Marco Meglio

For years, the conversations surrounding care for patients with 

 (MS) mainly centered around drug development and the optimization of disease-modifying therapies (DMTs). There are now more than a dozen DMTs approved for MS, administered in various forms such as tablets, injections, or infusions. Although, as clinicians have learned, the management of these patients extends past treating solely the relapses.

Integrative wellness is a practice based around the belief that treating patients involves much more than only disease and symptom management and has become an approach adopted by more clinicians in recent years. This all-purpose type of method encompasses aspects of diet and nutrition, exercise, sleep, and ongoing preventive care, among others.

 Although there are no set guidelines on how to conduct this care, there are several overlapping themes and ideas.

The conceptual idea of integrative wellness often also carries a stigma, with many assuming these practices are not backed by scientific evidence. Contrary to this belief, ongoing research and the COVID-19 pandemic have confirmed the need for alternative approaches, particularly for patients with MS, who may benefit from interventions tailored to their individual needs.

Kathy Zackowski, PhD, OTR, senior director of patient management, care, and rehabilitation research, National Multiple Sclerosis Society (NMSS), has been at the forefront of researching and advocating for this new style of care. Her organization funds work that ranges from better understanding the use of acupuncture and yoga, to the resilience of psychosocial approaches, to the relationship of dieting and changes in the gut microbiome.

“The whole idea with wellness is that this is something that everyone can do right now,” Zackowski told 

®. “You don’t need a lot of equipment, but you need to understand the important elements of a wellness strategy for you. For someone in pain, we might recommend some of these psychosocial strategies looking at resilience and pain management, but for someone who’s weak, they may need just exercise. Exercise is its own intervention. It's not simple to go out and say, ‘go exercise.’ We need to understand what elements of that intervention are important for that person.”

The variety and usage of these integrative wellness approaches differs from clinic to clinic, which has added to its natural phenomenon. At Cleveland Clinic,

 physicians recommend maintaining a low-salt Mediterranean diet, getting at least 150 minutes of moderate movement per week, maintaining vitamin D levels between 40-70 ng/mL, not smoking or using tobacco products, and undergoing routine mental health screening.

Although there is a migration towards a better understanding of the need for collaboration and comprehensive care, some specialties are not consistently included in the model. Registered dietitians, for example, have historically been excluded from the multidisciplinary care team, with information on nutrition coming instead from integrative or alternative practitioners.

Mona Bostick, RDN, LDN, a nutritionist living with MS with a dedicated passion for optimizing nutrition, commented on this exclusion, adding that while nutrition is often miscast as an “integrative” approach, diet and how patients eat is not an alternative treatment for MS, but it is rather a pivotal aspect of overall health. Bostick is the founder of her private practice, Food Matters 365, now called MSBites, a source for evidence-based nutrition and wellness advice to help patients with MS.

“I believe the shift toward the integrative exists precisely because dietitians have not been included in the care team. With MS being such a disease [that] steals control over the things you thought you had control over, when alternative practitioners are promising to heal, beat, reverse, or give you that control back, the vulnerability that MS presents is going to make someone take a risk on that,” she told 

®. “It’s important to know that nutrition and what you eat plays an important role in your overall health, but it doesn’t offset demyelination—nuance and context around what food can do is missing a lot of times in these integrative and alternative messages of this practitioners. I find that to be disconcerting because there is a vulnerability to the MS population, for sure.”

Zackowski echoed similar thoughts to Bostick, adding that even the general public should be exposed to nutritional dietitians. “With MS, it’s complicated. We don’t have the cure yet, and one of the ways the [National MS] Society talks about this is the pathway to cures. The idea that there’s not just one cure, there are multiple cures, and people define cure in a different way. One way of defining cure is taking away symptoms. If diet can provide some improvements in the symptoms people [with MS] have that’s one form of an MS cure,” she explained.

Sharing Best Practices for a Sense of Community

Amidst the ongoing COVID-19 pandemic, the shift to telemedicine challenged clinicians to provide care remotely, whether that be for symptom management or for integrative approaches. Interestingly, some clinicians say the use of telemedicine had a positive effect in increasing collaboration and information sharing within the MS field, as the unknowns associated with COVID-19 generated a need for experts to share timely data relating to the virus and overall best practices with one another.

Mitzi Joi Williams, MD, CEO, Joi Wellness Group Multiple Sclerosis Center, spoke on this increased sense of community within the MS field since the onset of the pandemic and over the course of 2021. Williams noted that her colleagues were not afraid to share findings and information from registries, whereas in the past, the scientific community had cultivated a sense of protectiveness in terms of clinical data that had yet to be published.

“The information sharing that has emerged from the COVID-19 pandemic has really been amazing, and to see the collaboration from people from different academic centers, from the academic centers in the community, to across the pond, across the world, across the globe, has really been astounding,” Williams told 

Social media has been crucial in establishing this sharing of information and collaborative attitude, allowing experts in the MS field to share information quickly and freely via online platforms like Twitter, Williams said. Monthly webinars and conferences also aided in the dissemination of updated data, with experts then able to implement practices in real time.

“I hope this collaborative approach amongst MS specialists, general neurologists, and my colleagues around the globe stays,” Williams said. “There has been this amazing unity amongst everyone to try to find the scientific answers we need to be able to adequately care for our patients. We've seen a lot of synergy with people creating registries fairly quickly—a lot of things that we thought couldn't get done are absolutely getting done, [and] a lot of things we thought couldn't be done remotely are absolutely being done remotely.”

Zackowski spoke on ongoing work of the NMSS to improve this collaboration and sharing of information as it pertains to wellness, which includes the development of the Wellness Research Group and 3 different subgroups: physical wellness, nutritional wellness, and psychosocial wellness.

 Information published online is tailored specifically to patients or clinicians, making it easier to access veritable, valuable sources, Zackowski said, noting that patients “do not need to be scientists” in order to understand findings from ongoing studies. This is not, however, a foolproof method for getting the word out about wellness, particularly due to the need for practices and information to be adjusted for individual patients.

“The idea of integrating just those 3 areas is challenging—and that's not really addressing everything—there's so many symptoms that people have with MS that I think can be addressed by different wellness approaches,” Zackowski said. “I think it's really hard to get the message out to people about what to do because there's no regulatory body on how to make sure the standards are the same everywhere, and that's something we as a society are trying to grapple with a little bit more.”

Although there is good reason to be excited about these integrative approaches, clinicians themselves also agree that there is a need for extended research that aims at understanding and optimizing these methods. As of now, clinicians use their better judgement, paired with what’s been observed in the literature and through the help of their multidisciplinary teams. There is no current law-abiding guideline that the community has developed or strictly follows.

“When you talk about exercise, diet, or even cognitive rehabilitation, no one knows exactly the right dose, Zackowski stressed. “How much do you need as a person with MS to address your particular issue? We do this automatically with medications because the FDA dictates that you have to put a particular dose and explain what that dose is. In the wellness area, we need to address those things, we need to understand the dose, the intensity, the setting that this is done in, and how that approach will be effective in people who have more than one symptom.”

Despite advances in research in recent years, the space is stilling being held back. Without backing from pharmaceutical companies or industry leaders, it has been difficult to conduct large scale trials that further help validate these methods. These groups have yet to formally recognize integrative wellness as something that has significant therapeutic benefit, especially since the data thus far has been hard to quantify.

That, ultimately, leaves supporters of integrative wellness practices like Bostick and Zackowski to fend for themselves in terms of powering research, or forces them to turn to organizations such as the NMSS in hopes of acquiring funding and materials.

“I’m thinking of getting pharmaceutical companies interested in this combined approach that uses a medication and a wellness strategy,” Zackowski said. “This might be another way to encourage greater funding for this, but it will take time and money to get this understood better. We are right on the forefront though—we’re at a place where this can be studied now, and I’m encouraged by that.”

In addition to the need for increased research, there remain complexities in the integration of dietitians into standard of care, according to Bostick. “Out in the community, there are dietitians everywhere. At this point, the obstacle is that continuing education hours are expensive and difficult to obtain. There’s not been a reason for a dietician to justify becoming educated and informed on this topic, because they’ve not yet been welcomed into the comprehensive care team,” she said.

Bostick added that once the talents of these specialists are more appreciated, they may go back to their communities and advocate for these roles as well as provide information for newcomers to feel more comfortable. While a dietitian may have a broad knowledge of nutrition, they may not be as equipped at that moment to treat the MS-specific component. “Broadly speaking, multiple sclerosis is not discussed in our education and training. That’s the obstacle,” she said.

Much like how the efficacy of drugs continues to be optimized in post hoc analyses, it will only be a matter of time before similar studies to further validate these wellness approaches. Overall, the commitment to these nontraditional, forward-thinking ideas represents the general trend within the medical system in recent years to treat the patient from a complete holistic perspective that addresses all downstream aspects of the disease, and not just the root cause.

This contribution to HCPLive’s 2021 This Year in Medicine series comes from sister publication 

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Articles

Clinicians have begun to incorporate more holistic ways to approach the treatment of multiple sclerosis symptoms by focusing on better overall health, exercising, and dieting.

The Expansion Toward Integrative Wellness Approaches in MS Care

This article was originally published in NeurologyLive.

The US Food and Drug Administration (FDA) has approved JZP-258 (Xywav) for the treatment of idiopathic 

, making it the first treatment cleared for this indication. The approval was granted to Jazz Pharmaceuticals. 

The combination agent of calcium, magnesium, potassium, and sodium oxybates will be available to patients in the fourth quarter of 2021 following Risk Evaluation and Mitigation Strategies (REMS) implementation.

The company announced the acceptance of its supplemental new drug application (sNDA) for JZP-258 in February, which included data from a positive phase 3 study (NCT03533114) that showed the investigational agent was effective and safe for adults with idiopathic hypersomnia. 

The oral solution received fast track designation from the FDA in September 2020 for this indication, and in December was granted a rolling submission, allowing for the submission of portions of the application as completed.

Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by chronic excessive daytime sleepiness (EDS). A majority of physicians in the space have turned to off-label use of wake-promoting therapies typically used in patients with narcolepsy to help address the sleepiness issues.

"We are excited that with today's approval Xywav will become the first and only medicine indicated to treat idiopathic hypersomnia, a unique medical condition that can have significant effects on the lives of those diagnosed with the condition," Bruce Cozadd, chairman and chief executive officer, Jazz Pharmaceuticals, said in a 

 "This milestone exemplifies our patient-focused R&D strategy and internal development capabilities, and underscores oxybate as a key growth opportunity for Jazz. With this launch we will have achieved our goal of five product launches in two years."

The double-blind, multicenter, randomized phase 3 trial featured patients who had EDS associated with idiopathic hypersomnia, and all of those treated with the agent experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores–the primary end point–during the open-label titration period.

A randomized withdrawal portion of the study included 115 patients who were assessed on primary and key secondary end points including Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS). 

Those who received JZP-258 reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. Furthermore, highly statistically significant worsening was observed for those who received placebo compared with JZP-258 for ESS (

Xywav has a Boxed Warning as a central nervous system (CNS) depressant and for its potential for abuse and misuse. The most common adverse reactions, occurring in at least 5% of adults in the phase 3 study, were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.

JZP-258 originally received approval for the treatment of cataplexy or EDS in patients 7 years of age or older with narcolepsy in July 2020. The basis of that approval was built on data from a phase 3 double-blind, placebo-controlled, randomized-withdrawal, multicenter study, for which the drug demonstrated statistically significant differences (

 <.0001) in the weekly number of cataplexy attacks and ESS scores compared with placebo.

"Idiopathic hypersomnia can have a significant impact on the social, educational and occupational functioning of people living with the condition. Today's FDA approval is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder," Dianne Powell, board chair and chief executive officer, Hypersomnia Foundation, said in a statement.

"Our mission and values have consistently centered around supporting patients and scientific discovery and this announcement truly provides a sense of hope for those living with idiopathic hypersomnia."

The combination agent breaks ground as the first treatment approved for this indication.

JZP-258 Receives FDA Approval for Idiopathic Hypersomnia

High-dose blarcamesine resulted in a significant improvements in symptom scores for patients with 

The full results from the proof-of-concept phase 2 study of blarcamesine suggests the drug’s impact on increasing sigma-1 receptor (SIGMAR1) mRNA expression corresponded significantly with responses on primary and secondary end points in this patient population.

Anavex Life Sciences noted it plans on submitting these data to the US Food and Drug Administration (FDA) to seek regulatory guidance.

Treatment with blarcamesine, formerly known as ANAVEX 2-73, resulted in significant (

= .035) mRNA expression increase of SIGMAR1, which correlated with clinical efficacy as measured by the Cognitive Drug Research (CDR) system Continuity of Attention (CoA; 

= .029) and CDR system Power of Attention (PoA; 

The correlation also remained true on secondary end points such as Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III (

"This is now the second independent placebo-controlled clinical ANAVEX 2-73 phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression,” Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement. "We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX 2-73 as a cross-platform [central nervous system] drug.”

The phase 2 study included 132 patients with PDD randomized 1:1:1 to blarcamesine 30 mg, 50 mg, or placebo for up to 14 weeks. Study participants were allowed to be on a stable regimen of anti-PD medications, including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone.

Those included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score (

By the end of the study period, the MDS-UPDRS total score improved by ­10.98 points in the 50-mg dose group and worsened by 3.53 points in the placebo group, corresponding to a relative improvement of 18.9%. This far exceeds an empirically established cutoff of a 7.1-reduction for detecting meaningful clinical change.

The clinically meaningful improvements observed in patients with PDD suggest that the agent has the capability of slowing and reversing symptoms that progress in PD, an urgent unmet need for this patient population. Notably, blarcamesine did not impair sleep and had a positive effect on rapid eye movement (REM) sleep behavior disorder.

Previously reported data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) 2020 Annual Meeting showed a dose-dependent (

= .003), statistically significant improvement of CDR system Episodic Memory of 42.22 points between 50-mg blarcamesine and placebo. CDR system Episodic Memory has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

Patients in the high-dose group also experienced an ADAS-Cog mean change from baseline of –1.9, an 8% mean improvement from baseline to 14 weeks. Investigators documented a 4-point improvement difference of calculated corresponding ADAS-Cog score between the blarcamesine treatment group and the placebo group from baseline to the end of the study period. Anavex is also evaluating blarcamesine in a phase 2b/3 study that features 

The company recently announced that they have exceeded their target enrollment goal of 450 patients, and topline results from the ongoing study are expected to be announced by mid-2022.

Patients included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score.

Blarcamesine Improves Symptoms for Patients with Parkinson Disease Dementia

A new study endeavor will explore US Food and Drug Administration (FDA) approved medications for efficacy in Alzheimer disease.

According to a recent announcement, the National Institutes of Aging (NIA) will be conducting a new innovative study to determine whether medicines currently FDA-approved to treat conditions other than dementia can help prevent or treat Alzheimer disease (AD).

Neurologist Madhav Thambisetty, MD, DPhil, will lead the project in collaboration with researchers at Harvard Medical School, Rutgers University, and Johns Hopkins University School of Medicine, to design a new approach that would be an alternative to traditional drug discovery.

The study, titled Drug Repurposing for Effective Alzheimer’s Medicines (DREAM), will focus on drugs that have already been shown safe and effective for other conditions. The investigators will forego observing data from animal testing models and will instead look at data from large numbers of people who have already been treated with these compounds for other disorders.

Plans for the DREAM study were recently published in 

Alzheimer’s and Dementia: Translational and Clinical Interventions

 Based on abnormal glycolysis as a primary progenitor pathway, researchers hypothesized that there may be greater than 20 related and distinct biochemical pathways that are dysregulated in the AD-related dementia (ADRD) brain. These abnormalities may precede or influence the brain changes that lead to dementia.

To further test this hypothesis, the investigators generated a list of 250 genes that are known to regulate individual reactions within the component pathways of the Alzheimer Disease Aberrant Metabolism (ADAM) network. Using these genetic regulators within the aforementioned dysregulated pathways, 35 FDA-approved drugs were identified as potential repurposing candidates. Of these 35, the team selected 15 drugs as the best candidates for further analysis.

The DREAM study leverages 2 large population-based data sources for pharmacoepidemiologic analyses, the first being the insurance claims data from the Medicare program, and the second is the Clinical Practice Research Datalink (CPRD) GOLD, which is a large United Kingdom primary care database containing de-identified data on nearly 15 million people. Results from the DREAM study could help guide future research, especially if an identified drug appears to reduce the risk or severity of AD and ADRDs.

The hypothesis of repurposing drugs for AD has become increasingly popular in recent years. Cleveland Clinic recently announced that it will conduct a 

, an FDA-approved anti-cancer drug, in early-stage AD or mild cognitive impairment (MCI). That project is comprised of 2 dual studies and is led by Marwan Sabbagh, MD, and Boris Decourt, PhD.

Sabbagh, along with colleagues including Jeffrey Cummings, MD, ScD, who serves as the director emeritus of the Lou Ruvo Center for Brain Health at Cleveland Clinic, and vice chair of the Department of Brian Health at the University of Nevada – Las Vegas, recently published a yearly report on the 

, in which the group noted there was an increase in the number of repurposed agents in the pipeline from 2019 to 2020.4 This datapoint drew Cummings’ attention as a potential area to prioritize.

One [thing that stuck out] was the great increase in the number of repurposed compounds that are in the pipeline. One of the things that alarmed me though was the relatively small number of agents coming into phase 1. We really have to get those drugs out of the lab, out of the animals, and into humans more successfully.”

The investigators generated a list of 250 genes that are known to regulate individual reactions within the component pathways of the Alzheimer Disease Aberrant Metabolism (ADAM) network.