MS that treatment with MSCs promoted, at least partially, oligodendrogenesis through the release of trophic factors, leading to enhanced functional remyelination.

Despite these concerns, in a number of phase 1 and 2 observations of infusing in vitro expanded autologous MSCs into humans with relapsing or progressive MS, the infusion was safe, though little or no clinical benefit was realized. This has been suggested as a failure of the use of autologous MSCs, although other works in experimental allergic encephalitis revealed that the cataloged molecular changes in these cells occur in more than 2000 genes linked to immune response and neural development, which will likely limit the use of MSCs for MS in the future.

In November, BrainStorm Cell Therapeutics announced plans for a phase 2 assessment of its cell therapy, NurOwn, in progressive MS. NurOwn utilizes a patient’s own modified MSCs to promote nerve cell-supporting mechanisms. The therapy previously showed promising results in a phase 2 trial in amyotrophic lateral sclerosis. 

Investigators also aim to better understand the remyelination process, which has and will continue to allow for a parallel improvement in therapeutic targets. 

In June 2018, a group of researchers from the University at Buffalo in New York identified the muscarinic type 3 receptor (M3R) as a target for therapeutic development. M3R, a key regulator in the process of remyelination, is found on OPCs, and the assessment showed that that activation of M3R blocked the differentiation of OPCs into myelin-making cells.

“Our data provide evidence that a drug targeting M3R specifically would be a useful strategy,” Fraser J. Sim, PhD, an associate professor of pharmacology and toxicology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and senior author, said in a statement.

Although this research was done in mice and has not been replicated in humans, the process allowed for remyelination to occur and is certainly promising. The work from Sim and colleagues built on previous data that identified solifenacin succinate (VESIcare; Astellas), already FDA approved for the treatment of overactive bladder, as able to inhibit M3R—though nonspecifically, which could relay AEs. 

“That work identified solifenacin succinate as a possible drug useful for remyelination, but we really weren’t sure which specific receptor the drug worked on,” Sim said. He and colleagues noted that a genetic approach was taken in their work to attempt to locate the specific receptor at work. Ultimately, Sim said, M3R has a functional role in remyelination and, if blocked, could improve repair of myelin. “It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients,” he said. 

Excitingly, the past few years have been marked by the introduction of proof-of-concept trials for remyelination in MS. Although this has moved the field a step closer toward the next frontier in treatment, questions remain. 

For one, optimal outcome measurements for assessing remyelination have yet to be fully explicated. In this realm, MRI, myelin-targeted positron emission tomography radiotracers, and optical coherence tomography have all been explored as possible options. Potential biomarkers that reveal axonal damage, such as neurofilament light, exist, though their clinical validation is awaited. On another note, the timing of remyelination therapy is an essential piece of the puzzle that still needs to be figured out. 

For Green, another debate also exists: the approach of therapies. From small molecule therapies to antibodies, there are options to explore, but which approach is favorable is not yet completely understood. Green, with all of his work alongside Jonah Chan, PhD, has his ideas, though. He and Chan conducted the first successful human clinical trial in patients with a chronic lesion. 

“My strong opinion is that a small molecule approach is much more likely to be successful than an antibody-mediated approach,” Green said. Although, as he has done consulting work with this approach, Green also noted his bias. 

“Some people have postulated the use of antibodies because of their specificity, which is an advantage of antibody approaches over small molecules,” he continued. “But their negative is that the target is in the CNS, and antibodies are huge and don’t get into the CNS via the blood brain barrier very easily.” 

He clarified that, in clinical trials, these antibodies have been given in extraordinarily high doses to produce a biological effect. In Green’s mind, that’s not an optimal setting. “Antibodies work well as immunomodulatory agents because the target is largely in the periphery [and] is largely in circulation,” he said. “Trying to get those drugs into the CNS is a challenge. Small molecules, I think, are really the way to go.” 

1. Chair DM. Remyelination in multiple sclerosis. Int Rev Neurobiol. 2007;79:589-620.

2. Franklin RJ. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci. 2002;3:705-714.

 of future remyelination therapies and their potential to stop multiple sclerosis progression. Adv Exp Med Biol. 2017;958:161-170. 

4. Eisen A, Greenberg BM, Bowen JD, Arnold DL, Caggiano AO. A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. Mult Scler J Exp Transl Clin. 2017;3(4). journals.sagepub.com/doi/10.1177/2055217317743097. Published November 21, 2017. Accessed October 29, 2018. 

5. Zorina Y, Stricker J, Caggiano AO, Button DC. Human IgM antibody rHIgM22 promotes phagocytic clearance of myelin debris by microglia. Sci Rep-UK. 2018;8(1):9392.

6. Mellion M, Edwards KR, Hupperts R, et al. Efficacy results from the phase 2b SYNERGY study: treatment of disabling multiple sclerosis with the anti-LINGO-1 monoclonal antibody

 S33.004). n.neurology.org/content/88/16_Supplement/S33.004. short?sid=f7aa004b-4c71-4f4e-8ed7-3dcf28ed1de8. 

7. Biogen announces AFFINITY phase 2 trial initiation for

 (anti-LINGO-1) in multiple sclerosis [press release]. Cambridge, MA: Biogen; October 25, 2017. investors.biogen.com/news-releases/news-release-details/biogen-announces-affinity-phase-2-trial-initiation-opicinumab. Accessed October 29, 2018. 

, an anti-LINGO antibody, in MS builds on lessons learned, Biogen says. Multiple Sclerosis News Today website. multiplesclerosisnewstoday.com/2017/10/25/msparis2017-interview-with-biogen-focused-on-opicinumab-an-anti-lingo-antibody. Published October 25, 2017. Accessed October 29, 2018. 

9. Tourbah A, Lebrun-Frenay C, Edan G, et al; MS-SPI study group. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a

, double-blind, placebo-controlled study. Mult Scler. 2016;22(13):1719-1731. 

10. Arnold D. MD1003 in progressive multiple sclerosis: 24-month brain MRI results of the MS-SPI trial. Abstract presented

With more than a dozen disease-modifying therapies, some have set their sights on developing an agent designed to promote remyelination.

December 2018

Genetics Fuel Parkinson Pipeline Growth

Telestroke Offers Opportunities, But Challenges Persist

Remyelination in Multiple Sclerosis: The Next Treatment Frontier

Investigators Unlock New Targets in Obstructive Sleep Apnea

Dystrophin Pathway and Treatments Offer Hope for Patients with Duchenne Muscular Dystrophy

Phase 3 Trial of Cenobamate Assesses Therapy for Primary Generalized Tonic-Clonic Seizures