Over the past several years, scientific teams have developed investigational methods for delivering a gene to correct a mutation in the 

 gene which causes Duchenne muscular dystrophy (DMD) by creating dysfunction in a patient’s dystrophin production. These gene therapies have become progressively more effective as delivery methods and the corrected genes have been improved.

Recently, the success of these therapies in patients with DMD has been related to the use of a shorter 

 gene, which produces a smaller completely functional protein, micro-dystrophin. Investigators have used antisense oligonucleotides to mask the deletion of exons in the coding of the 

 gene. This has been shown to be successful in preclinical studies as well as in humans.

“I’m absolutely thrilled to be seeing this hopeful technology come to fruition,” Crystal Proud, MD, a pediatric neuromuscular neurologist at Children’s Hospital of The King’s Daughters (CHKD) in Norfolk, Virginia, told 

. “I’m a reasonably young neuromuscular neurologist, and it’s such a fantastic time to be in this specialty.”

With a number of gene therapies and exon-skipping therapies being evaluated in ongoing clinical trials, clinicians treating muscular dystrophies have begun to discuss the potential clinical implications of applying these therapies for patients with DMD.

One of the treatments in development, suvodirsen, previously known as WVE-210201, has been designed by Wave Life Sciences for the 13% of patients with DMD who have a specific type of mutation in the DMD gene that makes them amenable to exon 51 skipping treatment. The safety, tolerability, and plasma concentrations of ascending doses of WVE-210201 are being assessed in an ongoing, multi-dose, open-label extension trial for boys with DMD aged 5 to 18 who carry the gene mutation amenable to exon 51 skipping.

Preclinical experiments showed that suvodirsen was associated with a 52% increase in the levels of dystrophin protein compared with normal skeletal muscle tissue.

 As well, it was granted both orphan drug and rare pediatric disease designations from the FDA, following its orphan drug status granted by the European Commission.

In December 2018, Wave Life Sciences announced that its investigational candidate produced positive results in phase 1 testing for boys with DMD who are amenable to exon 51 skipping. Based on the 4 (undisclosed) doses already tested, 1 has been selected to be used in an upcoming planned phase 2/3 trial. The phase 1 trial assessed 4 primary outcome measures of safety in 40 patients: the number of patients with adverse events (AEs), the severity of those AEs, the number of patients with serious AEs (SAEs), and the number of patients who withdrew due to AEs. Secondary outcomes consisted of the maximum observed concentration (C

) at day 1 day 2, and day 8; the time to Cmax (T

) at day 1, day 2, and day 8; and the area under the plasma concentration-time curve (AUC0-t) at day 1, day 2, and day 8.

In January, the FDA selected the treatment’s upcoming phase 2/3 trial as the first to be part of its Complex Innovative Trial Design (CID) pilot program, based on innovative features of the trial design and the therapeutic needs. The application to the program by Wave included its plan to leverage historical control data for DMD to augment the placebo arm of the phase 2/3 trial.

“It’s amazing to see the change that I have seen in just the past few years. Being able to offer patients more hope than we’ve ever been able to offer in the past has been just a phenomenal thing,” Proud said. “We’re really seeing the technology apply to many areas of neuromuscular medicine. For me, I get to see it not only in DMD, but in other neuromuscular conditions as well.”

Another treatment in development is Sarepta Therapeutics’ rAAVrh74.MHCK7.micro-dystrophin, a micro-dystrophin gene therapy candidate under evaluation in a phase 1/2 clinical trial (NCT03375164). This shorter gene provides instructions for the production of a smaller form of the dystrophin protein and is delivered via a viral vector.

As of this publication, positive results from the trial show that rAAVrh74.MHCK7.micro-dystrophin is able to improve the functional performance of boys with DMD, without causing SAEs. Ultimately, the therapy showed robust expression of transduced micro-dystrophin, as measured by immunohistochemistry, in 4 patients. The mean gene expression for the study, as measured by the percentage of micro-dystrophin positive fibers, was 81.2%, and the mean intensity of the fibers was 96.0% compared with normal control.

As measured by Western blot, the levels of micro-dystrophin were reported as 74.3% compared with normal using Sarepta’s method, equivalent to 95.8% compared with normal pursuant to Nationwide Children’s quantification of Sarepta’s method, which adjusts for fat and fibrotic tissue.

“We at Parent Project Muscular Dystrophy [PPMD] are very optimistic about the dystrophin restoration and replacement programs that are on the horizon, exon skipping and gene therapy delivering micro-dystrophin,” Abby Bronson, the senior vice president of research strategy at PPMD, told 

. “All these dystrophin restoration programs are as important as gene therapy is, even still in the early stages. Although, it continues to also show potential.”

Additionally, Solid Biosciences has developed its own micro-dystrophin gene transfer therapy, SGT-001. Recent data from its phase 1/2 dose-ascending IGNITE-DMD clinical trial found that there were low levels of micro-dystrophin protein expression in 3-month biopsies from 3 patients dosed with 5E13 vg/kg of the treatment. As a result, the company is planning to move forward with the dose escalation as soon as possible.

A potential confusion for these therapies is that they are mutation-specific—there is not a clear and efficient pathway for approval for exon-skipping drugs for additional mutations using the same backbone, so patients must have a particular DNA change to qualify for a gene therapy. There are additional considerations for which patients may be indicated and when, and what the duration of treatment could be.

“A lot of patients are not going to have that specific indication,” Proud explained. “We want to be able to utilize the drug with optimal efficacy at just the right moment.”

Proud detailed a number of questions which still need to be answered for these treatments, including the specifics about when to initiate treatment and what the specific threshold for initiation should be. Additionally, Proud posited that because many of the viral vector delivery systems in development permit a 1-time dose, there is some speculation about when and if the treatment will run its course, and if it were to only last a certain amount of time, it becomes paramount to decide when the best opportunity to give a treatment will be.

“Is that going to be when these boys are declining between the ages of 7 and 10? Is it going to be when they’re little and they’re still quite strong, so maybe 4 or 5 years old? And are there other combination therapies that we can continue to utilize to maintain that strength,” Proud said. And these unanswered questions may not be resolved by the time these treatments come before the deciding regulatory authorities.

“I still think we’re several years off from FDA approval,” she said. “Those are the things that we as neuromuscular neurologists are thinking about because we obviously want to be able to offer guidance to families on what’s best for their child. There are, right now, a lot more questions than there are answers. We’re still gathering a lot of data and we still have a lot of questions in the neuromuscular community.

“But we’re very hopeful,” she added.

Once suitability for gene therapy is determined for a patient with DMD, the determination of efficacy at the time of infusion, post-infusion, and in the subsequent weeks following infusion will be a vital step in the treatment plan. Immune response to DMD gene therapies is being taken into consideration, as the FDA has been both cautious and diligent about evaluating for potential AEs.

“When we’re thinking about the type of treatment, we believe that the highest risk, at least that we’re aware of, is during infusion and the next couple of weeks following infusion is for the systemic and inflammatory response that can happen in the body,” Proud said.

Recommendations for mitigating inflammatory response include a month-long dosage of an oral steroid (i.e., prednisolone) prior to infusion and monitoring the liver. A baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) measurement and trending over time can help to ensure that those levels are not increasing and demonstrating that inflammation is not reducing.

“It’s my understanding that with steroid treatment before infusion, inflammatory response has been kept under control, and this is continued after therapy as well,” Proud explained. “With many of these gene therapies, whether we’re talking about DMD, spinal muscular atrophy, or limb-girdle dystrophy, typically we’re talking about a premedication with an oral steroid medication for about a month before you would use the viral vector. It has been demon&shy;strated that this has been hopeful to reduce inflammation and, ultimately, that steroid is slowly weaned and reduced in dosage over several weeks while following certain laboratory parameters to ensure that the body’s inflammation is under control.”

She noted that immune and inflammatory response is some&shy;thing to be taken into consideration with these treatments, and that so far, the manufacturers and the clinical investigators have been thoughtful in their approaches to it.

Bronson clarified that currently, there is some concern about the introduction of this new dystrophin—generated from exon skipping or gene therapy&mdash;into the body will cause an immune response that will render the therapy less effective.

“Understanding this response is very important for optimizing the therapy,” Bronson said. “PPMD appreciates companies continuing to explore and enhance both exon skipping and gene therapy, and we are hopeful that both treatments will continue to broaden the number of patients they can treat.”

PPMD recently awarded a $329,000 grant to Kanneboyina Nagaraju, MD, PhD, and his team at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences in New York, to explore this concern. The researchers will examine the body’s immune response to the production of new dystro&shy;phin protein resulting from exon-skipping and gene therapy treatments.

To evaluate the role of the immune system on dystrophin resto&shy;ration, Nagaraju will explore the combination of exon-skipping or micro-dystrophin gene therapy with an immunosuppressive treat&shy;ment. They plan to utilize 1 of the following 3 tactics in combination with treatment: rituximab, an anti-CD20 antibody used to treat auto&shy;immune disorders and cancer, to block antibodies to newly produced dystrophin; abatacept (also known as CTLA4ig) to halt an anti-dystro&shy;phin immune response; or either prednisolone, vamorolone, or epler&shy;enone to test the respective reduction in inflammatory and anti-dys&shy;trophin immune response. These considerations are necessary to determine how to sustain the gene therapy and exon skipping.

“When you do gene therapy, there is an immune response to dystrophin,” Nagaraju, a professor and founding chair of the Department of Pharmaceutical Sciences at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, told 

. “You have an antigen that the body has never seen. The biologics are pretty advanced in treating protein diseases, so the question becomes, ‘Which biologic to use?’ By specifically targeting B cells, we may be able to reduce antibody response. Whether the responses are pathogenic or not, we know they’re there. Now, [do we have to] block T cell responses because they come first? It is better, probably, to block both.”

Proud explained that for the majority of physicians in the neuro&shy;muscular community, expectation if and when these treatments make it to market is that they’ll be used in combination.

“I would love to see these kids treated by one medication, but I don’t know how realistic that is,” she said. “The majority of us believe that combination therapy is the most realistic option, and it’s a matter of finding those components to make the most appro&shy;priate cocktail to being able to help support dystrophin produc&shy;tion, particularly in these boys with DMD.”

There are a number of pathological points within DMD that can be targets of these treatments, she said. Within the disorder, there is a need to produce dystrophin to a level that allows for muscle strength to be maintained, as well as a need to reduce muscle breakdown that would otherwise continue through the course of the patient’s life. Proud also expressed concern with how muscle membrane stabilization will occur. Ultimately, it appears that even the best option won’t be a magic bullet.

“Where we see things going in general with particular drug aiming at each of those points of vulnerability in pathophysiology of disease,” she explained. “Perhaps it’s going to gene therapy in combination with an anti-myostatin, or in combination an anti-inflammatory. But I do think the most likely thing is combination therapy aiming at a different piece of the puzzle.”

One area of important focus for Proud is biomarkers. Currently, the easiest to use and most available biomarker is creatine phosphokinase (CPK), which has been observed to decline in prelim&shy;inary data of the gene therapies in development. This, Proud said, “is extremely hopeful” as it has not been seen with any other treat&shy;ment modalities.

“The question that most of us have is whether that will persist,” she said. “But that is certainly a useful biomarker to follow. Perhaps that will become part of our routine clinical practice after a patient has received gene therapy for treatment of their DMD. Perhaps part of our routine laboratory work will be to monitor that CPK level and if it declines, that to a certain extent, indicated efficacy, as do the clinical assessments that we do.”

She said that she anticipates that, regardless of the treatment, physicians will continue to pursue those assessments using a multidisciplinary approach, with those outcomes and measure&shy;ments dictating the efficacy of these interventions.

“Our clinical practice of monitoring these parameters will be continued; I don’t think their functional outcomes are going anywhere,” Proud explained. “We just may be adding more observa&shy;tion to our repertoire to follow the boys’ responses to this treatment.”

The introduction of genetics into treatment has also included benefits from genetic testing. At CHKD, the ability to evaluate each patient who is clinically diagnosed with a neuromuscular disorder is being able to characterize them molecularly. The opportunities that clinicians have to pursue genetic testing have rapidly expanded in the last decade, and typically, Proud said she is able to offer many of her patients a diagnosis of neuromuscular disease with genetics.

“Furthermore, for patients with DMD, we’re able to characterize their genetic change and consider them for participation in clin&shy;ical research trials if that’s within the family’s wishes,” she noted. “We’re able to pursue all of the FDA-approved molecular-specific treatments. We’re able to say, ‘when this particular type of tech&shy;nology comes along in the future, this is the one that will apply to you.’ It allows me to really help prepare patients and families for potential opportunities down the line.”

With ongoing in-human clinical trials and potential FDA-approved treatments down the line, physicians are bringing genetics into the conversation more than ever before. For Proud, these treatments are discussed in almost every clinic visit. These treatments, even prior to approval, have offered her patients an option they never had. Whether patients choose to participate in clinical trials or not, Proud said she is having conversations about 3 to 5 years from now, when treatments may be approved, including what may or may not applicable to a specific patient.

Being able to offer enrollment in trials is one of the most important pieces of care for Proud. It’s something she described to 

 as part of her duty as a physician to propose partic&shy;ipation in clinical trials.

“Many families of boys with DMD are quite savvy and eager and interested to find something that may help their child in any way,” she said. “Part of my dedication to them is being able to offer them that option, and part of that also becomes being knowledgeable about the opportunities that are out there. When a patient comes to see me in clinic, yes, we’re talking about how they’re doing, we’re doing an assessment, but I’m also able to discuss with them the options that are available to them at CHKD or around the country.”

“That’s a critical piece of have in a neuromuscular clinic, being able to offer families opportunities because those are opportuni&shy;ties of hope for them,” she added.

1. M. Wood, J. Zhang, K. Bowman, et al. WVE-210201, an investigational stereopure oligonucleotide therapy for Duchenne muscular dystrophy, induces exon 51 skipping and dystrophin protein resto&shy;ration. 

. 2017;27(2):S217. doi: 10.1016/j.nmd.2017.06.442.

2. Wave Life Sciences announces positive phase 1 results for WVE-210201 in Duchenne muscular dystrophy (DMD) [press release]. Cambridge, MA: Wave Life Sciences; December 6, 2018. wave&shy;lifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-posi&shy;tive-phase-1-results-wve-210201. Accessed Janu-ary 28, 2019.

3. Wave Life Sciences Duchenne muscular dystrophy clinical trial selected for FDA Complex Innovative Trial Designs Pilot Program [press release]. Cambridge, MA: Wave Life Sciences; January 3, 2019. ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-duchenne-mus&shy;cular-dystrophy-clinical-trial. Accessed January 28, 2019.

4. Sarepta Therapeutics announces that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., presented positive updated results from the four children dosed in the gene therapy micro-dystrophin trial to treat patients with Duchenne muscular dystrophy [press release]. Cambridge, MA: Sarepta Therapeu-tics; October 3, 2018. globenewswire.com/ news-release/2018/10/03/1601085/0/en/Sarepta-Therapeutics-Announces-that-at-the-23rd- International-Congress-of-the-World-Muscle-Society-Jerry-Mendell-M-D-Presented-Positive- Updated-Results-from-the-Four-Children-Dosed.html. Accessed January 28, 2019.

5. Solid Biosciences Announces Preliminary SGT-001 Data and Intention to Dose-Escalate in IGNITE-DMD Clinical Trial for Duchenne Muscular Dystrophy [press release]. Cambridge, MA: Solid Biosciences; Published February 7, 2019. solidbio.com/about/media/press-releases/solid-biosci&shy;ences-announces-preliminary-sgt-001-data-and-intention-to-dose-escalate-in-ignite-dmd-clini&shy;cal-trial-for-duchenne-muscular-dystrophy-1. Accessed February 7, 2019.

6. Parent project muscular dystrophy awards $329,000 grant to Binghamton University to examine the role of the immune system on dystrophin restoration [press release]. Hackensack, NJ: PPMD; December 19, 2018. prnewswire.com/news-releases/parent-project-muscular-dystrophy-awards-329-000-grant-to-bingham&shy;ton-university-to-examine-the-role-of-the-immune-system-on-dystrophin-restoration-300768740.html. Accessed January 28, 2019.

Articles

Features

Over the past several years, scientific teams have developed investigational methods for delivering a gene to correct a mutation in the DMD gene which causes DMD by creating dysfunction in a patient’s dystrophin production.

Genetic Targets Invigorate Research for Duchenne Muscular Dystrophy

Parkinson disease is second only to Alzheimer disease as the most common neurodegenerative disorder in the United States, affecting more than 680,000 individuals.

 Notably, that large prevalence of Parkinson is expected to only increase as the population ages, estimated to affect more than 1 million Americans by 2030.

 The motor dysfunction associated with Parkinson is the result of the degeneration of dopamine neurons in the substantia nigra. One method to restore dopamine in the brain is to administer levodopa, a precursor of dopamine that can cross the blood-brain barrier and be converted into dopamine.

As dopaminergic cell loss becomes more advanced with disease progression, the associated motor symptoms often interfere with an individual’s ability to perform everyday activities, resulting in an inability to maintain control over motor symptoms that can negatively affect a patient’s quality of life.

Indeed, levodopa is the best available treatment for managing Parkinson motor symptoms. Although, a major drawback of this well-established medication is the fluctuation in its effectiveness. This common complication is known as off time, as it typically occurs toward the end of a dose, when levodopa is wearing off, and is defined by the reappearance of symptoms.

The traditional strategy to prevent off time is to modify the dosage of levodopa; however, this often leads to exacerbation of unwanted adverse effects, such as dyskinesia and increased difficulties with treatment adherence. More recently, though, investigators have discovered that catechol-O-methyltransferase (COMT) inhibitors can prolong the effects of levodopa, thereby limiting the off-time phenomenon.

“COMT inhibitors play an important role in modifying the pharmacokinetics of levodopa,” stated Werner Poewe, MD, the director of the Department of Neurology at the Medical University of Innsbruck in Austria, at the 2016 German Society of Neurology (DGN) Congress in Mannheim, Germany.

COMT is an enzyme that eliminates levodopa by catalyzing the conversion of levodopa to 3-O-methyldopa, a metabolite that has no known therapeutic value. COMT inhibitors block this metabolic pathway in the periphery, thereby increasing the amount of levodopa that is available to be converted into dopamine (see 

As a result of this process, COMT inhibitors enhance the therapeutic effect of levodopa by increasing its bioavailability and sustainability, thus preventing wearing off and improving clinical responsiveness.

 Importantly, COMT inhibitors have no direct effect on Parkinson symptoms, so they are effective only when administered in combination with levodopa.

Current FDA-approved COMT inhibition therapies include tolcapone (Tasmar; Valeant Pharmaceuticals) and entacapone (Comtan; Novartis). Both medications are indicated to treat the end-of-dose wearing off of levodopa in patients with Parkinson.

Entacapone is recommended as first-line treatment, whereas tolcapone is recommended as a second-line treatment because of liver toxicity adverse effects (AEs).

 More recently, a combination pill of entacapone, levodopa, and carbidopa (Stalevo; Novartis) was approved for the treatment of Parkinson in the United States.

Tolcapone was approved for use by the FDA in 1997 based on clinical trials that demonstrated its ability to significantly reduce time in the off state (ie, reduce wearing-off complications) compared with placebo.

 Unfortunately, tolcapone treatment was associated with elevations in liver enzymes, suggesting that its use may lead to liver toxicity.

As a result, its FDA approval was contingent on mandatory liver function monitoring during tolcapone treatment.

 Results from post&shy;marketing surveillance studies revealed that tolcapone treatment had been associated with 3 cases of fatal hepatoxicity and 1 case of severe liver injury. As such, tolcapone is currently recommended as a second-line treatment option for patients who have not responded to other adjunc&shy;tive therapies.

Entacapone was then approved for use by the agency in 1999. The efficacy and safety of entaca&shy;pone were established in a series of clinical trials, which demonstrated that entacapone signifi&shy;cantly reduced the amount of time in the off state compared with placebo.

 Recent studies and meta-analyses estimate that entacapone reduces off episodes by an average of 40 minutes.

 Although results from studies have shown the clinical efficacy of enta&shy;capone to be inferior to tolcapone, the safety profile of entacapone has improved.

The most common adverse effects associated with entacapone include nausea, urine discoloration, gastrointestinal disorders, and dyskinesia.

 Importantly, entacapone is not associated with hepatic dysfunction, so liver monitoring is not required during enta&shy;capone treatment.

Ultimately, entacapone is a favorable treatment alternative to tolca&shy;pone because of its superior safety profile. However, although enta&shy;capone is a well-tolerated COMT inhibitor, it must be taken concom&shy;itantly with each dose of levodopa, which can result in dosing up to 8 times per day, in addition to levodopa dosing.

A more convenient treatment regimen is, as noted, now available with the combination levodopa/ entacapone/carbidopa pill.9 The safety and efficacy of this combination pill were established in 2 clinical trials. In the FIRST-STEP trial (NCT00134966), the triad combination was found to significantly reduce time in the off state without increasing dyskinesia compared with just levodopa/ carbidopa treatment.

Interestingly, although the FIRST-STEP trial did not find an increase in dyskinesia with the combination pill, the STRIDE-PD trial did find that the levodopa/ entacapone/carbidopa amalgamation worsened dyskinesia AEs.

 Nonetheless, the combination pill has been found to be effective and reduces the number of pills that must be taken each day, providing a more convenient option for patients.

In the clinic, entacapone is the common first-line treatment strategy for Parkinson motor symptoms; however, it only moderately reduces time in the off state and must be taken with each levodopa dose. Tolcapone is more efficacious than entacapone, but its use is limited because of liver toxicity adverse effects.

“Thus, a more effective COMT inhibitor that can be easily used in routine clinical practice is needed,” stated Joaquim J. Ferreira, MD, from the University of Lisbon in Portugal, in 

Opicapone (Ongentys; Neurocrine Biosciences) is a novel, once-daily COMT inhibitor that was approved for use in Europe in 2016 based on the results of 2 clinical trials, BIPARKI and BIPARKII.

 It is currently under development for use in the United States.

The safety and efficacy of opicapone were established in the afore&shy;mentioned randomized, double-blind, placebo-controlled phase 3 clinical trials.

 In the BIPARKI trial, opicapone was compared with placebo and entacapone in 600 patients with Parkinson disease. Opicapone was found to be superior to placebo and equivalent to enta&shy;capone at reducing time in the off state. Specifically, it was estimated that opicapone reduced off episodes by an average of 60 minutes.

Compared with the estimated 40-minute reduction with entaca&shy;pone, this suggests that opicapone may have a greater magnitude of the effect. Importantly, these results were found for a once-daily dose of opicapone, establishing it as the first-ever COMT inhibitor that allows once-daily dosing.

The BIPARKII trial validated that once-daily opica&shy;pone is well tolerated and more effective at reducing end-of-dose wearing off than placebo.

 Further, both trials demonstrated that the effects of opica&shy;pone were maintained for 1 year, during which the levodopa dose was not increased.

The most common AEs associated with opica&shy;pone treatment included dyskinesia, constipa&shy;tion, and dry mouth.

“The simplicity afforded by the once-daily administration means that addition of this drug will not further complicate the patients’ current drug regimen,” stated Andrew J. Lees, MD, from the University College London in England, in 

“When combined with the favorable safety and tolerability profile, these characteristics position opicapone as a strong candidate for the adjunct treatment of motor fluctuations in Parkinson,” Lees and colleagues concluded.

In 2017, Neurocrine Biosciences announced that it would be responsible for developing and commercializing opicapone in the United States.

 After the manufacturer met with the FDA in 2017 to discuss a new drug application, the agency did not request that additional phase 3 clinical trials be conducted.

As a result, Neurocrine Biosciences stated it hopes to begin the regulatory review process of opicapone in early 2019.

 It is, therefore, possible that opicapone may be approved in the United States as a novel once-daily COMT inhibitor treatment for Parkinson motor symptoms in the near future.

“When thinking on the switch from entacapone to opicapone, patients should be closely monitored for development of dyskinesia; however, patients switching to opicapone will not show signs of urine discoloration, as would be the case with entacapone,” Thomas Mu&#776;ller, MD, head of the Department of Neurology at St. Joseph Hospital in Berlin, Germany, stated at the 2016 DGN Congress in Mannheim, Germany.4 “On the other hand, patients on opicapone have no need for liver monitoring, as is the case with tolcapone.

“In general, treatment changes should only be made if a patient is dissatisfied with their current treatment,” Mu&#776;ller concluded.

1. Parkinson’s disease information page. National Institutes of Neurological Disorders and Stroke website. ninds.nih.gov/disorders/All-Disorders/Parkinsons-Disease-Information-Page. Updated June 12, 2108. Accessed January 18, 2019.

2. Marras C, Beck JC, Bower JH, et al; Parkinson’s Foundation P4 Group. Prevalence of Parkinson’s disease across North America. 

3. Politis M, Wu K, Molloy S, G Bain P, Chaudhuri KR, Piccini P. Parkinson’s disease symptoms: the patient’s perspective. 

4. Poewe W. Levodopa-related ‘wearing off’ in Parkinson’s disease: current therapeutic options. Talk presented at: Deutsche Gesellschaft fu&#776;r

 (DGN) Congress; September 22, 2016; Mannheim, Germany. emjreviews.com/neurology/symposium/new-developments-for-parkinsons-therapy-with-comt-inhibitors. Accessed January 19, 2019.

5. Kaakkola S. Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. 

6. Comtan [package insert]. Basel, Switzerland: Novartis Pharmaceuticals; 2018.

7. Tasmar [package insert]. Quebec, Canada: Valeant Pharmaceuticals; 2015.

8. COMT inhibitors. Parkinson’s Foundation website. toolkit.parkinson.org/content/comt-inhibitors. Accessed January 19, 2019.

9. Stalevo [package insert]. Basel, Switzerland: Novartis Pharmaceuticals; 2016.

10. Rajput AH, Martin W, Saint-Hilaire MH, Dorflinger E, Pedder S. Tolcapone improves motor function in parkinsonian patients with the “wearing-off” phenomenon: a double-blind, placebo-controlled, multicenter trials. 

11. Adler CH, Singer C, O’Brien C, et al. Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. 

12. Assal F, Spahr L, Hadengue A, Rubbia-Brandt L, Burkhard PR. Tolcapone and fulminant hepatitis. 

13. Olanow CW. Tolcapone and hepatotoxic effects: Tasmar advisory panel. 

14. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. 

15. Deane KH, Spieker S, Clarke CE. Catechol-O-methyltransferase inhibitors for levodopa-induced complications in Parkinson’s disease. 

16. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P; Bi-Park 1 investigators. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomized, double-blind, controlled trial. 

17. Onofrj M, Thomas A, Iacono D, Di Iorio A, Bonanni L. Switch-over from tolcapone to entacapone in severe Parkinson’s disease patients. 

18. Entacapone to Tolcapone Switch Study Investigators. Entacapone to tolcapone switch: multicenter double-blind, randomized, active-controlled trial in advanced Parkinson’s disease. 

19. Li J, Lou Z, Liu X, Sun Y, Chen J. Efficacy and safety of adjuvant treatment with entacapone in

advanced Parkinson’s disease with motor fluctuation: a systematic meta-analysis. 

20. Hauser RA, Panisset M, Abbruzzese G, Mancione L, Dronamraju N, Kakarieka A; FIRST-STEP Study Group. Double-blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson’s disease. 

21. Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study [erratum in Ann Neurol. 2010;68(3):412-413]. 

22. Efficacy and Safety of BIA 9-1067 in Idiopathic Parkinson’s Disease Patients. (BIPARKII).clinicaltrials.gov/ct2/show/NCT01227655. Updated October 19, 2015. Accessed January 19, 2019.

23. The Efficacy and Safety of BIA 9-1067 in Idiopathic Parkinson’s Disease Patients With “Wearing-Off” Phenomenon. clinicaltrials.gov/ct2/show/NCT01568073. Updated September 18, 2015. Accessed January 19, 2019.

24. Lees AJ, Ferreira J, Rascol O, et al;

-2 Study Investigators. Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. 

25. Ongentys. European Medicines Agency website. ema.europa.eu/en/medicines/human/EPAR/

. Updated February 2, 2017. Accessed January 19, 2019. Pipeline: clinical trials. Neurocrine Biosciences website. neurocrine.com/pipeline/pipeline-overview_old/opicapone/parkinsons-disease/clinical-trials/. Accessed January 19, 2019.

 will file new drug application for opicapone for Parkinson’s disease based on existing pivotal clinical trial data [news release]. San Diego, CA: Neurocrine Biosciences; February 14, 2018. phoenix.corporate-ir.net/phoenix.zhtml?c=68817&p=irol-newsArticle&ID=2332500. Accessed January 19, 2019

NeuroPathways

More recently, investigators have discovered that catechol-O-methyltransferase inhibitors can prolong the effects of levodopa, thereby limiting the off-time phenomenon.

COMT Inhibitors Assist in Control of Parkinson Disease Motor Symptoms

Although only 2 drugs, riluzole (Rilutek; Sanofi) and edaravone (Radicava, Mitsubishi Tanabe Pharma America), are currently FDA approved for the treatment of amyotrophic lateral sclerosis (ALS), the number of promising therapies being explored for the condition has grown exponentially. One therapy under investigation is reldesemtiv (Cytokinetics, Astellas), a fast-skeletal muscle troponin activator that aims to slow the decline of muscle function.

The investigational drug candidate, formerly known as CK-2127107, is the subject of the phase 2b FORTITUDE-ALS trial (NCT03160898), which is assessing the effect of reldesemtiv compared with placebo on respiratory function and additional measures of skeletal muscle function.

Reldesemtiv is designed to bind and slow the rate of calcium release from the troponin complex, which boosts the sensitivity of the sarcomere to calcium, thus increasing the ability of the muscles to contract despite reduced nerve signaling.

“[FORTITUDE-ALS] is completely enrolled, so we’re just finishing treating patients, and we do believe that nothing should preclude presenting the data within the first half of the year at this point,” Andrew Wolff, MD, the chief medical officer of Cytokinetics, told 

Wolff explained that unlike what has been observed with reldesemtiv, in the 2 studies of Cytokinetics’ earlier fast skeletal muscle troponin activator, tirasemtiv, participants who discontinued from treatment tended to do so soon after randomization—often within the first week but ultimately within the first 2 or 3 weeks&mdash;because of adverse events (AEs) such as dizziness, nausea, and fatigue.

Wolff said that Cytokinetics has gleaned from previous data with reldesemtiv, including those with healthy volunteers, that it was likely to be better tolerated than its predecessor.

“Now we have evidence that, when looking at the blinded data again…overall there are fewer patients dropping off treatment. Furthermore, the pattern of the early terminations that we are seeing and the nature of them are different from what we saw with tirasemtiv,” Wolff said. In FORTITUDE-ALS, he added, the pattern of early terminations was related more to events that might be associated with disease progression in ALS.

FORTITUDE-ALS is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of approximately 450 participants with ALS from centers in the United States, Canada, Europe, and Australia. Participants are being randomized 1:1:1 to receive either placebo or a 150-mg, 300-mg, or 450-mg dose of reldesemtiv twice daily for 12 weeks.

To be enrolled in the study, participants were required to have a diagnosis of familial or sporadic ALS for ≤24 months prior to screening; an upright slow vital capacity of ≥60% predicted for age, height, and sex at screening; the ability to swallow tablets; the capability to perform reproducible pulmonary function tests; and preclinical laboratory findings within the normal range or, if outside the normal range, regarded as not clinically significant by the investigator; in addition, participants were required to be on riluzole for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and not be planning to start the therapy during the trial.

Enrollment criteria included that men who have not undergone a vasectomy and a confirmed sperm count of 0 must either use acceptable methods of contraception or remain abstinent after receiving the first dose of reldesemtiv until 10 weeks after the last dose. Participating women must be postmenopausal or sterile or not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the trial, and use acceptable methods of contraception or remain abstinent from heterosexual intercourse from screening until 10 weeks after the last dose of reldesemtiv.

The study’s primary end point is the change in vital capacity from baseline to the end of 12 weeks. Secondary end points include the slope of change from baseline in the megascore of muscle strength as measured by handheld dynamometry and handgrip dynamometry, the change in the ALS Functional Rating Scale-Revised score, the incidence and severity of treatment-emergent AEs, and the mean plasma concentrations of reldesemtiv at the sampled time points in the study.

The investigators are also measuring exploratory end points such as the effect of reldesemtiv versus placebo on self-assessments of respiratory function at home by the participant with aid from a caregiver, disease progression through quantitative measurement of speech production characteristics over time, disease progression through quantitative measurement of handwriting abilities over time, and the change in quality of life as measured by the ALS Assessment Questionnaire 5.

Reldesemtiv has been the subject of 5 completed phase 1 clinical trials that evaluated its safety, tolerability, bioavailability, pharmacokinetics, and pharmacodynamics in healthy volunteers. Its antifatigability was also assessed in a phase 1 trial including patients with limitations in mobility (NCT03065959); however, that trial was terminated early because of a lack of efficacy at the interim analysis. Additionally, the treatment was assessed in a phase 2 trial in spinal muscular atrophy (SMA), with the results announced in June 2018 at the Annual Cure SMA Conference in Dallas, Texas (NCT02644668).

The treatment showed a statistically significant concentration-dependent increase from baseline in the 6-minute walk test and maximal expiratory pressure in 70 patients, with improvements sustained for 4 weeks post-treatment. AEs were similar between patients receiving reldesemtiv and those on the placebo.

FORTITUDE-ALS is ongoing, and results are expected to be reported in the first half of 2019.

1. Day J. Update of CY 5021: a phase 2 clinical trial of

, a fast-skeletal muscle troponin activator (FSTA), for the potential treatment of spinal muscular atrophy. Presented at: 2018 Annual Cure SMA Conference; June 16, 2018; Dallas, TX.

Clinical Trial in Progress

The investigational drug candidate, formerly known as CK-2127107, is the subject of the phase 2b FORTITUDE-ALS trial, which is assessing the effect of reldesemtiv compared with placebo on respiratory function and additional measures of skeletal muscle function.

Reldesemtiv Displays Promise Over Predecessor for ALS, Currently in Phase 2b Trial

The field of neurology is gaining a more robust understanding of some of the mechanisms at play in excessive daytime sleepiness, but the progress has not spread evenly across different sleep disorders.

In many ways, sleep medicine is in its heyday. Sleep clinics have become ubiquitous, and both patients and physicians have a better understanding of the prevalence and seriousness of sleep-related disorders.

“There’s been a huge increase in awareness of sleep disorders,” James A. Rowley, MD, a professor of medicine and chief of the Division of Pulmonary/ Critical Care and Sleep Medicine at Harper University Hospital in Detroit, Michigan, told 

. Rowley explained that sleep specialists have worked hard to alert and educate primary care physicians and neurologists about the need to consider sleep disorders when evaluating patients who report excessive fatigue.

“People with daytime sleepiness really should have a full evalua&shy;tion to make sure there isn’t something beyond sleep deprivation,” Rowley said. “And if a patient comes in saying they get a full 8 hours of sleep each night, it ought to be a bright red flag that something is going wrong with their sleep.”

Unfortunately, Rowley pointed out, many individuals do not get a full 8 hours of sleep each night. Some patients do not get even close to that amount, resulting in numerous effects, excessive daytime sleepiness among them. According to Christian Guilleminault, MD, a professor of psychiatry and behavioral sciences at the Stanford Center for Sleep Sciences and Medicine in California, the most common causes of excessive daytime sleepiness are simply the rigors of modern life and sleep restriction.

“Most people need 7 to 7 hours and 30 minutes of nocturnal sleep with sleep onset and offset at the same time [each night],” Guilleminault said.

When patients do not get enough sleep, or when their sleep schedule is irregular because of personal or work-related issues, they end up feeling sleepy during the day, Guilleminault added. For these patients, lifestyle changes often solve the problem. For others, however, the problem of sleepiness is related to a much more complicated underlying issue.

Among the most common causes of daytime sleepiness are narcolepsy, insomnia, restless legs syndrome, and obstructive sleep apnea. Although a significant amount of recent research has helped explain many of the neurological issues at play in narcolepsy, the neurological factors associated with other conditions are less well described. And though it may seem logical that a sleep-disturbing disorder would cause sleepiness simply by lowering the quality of a patient’s sleep, experts and investigators see a more complicated picture, and a growing body of literature is helping to explain how neurological factors directly or indirectly cause excessive daytime sleepiness, or hypersomnolence.

Brian James Murray, MD, an associate professor of neurology and sleep medicine at the University of Toronto School of Medicine and an affiliate scientist at the Sunnybrook Research Institute in Canada, told 

 that the recent advances have given physicians more tools to make accurate diagnoses of sleep disorders. “Over the last 20 years, we have seen significant progress in the diagnosis of sleep disorders,” he said.

Like Rowley, Murray credited increased awareness of frontline physicians with helping to improve sleep disorder diagnoses. “Secondly, we have seen improvements in ambulatory devices to screen populations for sleep disorders such as obstructive sleep apnea,” he remarked.

Some of the biggest gains in neurological science have come in physicians’ understanding of narcolepsy. These, Murray said, include improvements in the diagnostic classification system and the recognition of spinal fluid orexin/hypocretin levels as an identifier of the condition “in the right clinical context.”

The discovery of the orexin/hypocretin system, Murray explained, has “revolutionized our understanding of sleep-wake control. We have a much better understanding of daytime sleepiness and have developed new medications to address this common problem.”

The insight that low orexin can lead to excessive sleepiness has implications for other sleep disorders, as well, such as insomnia. The association of narcolepsy with a deficiency of orexin prompted investigators to consider whether inhibiting orexin might be valuable in producing sleepiness in people who have trouble falling asleep.

In 2014, the FDA approved suvorexant (Belsomra; Merck), a first-of-its-kind orexin receptor antagonist, for the treatment of adults with insomnia. The drug works by restraining orexin and thereby inducing the same kind of sleepiness that is problematic in patients with narcolepsy. Its approval broke up a paradigm dominated by benzodiazepines, such as lorazepam and temazepam and nonbenzodiazepines, such as zolpidem and eszopiclone.

In a 2014 study of suvorexant, Michael W. Neville, PharmD, and colleagues pointed out that benzodiazepines and nonbenzodiazepines have significant drawbacks.

“Both classes exert effects on GABA [γ-aminobutyric acid] and have more global inhibitory effects in the brain,” they wrote. “This effect results in amnesia, next-day limited sedation, and rebound insomnia. In addition, both drug classes can be habit forming and have the potential to promote dependence.”

Suvorexant does not share the same drawbacks, largely because rather than inducing sleep, the therapy works by deactivating the mechanisms that cause wakefulness.

Around the same time that investigators began working on orexin-based therapies, another study exploring the role histamines play in narcolepsy was published.2 In addition to the loss of orexin/hypocretin neurons, narcolepsy is associated with an increase in histamine-producing neurons.

“This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy, such as preserved consciousness during cataplexy and fragmented nighttime sleep,” wrote principal investigator Thomas Scammell, MD, a professor in the Department of Neurology at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development.”

Scammell detailed that the results of his research suggested that drugs that reduce histamine signaling might help promote better sleep in patients with narcolepsy, and conversely, drugs that can boost histamine might help promote wakefulness and reduce daytime sleepiness.

Indeed, last May, the FDA gave fast track and breakthrough therapy designations to pitolisant, a drug currently being developed by Harmony Biosciences for the treatment of cataplexy in patients with narcolepsy and for excessive daytime sleepiness in patients with narcolepsy.

Pitolisant is a selective histamine 3 receptor antagonist/inverse agonist that enhances histaminergic neurons in the brain to boost wakefulness and reduce the risk of cataplexy. Data presented in 2018 showed that the drug led to long-term improvements in excessive daytime sleepiness. Under the Epworth Sleepiness Scale (ESS), patients in the study had scores of 16.8 at baseline, 13.4 after 1 year, and 10.6 by year 5. ESS scores of up to 10 are considered normal, according to the authors of that study.

Although pitolisant is not yet approved in the United States, it is currently offered through an expanded access program called Pitolisant Expanded Access Clinical Evaluation, or PEACE, to patients with excessive daytime sleepiness associated with narcolepsy as well as cataplexy associated with narcolepsy. Pitolisant is already on the market in Europe, under the brand name Wakix.

More recently, a study conducted by Guilleminault and colleagues looked at functional brain images in hopes of better understanding differences between the 2 types of narcolepsy.

 They noted that type 1 narcolepsy is characterized by cataplexy and the “destruction of hypocretin neurons in the lateral hypothalamus, with the elimination of 5 well-delineated axonal bundles.” They found that patients with type 1 narcolepsy and those with type 2 narcolepsy suffer from excessive daytime sleepiness, though cognitive impairment and other comorbidities are much more severe in patients with type 1 narcolepsy.

“These findings reflect the destruction of the 5 axonal bundles coming out of the destroyed hypocretin neurons,” Guilleminault and colleagues wrote. “Clearly, type 2 narcoleptics do not present with such severe handicap and are clinically closer from the so-called hypersomniacs than from the type 1 narcoleptics.”

Another common cause of excessive daytime sleepiness is restless legs syndrome (RLS), a condition famously characterized by individuals’ incessant urge to move their legs. Rowley said many patients who present with daytime sleepiness eventually receive a diagnosis of RLS. He added that the likely cause of that sleepiness is RLS-related sleep disturbance.

“A lot of those patients kick their legs during nighttime,” Rowley said. “They don’t get a good night’s sleep.”

It’s not known exactly how many patients with RLS have problems with daytime fatigue. Results from one study showed that about one-third (37%) of patients with RLS reported excessive daytime sleepiness. That 2009 study, however, included only 27 patients.

 Although genetic factors are believed to play a role in RLS, investi&shy;gators have recently focused on levels of dopamine and iron in the brain. Investigators at Johns Hopkins University have also found that glutamate levels are implicated, with too much glutamate leading to arousal.

Results from research published in 2018 suggest that hyper&shy;arousal in a part of the brain’s motor cortex is the underlying mech&shy;anism at play in RLS, with the brain essentially sending a signal to the legs in preparation of movement, even though the individual has no plans to actually move the legs.

Rowley said a number of questions about RLS remain, the answers to which might have implications for the excessive daytime sleep&shy;iness seen in some patients with RLS. In the meantime, existing treatments for RLS range from behavioral changes to therapies that increase dopamine. Other patients are prescribed opioids, which have been shown to relieve symptoms in some individuals.

Perhaps the biggest area of focus in the sleep medicine commu&shy;nity of late has been obstructive sleep apnea (OSA). A 2017 review found that the prevalence of OSA in the United States general population ranged from 9% to 38%, with men at the highest risk for the condition.

As the name suggests, the most obvious characteristic of OSA is the physical obstruction of the airway. Guilleminault recently published a study looking at the orofacial underpinnings of OSA, which “show that orofacial growth development may be impaired during the fastest growth time (birth to 6 years), and [this] leads to a narrow upper airway.”

 That narrowing can be exacerbated by the tonsils and adenoids and fat deposits in the tongue, both of which can also obstruct the airway.

Although, Guilleminault said the main problem in young people with OSA is maxillary deficiency. Though common, he explained, this deficiency is “never recognized by the pediatrician” but is sometimes recognized by well-informed orthodontists.

This condition leads “to abnormal upper airway resistance and continuous disturbance of sleep [not recognized with simple poly&shy;somnography],” according to Gulieminault. However, despite the physical conditions present in OSA, the condition is also closely tied to the brain.

February 2019

Genetic Targets Invigorate Research for Duchenne Muscular Dystrophy

COMT Inhibitors Assist in Control of Parkinson Disease Motor Symptoms

Reldesemtiv Displays Promise Over Predecessor for ALS, Currently in Phase 2b Trial

Advances Answer Some Questions in Excessive Sleepiness, But Raise New Ones

Neuromodulation and Stimulation Devices Offer Additional Options to Patients With Headache Disorders

Drawing on Blood for Biomarkers of Alzheimer Disease