 on Medical Economics, an MJH Life Sciences brand.

Many physicians are looking to hire a telehealth service company to expand access to care for patients during the coronavirus disease 2019 pandemic. Even though practices want to start their telehealth program quickly, do not rush due diligence. To help physicians evaluate potential vendors, the American Medical Association recently released its Telehealth Implementation Playbook, a guide with key tips and updates on telemedicine expansion. It includes criteria that physicians should consider when selecting a vendor.

What is the company’s organizational overview?

What is their funding source? Are they financially stable? With whom are they affiliated?

How will this company affect your program’s return on investment?

What are details on reimbursement rates, risk sharing, and more?

What is the cost, process, and timeline associated with integration and any product updates?

Do they have expertise in offering telehealth to your specialty?

Do they have knowledge of federal and private-payer requirements? Do they know the laws and regulations in your state?

Can they integrate with your information technology landscape, particularly your electronic health record platform?

Can their system capture data important to both the care team and the patient?

What are their customization capabilities?

Do they comply with the Health Insurance Portability and Accountability Act? Will they sign a business associate agreement with your practice?

What is their liability structure for managing security breaches?

Do they comply with local regulations, such as those of state medical boards?

How easy is their system for clinicians and patients to use? Does it provide engagement metrics?

How well do the dashboard and workflow systems work? How easy is the billing system?

Do they have documentation that supports improving clinical outcomes? Is there any published peer-reviewed research of their system?

How much initial training do they provide?

How much support do they provide beyond initial training? Patient education? Project management? Data analysis?

What is their technical support process like?

Do you have access to existing templates and procedure examples?

Articles

Medical World News

A look at the questions you should be asking during the decision-making process of picking a telehealth vendor. 

Eight Ways to Evaluate a Telehealth Vendor

As the ongoing battle against the spread of the coronavirus disease 2019 (COVID-19) continues, the medical community is learning more about the disease and at-risk populations by the day. Many symptoms and comorbidities associated with neurologic disorders place patients, especially those in the neuromuscular disease community, within those high-risk categories established by the Centers for Disease Control and Prevention (CDC).

To learn more about what health care providers for patients with conditions like spinal muscular atrophy, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis, among others, are doing in response to COVID-19, 

 connected with Barry J. Byrne, MD, PhD, chief medical adviser to the Muscular Dystrophy Association (MDA) and associate chair of pediatrics and director at the University of Florida’s Powell Center for Rare Disease Research and Therapy in Gainesville. Byrne discussed the MDA’s resource center, advice that has been shared with patients and care centers, and those in this community who are at particular risk.

: What are some of the best practices and precautions that the MDA has recommended for patients and providers?

: One of the more challenging aspects is that it’s not only [visibly] ill contacts that we advised against people interacting with, but it’s possible—particularly in the younger population&mdash;[for individuals to be] asymptomatic carriers. Really, the same precautions that are recommended for everyone are especially important for the neuromuscular community; caregivers and the patients themselves have to really practice very thorough handwashing procedures, [for instance], and [should] wear some kind of protective mask.

MDA developed a resource page and sent out a written document to all the care center directors and to the patient community with useful tips and a number of links that relied on CDC guidance information. Some aspects are particularly important to emphasize for the neuromuscular community: For instance, [the virus can be transmitted] not only in a respiratory [manner] when people are in the later stages of the disease, but you can have transmission through stool as well. Therefore, it’s very important to practice appropriate handwashing and disposal of those materials. We sent this out to everyone, but in real time we are learning more every day, so that information is being aggregated in the COVID-19 resource page that the MDA initiated [and updates].

How has the pandemic affected your ability to treat patients and manage their conditions?

In terms of general management of patients, we’ve had to make way for those coming into the hospital who experience respiratory difficulty. That means getting all of those other patients who are receiving regular care out of the hospital and back home. Sometimes they’re not entirely prepared to transition back to the home, but we’ve made that happen over the course of about a week.

It has been challenging to understand [what to do] when there’s some credible exposure and how to isolate 1 individual. That’s obviously been discussed. It’s very relevant to health care workers: Should anyone with a remote exposure but no confirmed direct exposure be out of the work schedule? That limits availability of care providers. That will be relevant in the home, too, for people with home nursing: Could that provider have encountered someone, or someone in their family, who might have had an exposure? Testing is really paramount to understanding whether exposure is real and whether someone should, in fact, be isolated.

The unavailability of DNA-based testing and/or the lengthy turnaround time has made that not the most practical solution.

Point-of-care tests detect exposure through the immune response; another test—an antigen test done at the bedside&mdash;looks at protein components of the virus, so that’s going to be very useful. You’ll see these serological tests or antibody tests becoming more prevalent because they are a lot faster to turn around than the DNA-based testing for the virus itself.

Have you used telemedicine to connect with your patients?

Absolutely. Without the ability to quickly pivot into a virtual format, I think a lot of patients would have been left without access to their care providers. It’s been important to have some relaxation of the regulatory guidelines and restrictions around that ability to visit remotely with patients who are even not within the state, who are across state boundaries or elsewhere in the country. Proper documentation and billing practices have been established to make sure these visits are properly tracked in the medical record. Having the ability to have an electronic medical record that integrates with the Zoom platform (which is secure for patient-protected health information) has been critical.

We have put these remote video platforms into place, as well, because of the impact on our science. Rather than face-to-face meetings, we’ve used this kind of platform to establish a basis for continuing collaborations and even for broadening our collaborative opportunities for people working on innovative approaches to solving this problem. For instance, we had a meeting in March among a half-dozen folks prepared to roll out some of this anti- body testing onsite with the rapid turnaround testing platform that we developed.

Virtual visits were not implemented in many places prior to this health crisis, but because of the network that was established by the MDA, we’re really leveraging the best-practices experiences that individual sites have had, to enable others to learn from them. We also expanded the MDA resource center, which has allowed care center specialists across the country to call the resource center and get access to the latest information.

Do you foresee retaining any of these telemedicine practices post pandemic?

I do. I think it will benefit our neuromuscular community because obviously many patients with mobility issues find it very challenging to travel to the site to be seen. We will have to implement some aspects of direct data collection that aren’t readily available by a telemedicine format. For example, especially now in the wake of these respiratory illnesses, we don’t have a ready means for doing [remote] pulmonary function testing nor do we have the best means for [remote] physical function assessment or clinical evaluations. We’re going to have to work out how those things are done in the home with remote tracking of activity. Activity monitors are useful as surro- gates for mobility testing, and there are Bluetooth accessories for pulmonary function testing as well as spirometers; these would have to be distributed to patients to use in conjunction with their [smartphones or other] personal devices.

For a while, there have been means to do home nursing—used more often in the research arena than in the clinical arena&mdash;but laboratory assessment can certainly be done through home nursing visits. The rest of the assessment can be adjusted to work on the telemedicine format, and then we can make sure that people have the needed health maintenance that’s required over time.

I don’t think this will completely replace face-to-face visits; it just will lessen their frequency. Probably, in fact, in many cases, this will improve access to care for some families who either can't be transported to an office or hospital or can’t coordinate visits with multiple providers at once. At the University of Florida, we’re setting up a virtual meeting room, so the patient actually stays in 1 place, and the multiple providers who are part of the multidisciplinary team have appointments. It forces everyone to be exactly on time because the next person comes in whether you’re finished or not. I think it also makes it much more convenient and comprehensive for patients.

Any thoughts on the future and returning to “normal”?

Of course there will be benefits to getting back to normal, for people traveling to be together and to share those common experiences that help us advance the field. It’s particularly important in the research realm. Obviously, this is an unprecedented time in history and certainly in medical care. It’s a [time of] high risk for the neuro- muscular community—possibly more than any other community of people&mdash;but the neuromuscular patient community has understood the gravity of the situation and the need to take it quite seriously so far, thank goodness. We feel that people have been safe in following those guidelines about handwashing and protecting themselves with the necessary protective equipment if needed, and we hope that everyone stays healthy and well throughout the course of this. I will say that we should not let our guard down, though, because although there is this attempt to lessen the rate of new-case acquisition and to come up with new strategies for treating those who are hospitalized, if relaxation of the guidelines against public gatherings comes too early, then there will be a resurgence of the infection for those who haven’t been exposed. We have to be vigilant about that and really think hard about who are the most vulnerable subjects, in both health care providers and our neuromuscular community, who’d be eligible for a vaccine as soon as it’s available because that’s really, honestly, going to be the only way to have a lasting impact in lessening the severity of this illness.

Clinical Viewpoint

In the wake of the COVID-19 pandemic, health care providers and patients have had to quickly adapt to new formats of care models to promote safety while retaining care standards.

Adapting Neurological Care Amid COVID-19

When we look back on changes in our lives during the novel coronavirus disease 2019 (COVID-19) pandemic, I hope we’ll remember how we confronted these challenges, adapted, innovated, and persevered. Resilience, whether individual or societal, can be an essential by-product of crisis.

During an initial surge in COVID-19 cases, neurologists reported 20% to 50% reductions in acute stroke imaging and clinical presentations to emergency departments (EDs).

 Among patients with COVID-19, multiple anecdotal cases of a variety of etiologies for stroke have emerged. Complications in patients with COVID-19 are being attributed to reported viral-induced thrombophilia,

Patients have expressed their uncertainty regarding the safety of presenting to the ED with stroke symptoms by staying home rather than seeking necessary emergency care. Patients’ self-selection from ED and hospitalized care has shifted an increasing burden of illness to outpatient management, with consequent delays in diagnosis and treatment. I have witnessed patients of mine who have suffered new acute stroke presentations and delayed their presentation to the ED until they were ineligible for thrombolytic therapy and could not manage their disability, out of fear of exposure to COVID-19.

Our dedicated cerebrovascular team of outpatient nurses, advanced practice providers, and physicians has spent considerable time reassuring patients and encouraging them to present to the ED so we can best care for their acute stroke.

An experience during the early stages of the COVID-19 surge in northeast Ohio illustrated the anxiety that prehospital providers experience when caring for patients with acute stroke. A patient with acute ischemic stroke and a negative COVID-19 symptom screen was transported on our mobile stroke unit. Immediately on arrival in the ED, he underwent a CT angiogram of the head and neck, which demonstrated ground-glass opacities concerning for viral pneumonia. Close exposure to a patient with suspected COVID-19 generates a variety of concerns among members of the health care team. Uncertainty regarding proper donning and doffing of personal protective equipment (PPE) and potential risk to self, patients, and family reach a crescendo during the uncertain interval while COVID-19 testing is pending.

In planning for the COVID-19 surge, I’ve spent countless hours developing new clinical workflows for the assessment of acute stroke symptoms in temporary hospitals we hope we will never need, restructured outpatient and inpatient clinician schedules to protect patients and providers, and designed staged redeployment plans for our stroke physician faculty. I have observed a significant increase in the efficiency of holding virtual faculty meetings but lamented the reduced banter among myself and my colleagues, as the usual exchange has always been for the betterment of our clinical and academic practice.

As a provider of telestroke services, I have learned a new appreciation for this capability and its timeliness in caring for patients during the COVID-19 pandemic. As a teaching physician and a section head for stroke services, I have had to develop new rounding practices and witnessed the impact on clinical care and trainee experience.

To reduce provider exposure risk, steward our PPE resources, and optimize clinical decision-making in the ED, we have employed a hybrid telemedicine model in our academic practice that uses a single neurological trainee at bedside with supervision from a vascular neurology fellow or staff member.

On stroke teaching rounds, we use a virtual meeting platform to present the patient history and physical, facilitate review of imaging, discuss clinical management, and review relevant literature. We have limited the number of team members who interact at the bedside and reduced redundant clinical examination for patients with suspected or confirmed COVID-19.

On an outpatient basis, we were already performing a small portion of our clinical visits using a virtual platform. With the emergence of the COVID-19 pandemic, we were challenged to rapidly shift the vast majority of outpatient services to virtual platforms to facilitate social distancing, reduce PPE use, and provide effective care for our patients. We have found new and innovative ways to conduct physical examinations through our virtual platforms. Patients have had to adapt their expectations of the virtual visit experience and manage previously unfamiliar application technology tasks using their smartphones. Hands-on outpatient rehabilitative care has suffered.

Stroke-related research involving COVID-19 has flourished with numerous anecdotal experiences, case reports, and case series popping up in the literature, reflecting the stroke community’s commitment to tackle the beast of uncertainty surrounding clinical management of acute stroke in patients with COVID-19. However, research involving patients without COVID-19 has suffered, with many important clinical trials being put on hold

 and institutional review boards delaying expedited review of minimal-risk, non—COVID-19–related research.

Stroke systems of care are rapidly evolving to meet the challenges of the COVID-19 pandemic. As we slowly emerge from stay-at-home orders, restart office clinical practices, and perform elective procedures, we must advocate for our patients by telling them what they don’t know—EDs and hospitals are safe for patients, and acute stroke needs to be managed emergently to reduce disability and prevent complications. I appeal to my neurology colleagues throughout the world: Engage with your local print and television media, tweet your support and post on other social media, make an impassioned video appeal, start a blog, and otherwise get the word out to patients with stroke that there is no time like the present to seek our care and expertise and confront their fears with our help, rather than doing harm to themselves by ignoring it.

1. Leira EC, Russman AN, Biller J, et al. Preserving stroke care during the COVID-19 pandemic: potential issues and solutions. Neurology. Published online May 8, 2020. doi:10.1212/WNL.0000000000009713 

2. Kansagra AP, Goyal MS, Hamilton S, Albers GW. Collateral effect of Covid-19 on stroke evaluation in the United States. N Engl J Med. Published online May 8, 2020. doi:10.1056/NEJMc2014816 

3. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847. doi:10.1111/jth.14768 

4. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286 

5. Zhang Y, Gao Y, Qiao L, Wang W, Chen D. Inflammatory response cells during acute respiratory distress syndrome in patients with coronavirus disease 2019 (COVID-19). Ann Intern Med. Published online April 13, 2020. doi:10.7326/L20-0227 

6. Meschia JF,&#8239;Barrett KM,&#8239;Brown RD, et al. The CREST-2 experience with the evolving challenges of COVID-19: a clinical trial in a pandemic. Neurology.&#8239;Published online May 1, 2020. doi:10.1212/WNL.0000000000009698 

Clinical Insights

Andrew Russman, DO, guest editor for NeurologyLive, provides insight on how stroke care has changed during the COVID-19 pandemic. 

Stroke Care Evolves During These Uncertain Times

Verdiperstat (Biohaven), a first-in-class, potent, selective, brain-penetrant, irreversible myeloperoxidase (MPO) enzyme inhibitor is the subject of the phase 3 M-STAR clinical trial (NCT03952806) for the treatment of patients with multiple system atrophy (MSA).

 The randomized, double-blind, placebo-controlled, parallel group study began enrollment in July 2019 and is expected to reach its estimated total enrollment of 250 subjects, age 40 to 80 years, by the fourth quarter of 2020, with a primary study completion date of October 2021 (

Verdiperstat is a unique orally administered MPO inhibitor. The MPO enzyme acts as a key driver of oxidative stress and inflammation that underlies neurodegeneration and is abundant in activated microglial cells found in the brains of patients with MSA.

“The goal of the M-STAR study is to determine whether verdiperstat can reduce MSA disease progression, for both subtypes of MSA: parkinsonism and cerebellar. The primary efficacy end point is the change from baseline to week 48 in verdiperstat- versus placebo-treated subjects on a modified UMSARS [Unified MSA Rating Scale] score, which consists of a subset of items from the UMSARS Part I (Activities of Daily Living) and Part II (Motor Exam) that directly assess clinically meaningful change in patients’ ability to function,” Irfan Qureshi, MD, vice president of neurology at Biohaven, told 

Patients eligible for inclusion in the trial must have a diagnosis of probable or possible MSA, be able to ambulate without the assistance of another individual, and have an anticipated survival of at least 3 years at the time of screening. Those who have any neurological disorders other than MSA or any condition that may interfere with the subject’s ability to adhere to study instructions are excluded from the study. Secondary outcome measures include change from baseline to week 48 on Clinical Global Impression of Improvement score as well as impact of verdiperstat on quality of life, measured by a change from baseline in the motor and nonmotor subscales of the MSA Quality of Life scale at week 48.

The history of verdiperstat has been well documented with the FDA as it has climbed through the clinical pipeline. In February 2019, the agent received orphan drug designation after completing its phase 1 and 2a clinical trials.

The 12-week, randomized, double-blind, placebo-controlled phase 2a study (NCT02388295) was designed to evaluate the safety and tolerability of 2 doses of verdiperstat in patients with MSA. Fifty-nine patients were randomly assigned to receive either verdiperstat 300 mg or 600 mg twice daily (n = 19, n = 20, respectively) or placebo (n = 20).

Results indicated that the drug significantly decreased MPO activity in plasma, with favorable trends over 12 weeks on UMSARS. Over the treatment period, patients in the placebo group experienced greater worsening on the UMSARS, with a 4.6-point decline (standard error [SE], 1.1; 90% CI, 2.5-6.8) compared with 3.7- (SE, 1.2; 90% CI, 1.4-5.7) and 2.6-point (SE, 1.4; 90% CI, 0.5-4.7) declines in patients treated with verdiperstat 300 mg or 600 mg, respectively.

 The investigators also noted positive effects on outcome measures, such as the Composite Autonomic Symptom Score and MSA Quality of Life scale.

This past March, the FDA granted the drug fast track designation for the treatment of MSA.

“Biohaven sees the potential for verdiperstat to be the first disease-modifying treatment for MSA. No disease-modifying treatments currently exist for MSA; only symptomatic and palliative therapies are available,” Qureshi said.

Biohaven is expected to submit a new drug application to the FDA in late 2021 or early 2022 if the M-STAR study demonstrates that verdiperstat is effective against MSA.

1. Biohaven enrolls first patient in phase 3 clinical trial of verdiperstat, oral myeloperoxidase inhibitor, for the treatment of multiple system atrophy. News release. Biohaven Pharmaceutical. July 31, 2019. Accessed May 6, 2020. https://www.biohavenpharma.com/investors/news-events/press-releases/07-31-2019 

2. Biohaven’s verdiperstat receives orphan drug designation from FDA for multiple system atrophy. News release. Biohaven Pharmaceutical. February 19, 2019. Accessed May 6, 2020. https://www.biohavenpharma.com/investors/news-events/press-releases/02-19-2019 

3. Biohaven’s verdiperstat receives fast track designation for the treatment of multiple system atrophy. News release. Biohaven Pharmaceutical. March 18, 2020. Accessed May 6, 2020. https://www.prnewswire.com/news-releases/biohavens-verdiperstat-receives-fast-track-designation-for-the-treatment-of-multiple-system-atrophy-301025830.html 

Clinical Trial in Progress

Biohaven’s verdiperstat has entered a phase 3 trial for the treatment of multiple system atrophy, with a new drug application submission on the agenda for late 2021.

Verdiperstat Aims to Be First DMT for Multiple System Atrophy

Bruton Tyrosine Kinase (BTK), a Tec family nonreceptor tyrosine kinase

 critical for the development of B cells and several other hematopoietic lineages

 (except for T cells, plasma cells, and natural killer cells

 BTK informs immune responses by acting as an early downstream amplification enzyme of the B-cell antigen receptor (BCR)

 BTK signaling influences antigen presentation on B cells

 and is essential to the production of antibodies, proinflammatory cytokines and chemokines, and cell adhesion molecules.

Through these mechanisms, BTK helps transmit the signals that allow immune cells to respond to foreign antigens by targeting the cells presenting them for destruction.

Harmful consequences arise when the immune system mistakes self-proteins as foreign antigens, with BTK promoting autoantibody secretion by autoreactive B cells.

 Autoimmune diseases such as multiple sclerosis (MS)

 result from this dysregulated production of autoantibodies, which leads to destruction of normal tissue.

 Malfunctioning BTK mutants have been linked to increased disease susceptibility, correlating with diminished numbers of mature B cells and immunoglobulin isotypes.

 BTK therefore serves as an important target for therapeutic agents that modulate innate immunity.

Interactions between T cells, B cells, and myeloid cells promote MS pathology,

 and BTK is a component of signaling events with a critical role in regulating hematopoietic cell circulation.

 MS is a chronic, inflammatory, demyelinating disease of the central nervous system

 and is the most common, nontraumatic, disabling neurological autoimmune disease, with approximately 2.3 million cases diagnosed worldwide.

 B cells contribute to MS pathogenesis as a result of being skewed toward a proinflammatory profile involving antibody production, antigen presentation, T-cell stimulation, production of proinflammatory cytokines, formation of ectopic meningeal germinal centers, and deposition of oligoclonal bands of immunoglobulin in areas of active demyelination.

 Briefly, the body’s immune system begins to attack myelin, a protective sheath covering nerve fibers. The nervous system is consequently “short-circuited,” potentially permanently.

Treatments for MS aim to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability.

 The most well-studied type of therapy targeting B cells consists of monoclonal antibodies (mAbs) that deplete B cells through mechanisms of antibody-dependent cellular cytotoxicity and apoptosis.

 Rituximab, for example, a mAb targeting the B-cell antigen CD20, depletes B cells and reduces T cells in the cerebrospinal fluid. However, rituximab is incapable of penetrating the blood-brain barrier (BBB) or lymphoid organs and is unsuccessful in slowing disease progression.

 MS treatment efforts have turned to BTK inhibitors (

The ideal BTK inhibitor would be a rapidly reversible, BBB-penetrant, highly selective, modulatory approach to target B-cell activation without widespread depletion of B cells.

 Rather, the B-cell response to BCR stimuli is lowered, tolerogenic B cells are maintained, and antigen-mediated proinflammatory activation is neutralized.

 BTK is already a target in treatment of lymphoma, leukemia, and rheumatoid arthritis via the prominent BTK inhibitor ibrutinib. However, ibrutinib exhibits off-target kinase-inhibitory effects and is associated with immunosuppression and bleeding complications.

 BTK inhibitors in development for chronic administration thus have more refined pharmacologic profiles, including high BTK selectivity and moderate clearance.

Three BTK inhibitors are in clinical development for treatment of MS: Merck KGaA’s M2951 (evobrutinib), Principia Biopharma and Sanofi’s PRN2246 (SAR442168), and Biogen’s BIIB091. Evobrutinib is a potent, obligate-type covalent, selective, BBB-penetrant BTK inhibitor for the treatment of autoimmune diseases, including MS.

 Evobrutinib’s constrained acrylamide warhead confers BTK selectivity, biochemical and cellular potency, and plasma stability.

 Evobrutinib is the subject of an ongoing phase 2 trial which reached its primary completion date in January 2018 (NCT02975349).

 An analysis of that data published in the 

 in 2019 compared 3 doses of evobrutinib (25 mg once daily, 75 mg once daily, 75 mg twice daily) with placebo or dimethyl fumarate (Tecfidera; Biogen) in patients with relapsing MS.

 The primary end point was total number of T1 gadolinium-enhancing lesions at 12, 16, 20, and 24 weeks. Secondary end points included annualized relapse rate and change from baseline on the Expanded Disability Status Scale.

 Among the 267 patients randomized, those who received 75 mg evobrutinib once daily had significantly fewer gadolinium-enhancing lesions at weeks 12 through 24 compared with placebo; however, covalent binding combined with a high daily dose was found to induce liver injury.

 Additional statistical analysis revealed no dose response nor any effect of evobrutinib on annualized relapse rate or disability progression.

SAR442168 is also a potent, covalent, selective, BBB-penetrant BTK inhibitor that has demonstrated a dose-dependent protection from MS induction alongside no serious medication-related adverse events in participants (with 7.5- to 120.0-mg daily doses) in a phase 1 trial (NCT04171310).

 Encouraging results from the phase 2B trial

 reported in April 2020 revealed an 85% relative reduction in new gadolinium-enhancing lesions in the 60-mg group with a mean number of new lesions of 0.13 (

 = .03) compared with 0.76 in the 30-mg group, 0.77 in the 15-mg group, 1.39 in the 5-mg group, and 1.03 with placebo.

 In addition, patients in the 60-mg group demonstrated an 89% relative reduction in new or enlarging T2 hyperintense lesions (

 <.0001) at 12 weeks, with a mean number of lesions of 0.23 compared with 1.30 in the 30-mg group, 1.32 in the 15-mg group, 1.90 in the 5-mg group, and 2.12 in the placebo group; however, the trial did not consider disease development readouts such as relapse rates and MS progression.

 Based on the results, manufacturer Sanofi plans to initiate 4 phase 3 pivotal trials.

Biogen’s BIIB091 is still in early stages of development, with its ongoing phase 1 clinical trial (NCT03943056) expected to reach primary completion sometime in spring 2020.

Although early data appear promising, comprehensive trials with stringent statistical analysis are required to confirm the efficacy and safety of BTK inhibitor use for treatment of MS.

1. Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal. 2010;22(8):1175-1184. doi:10.1016/j.cellsig.2010.03.001 

2. Mangla A, Khare A, Vineeth V, et al. Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses. Blood. 2004;104(4):1191-1197. doi:10.1182/blood-2004-01-0207 

3. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72(2):279-290. doi:10.1016/0092-8674(93)90667-F 

4. Tai Y-T, Chang BY, Kong S-Y, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012;120(9):1877-1887. doi:10.1182/blood-2011-12-396853 

5. Rawlings DJ, Scharenberg AM, Park H, et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science. 1996;271(5250):822-825. doi:10.1126/science.271.5250.822 

6. Tsukada S, Simon MI, Witte ON, Katz A. Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. Proc Natl Acad Sci U S A. 1994;91(23):11256-11260. 

7. Lowry WE, Huang X-Y. G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton’s agammaglobulinemia tyrosine kinase. J Biol Chem. 2002;277(2):1488-1492. doi:10.1074/jbc.M110390200 

8. Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL. The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol. 2016;12(7):763-773. doi:10.1586/1744666X.2016.1152888 

9. Whang JA, Chang BY. Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today. 2014;19(8):1200-1204. doi:10.1016/j.drudis.2014.03.028 

10.  Gabhann JN, Hams E, Smith S, et al. BTK regulates macrophage polarization in response to lipopolysaccharide. PLOS One. 2014;9(1):e85834. doi:10.1371/journal.pone.0085834 

11.  Schmidt U, Boucheron N, Unger B, Ellmeier W. The role of Tec family kinases in myeloid cells. Int Arch Allergy Immunol. 2004;134(1):65-78. doi:10.1159/000078339 

12. Menzfeld C, John M, Rossum D van, et al. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia. 2015;63(6):1083-1099. doi:10.1002/glia.22803 

13. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34-47. doi:10.1038/nri2206 

14. Engel P, Gómez-Puerta JA, Ramos-Casals M, Lozano F, Bosch X. Therapeutic targeting of B cells for rheumatic autoimmune diseases. Pharmacol Rev. 2011;63(1):127-156. doi:10.1124/pr.109.002006 

15.Satterthwaite AB. Bruton’s tyrosine kinase, a component of B cell signaling pathways, has multiple roles in the pathogenesis of lupus. Front Immunol. 2018;8. doi:10.3389/fimmu.2017.01986 

16. Mishra MK, Yong VW. Myeloid cells — targets of medication in multiple sclerosis. Nat Rev Neurol. 2016;12(9):539-551. doi:10.1038/nrneurol.2016.110 

17. Rankin AL, Seth N, Keegan S, et al. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. J Immunol. 2013;191(9):4540-4550. doi:10.4049/jimmunol.1301553 

18. Anderson JS, Teutsch M, Dong Z, Wortis HH. An essential role for Bruton’s [corrected] tyrosine kinase in the regulation of B-cell apoptosis. Proc Natl Acad Sci U S A. 1996;93(20):10966-10971. doi:10.1073/pnas.93.20.10966 

19. Solvason N, Wu WW, Kabra N, et al. Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells. J Exp Med. 1998;187(7):1081-1091. doi:10.1084/jem.187.7.1081 

20. Sic H, Kraus H, Madl J, et al. Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis. J Allergy Clin Immunol. 2014;134(2):420-428. doi:10.1016/j.jaci.2014.01.037 

21. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23(1):683-747. doi:10.1146/annurev.immunol.23.021704.115707 

22. Filippi M, Bar-or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. doi:10.1038/s41572-018-0041-4 

23. Milo R. Therapies for multiple sclerosis targeting B cells. Croat Med J. 2019;60(2):87-98. 

24. Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H. Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann Neurol. 1998;43(4):465-471. doi:10.1002/ana.410430409 

25. Miyazaki Y, Niino M. Molecular targeted therapy against B cells in multiple sclerosis. Clin Exp Neuroimmunol. 2014;5(s1):16-27. doi:10.1111/cen3.12160 

26. Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CCA, Oksenberg JR. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol. 1999;163(9):5133-5144. 

27. Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609. doi:10.1007/s40263-013-0080-z 

28. Voge NV, Alvarez E. Monoclonal antibodies in multiple sclerosis: present and future. Biomedicines. 2019;7(1). doi:10.3390/biomedicines7010020 

29. Caldwell RD, Qiu H, Askew BC, et al. Discovery of evobrutinib: an oral, potent, and highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of immunological diseases. J Med Chem. 2019;62(17):7643-7655. doi:10.1021/acs.jmedchem.9b00794 

30. Nyhoff LE, Clark ES, Barron BL, Bonami RH, Khan WN, Kendall PL. Bruton’s tyrosine kinase is not essential for B cell survival beyond early developmental stages. J Immunol Baltim Md 1950. 2018;200(7):2352-2361. doi:10.4049/jimmunol.1701489 

31. Häusser-Kinzel S, Weber MS. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.00201 

32. Bitar C, Sadeghian A, Sullivan L, Murina A. Ibrutinib-associated pityriasis rosea-like rash. JAAD Case Rep. 2018;4(1):55-57. doi:10.1016/j.jdcr.2017.06.035 

33. de Weerdt I, Koopmans SM, Kater AP, van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017;102(10):1629-1639. doi:10.3324/haematol.2017.164103 

34. McMullen JR, Boey EJH, Ooi JYY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829-3830. doi:10.1182/blood-2014-10-604272 

35. Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80. doi:10.1186/s13045-016-0313-y 

36. A study of efficacy and safety of M2951 in subjects with relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/show/NCT02975349 

37. Montalban X, Arnold DL, Weber MS, et al; Evobrutinib phase 2 study group. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. 2019;380(25):2406-2417. doi:10.1056/NEJMoa1901981 

38. Study of excretion balance and pharmacokinetics of [14C]-SAR442168 in healthy male subjects. https://clinicaltrials.gov/ct2/show/NCT04171310 

39. Dose-finding study for SAR442168 in relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/show/NCT03889639 

40. Sanofi brain-penetrant BTK inhibitor significantly reduced disease activity in Phase 2 trial in relapsing multiple sclerosis. News release. Sanofi. April 23, 2020. Accessed May 26, 2020. https://sanofi.com/en/media-room/press-releases/2020/2020-04-23-07-00-00 

41. A safety, tolerability, pharmacokinetic, and pharmacodynamic study of BIIB091, a Bruton's tyrosine kinase (BTK) inhibitor, in healthy adult participants. 

https://clinicaltrials.gov/ct2/show/NCT03943056  

NeuroPathways

An in-depth look into the expanding landscape of multiple sclerosis treatments that target bruton tyrosine kinase. 

Targeting Bruton Tyrosine Kinase for Multiple Sclerosis Treatment

Although the number approved treatments for narcolepsy has increased, challenges remain in addressing the underlying causes of the disease, as well as in identifying individuals with the condition. When left untreated, narcolepsy can interfere with psychological, social, and cognitive functions, and one needs, the use of new therapeutic options, and the latest clinical trials to provide practical perspective on how recent data might apply to clinical practice.

® Peer Exchange, Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore Medical Center and professor of neurology at Albert Einstein College of Medicine in Bronx, New York, led a panel of sleep experts in a discussion about these unmet needs, the use of new therapeutic options, and the latest clinical trials to provide practical perspective on how recent data might apply to clinical practice.

For Eveline Honig, MD, MPH, executive director of the Narcolepsy Network, patients have always complained about the lack of medications available to them, and rightfully so, as they and their physicians have fewer than 10 options from which to choose. 

“It takes forever to get a medication approved,” she said. “That’s also why we’ve been going to the FDA and requesting more medications. That’s really very important so people have a choice; not everything works for everybody. People need to experiment. It takes a while. It’s good when there is more of a choice. I think that’s really important.”

Russell Rosenberg, PhD, DABSM, CEO and chief science officer at NeuroTrials Research, echoed the sentiment, explaining that quite a long period passed between the FDA’s approval of the modafinils in the late 1990s and some of the new agents approved in 2019. “I think that physicians need to understand that it’s not stopping here. We still need more tools,” he said.

Additionally, a number of challenges exist in the treatment of symptoms beyond sleepiness. Kiran Maski, MD, MPH, assistant professor of neurology at Harvard Medical School and director of the Sleep Clinic at Boston Children’s Hospital in Massachusetts, described the nonspecific symptoms as her biggest challenge. “It’s the fatigue, what’s described as brain fog. This difficulty thinking, conveying thoughts, or speaking—the symptoms that are not studied or not responsive to medications are really functionally limiting to patients,” she said.

Rosenberg noted that his experience in research has been similar, with patients explaining that medication will help them stay awake but rarely seem to provide mental clarity at the same time. He said that for many of these patients, simply staying awake is not enough to solve their problems.

“I think some of the newer drugs are a bit better than the older ones in that regard,” Thorpy added. “Very rarely will you hear a patient who is on sodium oxybate say, ‘This has dramatically changed my life. I really feel more normal.’ Unfortunately, it doesn’t happen enough. But it does happen occasionally.”

The older agents—particularly the amphetamines and methylphenidate&mdash;appear to have their faults, as well, Thorpy pointed out, as many help patients stay awake only to an extent. He explained that if a patient with narcolepsy, even one on a high-dose therapeutic, entered a darkened room and turned out the lights, they would be asleep right away.

“Patients are able to do things better with these medications, but there’s still that background pressure for sleep, even though they are seemingly more awake,” Thorpy said. “Hopefully, in the future, the drugs will be more effective at actually eliminating that pressure for sleep that’s in the background.”

Despite not having a completely unique mechanism of action, Jazz Pharmaceuticals’ recently approved solriamfetol (Sunosi) offers another interesting approach to narcolepsy, according to Alon J. Avidan, MD, MPH, professor in the Department of Neurology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA) and director of the UCLA Sleep Disorders Center.

The dual-acting dopamine and norepinephrine reuptake inhibitor was approved for the treatment of excessive daytime sleepiness in both obstructive sleep apnea (OSA) and narcolepsy in March 2019. Its safety and efficacy were established through the TONES clinical trial program, whose results showed statistically significant changes in sleepiness and wakefulness in those with narcolepsy.

“It targets the structures in the brain that are promoting wakefulness,” Avidan explained. “So in my mind, it has the unique ability to promote a level of alertness that you would see with the psychostimulants but without the sympathomimetic adverse effects.”

Rosenberg and Thorpy noted that the performance of solriamfetol in clinical trials was impressive on self-reported measures like the Epworth Sleepiness Scale, as well as the Maintenance of Wakefulness Test, which Rosenberg described as the “flip side of the Multiple Sleep Latency Test. We put patients in a dimly lit room, a boring situation, and ask them to try to stay awake. Patients who are pathologically sleepy have great difficulty staying alert. And this drug did show pretty impressive results on those tests,” Rosenberg said. Additionally, he noted that with the need to manage poly- pharmacy in many of these patients, solriamfetol presents a good option for the physician’s toolbox.

Although the Jazz product is not indicated for use in children, Maski noted that she has had some experience with it and that its long-acting nature is an advantage for patients.

In August 2019, another long-acting agent, Harmony Biosciences’ selective histamine 3 receptor antagonist/inverse agonist pitolisant (Wakix), received FDA approval for the treatment of excessive daytime sleepiness in adults with narcolepsy. Additionally, it was the first treatment for narcolepsy to not be scheduled as a controlled substance by the Drug Enforcement Administration.

“It’s nice because this is the only wakefulness drug that is nonscheduled, so it’s easier for physicians to prescribe. It may be easier to get multiple prescriptions, or [at least] enough so the patient doesn’t have to come back every month to get a new prescription,” Rosenberg said. “But it’s not without its potential adverse effects and issues that physicians need to be cautious about. Similar to the modafinils, it can reduce the efficacy of oral contraceptives. But it’s certainly a nice new tool for physicians to have in their toolbox for treating narcolepsy.”

Pitolisant also has a unique mechanism of action as a selective histamine 3 receptor antagonist/inverse agonist, which separates it from what Rosenberg described as the “usual suspects”: dopamine, norepinephrine, acetylcholine, and serotonin.

“This is the only drug that does actually have an impact on increasing histamine in the brain, therefore causing wakefulness. Others may be coming down the line after pitolisant, but this is currently the only drug to address that mechanism of action,” Rosenberg said.

The therapy showed success in its clinical development for excessive daytime sleepiness associated with narcolepsy based on improvements in Epworth Sleepiness Scale scores. It has been additionally approved for the treatment of cataplexy in Europe, although it has not received that indication in the United States. Rosenberg noted that it does appear to have a positive impact on reducing cataplexy, and some sleep specialists have begun using it off label for that particular purpose.

“I should also mention that this is a once-a-day dosing. There’s no need to give a second dose,” Rosenberg said. “We participated in an early-access program for this drug and found that it seemed to carry most patients through the late afternoon, in terms of keeping them alert and awake. It didn’t run out of steam by lunch- time. It just kept going. One of the adverse effects of any poten- tial wake-promoting drug is causing insomnia in patients. We did see a little bit of that, but I don’t think that’s unique to pitolisant. I think you have to be careful and make sure patients are taking the dose right when they wake up in the morning, especially if they’re having any difficulty falling asleep at night.”

In addition to excessive daytime sleepiness, another area of narcolepsy treatment that has long faced challenges is the treat- ment of pediatric patients, which has been particularly limited by a lack of clinical trials and thus a reliance on case-based reports and observational data. Pitolisant, however, is being assessed in chil- dren in a clinical trial based in Europe.

In this Peer Exchange, sleep experts provide insight into the latest narcolepsy treatments and areas that require further research.

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