Possibly the most well-known impact of epilepsy involves the symptom of seizures, which have a strong impact on the life of individuals affected. Despite the available therapies, many patients receiving treatment continue to experience seizures and/or other adverse effects, and there remains an unmet need for new options. One antiepileptic drug being investigated as an adjunct therapy is cenobamate. 

Because the drug candidate has shown a competitive efficacy and safety profile compared with existing drugs in recent partial focal epilepsy studies, a phase 3 study was initiated to evaluate the safety and efficacy of cenobamate’s use in adults with primary generalized tonic-clonic seizures. 

“Epilepsy affects millions of people worldwide and is a condition with substantial unmet need,” Allison Mann, MD, the executive director of Clinical Development in Neurology at SK Life Science, told NeurologyLive™. “Studies have estimated that 30% or more of epilepsy patients remain refractory to treatment. Cenobamate is a new chemical entity that has demonstrated strong efficacy in partial-onset seizure studies with respect to seizure freedom. Therefore, we are hopeful and excited that cenobamate will help address this unmet need.” 

The randomized, double-blind, placebo-controlled phase 3 trial is designed to study the efficacy safety of cenobamate as adjunctive therapy in approximately 150 adults with idiopathic generalized epilepsy across multiple sites in the United States and Europe. Subjects will be randomized 1:1 to receive either cenobamate or placebo (see 

Eligible participants must have a clinical diagnosis of primary generalized tonic-clonic seizures, with or without other subtypes of generalized seizures, in the setting of idiopathic generalized epilepsy; experience at least 3 primary generalized tonic-clonic seizures during the 12-week prerandomization period; have had a routine electroencephalogram (EEG) within 5 years prior to baseline or during the prerandomization period, with EEG features consistent with idiopathic generalized epilepsy; have had computed tomography or magnetic resonance imaging within 10 years prior to baseline or during prerandomization that ruled out a progressive cause of epilepsy; and be currently receiving 1 to 3 concomitant antiepileptic drugs with fixed dosing regimens for at least 30 days prior to baseline. 

The study will have 3 periods: prerandomization, when a baseline seizure frequency is established; treatment; and follow-up. The treatment period is 22 weeks and includes a 10-week titration phase, during which subjects will be titrated with cenobamate 12.5 mg, followed by 25, 50, 100, and 150 mg every 2 weeks until a target dose of 200 mg is reached; during the subsequent 12 weeks of maintenance, participants will receive 200 mg of the drug. They are to take the once-daily dose at approximately the same time in the morning with or without food; if tolerability arises, the dose can be switched to evenings. There is also a one-time option to down-titrate; however, if tolerability issues persist, participation may be discontinued. 

The primary study objective is to evaluate efficacy of adjunctive cenobamate at 200 mg compared with placebo. Secondary efficacy objectives are to evaluate safety and tolerability, as well as the level of seizure freedom—once participants reach a steady dose&mdash;and then explore other seizure types and the pharmacokinetics of cenobamate. 

The primary efficacy end point is the change from baseline in primary generalized tonic-clonic seizures for 28 days during the maintenance phase. Participants will record seizure type and frequency in a daily diary. 

Upon completion of the study, eligible participants can enroll in an open-label safety study. Those who discontinue or choose not to participate will complete a 3-week follow-up period, during which they will either come off cenobamate directly or receive a 1-week down-titration and then return for a final follow-up. 

According to Mann, cenobamate’s safety profile is very similar to that of other antiepileptic drugs on the market. 

This is the first clinical trial in primary generalized tonic-clonic epilepsy in humans, Mann said. However, several preclinical studies of cenobamate show broad-spectrum activity in animal models, which is 1 reason researchers moved forward with this indication. 

“Cenobamate has a unique chemical structure, preferentially inhibits the persistent sodium current, to a lesser extent is a modulator of GABAergic inhibition and to date has shown good efficacy and tolerability in clinical studies,” Mann said. “We want to see the overall options for people with epilepsy to improve, and we’re hoping that our drug, with its mechanism of action and with its good results in partial-onset seizures, will be able to advance those goals.” 

The trial has recently been activated and is expected to be completed in November 2021 (NCT03678753). 

Articles

Clinical Trial in Progress

Because the drug candidate has shown a competitive efficacy and safety profile compared with existing drugs in recent partial focal epilepsy studies, a phase 3 study was initiated.

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

Gene therapy has generated excitement as a treatment or even a potential cure for inherited diseases. Among them: Duchenne muscular dystrophy (DMD), a rare neuromuscular disorder characterized by progressive muscle weakness and degeneration. 

The most common of muscular dystrophies, DMD affects 1 in 3500 to 5000 live newborn boys, has an early childhood onset, and the most severe clinical symptoms.

 Though DMD is predominant in males, a minority of female carriers are symptomatic, with high variability in age at onset and disease severity.

Early signs of DMD include delayed motor development. The clinical signs of weakness appear between 2 and 3 years of age and usually begin in the proximal muscles before the distal limb muscles.

 Affected children may have a waddling gait, enlarged calves, and difficulty walking. Other features include cardiomyopathy, respiratory, and orthopedic complications. Varying degrees of cognitive impairment and developmental delay may be present. Patients with DMD lose ambulation by the age of 12 and die in their late teens or 20s from respiratory and cardiac complications.

Given the very limited number of DMD treatments available, any developments in the pipeline are welcomed. Because DMD is a genetic disease, the most promising advancements for the condition involve gene therapies. 

DMD is an X-lined disorder caused by recessive mutations in the DMD gene, leading to loss of the protein dystrophin. DMD is the largest known human gene, spanning 2.3 Mb of genomic DNA, and consists of 79 exons.

 About 68% of DMD mutations are from deletions of 1 or more exons; approximately 11%, from duplications; and 20%, from small mutations.

 Becker muscular dystrophy (BMD), caused by DMD mutations that lead to a reduced amount or size of the dystrophin protein, has a later onset and milder symptoms than DMD.

Dystrophin is a 427 kDa cytoplasmic protein, located primarily in skeletal and cardiac muscles. This vital component of the dystrophin-associated glycoprotein complex (DGC) connects the internal cytoskeleton of the muscle fibers to the extracellular matrix. The DGC includes the dystroglycans, sarcoglycans, integrins, and caveolin; mutations in any of these components lead to muscular dystrophies.

 Dystrophin provides structural stability to the sarcolemma of skeletal muscle, protecting it from contraction-induced mechanical injury, and acts as a scaffold for various signaling pathways.

 In the absence of dystrophin, the DGC is destabilized, leading to progressive muscle fiber damage and premature death.

 Activation of aberrant intracellular signaling pathways from loss of dystrophin or DGC components contributes to the pathogenesis.

No known cure for DMD exists at present, but current treatments help control symptoms. FDA-approved therapies include deflazacort (Emflaza; PTC Therapeutics) and eteplirsen (Exondys 51; Sarepta Therapeutics). Ataluren (Translarna; PTC Therapeutics) is approved by the European Medicines Agency for eligible patients with DMD but did not receive FDA approval. 

Treatment with the prednisone or deflazacort is recommended for children with DMD aged 4 years and older. The anti-inflammatory and immunosuppressive properties of these glucocorticoids may slow the decline of muscle strength and function and possibly the onset of cardiomyopathy in patients with DMD. 

A 52-week phase 3 study involving 196 boys with DMD compared the effectiveness of daily doses of either deflazacort (1 arm used 0.9 mg/kg; another, 1.2 mg/kg) or prednisone (0.75 mg/kg daily) against placebo. At 12 weeks of this 4-arm study, both prednisone and deflazacort improved muscle function compared with placebo, but deflazacort was associated with less weight gain than prednisone.13 Increased muscle strength persisted through week 52. Common adverse events (AEs) in all treatment groups were cushingoid appearance, erythema, hirsutism, weight gain, headache, and nasopharyngitis. Approved in February 2017 to treat patients aged 5 years and older, deflazacort is the first FDA-approved corticosteroid for DMD.

Another approach is the injection of antisense oligonucleotides such as eteplirsen, which excise selected exons (at or near a frameshift or nonsense mutation) during premessenger RNA splicing, thus correcting the disrupted reading frame and producing shortened functional dystrophin. 

About 13% of patients with DMD have mutations amenable to skipping exon 51.

 Treating these patients with the exon 51—skipping drug eteplirsen leads to increased dystrophin in muscle.

 Twelve DMD patients aged 7 to 13 years with confirmed exon 51— amenable mutations were treated with eteplirsen (30 or 50 mg/kg a week) or placebo for 24 weeks. The placebo group was switched to 30 or 50 mg/kg eteplirsen during the subsequent 24-week extension phase. At week 48, eteplirsen increased dystrophin expression by 52% and 43% in the 30 and 50 mg/kg cohorts, respectively, with no AEs.

 This study led to accelerated FDA approval of eteplirsen in September 2016 for patients with a confirmed exon 51—amenable DMD gene mutation.

The approval was contentious due to the study’s methodological limitations, including the small number of patients, reliance on dystrophin in muscle biopsy for outcome, and speculation around whether the level of new dystrophin expression was sufficient to produce a clinical benefit.

 An open-label extension phase with 3 years of follow-up showed increased walking performance with eteplirsen compared with historical controls.19 A phase 3 trial (NCT02255552) is underway to determine whether eteplirsen improves motor function in patients compared with an untreated control group. 

Two other exon-skipping drugs, SRP-4045 and SRP-4053 for patients with DMD mutations amenable to exon 45 or exon 53 skipping, respectively, are being evaluated in a placebo-controlled phase 3 trial (NCT02500381). 

Another agent that showed promise, ataluren, failed to receive FDA approval after review of data, including the results of 2 clinical trials (NCT00847379 and NCT01826487).

 The advisory panel concluded that additional well-controlled studies were needed to provide substantial evidence of ataluren’s effectiveness as therapy.

The small-molecule compound was developed for the treatment of patients with DMD who harbor stop mutations in the DMD gene. Ataluren allows ribosomal read-through of the stop mutations, bypassing the mutation so production of functional dystrophin continues. 

More recent preliminary data from the first international drug registry for patients with DMD showed long-term clinical benefit with ataluren compared with published natural history. Of 216 patients with DMD caused by a nonsense mutation and a median age of 9.8 years, those on ataluren had loss of ambulation at a median age of 16.5 years—up to 5 years later than seen with natural disease progression in untreated children.

PTC Therapeutics is recruiting patients for a 144-week placebo-controlled phase 3 trial to characterize the long-term effects of ataluren-mediated dystrophin restoration on disease progression, with expected completion by the end of 2021 (NCT03179631). 

Considerable progress has been made in gene therapies for DMD.

 Advantages of this approach include longer duration per dose and the potential to cover more patients with a single agent. Disadvantages include the possibility of immune reactions and the inability to incorporate the large full-length dystrophin into a vector.

 Most gene therapy trials using adeno-associated viral (AAV) vectors have been safety studies with direct muscle injections.

 Targeting the cardiac and diaphragm muscles is critical for patients with DMD, who typically die from cardiorespiratory complications, but these muscles are not easily accessible for direct intramuscular delivery. The use of systemic AAV delivery and muscle-specific promoters to target all the muscles, along with shortened dystrophin constructs (mini- or microdystrophin) to enable packaging into the vector, may solve these problems.

Current gene therapy trials for DMD employ either of 2 main strategies: restoring dystrophin expression or increasing the expression of a surrogate protein that compensates for dystrophin loss. 

For restoring dystrophin expression, preclinical data from murine and canine DMD models support the use of systemic AAV microdystrophin gene therapy to treat DMD.27 Three clinical trials using this approach were recently initiated. 

Jerry Mendell, MD, of Nationwide Children’s Hospital in Columbus, Ohio, conducted a phase 1/2a gene therapy clinical trial (NCT03375164) of the investigative therapy rAAVrh74.MHCK7 micro-dystrophin. AAV micro-dystrophin was infused (2 x 1014 vector genomes/kg in 10 mL/kg) via peripheral arm vein to target all muscles in the body. MHCK7 promoter was chosen based on preclinical data showing that it drives robust microdystrophin expression in the heart. In June 2018, Sarepta Therapeutics announced positive interim results.28 Preliminary results from the first 3 children dosed showed 76.2% microdystrophin expression in day 90 muscle biopsies, 87% decrease in serum creatine kinase (a biomarker for muscle damage) at day 60, and no serious AEs.

“I have been waiting my entire 49-year career to find a therapy that dramatically reduces CK levels and creates significant levels of dystrophin,” Mendell said. “Although the data are early and preliminary, these results, if they persist and are confirmed in additional patients, will represent an unprecedented advancement in the treatment of DMD.” 

The second study, a phase 1b trial (NCT03362502) by Pfizer, is evaluating the safety and tolerability of PF-06939926 in patients with DMD. In March 2018, the first patient received a single intravenous infusion of PF-06939926.30 Early data are expected in the first half of 2019. 

SGT-001 (AAV9 micro-dystrophin) is also being investigated. In a phase 1/2 study (NCT03368742) by Solid Biosciences, the drug’s safety, tolerability and efficacy will be evaluated in children and adolescents with DMD. Initial data from a prespecified interim analysis are expected in the second half of 2019.

Notable differences between these 3 trials include the AAV serotype and dose, promoter, micro-dystrophin configuration, patient age, and gene mutation. The Sarepta trial involves AAV-rh74, whereas AAV-9 is used in the Pfizer and Solid trials. All 3 trials include a muscle-specific promoter: MHCK7 (Sarepta), MCK (Pfizer), or CK8 (Solid). The Pfizer and Solid trials are dose-escalation studies and open to patients with all DMD mutations, whereas the Sarepta trial is a single-dose study and just for patients with frameshift or nonsense mutation between exons 18 to 58.

Increasing the expression of surrogate genes to substitute for the loss of dystrophin can potentially treat DMD regardless of the type or location of mutation and may have utility in other muscular dystrophies. Two notable clinical trials using surrogate gene therapy have been recently launched. 

In an ongoing phase 1/2a clinical trial (NCT03333590) by Sarepta, the gene therapy rAAVrh74.MCK.GALGT2 will be delivered via the femoral artery to the muscles of both legs of patients with DMD. The primary objective is to assess the safety of intravascular administration of AAVrh74 carrying the GALGT2 gene under the control of muscle-specific MCK promoter. The gene encodes the protein β-1,4-N-acetylgalactosaminyltransferase (GalNAc transferase) which can cause glycosylation of specific proteins including α-dystroglycan, a component of the DGC. In the mdx mouse model of DMD, viral transfer of GALGT2 results in expression of GalNAc transferase across the entire muscle membrane, along with upregulation of proteins such as utrophin, and functional improvement equivalent to that seen with microdystrophin.

Finally, rAAV1.CMV.huFollistatin344 (follistatin) is a secretory  protein and potent inhibitor of the myostatin signaling pathway.33 Preclinical studies with intramuscular delivery of the FS344 isoform demonstrated safety and efficacy in enhancing muscle mass.

 A phase 1/2a trial in patients with BMD (NCT01519349) showed that intramuscular delivery of FS344 into the quadriceps improved walking performance in 4 of the 6 patients without AEs.

 This prompted the initiation of a similar phase 1/2 trial for patients with DMD aged 7 years and older (NCT02354781). The vector will be distributed more widely than in the BMD study via multiple injections to gluteal muscles, quadriceps, and tibialis anterior muscles. 

1. Learning about Duchenne muscular dystrophy. National Institutes of Health National Human Genome Research Institute website. genome.gov/19518854. Updated April 18, 2013. Accessed November 6, 2018. 

2. Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71(3):304-313.

3. Soltanzadeh P, Friez MJ, Dunn D, et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord. 2010;20(8):499-504.

4. Gardner-Medwin D. Clinical features and classification of the muscular dystrophies. Br Med Bull. 1980;36(2):109-116.

5. Bach JR, O’Brien J, Krotenberg, R, et al. Management of

 respiratory failure in Duchenne muscular dystrophy. Muscle Nerve. 1987;10(2):177-182. 

6. Ahn AH, Kunkel LM. The structural and functional diversity of dystrophin. Nat Genet. 1993;3:283—291.

7. Bladen CL, Salgado D, Monges S, et al. The TREAT-NMD DMD global database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. 2015;36(4):395-402.

8. Guiraud S, Davies KE. Pharmacological advances for treatment in Duchenne muscular dystrophy. Curr Opin Pharmacol. 2017;34:36-48.

9. Nowak KJ, Davies KE. Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep. 2004;5(9):872-876.

10. Dalkilic I, Kunkel LM. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev. 2003;13(3):231-238. 

11. Ervasti JM, Ohlendieck K, Kahl SD, Gaver MG, Campbell KP. Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature. 1990;345(6273):315-319.

12. Blake DJ, Weir A, Newey SE, Davies KE. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev. 2002; 82(2):291-329.

13. Griggs RC, Miller JP, Greenberg CR, et al. Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy. Neurology. 2016;87(20):2123-2131.

14. FDA approves drug to treat Duchenne muscular dystrophy [press release]. Bethesda, MD: FDA; February 9, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm540945.htm. Accessed November 06, 2018. 

15. Aartsma&#8208;Rus A, Fokkema I, Verschuuren J, et al. Theoretic applicability of antisense&#8208;mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat. 2009;30:293—299.

16. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):6376-47.

17. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy [press release]. Bethesda, MD: FDA; September 19, 2016. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.

 for Duchenne muscular dystrophy: the next chapter in the 

 saga. Nucleic Acid Ther. 2017;27(1):1-3. 

19. Mendell JR, Goemans N, Lowes LP, et al; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of

 versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016;79(2):257-271. 

20. McDonald CM, Campbell C, Torricelli RE, et al; Clinical Evaluator Training Group; ACT DMD Study Group. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10101):1489-1498.

21. Bushby K, Finkel R, Wong B, et al; PTC124-GD-007-DMD Study Group. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50(4):477-487.

NeuroPathways

Gene therapy has generated excitement as a treatment or even a potential cure for inherited diseases. Among them: Duchenne muscular dystrophy.

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

Obstructive sleep apnea (OSA) has long faced a shortcoming of reliable therapeutic options. The first-line treatment, continuous positive airway pressure (CPAP), has poor long-term compliance, with adherence rates of 50% or less. Second-line therapies, such as mandibular advancement splints and upper airway surgery, are not predictably effective. 

Recent advances in OSA pathogenesis using upper airway and respiratory phenotyping techniques have unlocked new approaches for targeted treatment. Investigators have identified 4 key causes of OSA, a heterogenous disorder involving both anatomical and nonanatomical factors. The primary cause: an impaired anatomy or narrow or collapsible upper airway. The 3 main nonanatomical contributors: impaired upper airway dilator muscle function, a low respiratory arousal threshold, and unstable respiratory control (high loop gain). 

Despite the advances, there remains a great need for additional tools to identify and focus on the 4 phenotypic causes of sleep apnea in patients in the clinical setting, but the existing framework holds promise. Each phenotype is a potential therapeutic target, and these prospective pharmacotherapies will be a major advance for the field.

To provide more insight into the latest knowledge regarding sleep apnea phenotyping and its role in the development of targeted pharmacotherapies, 

™ sat down with Danny Eckert, PhD, principal research scientist at Neuroscience Research Australia and an associate professor of medicine at the University of New South Wales in Sydney, Australia, at the 24th Congress of the European Sleep Research Society in Basel, Switzerland. 

Q: Could you describe OSA pathophysiology? 

For a long time, we’ve been trying to come up with a pharmacotherapy to treat this very common disorder, but unfortunately, despite multiple attempts, we have not yet succeeded. It’s an exciting time in the field, because we now have not only identified new therapeutic targets for the reasons people get sleep apnea but also unlocked new therapeutic targets for pharmacotherapies. There are 4 main causes of sleep apnea: the anatomy, or how collapsible the upper airway is—from the back the throat to the back of the nose&mdash;as well as 3 nonanatomical causes. These include how well the muscles around the throat are able to open the airway during sleep, a muscle trait. The next is how easily a person sleeps, or what we call arousal threshold, and the fourth point is what we call respiratory control or loop gain. The latter 3&mdash;the nonanatomical ones&mdash; are quite recent in terms of our knowledge, and these are all novel therapeutic targets. 

We’ve identified these 4 main reasons people get sleep apnea (see 

). We’ve always known that it’s an anatomical issue. Crowded or narrow airways, whether due to obesity or skeletal issues, can be a main driver of sleep apnea, but now we know about these other 3 causes and how the muscles respond. One-third of all people are not able to activate their muscles during sleep, which further progresses the condition for those with sleep apnea. A third of people also have problems with how easily they wake up—they’re light sleepers, if you like, or have what we call a low arousal threshold. The remaining cause is respiratory control; some people are just too sensitive to carbon dioxide during sleep, and that causes all sorts of problems in terms of cyclic breathing and feeds into sleep apnea. Those latter 3 nonanatomical causes really have opened new targets for pharmacological therapy for this common disorder. 

Q: What treatment options are available for reducing OSA severity? 

If I start with the control of breathing trait, oxygen therapy, a nonpharmacologic intervention can reduce the unstable control of breathing in people that have that issue. A drug called acetazolamide, which is a common generic agent that people take to reduce mountain sickness when they go to high altitudes, can also help sleep apnea in certain people. 

Other drugs can stabilize sleep or promote sleep, if you like— common hypnotics; sleeping pills; things like zolpidem, zopiclone, trazodone, and temazepam. These agents can actually promote sleep. We used to think that was really bad for those with sleep apnea and would actually make them worse, but a lot of work that we and others have done in the past 10 years or so has shown that certain sleeping pills can promote breathing stability and, in fact, reduce sleep apnea in certain people who have the problem of waking up too easily, which contributes to their sleep apnea. For others, however, using these agents can worsen the problem, so it really does involve a targeted approach of giving it to the right patients. 

The other main trait that we’ve long tried to target involves the muscles. We used to think that serotonin was a really important driver of pharyngeal muscle control, and it turned out that a lot of that knowledge was based on really reduced preparations in animal models where there were a lot of anesthetic agents on board. When we did those human studies, it turned out that the endogenous serotonin was really playing a minor role. We now know from more detailed animal studies and freely behaving animals—work from Richard Horner’s lab and others in Toronto&mdash;that these cholinergic and muscarinic processes are really important in mediating pharyngeal muscle control. A body of work that is trying to use agents for those particular targets is showing some exciting results in the proof-of-concept work in terms of reducing sleep apnea severity. 

Q: What role does phenotyping play in sleep apnea? 

The main therapy for sleep apnea, continuous positive airway pressure (CPAP) therapy, that opens up the airway, with that, it really doesn’t matter why you get your sleep apnea, if you can tolerate the therapy it will keep your airway open and stabilize breathing during sleep. The problem is that half or more of patients that try that therapy are unable to tolerate it and others are unwilling to even try it. We hope that phenotyping—and by phenotyping, I mean understanding those specific 4 causes on a per-patient basis&mdash;will help us knew exactly why each individual is getting their sleep apnea. We could then target each of the individual specific problem with an individualized therapy. We’ve developed quite complex techniques to measure those in the research lab, and our next challenge is to roll those out into the clinic and simplify them. We’re having some progress in obtaining that goal, which will really be necessary in terms of rolling out targeted or precision medicine for sleep apnea. 

Q: How is phenotyping making an impact on these patients in the clinic? 

Recognition and awareness that most patients have 1 or more nonanatomical contributors to their sleep apnea is changing the way clinicians evaluate their patients and is beginning to inform treatment decisions. This is especially true for those who do not respond to traditional therapies. For example, there is greater recognition that a key reason many patients do not respond to second-line therapies that target the anatomical problem, such as mandibular advancement therapy and upper airway surgery, involves residual issues with unstable control of breathing—high loop gain&mdash;which these therapies do not address. 

Q: What aspect of this area most excites you right now? 

Because of this new framework and understanding of why people get their sleep apnea, it really is an exciting time for the field. These new potential pharmacotherapies will be a major advance, and we’re all very hopeful that this approach will help many patients. 

We currently do not have simple, accurate tools to estimate the 4 phenotypic causes of sleep apnea in individual patients in the clinical setting. These tools are essential for making targeted therapy for sleep apnea a reality. Exciting work is under way in this area, but these new techniques have yet to translate to the clinic. There is also a need to develop therapies that target the nonanatomical phenotypes and to combine them with existing second-line anatomical therapies [eg, mandibular advancement therapy and upper airway surgery] to achieve therapeutic efficacy for the many patients who have an incomplete response to existing second-line monotherapies. 

1. Eckert DJ. Phenotypic approaches to obstructive sleep apnoea — new pathways for targeted therapy. Sleep Med Rev. 2018;37:45–59.

Clinical Viewpoint

The principal research scientist at Neuroscience Research Australia and an associate professor of medicine at the University of New South Wales provided more insight into the latest knowledge regarding sleep apnea phenotyping and its role in the development of targeted pharmacotherapies.

Investigators Unlock New Targets in Obstructive Sleep Apnea

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The most intriguing bit of data from the substudy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

7. Biogen announces AFFINITY phase 2 trial initiation for

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

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

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

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

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

 7th Joint ECTRIMS-ACTRIMS Meeting; October 25-28, 2017, Paris, France. Abstract 130. 

.ectrims-congress.eu/ectrims/2017/ACTRIMS-ECTRIMS2017/202483/douglas.l.arnold. md1003.in.progressive.multiple.sclerosis.24-month.brain.mri.html%3Ff%3Dmedia%3D1. 

11. Abu-Rub M, Miller RH. Emerging cellular and molecular strategies for enhancing central nervous system (CNS) remyelination. Brain Sci. 2018;8(6):111. mdpi.com/2076-3425/8/6/111. Accessed October 29, 2018. 

12. Tejedor SL, Berner G, Jacobsen K, et al. Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system. Brain Behav Immun. 2015;50:155-165.

13. Bai L, Lennon DP, Eaton V, et al. Human bone marrow-derived mesenchymal stem cells induce

 immune response and promote endogenous repair in animal models of multiple sclerosis. Glia. 2009;57(11):1192-1203. 

 I, Petrou P, Halimi M, Karussis D. Mesenchymal stem cells (MSC) derived from mice with experimental autoimmune encephalomyelitis (EAE) suppress EAE and have similar biological properties with MSC from healthy donors. Immunol Lett. 2013;154(1-2):70-76. 

15. Sargent A, Shano G, Karl M, Garrison E, Miller C, Miller RH. Transcriptional profiling of mesenchymal stem cells identifies distinct neuroimmune pathways altered by CNS disease. Int J Stem Cells. 2018;11:48-60.

Features

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

Remyelination in Multiple Sclerosis: The Next Treatment Frontier

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

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

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

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

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

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

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

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

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

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

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

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

Evolving Technology for Precise Evaluation and Treatment 

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

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

December 2018

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Remyelination in Multiple Sclerosis: The Next Treatment Frontier

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