As scientists continue to unravel the complex brain changes involved in the onset and progression of Alzheimer disease, many questions remain, despite significant advances in our understanding of the pathophysiology and clinical presentation of the disease. Although disease modification is an important goal, symptom-controlling medications are needed.

Alzheimer disease and other related dementias are best known for their decreases in cognitive abilities, but a host of other symptoms—agitation, anxiety, depression, psychosis, insomnia&mdash;often reduce patients’ quality of life, create additional challenges for caregivers, and lead to institutionalization. Neuropsychiatric symptoms are now recognized as hallmarks of dementia and are important targets for the development of effective treatments.

These core symptoms of mild and major neurocognitive disorders tend to be some of the more distressing and challenging effects of the disease. Despite this, the FDA has yet to approve any pharmacological treatments for these symptoms, leaving off-label treatments for alleviating noncognitive behavioral symptoms as first-line options. Since these are repurposed drugs, they provide only modest benefits and harmful adverse events (AEs) and are often associated with increased apathy, stroke, and mortality.

There is a great need for safe and effective treatments of neuropsychiatric symptoms of patients in the symptomatic phases of Alzheimer disease in order to improve their memory and behavior. As such, several therapies are being assessed to meet this need, with the majority of them having progressed to phase 3 trials (

The risk of developing psychotic symptoms associated with Alzheimer disease and related neurodegenerative disorders is high: Approximately 20% to 40% of patients will have these symptoms. Their presence, often the first manifestation of the condition, is concomitant with greater adverse outcomes, such as mortality, rapid disease progression, functional deterioration, and increased behavioral symptoms.

“At the moment, there’s a huge unmet need in treating psychosis in people with Alzheimer disease,” Clive Ballard, MD, told 

. “It’s a common symptom in people with Alzheimer disease, depending on the stage of the illness, and over the course of the illness, the majority [of patients have it]. The symptoms are distressing for the persons themselves or for caregivers, they accelerate in placement in nursing homes and other types of institutions, and they’re associated with more rapid decline.

“They’re not just distressing. They actually have a major impact on disease outcome for individuals,” he added. The professor of age-related diseases and dean of the University of Exeter Medical School said that, unlike other neuropsychiatric symptoms in those with Alzheimer disease that respond well to nonpharmacological interventions, suych as agitation, there is a lack of evidence that patients with psychosis respond antipsychotic medications.

One such treatment being studied for Alzheimer disease psychosis is pimavanserin (Nuplazid), an oral 5-HT2A inverse agonist that targets serotonin. It is currently licensed in the United States as a treatment for psychosis in those with Parkinson disease.

After a 6-week period in a phase 2 trial (NCT02035553) of 179 participants, a daily dose of 34 mg of pimavanserin showed significant benefit in the reduction of psychosis in study participants with severe psychosis related to Alzheimer disease.

 In the trial, researchers randomized nursing home patients likely to have psychosis related to Alzheimer disease in a 1:1 ratio to either 17-mg, twice-daily tablets of pimavanserin or placebo. Symptoms were measured utilizing the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) psychosis score at 2, 4, 6, 9, and 12 weeks of dosing.

With regard to the primary end point, the pimavanserin-treated group had a 3.76-point improvement in psychosis compared with a 1.93-point improvement in the placebo group (delta, —1.84; Cohen’s 

 = .0451), as measured by the NPI-NH psychosis score at week 6. Following the 6-week efficacy evaluation, investigators continued pimavanserin therapy for another 6 weeks to test its safety. There was no significant advantage reported between pimavanserin and placebo at week 12.

Investigators found that pimavanserin was well tolerated. Common AEs in both groups included falls, urinary tract infection, and agitation. No negative effect on cognition or motor function measured by the Mini-Mental State Examination (MMSE) was reported.

A prespecified subgroup analysis demonstrated that pimavanserin-treated participants with more severe psychosis—those with a total score above 12 on the 2 main NPI-NH psychosis items&mdash;had a substantively larger and significant reduction in psychosis.

 Pimavanserin demonstrated a statistically significant reduction in psychosis versus placebo on the NPI-NH psychosis score at week 6 (delta, —4.43; Cohen’s 

 = .0114;). The amount of those achieving ≥30% improvement was 88.9% versus 43.3% (

 <.001) and ≥50% improvement, 77.8% versus 43.3% (P = .008) for pimavanserin and placebo, respectively. The results show that this patient population saw a greater benefit than the overall trial population.

“What’s really encouraging about the results is that these are the patients we really feel we need to treat with pharmacological therapies,” Ballard said. “These are the patients that we want to really improve and respond, so it was a really good signal that those were the patients who were doing really well with the pimavanserin treatment.”

Pimavanserin has been granted breakthrough therapy designation status by the FDA for dementia-related psychosis. Researchers are currently conducting the phase 3 HARMONY study (NCT03325556), which began September 2017, to evaluate the ability of pimavanserin to prevent relapse of psychotic symptoms associated with dementia-related psychosis and will include patients with Alzheimer disease, dementia with Lewy bodies, Parkinson disease dementia, frontotemporal dementia, and vascular dementia.

HARMONY consists of a 12-week open-label stabilization period where all participants receive 34 mg of pimavanserin once daily, however, a dose reduction to 20 mg daily will be allowed if clinically justified. Following the 12-week stabilization period, participants that meet pre-specified criteria for treatment response will be randomized either to continue receiving 34 mg, switch to a 20-mg dose, or be given placebo. The primary outcome measure is the time from randomization to relapse in the double-blind period, and the secondary measure is the time from randomization to discontinuation in the double-blind period, for any reason. The study is expected to be completed March 2020. 

“We’ve been in a very difficult position where [antipsychotics] have been the only available pharmacological treatments, but even then, they’re off-label and they’re associated with a lot of harms. So actually, if pimavanserin does turn out to be a more effective and safer alternative, that would be a great step forward in treating these distressing symptoms,” Ballard noted. 

When asked about what’s garnering his excitement in the Alzheimer space, Ballard responded by citing the increasing number of treatments for psychiatric and neuropsychiatric symptoms, like psychosis and agitation, beginning to progress through clinical trials. “That’s been a huge unmet need. We’ve been in the same sort of void for 20 years, so it’s great to see more stuff coming into that space,” he said.

Mediti Pharma’s MP-101 is another agent currently under evaluation in a phase 2 trial (NCT03044249) as a possible treatment option for dementia-related psychosis and agitation and aggression. The 10-week, proof-of-concept trial, set to be completed January 2021, is studying an escalating dose of MP-101 administered orally once daily, from 20 mg up to 60 mg. The primary outcome includes the change from baseline in the NPI-NH score.

Lack of Medications for Distressing Behavioral Symptoms

Behavioral symptoms such as agitation and aggression affect almost 4.3 million of the 5.4 million persons with Alzheimer disease. Agitation is common and persistent and is often a major cause of distress. Although intervention may have a positive clinical impact, the current approaches lack efficacy, safety, and/or acceptability. Sedatives, anxiety drugs, and other medications are often given to these patients, as there are no available dedicated treatments. 

Nabilone, a synthetic cannabinoid currently approved in the United States for treating nausea caused by chemotherapy, is one agent under investigation for treatment of agitation and aggression among patients with Alzheimer disease. Krista Lanctôt, PhD, a psychiatry and pharmacology professor at the University of Toronto, presented preliminary results from a phase 2, 14-week clinical trial that investigated the safety and efficacy of nabilone in patients with moderate to severe Alzheimer disease at the 2018 Alzheimer’s Association International Conference (AAIC) in Chicago, Illinois. The trial compared 6 weeks of nabilone 0.5 mg to 2 mg to 6 weeks of placebo, with a 1-week washout between phases in 39 participants.

“Treating agitation, currently, is very challenging,” Lanctôt said. “We know that the medications that are on the market that have the best results for efficacy also have the biggest problems for safety, so we’re excited if we can open a new therapeutic group to help treat these very challenging behaviors.”

The primary outcome of the trial was agitation measured by the Cohen Mansfield Agitation Inventory (CMAI), while secondary outcomes included safety, overall neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI] total), cognition (standardized MMSE [sMMSE]), Severe Impairment Battery, and global impression (Clinician’s Global Impression of Change [CGIC]). In addition, researchers assessed subjects’ pain with the Pain Assessment in Advanced Dementia scale, nutritional status with the Mini-Nutritional Assessment-Short Form, and safety. 

Preliminary results demonstrated significant differences in CMAI (

 = .003), the NPI’s agitation/aggression domain (

 value = —1.5; 95% CI, –2.3 to –0.6; 

 value = —4.6; 95% CI, –7.5 to –1.6; 

 = .026) in favor of nabilone, providing rationale for the feasibility of a larger, confirmatory phase 3 trial.

 Lanctôt stressed the importance of closely monitoring sedation, as it was experienced by 45% of participants.

Not only were the preliminary results of this proof-of-concept trial positive, but the benefits of nabilone went beyond the patients, as caregiver distress was significantly reduced. Larger trials and replication of the findings are needed to provide confirmatory evidence regarding the safety of nabilone and make recommendations to change clinical practice.

“Because this is a synthetic version of [tetrahydrocannabinol], it doesn’t tell you anything about what medical marijuana would do, so these results should not encourage you to use medical marijuana or recreational marijuana to try and treat these symptoms in Alzheimer disease,” Lanctôt explained. “We hope that this trial opens the door for evaluating this particular group of medications for future treatment of agitation.”

Another agent being studied for agitation is Avanir Pharmaceuticals’ AVP-786, which was designed as a second-generation version of dextromethorphan/quinidine (Nuedexta). AVP-786 is a combination of dextromethorphan and quinidine, but unlike Nuedexta, it also contains deuterium. Researchers hypothesize that the penetration of this molecule into the brain leads to the activation and repression of certain neuronal pathways, leading to a reduction of agitation. In 2015, AVP-786 was granted a fast track designation by the FDA for treatment of agitation in patients with Alzheimer disease.

Currently, AVP-786 is being studied in the TRIAD program for agitation, which includes 2 placebo-controlled phase 3 clinical trials: TRIAD-1 (NCT02442765) and TRIAD-2 (NCT02442778). The phase 3 studies will evaluate 2 doses of AVP-786 versus placebo administered orally twice daily for 12 weeks in participants with agitation secondary to dementia of the Alzheimer type. 

TRIAD-1 is expected to enroll 380 participants in 60 centers in the United States and has an estimated completion date of April 2019. TRIAD-2 is expected to be completed December 2019 with 470 participants enrolled in 75 centers. The primary outcome measure in both studies is change from baseline to week 12 in the CMAI, with secondary outcomes including the agitation/aggression domain of NPI, other domains of NPI, measures of global clinical change, measures of caregiver burden and quality of life, and standard safety measures.

In addition to these 2 US-based trials, additional global trials will be conducted as part of the TRIAD program. A long-term phase 3 extension study (NCT02446132) of AVP-786 is currently recruiting participants who have successfully completed TRIAD-1 (NCT02442765), TRIAD-2 (NCT02442778), or an earlier phase 2 study of AVP-923 (NCT01584440). Approximately 700 participants will be enrolled at 135 centers in North America for roughly 56 weeks total, however, those who have a follow-up visit 3 months after their last dose will be enrolled for 64 weeks total. Participants will receive either a low or high dose of AVP-786.

Primary outcome measures include the number of participants with any treatment-emergent AEs or serious AEs; any abnormal, clinically significant clinical laboratory value, 12-lead electrocardiography value, physical and neurological examination finding, vital sign value; changes in the Sheehan Suicidality Tracking Scale (S-STS) score, the MMSE score, Alzheimer’s Disease Assessment Scale-Cognitive Subscale score, the Timed Up and Go Test score, and the Epworth Sleepiness Scale score. The extension study is expected to be completed March 2021. 

ITI-007 (lumateperone, Intracellular Therapies), an atypical antipsychotic with both serotonin and dopamine effects, is another candidate under investigation as a potential treatment option for agitation in patients with dementia, including Alzheimer disease. The first-in-class molecule provides selective and simultaneous modulation of serotonin, dopamine, and glutamate—3 neurotransmitter pathways implicated in mental illness.

The unique pharmacological features of ITI-007 predict enhancement of sleep and reduction of agitation and aggression at lower doses and antipsychotic and antidepressant efficacy at higher doses, Andrew Satlin, MD, the chief medical officer with Intra-Cellular Therapies, told 

The safety, tolerability, and pharmacokinetics were first assessed in healthy older volunteers and patients with dementia in a dose-escalation phase I/II trial (NCT02078310).

 The agent was shown to be safe and well tolerated across a range of low doses among the patient population, showing clinical signs for improved cognition and no clinically significant impact on the extrapyramidal, endocrine, and cardiovascular systems. Study results confirmed no cognitive impairment by ITI-007 and demonstrated clinical signals for improved cognition with only 1 week of treatment.

ITI-007 is currently being investigated in a phase 3 clinical trial (NCT02817906) to evaluate its safety and efficacy versus placebo in participants with a clinical diagnosis of probable Alzheimer disease and clinically significant symptoms of agitation. The 9-mg dose being studied is administered to participants as a solid oral formulation once daily for 4 weeks. The primary outcome is treatment efficacy, measured by the CMAI-community form; secondary outcomes include efficacy measures using the CGIS. 

Underrecognized and Undertreated Neuropsychiatric Symptoms 

Although the cognitive symptoms associated with Alzheimer disease are the most recognized, the neuropsychiatric symptoms are often the greatest challenge. If left untreated, these symptoms can accelerate decline and significantly impact the quality of life. 

For Marwan Sabbagh, MD, director of the Cleveland Clinic Lou Ruvo Center for Brain Health, there is an incredible amount of pressure to address this challenge that has implications for patients, caregivers, and families alike.

“It’s a big deal. When we really talk about the dementia state now, we draw down on staging it as mild, moderate, and severe, and we start to see the emergence of the neuropsychiatric features in the late mild, early moderate stage, and oftentimes they can eclipse the entire disease,” Sabbagh told NeurologyLive. “After a while, patients and family don’t care about the forgetfulness, they care about the wandering, the paranoia, the delusion, the agitation, the trouble sleeping, and that really starts to take over the disease. And so it becomes a huge amount of the burden of the disease.”

Sabbagh added that while physicians have tried to address these issues through off-label uses of drugs, there is still no clear consensus or guidelines. “We’re winging it when it comes to managing neuropsychiatric features,” he said. Although he did point out that there are therapies being developed for behavioral symptoms, some of which are close to achieving FDA approval.

“I suspect we’ll see more drugs approved to treat behavioral symptoms within a year or 2,” he said. “That is a huge area of unmet need, and I suspect we’ll see some drugs to fill the gap.”

1. Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomized, placebo-controlled, double-blind study. Lancet Neurol. 2018;17(3):213-222. doi: 10.1016/S1474-4422(18)30039-5.

2. Ballard C, Youakim JM, Coate B, Stankovic S. Pimavanserin in Alzheimer’s disease psychosis: efficacy in patients with more pronounced psychotic symptoms. JPAD. 2018;1(3):1-7.

3. Ruthirakuhan M, Herrmann N, Abraham E, et al. A randomized, placebo-controlled, cross-over trial investigating nabilone as a treatment for agitation in patients with moderate-to-severe Alzheimer’s disease: blinded, interim safety results. Alzheimers Dement. 2017;13(7):1254.

4. Intra-Cellular Therapies announces topline safety results from

 I/II clinical trial for ITI-007 in healthy geriatric subjects and patients with dementia [news release]. New York, NY: Intra-Cellular Therapies; October 13, 2014. ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-topline-safety-results-phase. Accessed September 15, 2018. 

5. Intra-Cellular Therapies announces additional results from phase I/II clinical trial for ITI-007 in healthy geriatric subjects and patients with dementia [news release]. New York, NY: Intra-Cellular Therapies; November 21, 2014. ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-additional-results-phase-iii. Accessed September 15, 2018.

Articles

Features

Neuropsychiatric symptoms are now recognized as hallmarks of dementia and are important targets for the development of effective treatments.

Alzheimer Disease Symptoms: More Than Memory Loss and Confusion

The history of treatments for multiple sclerosis (MS) has been marked by eras, each defined by the introduction of new groups of medications and, importantly, the modification of the disease by suppression or alteration of the immune system.

The first was that of the ABC drugs—interferon ß-1a (Avonex), interferon ß-1b (Betaseron), and glatiramer acetate (Copaxone)&mdash;an era marked by the ability to treat patients long-term with self-administered injections that allowed them easier access and produced manageable adverse events (AEs).

 Still widely utilized, these therapies were joined by additional formulations of interferon ß-1a (Rebif) and interferon ß-1b (Extavia) in 2002 and 2009, respectively, among others, which helped build the class of disease-modifying therapies (DMTs). After this period, there was a new era characterized by oral medications and intravenous (IV) monoclonal antibodies. 

“We got fingolimod [Gilenya], then dimethyl fumarate [Tecfidera], then teriflunomide [Aubagio],” Tanuja Chitnis, MD, told 

. “Dispersed in between, we got the first intravenous monoclonal antibodies—natalizumab [Tysabri] was introduced and then taken off the market, then reintroduced. That has also been an important treatment for severe forms of MS. Most recently, we have alemtuzumab [Lemtrada] and then ocrelizumab [Ocrevus]. Many physicians have also used its precursor, rituximab [Rituxan].”

As of 2018, the list of DMT options for clinicians treating MS extends to 15 therapies. Chitnis, the director of the Partner Pediatric Multiple Sclerosis Center at Massachusetts General Hospital, explained that having the breadth of selections—something that is not available in many other neurological conditions&mdash;is wonderful for both patients and physicians. Having choices, she said, allows for clinicians to adjust treatment when efficacy issues or AEs arise.

“I think the choices that are available are very helpful and important, and I think now physicians are entering an era, at least I am, where they’re trying to very carefully consider what would be the right match of treatment for a specific patient,” Chitnis said.

Amidst a robust pipeline and strong stockpile of options, the MS field has arguably never been more exciting. As the use of DMTs expands to different approaches and subtypes of MS, fresh challenges and unanswered questions remain. 

The oral era has been dominated by fingolimod, which ushered in the era with its approval in 2010; dimethyl fumarate, and teriflumonide.

 Choosing between each oral agent can represent a challenge, given a lack of head-to-head comparisons for the available treatments, according to Chitnis. However, due to the difficulty of conducting those trials in MS, head-to-head comparisons will likely never come to fruition, Darin Okuda, MD, told 

“The therapies, when they’re super effective, are so effective that you would need over 5000 to 10,000 patients for that study to be appropriately powered,” said Okuda, a professor of neurology and neurotherapeutics, director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of neuroinnovation, and deputy director of the Multiple Sclerosis Program and Clinical Center at UT Southwestern Medical Center. 

For Okuda, the future in MS does not include head-to-head trials. “If we ran that experiment over and over again, we may have answers that are completely different versus the first observation,” he said.

“One of the biggest challenges that we have is understanding which therapy is really more effective than the other, and I think that from a 30,000-foot view, we can somewhat arrive at conclusions in our head on which agent might be better than the other,” Okuda explained. “But know that this list is not going to be uniform in the minds of all clinicians.”

Help deciding which therapies are more efficacious could come from other analyses. Most pertinent, for Chitnis, would be advancements in predictive models and biomarkers, an ability to predict or associate patient response with a certain DMT. Given the variation from patient to patient, biomarkers could mitigate guesswork.

“That could be a combination of early biomarkers of treatment response, biomarkers of the mechanism of action for each drug,” she said. “Then [we could use biomarkers] to match the baseline characteristics of a patient to a particular drug that would match their own biology.”

There are several biomarkers that are under exploration. One of particular interest to Chitnis is serum neurofilament light chain (sNfL), a marker of axonal or neuronal damage in the central nervous system (CNS). It is now measurable in serum using a single molecular array assay with high sensitivity “with fairly good correlation to CSF [cerebral spinal fluid] values,” Chitnis said.

In a study, patients with higher levels of sNfL were more likely to relapse or experience a worsening in expanded disability status scale, particularly for those with levels in the 97.5 percentile.

 The marker was also associated with acute inflammation, correlated with gadolinium-enhancing lesions, and could predict future brain atrophy.

“It is a way to potentially understand response to a DMT,” she added. “We typically have used either relapses or new MRI lesions, however, this could potentially give another correlate of response to DMT or possibly an earlier response to DMT markers.”

Research into optimal management approaches for DMTs in MS has increased with the wealth of current options. Whether to use an induction or escalation strategy remains an area of debate, however. With the induction approach, patients are treated with the most potent therapies in a more aggressive strategy earlier compared with an escalation strategy, which is when patients are treated with less potent, but safer, therapies earlier that are later adjusted based on the disease state.

Currently, the Multiple Sclerosis Coalition suggests that physicians have access to the full repertoire of treatments due to the variability in patients. They recommend that treatment should begin as soon as possible and continue indefinitely, unless there is a suboptimal treatment response, inadequate adherence, or intolerable AEs or a more appropriate regimen becomes available.

Although the recommended strategy has long been one of escalation, there seems to be a shift, according to Chitnis. “Among experienced clinicians, there is a consensus toward induction therapy, especially in those earlier inflammatory patients and especially now that we have more choices that are relatively safe,” she said.

A marked moment occurred at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016 Congress, where the leading hot topic centered around this debate and included an argument for induction therapy from Gilles Edan, MD.

 In this talk, induction therapy was ruled the superior option. 

Okuda noted that clinical trials are currently looking at whether starting with a highly effective therapy is the correct approach compared with a step-wise strategy. “We really don’t know which the more effective approach is right now,” Okuda said. 

Adding to this, the challenge of treatment selection may become even more difficult, as the pipeline continues to grow. Another emerging therapy that’s exciting is oral cladribine, Okuda said, due to its effects on the immune system. 

“It’s like [alemtuzumab], in the sense that it can actually reset the given immune system to a certain degree,” he explained. “Is that approach meaningful? Or this induction approach, where you’re allowing for the resetting of the immune system in hopes that the immune system that reconstitutes is one that’s more hospitable to that one individual.”

For Okuda, a strategy all clinicians can come to agreement on is general health. When managing MS, the need for healthy habits should be underscored more than it is currently. 

“Ensuring that, number one, their general health is optimized. A lot of these patients are overweight, blood sugars out of control, they have habits like smoking,” Okuda said. “There’s emerging science to suggest that general health outcomes are more meaningful than some of the important factors that we have identified in multiple sclerosis before. General health outcomes may be more meaningful than focusing on vitamin and mineral supplementation for patients with MS.”

In March 2017, ocrelizumab became the first therapy approved for relapsing forms of MS and primary progressive MS (PPMS), marking the first indication specifically for PPMS. The IV infusion was notably successful in the ORATORIO trial, resulting in lower rates of confirmed disability progression, lower lesion volume as measured by MRI, and less brain-volume loss compared with placebo.

The approval of ocrelizumab launched another era in MS treatment, on that focused on the PPMS space—although this is also surrounded by debate. Even with ocrelizumab, “There are a number of passionate opinions regarding the magnitude of the agent’s effectiveness within that cohort,” Okuda said. Moreover, the disease stage itself is still in its infancy, representing a fresh obstacle. 

“The opinions are split as to whether PPMS represents a continuum of disease or if it indeed represents its own distinct genotype,” Okuda explained. “We don’t have 100% agreement among specialists regarding that point. We know that early spinal cord disease can occur in individuals well before symptom onset. Well before patients become symptomatic, we know that spinal cord lesions can be present or can result from the immune system misbehaving.”

Because of this, Okuda believes manufacturers could develop treatments for those with progressive genotypes. “Should we really be focusing on primary prevention?” Okuda posited, “Because really, the most effective drug for any progressive form of MS is a myelin repair and axonal repair agent versus an anti-inflammatory agent.”

For Chitnis, the focus for progressive forms of MS should be on the biological mechanisms in the CNS that therapies can target, whether they’re inflammatory or neurodegenerative. “There are treatments [that] are focused on astrocytes in the CNS, and there is one—siponimod, which, of course, is a sphingosine 1-phosphate modulator&mdash;that seems to have sensitivity towards CNS and possibly CNS mechanisms, and seems to have some effect in progressive forms of MS,” she said.

Siponimod was evaluated in the phase 3 EXPAND trial, which included 1645 patients with secondary progressive MS.

 The trial results showed that 26% of patients receiving siponimod (288 of 1096) and 32% receiving placebo (173 of 545) had 3-month confirmed disability progression, for a relative risk reduction of 21% (hazard ratio [HR], 0.79; 95% CI, 0.65-0.95; 

In the words of Dan Bar-Zohar, MD, BSc, the global head of Novartis, siponimod’s developer, EXPAND was essentially the “first and only study in secondary progressive MS that showed meaningful results.”

 Bruce Cree, MS, PhD, MAS, a study steering committee member for the trial, said that the beneficial effect on disability progression shown by siponimod was revealed to be independent from its reduction in relapse frequency.

 Cree called the therapy “very exciting” due to the oft-occurring transition patients face from relapsing-remitting MS to secondary progressive MS, a condition that truly lacks efficacious and new treatments. 

“[These patients] experience gradual worsening of disability despite infrequent relapses,” Cree said, highlighting the hole in treatment that siponimod, and similar agents, seem poised to fill. 

“Along [the lines of siponimod], new treatments that target CNS mechanisms, whether they’re neuro-inflammatory, astrocytes/microglia, the neurodegenerative component itself, or remyelination,” Chitnis said, “those are important targets for progressive MS.”

In addition, recent phase 2 study results have bolstered the support for another agent in progressive MS, ibudilast.

 For those taking the therapy over the study course of 2 years, the rate of change in brain parenchymal function was —0.0010 per year (95% CI, −0.0016 to −0.0004) compared with –0.0019 per year (95% CI, −0.0025 to −0.0013) for those given placebo, for a difference of 0.009 (95% CI, 0.00004-0.0017; 

 = .04). Ultimately, it was equivalent to approximately 2.5 mL less brain tissue loss over 96 weeks, a relative difference of 48%.

“We found a drug that slows [the] progression of brain atrophy by about half, and although we don’t exactly know the clinical relevance of that because we haven’t validated brain atrophy in progressive MS—because we don’t have much in the way of therapies for progressive MS&mdash;it was still encouraging in pointing toward a potential therapy for progressive MS. The safety was quite strong and the tolerability was quite good,” Robert J. Fox, MD, lead author and neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, told 

For comparison, although in separate trials with different patient populations, ocrelizumab, the only therapy with a progressive MS indication, slowed brain atrophy by 17.5%. Likewise, siponimod has shown a slowing of 15% in brain atrophy. While Fox noted the phase 3 data need to be included before he’s completely certain of the therapy’s ability to slow disease progression, the magnitude of the comparison with other successful agents is heartening.

“This was not just driven by a couple outliers. This wasn’t driven by a hydration shift in the first few months [and] then everything was the same. It was really an ongoing, continued, consistent effect over the course of the entire 96-week study. That’s as encouraging as it can be,” Fox said.

As is always the case in medicine, regardless of the amount of available treatments, there is always an effort to improve or add to existing options, to further improve outcomes. Certainly, though, there is more satisfaction with the therapies that are available for relapsing or remitting MS now than there was 10 to 15 years ago.

“We’re in a good place,” Chitnis explained. “There’s always room for improved or safer drugs that fit a different profile, but we do have many options now. I think the area has really progressed. Next, we’re looking toward the potentially remyelinating therapies. The anti-LINGO-1 antibody, [opicinumab], that one is in a clinical trial, and I’m interested in seeing the next set of results that come out for that.”

The pipeline is full of novel developments, but the most exciting examples for Okuda and Chitnis are myelin-repair therapies. With demyelination existing as a main characteristic of MS, these therapies have been a long-sought target in the field.

“Recombinant humanized-IGM 22 [rHIgM22], that was really founded by Moses Rodriguez, MD, a clinician-scientist at the Mayo Clinic in Rochester, Minnesota,” Okuda said. “That compound is now being championed by Acorda Therapeutics, and it’s currently under study. Biogen has their own version of it called opicinumab, also known as anti-LINGO 1, and that drug is also being studied actively as well.”

“This is a new treatment path for us because these are therapies aimed at not modulating the immune system but allowing for actual repair of myelin and the ultimate protection of axons,” he added.

Another option of interest to both Okuda and Chitnis is cladribine, an oral therapy approved in Europe under the trade name Mavenclad, which is being investigated for relapsing MS in the United States. Thus far, it has shown promise in patients who experience relapses despite interferon-ß therapy.

 In a 96-week trial, the therapy added to interferon-ß reduced the chances of patients experiencing a relapse by 63% compared with placebo. Moreover, cladribine reduced most MRI-measures of disease activity. In addition to pharmaceuticals, nutritional studies are underway, to explore the potential of improving outcomes. 

“Adding to the myelin repair list is the recent introduction, within clinics, of the use of biotin, vitamin B7,” Okuda said. “There’s 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.”

MedDay Pharmaceuticals in Paris, France, has a high-concentration version of the biotin therapy available, Okuda said. “It’s a dose that is 30 times higher than what you can buy at Target, Walgreens, or Costco. Thirty times the highest over-the-counter preparation,” he said.

A real investment of the future of treatment for Okuda is looking toward better measures for disease surveillance. An inability to observe the disease progression as effectively as necessary outside of large institutions has led to an inability to use some of the more potent therapies.

“Maybe comfort levels differ as well,” Okuda said. “If you’re a general neurologist, it may be tough for one to fully advocate for a therapy that’s not well understood and a therapy in which they’re not necessarily keeping track of all the safety outcomes that are occurring from a week-to-week basis.”

 A welcomed benefit of the DMTs and other therapies is that patients are beginning to live longer. With that finding, however, a fresh batch of questions are now coming into play, as patients grow older with the disease. 

“What’s really happening in our field is that we have patients with MS who are advancing in age, and for every 5 or 10 years they’re putting under their belt, the chance of them having acute inflammation is much lower than if they were younger,” Okuda said. “What do we do with that population of patients? They’re growing, and we know that inflammatory treatments are not so robust and inflammation is not really a robust finding in patients who are more advanced in age with MS.”

1. Long-term treatments for multiple sclerosis. Multiple Sclerosis Association of America website. mymsaa.org/ms-information/treatments/long-term. Updated March 2018. Accessed August 22, 2018.

2. Torkildsen Ø, Mhyr KM, Bø L. Disease-modifying treatments for multiple sclerosis — a review of approved medications. Eur J Neurol. 2016;23(suppl 1):18-27. doi: 10.1111/ene.12883.

3. Olek MJ, González-Scanrano F, Dashe JF. Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults. UpToDate website. uptodate.com/contents/disease-modifying-treatment-of-relapsing-remitting-multiple-sclerosis-in-adults. Updated August 6, 2018. Accessed August 22, 2018.

4. Disanto G, Barro C, Benkert P, et al; Swiss Multiple Sclerosis Cohort Study Group. Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017;81(6):857-870. doi: 10.1002/ana.24954. 

5. Siller N, Kuhle J, Muthuraman M, et al. Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis [published online March 1, 2018]. Mult Scler. doi: 10.1177/1352458518765666. 

6. Costello K, Halper J, Kalb R, et al. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence. Multiple Sclerosis Association of America website. mymsaa.org/PDFs/dmt_consensus_ms_coalition042017.pdf. Published July 2014. Updated March 2017. Accessed August 22, 2018.

7. Edan G. The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather than standard immunomodulation then escalation. Presented at: ECTRIMS; September 14-17, 2016; London, UK. onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/146950/gilles.edan.the.initial.treatment.of.early.active.relapsing.remitting.ms.html. Accessed August 22, 2018.

8. Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220. doi: 10.1056/NEJMoa1606468.

9. Kappos L, Bar-Or A, Cree BA, et al; EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6.

10. Carroll J. Poised for an FDA pitch, Novartis lays out all its PhIII cards on MS drug siponimod. Endpoints News. March 22, 2018. endpts.com/poised-for-an-fda-pitch-novartis-lays-out-all-its-phiii-cards-on-ms-drug-siponimod. Accessed September 5, 2018.

11. New Novartis analyses at AAN show siponimod’s efficacy on disability and cognition in secondary progressive MS patients [press release]. Basel, Switzerland: Novartis; April 20, 2018. novartis.com/news/media-releases/new-novartis-analyses-aan-show-siponimods-efficacy-disability-and-cognition-secondary-progressive-ms-patients. Accessed September 5, 2018.

12. Fox RJ, Coffey CS, Conwitt R, et al; NN102/SPRINT-MS Trial Investigators. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med. 2018;379(9):846-855. doi: 10.1056/NEJMoa1803583.

13.Montalban X, Leist TP, Cohen BA, et al. Cladribine tablets added to IFN-β in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e477. doi: 10.1212/NXI.0000000000000477. 

With more than a dozen available therapies, disease-modification in multiple sclerosis is entering a new era of development.

New Era Arrives for Disease Modification in Multiple Sclerosis

Levodopa (L-3,4 Diyhyrozyphenylalanine) is the gold standard therapy in the treatment of Parkinson disease, but its effectiveness decreases with chronic use. As it wears off, patients experience fluctuating and debilitating return of Parkinsonian symptoms, known as off episodes, which can occur for several hours per day. 

Clinical treatment goals focus on increasing on-time and managing or reducing off episodes, with pharmacological options to provide more continual dopaminergic stimulation as levodopa wears off. To this end, several agents are currently in development geared at the relief of off-time for patients with Parkinson. 

“One of the other things we’re looking at very intensively in research is finding new ways of delivering medicine,” said Fernando Pagan, MD, the medical director of the Georgetown University Hospital National Parkinsonism Foundation Center of Excellence. “We’re changing the way medications are delivered and the way we’re going to have therapeutics for our patients in the future.” 

Off symptoms, broadly known as levodopa-induced dyskinesia, can include 3 types of dyskinesia: peak-dose dyskinesia, wearing-off or off-period dyskinesia, and diphasic dyskinesia.

 Symptoms are marked by motor and nonmotor symptoms, such as bradykinesia, tremor, dystonia, cognitive impairment, mood swings, anxiety, panic attacks, and sleep disturbances. Risk factors for earlier onset of off episodes include early onset of disease, more severe disease at baseline, and higher levodopa dosage. 

Initial symptoms of off episodes can begin as early as just a few months after beginning treatment with levodopa. Most patients describe these symptoms as their greatest challenge in the management of the disease, with profound impacts on their functionality and quality of life. Off episodes may be somewhat predictable upon onset early in disease course, coming on in the mornings and correlating with the time between doses. Symptoms reappear, or worsen, prior to the next dose of levodopa and then improve once the dose is taken. As the disease inevitably progresses, however, the off episodes become less predictable and on-time is punctuated by the return of symptoms that can occur at any time of day and several times a day, correlating less with timing of the levodopa dose. 

Different Delivery Systems of Apomorphine 

Subcutaneous delivery of apomorphine, a dopamine agonist, is a clinically established therapy shown to be effective in reducing off-time in patients with motor fluctuations. The first double-blind, placebo-controlled, randomized test of this delivery of apomorphine was conducted in the phase 3 TOLEDO study.

 The subcutaneous infusion resulted in an absolute change in off-time, with achieved secondary endpoints of the percentage of patients with off-time reduction of at least 2 hours, absolute change in on-time without troublesome dyskinesia, change in oral levodopa and levodopa equivalent dose, change in the United Parkinson’s Disease Rating Scale (UPDRS) during on periods, and change in quality of life (using Parkinson’s Disease Questionnnaire-8). 

“The results of the TOLEDO study confirm what clinicians had observed and reported in uncontrolled studies for several decades: good efficacy and tolerability of apomorphine subcutaneous infusion,” principal investigator Regina Katzenschlager, MD, the head of the Department of Neurology at the Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders at Danube Hospital in Vienna, told 

Although the apomorphine infusion allows for fairly constant delivery to the bloodstream, 100% reduction in off-time remains elusive. Peter LeWitt, MD, MMedSc, editor-in-chief of Clinical Neuropharmacology, told NeurologyLive that without that full reduction, there may not be much to write home about. “In the recently published results of the TOLEDO study, using apomorphine infusion, patients improved who’d had motor fluctuations of up to 6 hours per day. They improved substantially, but their improvement was about 2 hours of the 6 hours of off-time. What about the rest of it?” said LeWitt, professor of neurology and psychiatry at Wayne State University School of Medicine. 

“There’s no doubt the drug achieved constant levels in the bloodstream and the brain. There’s no problem with absorption, because it’s being infused and taken up in the bloodstream, and yet the patient isn’t on. They still have off episodes throughout the day,” he said. “The same is true of Duopa, the continuous infusion of carbidopa and levodopa, to provide near-constant blood levels of levodopa, and yet patients only improve about one-third of their off-time, not the entire 100%.” 

A new drug application (NDA) with a January 29, 2019, the Prescription Drug User Fee Act deadline for a new mode of apomorphine delivery, APL-130277, was submitted by Sunovion to the FDA. APL-130277 will be a rescue therapy utilizing fast-acting sublingual delivery of an apomorphine-coated thin strip. The results of a phase 3, randomized, double-blind, placebo-controlled clinical trial with 109 patients showed significant mean reduction in the Movement Disorder Society-UPDRS Part III scores, with effects lasting from 30 to 90 minutes.

The difference in UPDRS Part III scores between the treatment group and the control group from baseline to 30 minutes after dosing was 7.6 (

 = .0002). The ease and accessibility of this quick delivery may be welcomed by patients for whom subcutaneous delivery of apomorphine presents unwanted side effects. Six of the 53 patients in the treatment group of the TOLEDO study withdrew due to treatment-related adverse events.

“Sublingual delivery seems to be effective, and it’s got a good data set of recorded results,” LeWitt said. “I’m not sure about a comparison with subcutaneous injection of apomorphine. I’m sure patients would prefer to have something as convenient as [sublingual delivery] and not have to use the injection form. The sacrifice is perhaps less efficacy, and maybe the speediness of its effect may be somewhat diminished.” 

“In the case of the sublingual apomorphine, the pharmacokinetics findings show that 15 to 30 minutes are when patients will start to get a substantial transfer of apomorphine, because the mucosa is not the fastest and also because the dose given may not hit the threshold for typical effect as quickly as hitting that threshold with subcutaneous administration,” he said. 

An NDA was filed for another potential rescue therapy, an inhaled powder form of levodopa known as CVT-301 (Inbrija), which was submitted by Acorda Therapeutics with an anticipated approval date of October 5, 2018. CVT-301 is intended for use during off episodes in between doses of oral levodopa. 

The application included data from the phase 3 SPAN-PD study,

 along with other long-term findings, which showed significant improvement in motor function for patients with Parkinson disease. Two doses of CVT-301 (84 and 60 mg, equivalent to 50- and 35-mg fine particle doses, respectively) were compared with placebo, with the change at week 12 in the UPDRS Part III score as the primary end point (—9.83 for 84-mg CVT-301 vs –5.91 for placebo; 

CVT-301 was evaluated for safety in spirometry and diffusing capacity tests of the lung for carbon monoxide and showed no notable pulmonary safety signals. The inhaler was well tolerated by patients. 

“Nearly everyone with Parkinson [disease] can manage the device and make the necessary big breath to make the inhaler drug enter their lungs,” Donald Grosset, MD, the clinical director of UK Parkinson’s Excellence Network and a consultant neurologist at the Institute of Neurological Sciences at Queen Elizabeth University Hospital in Glasgow, United Kingdom, told NeurologyLive. “We were pleased to see this, as it might be thought that people with Parkinson, particularly when they are having a ‘dip’ in their motor control, would find it difficult to use the device, but this turned out not to be the case. It might be tried for early morning off episodes, rather than ‘later in the day’ ones.” 

Rapid delivery of levodopa has potential to become an effective rescue therapy for patients experiencing troublesome dyskinesia in need of quick relief. “The published findings of the pharmacokinetics of CVT-301 show that it gets into the bloodstream and gets to the brain very rapidly, and levodopa translates into a dopaminergic effect within 5 to 8 minutes,” LeWitt explained. 

Other mechanisms of action are being explored, in addition to new formulations of levodopa and apomorphine. The monoamine oxidase B (MAO-B) inhibitor safinamide (Xadago) has shown promise in the SETTLE study, and the third-generation catechol-O-methyltransferase (COMT) opicapone showed superiority in the BIPARK trials. 

Safinamide’s dual mechanism of action includes modulation of dopaminergic metabolism through selective reversible inhibition of MAO-B and blockade of voltage and use-dependent sodium channels that leads to inhibition of stimulated glutamate release. The action of the sodium channel blocker is important, because it does not influence physiological activity, avoiding depressant effects on the central nervous system. Accordingly, it does not have an effect on blood pressure or heart rate, expanding the patient populations who could tolerate this medication. Safinamide also has low potential for drug—drug interactions. 

 the daily oral dose of 50 or 100 mg of safinamide showed significant improvement in motor fluctuations, motor symptoms, nonmotor symptoms, and mobility compared with placebo. The study results suggested that the daily dose should be started at 50 mg and increased to 100 mg, based upon clinical evaluation of patient need. Used in tandem with levodopa, these data suggest that safinamide could be an appropriate choice as a first-line add-on therapy to levodopa. 

The SETTLE study showed that 100 mg of safinamide significantly increased mean daily on-time by 0.96 hours compared with placebo, meeting its primary endpoint of reducing troublesome dyskinesia. Long-term (24-month) analysis of safinamide show significant improvement in quality of life when used in tandem with levodopa. Importantly, positive motor and nonmotor improvements with safinamide have been proved for both the short term (6 months) and long term. 

Opicapone is a novel once-daily COMT inhibitor developed by Neurocrine Bio, which plans to submit an NDA with the FDA in the first half of 2019. Opicapone was shown to significantly decrease off-time compared with placebo in 2 pivotal phase 3 trials used for European approval, BIPARK-1 and BIPARK-2.

The BIPARK-I trial,6 which had 600 patients, showed that opicapone was noninferior to the earlier generation COMT inhibitor, entacapone (Comtan). The mean reduction in off symptoms was 96.3 minutes with entacapone compared with 116.8 minutes for 50-mg opicapone. In BIPARK-2,7 there was a 54.3-minute decline in off-time versus placebo for the 50-mg/day dose of opicapone. After 1 year of treatment, daily off-time was reduced by 126.3 minutes with opicapone.

Opicapone is thought to reduce off-time and extend on-time periods by decreasing the conversion rate of levodopa into 3-O-methyldopa, thereby increasing the plasma elimination half-life of levodopa and decreasing peak-trough variations. 

“Using a COMT inhibitor or a MAO-B inhibitor makes sense, because their mode of action is different in terms of extending the effects of levodopa,” said LeWitt. “We do that all the time—we’ve been doing that for 20 years. But the important thing about the medication effect is that it’s still not going to keep the patient on all the time. In fact, it may be no more effective than using one or the other.” 

Dopaminergic stimulators and drugs that block the breakdown of dopamine in the brain have been proven to extend on-time and reduce off-time, but no medication or combination thereof has been proven to work all of the time to keep patients free of off episodes, especially as Parkinson disease progresses. The duration of effectiveness of levodopa seems to start diminishing from the onset of treatment and continues to diminish with duration of the disease. 

“While you can improve off-time pharmacologically, you might not be able to achieve 100%,” said LeWitt, author of “Levodopa Therapy for Parkinson’s Disease: Pharmacokinetics and Pharmacodynamics.

 “There may be more going on in the brain in Parkinson that prevents you from achieving near-constant on states from even the most continuous of dopaminergic stimulation, whether it’s with levodopa or a drug that mimics the effects of dopamine. All of the therapies we’ve thrown at this, ways to make the oral delivery of levodopa better, COMT inhibitor drugs, or any new MAO-B inhibitors, which partially block the breakdown of dopamine in the brain, are no better than drugs that have been around for more than 20 years.” 

LeWitt noted that in the studies that have been done, patients observe that they’ve experienced approximately 5 to 6 hours of off-time—but that may be the limit. Seemingly, he said, it cannot get better than improving 2 hours of off-time per day in a patient who has off-time for 5 to 6 hours per day on average. 

“It’s something that we occasionally simplify too much, to say ‘If only we had continuous dopaminergic stimulation or if we could bring the doses close enough together and use the COMT inhibitors and MAO-B inhibitors together and put this polypharmacy together, we could get constant dopaminergic stimulation.’ As if that’s the whole goal of helping the patient,” LeWitt continued. “And these therapies do work to some extent, but they do it imperfectly and there seems to be this glass ceiling, if you will, of keeping the patient fully on all the time that just can’t be achieved with current therapeutics.” 

Implications of Elusive On-Time Constancy 

Trials to establish the efficacy of established medications utilizing perhaps more efficient delivery systems have so far failed to prove complete reduction in off-time. 

“There’s a lot that isn’t logical about it, or conceptually, we have the wrong message that off-time is always a deficiency of dopaminergic stimulation to be improved by better delivery of drugs or blocking the breakdown of drugs we currently use,” said LeWitt. To him, the emerging story has been that the emergence of Parkinsonian symptoms can be, and is, a complex tale. 

“You can also criticize the studies, like the TOLEDO study, that maybe they didn’t [administer] enough apomorphine in the dosing with levodopa, to try to explain why the effect was as limited as it was. But that might not be the right answer to it,” LeWitt said. “It might just be that there’s some black box in the brain that fails to respond fully to continuous dopaminergic stimulation to relieve all of the Parkinsonian symptoms. I’m thinking more and more that it might be something we’ve yet to learn about this disorder, that as the disease goes by the responses to dopaminergic stimulation may fluctuate in a manner that doesn’t really suggest what to do about it now.” 

Disease progression can likely be implicated in the decreasing effectiveness of levodopa and the increasing incidence of off episodes that, at a clinical level, seem to take place simultaneously with progression. Inability to remain in an on state, even with constant dopaminergic stimulation, is a hallmark of disease progression. Duration of response to therapies can explain corresponding effectiveness of treatment. 

“The long duration of response essentially describes the initial state of responsiveness to levodopa, which is many hours, if not days, of benefit from a very short-acting drug that nonetheless transduces its benefits in a manner that goes beyond simply generating dopamine, which has a very rapid turnover in the brain,” LeWitt said. 

“What happens over time, at least conceptually, is that the long-duration response turns into the short-duration response, which is sort of a dose-by-dose effect, where not producing dopamine means the patient is off,” he added. “But having lost that long duration response, it may be that a number of other phenomena that are part of that are also lost. It could be that progression of the disease includes some mechanism whereby patients cannot achieve constancy from constant dopaminergic stimulation. But that isn’t really part of our current understanding, or dogma, about what progression is.” 

1. Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 1: treatment of levodopa-induced dyskinesia. Drugs. 2016;76(7):759-777.

2. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with 

 disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, 

, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759. 

3. Navia B, Factor S, Pahwa R, et al. Efficacy and safety of sublingual apomorphine film (APL-130277) for the treatment of OFF episodes in patients with Parkinson’s disease: results from a double-blind, placebo-controlled trial. Presented at: 2nd Pan American Parkinson’s Disease and Movement Disorders Congress (MDS-PAS); Miami, Florida; June 22-24, 2018. Abstract LBA03. https://www.pascongress2018.org/MDS-PAS-2018-Files/PDFs/FinalLBAs.pdf 

4. LeWitt PA, Fernandez HH, Hauser RA, et al. Inhaled levodopa (CVT-301, 84-mg dose) significantly improves motor function during OFF periods in Parkinson’s disease (PD) subjects: a phase 3 study [SPAN-PD]. Presented at: 2017 International Congress of Parkinson’s Disease and Movement Disorders; June 4-8, 2017; Vancouver, British Columbia, Canada. Abstract LBA34. https://www.mdscongress.org/Congress-2017-Files/PDF/LBASGGPT.pdf 

5. Olanow CW, Stocchi F. Safinamide—a new therapeutic option to address motor symptoms and motor complications in mid- to late-stage 

 disease. Eur Neurol Rev. 2016;11(suppl 2):2-15. 

6. Ferreira JJ, Lees AJ, Rocha JF, et al; BiPark 1 Investigators. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a 

, double-blind, controlled trial. Lancet Neurol. 2016;15(2):154-165. 

7. Lees AJ, Ferreira JJ, Rascol O, et al. Opicapone as

 to levodopa therapy in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol. 2017;74(2):197-206. 

 disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2014;30(1):64-72. 

Several agents are currently in development geared at the relief of off-time for patients with Parkinson.

Searching for Off-Time Relief in Parkinson Disease

Cannabis has gained momentum and legal status for medicinal use in the majority of the United States. Expanding legalization for both its medicinal and recreational uses is anticipated in the coming years.

 Although advocates for medicinal use describe its therapeutic applications for a number of conditions, formal scientific inquiry into its efficacy and safety for most of these conditions remains in its infancy.

 Epilepsy has been the focus of a recent foray in research, and early trial results recently led to the FDA approval of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals), the first cannabis-derived medication for intractable childhood seizures.

Additionally, cannabis is now being investigated for a variety of other neurologic conditions, such as Alzheimer disease, Parkinson disease, and migraine. As its use expands and its efficacy is better understood, the rudiments of the endocannabinoid pathway, the cannabinoid mechanisms of action, FDA guidelines, and the emerging neurotherapeutic applications become paramount.

CBD is the most widely described of up to 113 phytocannabinoids found in cannabis.

Cannabinoids are being explored in a variety of conditions, ranging from Alzheimer disease to migraine.

October 2018

Alzheimer Disease Symptoms: More Than Memory Loss and Confusion

New Era Arrives for Disease Modification in Multiple Sclerosis

Searching for Off-Time Relief in Parkinson Disease

Exploring CB1, CB2 in Various Neurological Conditions

Phase III Study Brings Hope to ALS

Rapid Development of Migraine Therapies Offers New Hope

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