Kenneth Bender, PharmD, MA

Three disease-modifying treatments for spinal muscular atrophy (SMA) that have been approved all have different mechanisms of action but at least 1 shared property: They work best when early detection of SMA enables affected patients to receive them sooner rather than later.

Prior to the approval of the first gene-modifying therapies for SMA—nusinersen (Spinraza; Biogen) in 2016,

 onasemnogene abeparvovec (Zolgensma; AveXis) in 2019,

 and risdiplam (Evrysdi; Genentech) most recently in August 2020,

 only supportive therapy was available and its timing did not alter the progressive loss of motor neurons in this autosomal recessive neuro-degenerative disorder.

“Time is neurons,” commented Mary Schroth, MD, chief medical officer at Cure SMA, a national patient advocacy and educa-tion organization. “Both the treatments that are available are disease-modifying treatments. Neither of them are cures, but they are life-changing.”

Although SMA is the leading genetic cause of infant mortality,

little progress had been made toward widespread newborn screening for early detection before the advent of gene therapies. The incorporation of SMA into newborn screening quickened with the evident success and FDA approval of nusinersen.

In response to encouraging data, the Maternal and Child Health Bureau of the Health Resources and Service Administration (HRSA) advised in 2018 that SMA be added to the Recommended Uniform Screening Panel (RUSP) in the United States.

“Based on what is known about screening and the risk of being born with SMA, experts think that screening all newborns in the United States for SMA would find about 36 babies with the disorder each year,” the HRSA report stated.

 “Each year, screening could prevent about 50 infants from needing a ventilator and about 30 deaths due to SMA Type 1.”

Inclusion in the RUSP does not mandate nationwide implementation, however, as implementation of the screen for newborns is determined by each state. According to tracking by Cure SMA, newborn screening for SMA has currently been adopted and implemented in 23 states, adopted but not yet implemented in 14 states, and undertaken as a pilot project in 3 states (

“Each state is independent in their identification of a specific SMA screening test, and the way that they go about launching it,” Schroth told NeurologyLive®. “In some states, it’s mandated by their state law that implementation occurs within a certain period of time after inclusion in RUSP.

“It is a state-by-state process,” she said, “which makes it challenging for patient advocacy organizations such as Cure SMA, and also for families because it may depend on which side of a state line you’re on as to whether the infant born today is screened or not for SMA.”

Initiatives from Cure SMA to promote newborn screening and early diagnosis include outreach to state legislators and public health laboratories, as well as maintaining an online newborn screening registry

 for data that could help support new therapy development and improve clinical care. One of its education programs, SMArt Moves, provides separate materials for families and for health care providers to increase knowledge about SMA and recognition of the disorder’s signs and symptoms.

With the increased emphasis on newborn screening for SMA that followed the advent of gene therapies, there has also been increased consideration of testing for carriers. Carrier testing for SMA had previously been recommended for all pregnant women by the American College of Medical Genetics and Genomics

 and the American College of Obstetricians and Gynecologists.

In a recent article, bioethicists argued for increasing the availability of carrier screening to identify potential risk and inform family planning.

“The dual developments of increased treatment options for SMA, Zolgensma and Spinraza, and the increased sophistication of genetic screening technologies prompted us to look at this topic,” Christopher Gyngell, PhD, of the Department of Pediatrics at the University of Melbourne and the Murdoch Children’s Research Institute in Australia, told NeurologyLive

“These developments are leading to novel ethical challenges from both a clinical and policy standpoint,” Gyngell said.

In their analysis, Gyngell and colleagues argued that a moral imperative exists to pursue ex-ante interventions, such as carrier screening, in combination with prenatal testing and preimplantation genetic diagnosis or gene editing to reduce the incidence of SMA. They argue further that such ex-ante methods should be prioritized over ex-post methods for reasons related to autonomy, beneficence, and justice. 

“One thing we touch on,” Gyngell commented, “is that carrier screening can lead to cost savings for health systems, which can be reinvested into other programs. Screening programs can therefore help build more sustainable health systems.”

Treatment Recommendations Follow New Evidence

The genetic screen for SMA is based on the determination that 95% of cases result from a homozygous deletion in the SMN1 gene that encodes the survival motor neuron (SMN) protein. In the other 5% is a mutation rather than an SMN1 deletion, which is not detected in screening.

The loss of SMN protein results in degeneration of anterior horn cells in the spinal cord, with resulting fatigue, paralysis, and atrophy of the proximal muscles.

 There is, however, an inherent mitigation, in that most individuals retain function of 1 or more copies of the paralogous SMN2 gene.

SMN2 also encodes the SMN protein, albeit in a lower amount.

 As the severity of the condition is related to the amount of available SMN, the severity is less in individuals with more copies of SMN2 (

An SMA treatment algorithm based on early detection was developed through expert consensus by a working group convened in 2018 by Cure SMA.

 The group considered preclinical and clinical data (notably from presymptomatic infants in the ongoing NURTURE trial)

 to confirm that the best outcomes occur when disease-modifying therapy agents are given as early as possible.

They found strong evidence, however, that irreversible loss of motor neurons with SMA type 1 begins early in the perinatal period, “with severe denervation in the first 3 months and loss of more than 90% of motor units within 6 months of age.”

The working group recognized that the majority of infants with SMA who have 1 copy of SMN2 would be symptomatic at birth, and they would be likely to have sustained loss that would not be remediated with disease-modifying therapy.

“In this case, the consensus is to defer to the attending physician to determine if the infant and family would benefit from treatment given his or her current disease state,” they indicated. “In the rare event that an infant with SMA with 1 copy of SMN2 is truly presymptomatic, the strong consensus is that the infant should be treated immediately.”

The 2018 working group was unanimous in recommending that immediate, presymptomatic treatment should be provided for all infants with 2 or 3 copies of SMN2. The group was split, however, on whether to extend that recommendation to infants with 4 or more copies.

They reached a consensus that infants with 4 or more copies of SMN2 should be “screened carefully for the first presentation of symptoms” rather than receive gene-modifying therapy immedi- ately after the condition is detected.

The working group was reconvened in 2019 to consider newly emerging data, including additional findings in the NURTURE trial that nusinersen treatment, when given to infants with 2 or 3 copies of SMN2 who were aged under 6 weeks, was associated with significantly better outcomes than treatment given after the age of 6 weeks.

“Patients enrolled in this trial with 2 copies of SMN2 have a dramatically altered disease course with 100% alive, 100% sitting, 88% walking with assistance, 77% walking independently, and none needing the use of permanent ventilation assistance,” the 2019 working group recounted.

From these results, the group extrapolated that such outcomes were as likely to be attained in infants with 4 copies of SMN2 as in those with 3 copies. The working group now recommends that these infants also receive disease-modifying therapy while presymptomatic, immediately after detection in newborn screening.

“With early treatment, disease should be mostly eradicated in presymptomatic patients with 4 copies of SMN2,” they concluded. Schroth emphasized that the rapid progress in treatment and notable clinical trial data that emerged after the first meeting had compelled the working group to reconvene.

“As a result of these therapies being available and clinical trials with additional treatments, clinicians have had more experience utilizing these treatments and understanding the risks and benefits,” she said. “There was a clear majority when they reconvened.”

Addressing, Averting a Devastating Course

SMA phenotypes have traditionally been categorized by the severity of symptoms and the age at onset, in the natural course without disease-modifying therapy, as well as by life expectancy and the motor function milestones that are attained.

In a 2020 journal article, Janbernd Kirschner, MD, of the Department of Neuropediatric and Muscle Disorders at the Medical Center—University of Freiburg in Germany, and colleagues described the presentations associated with the traditional phenotypes, noting that the most severe, type 1, affects more than half of patients with SMA and manifests within the first 6 months of life.

“A ‘floppy infant’ presentation, [with] reduced spontaneous movements, and a paradoxical breathing pattern are characteristic; these infants fail to achieve the free sitting milestone,” Kirschner and colleagues wrote. “SMA type 2 is characterized by a milder course,” they continued, “with onset of symptoms between the ages of 6 and 18 months. Per definition, these patients do manage free sitting, but not independent walking. The latter is achieved, at least temporarily in patients with SMA type 3, whose symptoms’ onset is during infancy or adolescence.

“In addition, some classifications define SMA type 0 and SMA type 4 with prenatal onset or a very mild phenotype entailing an adult onset of symptoms, respectively,” Kirschner and colleagues added.

They point out that disease-modifying drugs, age of onset, number of SMN2 copies, and the age at start of drug treatment will better define a clinical phenotype of SMA going forward than the traditional subtypes.

“These new disease trajectories also mean [that] we must modify and adapt the clinical approach taken,” they wrote.

This is especially relevant with the longer survival that is achieved without ventilation support following initiation of drug treatment. This “needs to be considered when counseling the parents of patients with early-onset types of SMA,” they suggested.

Kirschner and colleagues also pointed out that, despite the improved survival and motor development of symptomatic patients with early-onset SMA, these children also exhibit a higher rate of scoliosis during the first years of life.

“Greater awareness of this risk, and close monitoring of spinal deformities, [appears] crucial to react early and enable the spine to be stabilized via medial orthosis,” they wrote.

Optimal long-term outcomes will require multidisciplinary care, according to Jule Parsons, MD, professor of clinical pediatrics and neurology and codirector of the Neuromuscular Clinic at the University of Colorado Anschutz Medical Campus/Children’s Hospital Colorado in Aurora.

“We are following them to see what that actually is going to mean and look like,” Parsons told 

. “So, it is important to have assess- ments by expert clinicians, in terms of looking at motor outcomes, pulmonary outcomes, growth and weight gain, bone health—we look at and monitor a number of different issues.

“We also have to remember the current population of patients— children and adults with SMA&mdash;and [they] can be extremely complex patients who may also benefit from some of the new therapies that are coming,” Parsons said, referring mainly to risdiplam, Roche/ Genentech’s recently-approved therapy

 that has proved safe and effective in a wide range of patients with SMA, from infants to adults. The therapy, which was approved for use in adults and children with SMA types 1, 2, or 3 age 2 months and older,

 is an orally adminis- tered SMN2 splicing modifier associated with a range of benefits, including significant change in total Motor Function Measure 32 in younger patients and disease stabilization in older ones.

 Parsons and colleagues noted that updated standards of care

 offer 3 general phenotype categories that are determined by motor function class: nonsitters, sitters, and ambulant. Each, they explained, has particular considerations and care needs.

“What I’m seeing is that these patients benefit from the new therapies. They continue to have enhanced motor skills,” Parsons said, “and, frankly, some of the children that we’ve followed have actu- ally met normal motor milestones, the same as for a child who doesn’t have SMA.

“With early [disease-modifying] treatment, we don’t necessarily need to use nonoral therapy, such as feeding tubes, and the respiratory support may be less than what we would have needed in the previous standard of care,” Parsons said.

Schroth agreed that the treatment landscape has changed with the advent of new, effective therapies, and that this has posed both opportunities and challenges to realize them.

“There’s less confidence about what sort of intervention the baby will require,” she acknowledged. “And so now we’re in the stage of trying to better understand the impact of these treatments across the disease spectrum, and what things need to be carefully monitored and acted upon.”

1. FDA approves first drug for spinal muscular atrophy. News release. FDA; December 23, 2016. Updated March 28, 2018. Accessed June 12, 2020. https://www.fda.gov/news-events/press-announcements/ fda-approves-first-drug-spinal-muscular-atrophy

2. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. News release. FDA; May 24, 2019. Accessed June 12, 2020. https://www.fda.gov/news-events/press-announcements/ fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease

3. PTC Therapeutics announces FDA approval of Evrysdi (risdiplam) for the treatment of spinal muscular atrophy in adults and children 2 months and older. News release. PTC Therapeutics; August 7, 2020. Accessed August 7, 2020. https://www.finance.yahoo.com/news/ptc-therapeutics-announces-fda-ap- proval-175400735.html

4. Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 2010;12(3):145-152. doi:10.1097/GIM.0b013e3181c5e713

5. Newborn screening for spinal muscular atrophy. a summary of the evidence and advisory committee decision. Health and Resources and Services Administration. March 13, 2018. Accessed June 12, 2020. https://www.hrsa.gov/sites/default/files/hrsa/advisorycommittees/heritable-disorders/rusp/previ- ous-nominations/sma-consumer-summary.pdf

6. Newborn screening for SMA. Cure SMA. Updated July 1, 2020. Accessed July 6, 2020. https://www. curesma.org/newborn-screening-for-sma/

7. Cure SMA newborn screening registry (NBSR). Cure SMA. Accessed June 15, 2020. https://www. curesma.org/nbsr-sep2019/

8. SMArt Moves. Cure SMA. Accessed June 15, 2020. https://www.curesma.org/smartmoves/

9. Prior TW; Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med. 2008;10(11):840-842. doi:10.1097/GIM.0b013e318188d069

10. Committee Opinion No. 691 summary: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):597-599. doi:10.1097/AOG.0000000000001948

11. Gyngell C, Stark Z, Savulescu J. Drugs, genes and screens: the ethics of preventing and treating spinal muscular atrophy. Bioethics. 2020;34(5):493-501. doi:10.1111/bioe.12695

12. Schorling DC, Pechmann A, Kirschner J. Advances in treatment of spinal muscular atrophy—new phenotypes, new challenges, new implications for care. J Neuromusc Dis. 2020;7(1):1-13. doi:10.3233/JND-190424

13. Glascock J, Sampson J, Haiet-Phillips A, et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromusc Dis. 2018;5(2):145-158. doi:10.3233/JND-180304

14. De Vivo DC, Hwu W-L, Reyna SP, et al. Interim efficacy and safety results from the phase 2 NURTURE study evaluating nusinersen in pre-symptomatic infants with spinal muscular atrophy. Neurology.2017;88(16 Supplement):S46.003.

15. Biogen announces new data further establishing Spinraza (nusinersen) as a foundation of care in spinal muscular atrophy for a broad range of patients. News release. Biogen; July 1, 2019. Accessed June 16, 2020. https://investors.biogen.com/news-releases/news-release-details/ biogen-announces-new-data-further-establishing-spinrazar

16. Glascock J, Sampson J, Connolly AM, et al. Revised recommendations for the treatment of infants diag- nosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromusc Dis. 2020;7(2):97-100. doi:10.3233/JND-190468

17. Genentech’s risdiplam showed significant improvement in motor function in people aged 2-25 with type 2 or 3 spinal muscular atrophy. News release. Genentech; February 6, 2020. Accessed April 7, 2020. https//www.gene.com/media/press-releases/14836/2020-02-06/ genentechs-risdiplam-showed-significant-

18. Gibbons M, Stratton A, Parsons J. Spinal muscular atrophy (SMA) in the therapeutic era. Curr Genet Med Rep. 2019;7:162-167. doi:10.1007/s40142-019-00172-9

19. Mercuri E, Finkel RS, Muntoni F, et al; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. doi:10.1016/j.nmd.2017.11.005 

Articles

Efforts to cut through regulatory red tape will help ensure earlier access to potentially lifesaving treatments.

Early Intervention in SMA: How Access to Therapy Will Alter Disease Management As We Know It

Despite the medical breakthrough of an orally available precursor compound that is converted after crossing the blood- brain barrier to replenish a diminished dopamine neurotransmitter in the brain, the initial consistent therapeutic response to levodopa in patients with Parkinson disease (PD) will eventually wane into “off” periods.

“After several years, sometimes as early as 1 or 2 years, sometimes in 4 or 5 years, but usually in the first couple of years, this so-called honeymoon period begins to end, and many patients begin to notice that 3 or 4 hours after taking a dose of carbidopa/levodopa, their symptoms return and break through,” Stuart Isaacson, MD, director and founder of the Parkinson’s Disease and Movement Disorders Center of Boca Raton in Florida, told NeurologyLive®. “These symptoms can be motor or nonmotor, but when these symptoms come out at the end of a dose, we call it the beginning of an off period.”

Practitioners can address the emergence of PD symptoms in off periods of response to the treatment mainstay levodopa by ensuring therapeutic levels, as well as with adjunctive treatment or alternative dopaminergic agents. Yet even with optimizing therapeutic interventions, symptoms can worsen with the degeneration of dopaminergic neurons as the disease progresses. The challenge of maintaining optimal levodopa therapy also increases over years of treatment and with disease progression. Paolo Calabresi, MD, of the Clinica Neurologica at the Universita&#768; degli Studi di Perugia in Italy, and colleagues described a narrowing window for therapeutic effect and a widening likelihood of either peak-dose dyskinesias or subtherapeutic off dystonia (

The manifestations of oscillation between on and off response to treatment include wearing off, delayed on, no on, and akinesia, typically in the early morning. “These are generally considered to be among the most troublesome symptoms by [patients with] advanced PD,” observed Werner Poewe, MD, and Philipp Mahlknecht, MD, PhD, of the Department of Neurology at the Medical University of Innsbruck in Austria.

Poewe and Mahlknecht related the dyskinesias to an on-off cycle with on-period chorea, biphasic dyskinesias, and off-period dystonias that are often painful. Although severe, disabling dyskinesias are less frequent, but they do require medical attention. Milder forms of dyskinesia are more frequent but generally do not require changes in treatment, Poewe and Mahlknecht suggested, “if other components of motor function are adequately maintained.”

The risk of levodopa-induced motor complications has previ- ously given rise to debate about withholding levodopa therapy until required in later PD, particularly in patients younger than 70 years, Poewe and Mahlknecht noted, with the hope that these adverse effects might also be delayed. That position is supported by the association of levodopa-induced motor complications with a cumulative amount of levodopa, as well as higher daily doses (≥400 mg and/or >4 mg/kg). However, an association exists with longer duration of PD at the initiation of levodopa and with early-onset PD.

In a recent Viewpoint column in JAMA Neurology, Jorik Nonnekes, MD, PhD, of the Radboud University Medical Centre; Donders Institute for Brain, Cognition and Behaviour; Department of Rehabilitation, in Nijmegen, the Netherlands, and colleagues suggested that freezing of gait (FOG) might also be a manifestation of levodopa treatment and a reflection of the peak and valley levels from traditional levodopa regimens.

“It is accepted that long-term levodopa treatment, possibly because of its pulsatile administration, results in loss of compensatory postsynaptic dopaminergic receptor upregulation and maladaptive plasticity of the striatum via influence on physiological forms of synaptic plasticity,” Nonnekes and colleagues wrote.

They posited that FOG may reflect levodopa-induced aberrant plasticity, with increased thresholds of postsynaptic receptors within the motor circuitry connecting the striatum, premotor area, and supplementary motor area, necessitating higher dopamine concentrations for activation. “In the off-medication state, it is more difficult to overcome the higher-than-normal stimulation thresholds within the motor circuitry, so FOG is typically more severe in this state than the on-state,” Nonnekes and colleagues wrote.

 Although increasing levodopa dosage would initially meet the higher threshold, they suggested, over the long term, the higher dosage will further stimulate maladaptive plasticity, producing higher thresholds and greater FOG severity.

Arguing against delaying levodopa until later stages of PD to avoid motor complications, however, Poewe and Mahlknecht pointed out that delaying the treatment, particularly with the need to start with

a higher dosage for more severe symptoms, is generally associated with a shortened period of therapeutic effect before motor complications begin.

 “Therefore, the current common approach is to introduce levodopa as soon as needed to maintain good symptom control

At the onset of response oscillations and levodopa-induced motor complications, practitioners must manage the pharmacological regimen to provide more continuous and reliable dopaminergic drug delivery.2 This is typically accomplished by increasing the dosage, dividing the levodopa dosage into smaller but more frequent doses, or by modifying the pharmacokinetics of the levodopa administration.

“We believe that levodopa continues to work throughout the decades-upon-decades—long course that some patients have Parkinson disease,” Isaacson said. “That is, you do not become ‘resistant’ to levodopa. The need for taking higher doses of levodopa or doses closer together or both reflects, we think, both problems that occur in changes in the brain itself and problems that occur in its absorption through the [gastrointestinal] system,” he added.

The factors that can affect the pharmaco- kinetics and contribute to loss of levodopa effect include changes in the absorption and assimilation of the medication, according to Harsh V. Gupta, MD, of the Department of Neurology at The University of Kansas Medical Center in Kansas City, Kansas, and colleagues.

 “As the disease progresses, variations in plasma levodopa levels lead to motor fluctuations,” they wrote.

 “The common reasons behind variations in the plasma levels include delayed gastric emptying, small intestinal overgrowth, protein interaction with levodopa absorption, and limited oral bioavailability of levodopa.”

Isaacson elaborated on these pharmacokinetic and pharmaco-dynamic challenges. “This really reflects the combination of trying to replace an essential neurotransmitter like dopamine by swallowing its precursor, the circuitous route it takes and the short half-life in the bloodstream, and the difficulty with storage in the brain,” he said. “So we always look for ways of trying to adjust the timing of taking the oral [dose]. We try to use extended deliveries of levodopa, either in oral or nonoral formulations, or we look at ways of trying to make a dose begin to work quicker.”

Gupta and colleagues described a variety of formulations of levodopa or levodopa-carbidopa that circumvent or mitigate these potential barriers to maintaining optimal levels. The products—now available, in development, or currently used outside the United States&mdash;include controlled or extended-release oral formulations, orally disintegrating and inhaled formulations, and frequently dosed microtablets, as well as more invasive formulations such as intrajejunal infusion and subcutaneous injection and infusion.

Among the novel formulations is the inhaled form of levodopa, Inbrija (Acorda), approved by the FDA in 2018 for treatment of off episodes.5 Gupta and colleagues noted that in the pivotal randomized trials, self-administration during off periods led to a rapid improvement in symptoms.

Another distinctive formulation of carbidopa-levodopa is a pellet-like microtablet, currently available in Sweden. The microtablets are taken from an automatic dose dispenser, programmed with an alarm to remind patients. “The concept behind using a microtablet is to give a more frequent but decreased individual dose of levodopa, which leads to a reduction in fluctuations,” Gupta and colleagues said.

Adjuncts and Alternatives to Reduce Off Periods

In addition to modifying carbidopa-levodopa formulations to optimize drug levels, enzyme inhibition strategies are used to increase drug effect by prolonging synaptic availability of dopamine. Monoamine oxidase B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors have been used as add-on treatments to reduce off periods, as well as in levodopa-carbidopa “sparing” regimens.

Since the introduction of MAO-B and COMT inhibitors, novel formulations have also been developed to facilitate the administration and enhance the bioavailability of these products. The MAO-B inhibitor selegiline, for example, received initial FDA approval as a 10-mg oral tablet in 1989, and in 2006, the FDA approved a 1.25-mg orally disintegrating tablet, Zelapar (Valeant Pharmaceuticals), based on data demonstrating it provided similar plasma levels.

 In April 2020, the agency also approved the first once-daily dosage form of the COMT inhibitor opicapone (Ongentys; Neurocrine Biosciences) as add-on treatment to decrease off periods and increase on time without dyskinesia.

An additional approach to reduce off periods with a recently approved adjunct targets the adenosine A2a receptors, which are localized on cell bodies and terminals in the indirect striatal output pathway and are involved in development of motor fluctuations. Intermittent, pulsatile levodopa therapy leads to upregulation of A2a receptors, increasing stimulatory output and reduced motor activa- tion and contributing to the off periods in treatment response.

 receptor antagonist istradefylline (Nourianz; Kyowa Kirin) received approval

 in August 2019 as an adjunct to treat off episodes in patients with PD receiving levodopa. The FDA initially turned it away in 2008, requesting more data.

"I think we have to have more treatment strategies where we try to educate our patients to recognize the symptoms, motor and nonmotor, that they experience and to recognize fluctuations that can occur... and the types of off episodes and when they can occur," stated Stuart Isaacson, MD. 

The subsequent application to the FDA was supported by four 12-week, placebo-controlled trials that included a total of 1143 participants (NCT00456586, NCT00199407, NCT00455507, NCT00955526). “In all 4 studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time compared to patients receiving a placebo,” the FDA indicated in announcing the approval.

In their review of the clinical trials with istradefylline, Alok Singh, MD, of the Department of Pharmacology, All India Institute of Medical Sciences, Raipur in Chhattisgarh, India, and colleagues found a comparable efficacy with the COMT and MAO-B inhibitors in reducing daily off periods.

 One advantage of istradefylline over these agents, they pointed out, is that it lacks the potential drug interactions with antidepressants and many other drugs acting on the central nervous system.

If these measures fail to substantially reduce off periods, alternative dopaminergics may be useful. Apomorphine has been particularly valuable as a rescue measure. Gupta and colleagues attributed this to apomorphine acting on all dopamine receptor subtypes as well as on serotonergic and adrenergic receptors, in contrast with other dopamine agonists such as pramipexole and ropinirole, which have relatively selective affinity for the dopamine D2 receptor.

In addition to the currently available intermittent subcutaneous injection (Apokyn; US WorldMeds), the FDA recently approved 2 new acute options. In May, the agency granted approval to Sunovion Pharmaceuticals’ apomorphine sublingual film (Kynmobi), the first sublingual therapy for this indication.

 The novel delivery route is meant to avoid gastrointestinal absorption issues commonly observed in patients with PD, allowing for improvement in motor symptoms in as little as 15 minutes post dose. The new drug application was supported by data from the phase 3 CTH-300 trial (NCT02469090), in which apomorphine sublingual film demonstrated significant improvements in motor function compared with placebo. The mean change in Unified Parkinson’s Disease Rating Scale (UPDRS) part III at 30 minutes post treatment at week 12 was —11.1 points with apomorphine sublingual film compared with –3.5 points with placebo, representing a 7.6-point difference between the 2 groups (

 = .0002).12 During the maintenance phase, more patients treated with the study drug reported being fully on at 30 minutes post dose compared with those receiving placebo (

Late in 2018, the FDA approved Acorda Therapeutics’ inhaled levodopa powder, Inbrija.

 The application was supported by findings from the pivotal phase 3 SPAN-PD trial (NCT02240030), a 12-week, randomized, double-blind, placebo-controlled study in patients with mild to moderate PD experiencing off periods. The trial met its primary end point, with patients on the study drug experiencing a 9.83-point reduction on the UPDRS part III 30 minutes post dose compared with a 5.91-point reduction in the placebo group (

 = .009). Notably, onset of action was observed as early as 10 minutes post dose.

Such new delivery systems and formulations not only provide additional treatment options, Gupta and colleagues wrote, “but, in many cases, have also allowed for improved symptom control and improved quality of life for those living with PD.”

The array of therapeutic agents and formulations and the number in clinical testing are a welcome but challenging development, Isaacson indicated. “It’s both challenging [and exciting], and we’re quite lucky to have so many treatment options for people who live with Parkinson disease. I think we have to have more treatment strategies where we try to educate our patients to recognize the symptoms, motor and nonmotor, that they experience,” he said, “and to recognize fluctuations that can occur, resulting in off episodes, and the types of off episodes and when they can occur.”

To facilitate patient education and elicit details about the patient’s experience that could help to inform treatment choice, Isaacson recommended that patients keep a diary of symptoms for 2 or 3 days prior to a visit, addressing the following questions:

How long does it take for the first oral levodopa dose to begin to work?

What symptoms improve when it begins to work?

How long does the improvement last during that on period?

What symptoms begin to return at the end of a dose interval?

At what time (interval) do they take each subsequent dose?

How long does it take for each dose to work, before the symptoms improve again and the off episode ends?

“It’s a combination of educating ourselves and our patients and their caregivers about all the different treatment options,” Isaacson explained. “We have a number that are approved and a couple dozen medicines in research programs that give us great hope in trying to treat the motor and nonmotor symptoms and the fluctuations even better over time. Through shared clinical decision-making with our patients and their families and caregivers, [we can] find which option is best.”

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2. Poewe W, Mahlknecht P. Pharmacologic treatment of motor symptoms associated with Parkinson disease. Neurol Clin. 2020;38(2):255-267. doi:10.1016/j.ncl.2019.12.002 

3. Nonnekes J, Bereau M, Bloem B. Freezing of gait and its levodopa paradox. JAMA Neurol. 2020;77(3):287-288. doi:10.1001/jamaneurol.2019.4006 

4. Gupta HV, Lyons KE, Pahwa R. Old drugs, new delivery systems in Parkinson’s disease. Drugs Aging. 2019;36(9):807-821. doi:10.1007/s40266-019-00682-9 

5. Drug approval package: Inbrija. FDA. Updated May 28, 2019. Accessed May 5, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209184Orig1s000TOC.cfm 

6. Valeant Pharmaceuticals receives FDA approval of Zelapar for patients with Parkinson’s disease; Zelapar significantly reduces “off” time through unique delivery mechanism. News release. Valeant Pharmaceuticals. June 15, 2006. Accessed May 5, 2020. https://www.businesswire.com/news/home/20060615005238/en/Valeant-Pharmaceuticals-Receives-FDA-Approval-Zelapar-Patients 

7. Neurocrine Biosciences announces FDA approval of once-daily Ongentys (opicapone) as an add-on treatment for patients with Parkinson’s disease experiencing “off” episodes,. News release. Neurocrine Biosciences. April 27, 2020. Accessed May 5, 2020. http://www.multivu.com/players/English/8719751-neurocrine-biosciences-ongentys/ 

8. Sahoo AK, Gupta D, Singh A. Istradefylline: a novel drug for ‘off’ episodes in Parkinson’s disease. Drug Ther Perspect. 2020;36:208-212. doi:10.1007/s40267-020-00718-w 

9. FDA approves new add-on drug to treat off episodes in adults with Parkinson’s disease. News release. FDA. August 27, 2019. Accessed May 5, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-add-drug-treat-episodes-adults-parkinsons-disease 

10. Kyowa Hakko receives not approvable letter from FDA for Istradefylline (KW-6002). News release. Kyowa Hakko Kogyo. February 28, 2008. Accessed May 5, 2020. https://www.fiercebiotech.com/biotech/kyowa-hakko-receives-not-approvable-letter-from-fda-for-istradefylline-kw-6002 

New drug classes and formulations may help hold off breakthrough activity as the research community works to optimize levodopa delivery and absorption.

Keeping Treatment Response "On" in Parkinson Disease

A platform clinical trial, an innovative design with a single master protocol and placebo control arm for multiple candidate treatments that has been used to efficiently test and successfully launch new drugs for cancer, is now being applied by the Healey Center for ALS (amyotrophic lateral sclerosis) at Massachusetts General Hospital (MGH) to expedite clinical assessment of investigational agents for the terminal neuromuscular disease.

In contrast to the more lengthy and costly process of conducting controlled clinical trials of 1 candidate drug at a time—which has yielded only 1 FDA-approved compound for ALS (edaravone) since the first (riluzole) was approved in 1995&mdash;the Healey Center announced in September 2019 that it will launch a 

 in 2020 with initially as many as 5 candidate drugs.

“As the field develops more understanding of disease pathophysiology and targets, and has a larger pipeline of treatments, the platform trial approach is a much more efficient, patient-supportive way to develop treatments,” Merit Cudkowicz, MD, MSc, director of the Healey Center, chief of neurology at MGH, and principal investigator of the platform trial, told 

The Sean M. Healey & AMG Center for ALS is named for its benefactor, then chairman and chief executive officer of the international asset management firm, Affiliated Managers Group, Inc. Within 6 months of being diagnosed with ALS in May 2018, Healey had raised approximately $40 million for the center to launch the platform trial initiative.

The Healey Center is collaborating with the network of clinical research and treatment sites in the Northeast ALS Consortium (NEALS) and working with each of the selected biotechnology firms to tailor platform trial study arms to the respective investigational products.

Bayesian statistical tools and a common control arm will facilitate the testing of multiple investigational drugs at the same time.

“We calculate that this approach cuts in half the time to finding effective treatments, lowers the number of people needed in trials by one-third, and increases participants receiving active treatment by two-thirds,” Cudkowicz said.

Cudkowicz and colleagues designed the platform trial and selected the most promising candidate products from proposals received from biotechnology innovators whom, Cudkowicz relayed in a previous interview, “have great ideas but not deep pockets.”

The Healey Center received approximately 30 applications from 10 countries from its initial request for proposals. Ultimately, the center’s Therapy Evaluation Committee selected 5 therapies (TABLE).

“Each of the investigational products that will be tested in the platform trial has been tested in preclinical and early-phase trials in either ALS or other neurodegenenerative diseases,” Sabrina Paganoni, MD, PhD, assistant professor of PM&R at Harvard Medical

School and coprincipal investigator of the platform trial, told 

®. “These other trials demonstrated the biological value of the products for ALS and the ability to engage their respective targets. They also helped guide dose selection and provided important information about the drugs’ safety profile,” Paganoni said.

Although large pharmaceutical manufacturers were welcome to propose candidate products for the platform trial, and companies like Biogen and Sanofi participated in trial design discussions, the proposals were received from smaller firms, with promising candidate products but fewer development resources.

Clene Banks on Novel Gold Nanotherapeutic for ALS and Beyond 

“As a virtual biotech company, with a low head count and a focus on capital efficiency, the Healey platform provides an ideal framework for us to move our biologic into large-scale ALS clinical development,” Garry Redlich, chief executive officer of Implicit Bioscience, told 

®, describing the opportunity that the platform trial provides for developing their investigational product, IC14. “Not only will the study be established and run by the most accomplished clinical researchers in the field, but NEALS and the Healey Center at MGH have established a great working relationship with the FDA,” he noted. “The biostatistical design supporting the platform study is based on more than 10,000 patient disease histories.”

“This is not a resource that any company, let alone a small biotech like Implicit Bioscience, could bring to bear in the effort to get this job done convincingly in such a short time frame,” Redlich acknowledged.

This sentiment was shared by Rob Etherington, president of Clene Nanomedicine. “What’s particularly important for a company such as Clene, and frankly all the companies involved, is that this is likely to be a registration study,” he told 

“There’s already been extensive conversation with the FDA,” Etherington said, “that if 1 or more of these drugs hits its primary end point and shows change in the ALS functional composite score ... that should be sufficient to take the drug to approval for a high-medical-need disease—patients in desperate need of care&mdash;such as ALS.”

The investigational new drug application for the platform trial was approved by the FDA in January 2020, ultimately granting a “may proceed” to 3 of the 5 drugs selected by the Therapy Evaluation Committee: CNM-Au8, verdiperstat, and zilucoplan. Paganoni said that the research team will work to incorporate IC14, pridopidine, and several other therapies over the next few months. Cudkowicz is confident that their approach to facilitating clinical research for ALS is consistent with FDA priorities and with the criteria in recently issued guidance.

“We have had excellent meetings with the FDA, and they have been very helpful and supportive,” Cudkowicz said. “We plan to use a common DSB [data and safety monitoring board] and common safety monitoring approach for all regimens. The shared placebo group is critical to the purpose and success of the platform trial.”

The FDA’s role in encouraging such innovative trial design and drug development was described by Janet Woodcock, MD, director of the FDA Biologics Evaluation and Research, and Norman Sharpless, MD, director of the agency’s Center for Drug Evaluation and Research, in a joint statement in September 2019.

“We recognize that scientific progress across different disease and therapeutic areas has been uneven, particularly lagging for complex neurological diseases, such as ALS,” Woodcock and Sharpless said.

 “We know that an important element of product development is working early and often with researchers and companies to help facilitate their clinical development programs. That’s why our final guidance recommends that researchers and companies interact with the FDA early in product development so that we can best advise on proposed development programs and the efficient design of trials to produce the data needed for FDA approval in order to get effective therapies to patients as efficiently as possible.”

The agency’s guidance for industry encourages trial design with master protocols that use a single infrastructure for the simultaneous evaluation of multiple drugs and to employ a common or shared placebo group. The guidance also promotes the use of adaptive designs, including the use of Bayesian features and enrichment strategies.

In addition, the agency's guidance to the industry also emphasizes the importance of evaluating agents across the severity stages of ALS.

“Although sponsors may have good reason to use prognostic enrichment to increase the likelihood of demonstrating a drug effect (eg, to enroll patients who are more likely to experience rapid progression) or to use predictive enrichment to direct therapy to patients with a particular disease characteristic (eg, a specific genotype or phenotype), sponsors should not unnecessarily exclude patients from trial enrollment based on characteristics such as age or disease stage unless scientifi- cally justified,” the guidance cautions.

Each of the developers expressed agreement that the platform clinical trial should evaluate the investigational agents in a range of patients with ALS.

“We believe that all patients, including those with both familial and sporadic forms of ALS, could benefit from complement inhibition. For this reason, aside from the general patient entry criteria for the platform trial, we have not added any further requirements to the zilucoplan arm of the trial,” Simon Read, PhD, chief scientific officer of Ra Pharmaceuticals, told 

In addition to evaluating safety and efficacy of the interventions, the platform trial is also designed to inform the field on new biomarkers and outcome measures for ALS, according to Cudkowicz.

“We will include the best-known biomarkers and also collect data and samples to discover new ones,” she said. “In particular, we are planning on whole-genome sequencing in all participants; neurofilament [levels]; urine [neurotrophin receptor] P75; banking serum and plasma; and banking peripheral blood mononuclear cells for future induced pluripotent stem cell motor neuron—type studies.”

“We will also use a new approach for speech monitoring remotely,” Cudkowicz said. “Each arm may also include drug-specific biomarkers. The study is also designed for flexibility to easily add additional biomarkers if relevant.”

Platform for First-in-Class Interventions

The selected investigational agents are all first-in-class biotherapeutic innovations that were developed to treat neurodegenerative disorders, although not necessarily targeting ALS. Their inclusion in the platform clinical trial, however, could leapfrog other development directions to position them as viable therapeutic options for patients with ALS.

The formulation of CNM-Au8 is described as an orally adminis- tered, concentrated, aqueous suspension of pure faceted nanocrystalline gold that acts catalytically to support various intracellular biological reactions.

Etherington said that the product is directed at improving cellular bioenergetics which, he explained, is the improvement in the degenerative processes that increase with aging and accelerate in neurodegenerative disorders.

“We’re looking at an increase in both the NAD-positive/NADH ratio (ratio of the oxidized to reduced form of nicotinamide adenine dinucleotide, measured by phosphorous magnetic resonance spectroscopy) and a reduction in reactive oxygen species, which is effectively the by-product of what happens in cellular energy,” Etherington said.

“Mechanistically, what we see in the assays we’ve explored, in fact in the REPAIR trial program in Parkinson disease and patients with MS, is looking specifically at a sensitive quantification of what is happening with the bioenergetics metabolites within the brain and the bioenergetics membrane markers,” he said. “So, we’re looking at not just NAD-positive/NADH, but also at phosphocreatine, extracellular phosphate—a series of phosphate measures.”

The orally administered verdiperstat is an irreversible inhibitor of the enzyme myeloperoxidase (MPO), which is associated with increased oxidative stress and inflammation levels in the brain and spinal cord, according to Irfan Qureshi, MD, vice president of neurology at Biohaven Pharmaceutical.

Biohaven is now conducting a phase 3 clinical trial of verdiperstat in multiple system atrophy, for which there are now only symptom- atic and palliative therapies. The agent was originally developed by AstraZeneca, which conducted phase 1 and 2 trials that suggest it is generally safe, well tolerated, and has the potential to reduce microglial activation.

“The presence of large numbers of activated microglia is 1 of the hallmarks of neurodegeneration in ALS. MPO is a powerful pro-oxidant enzyme that is present in activated immune cells, including microglia,” Qureshi explained. “Inhibiting MPO is anticipated to ameliorate these pathological mechanisms, which are strongly implicated in the onset and progression of ALS,” he told NeurologyLive®.

Zilucoplan is a macrocytic peptide that binds to complement C5 to inhibit its cleavage into C5a and C5b in activation pathways, which have been linked with inflammation that can contribute to chronic central nervous system diseases.

“The complement pathway is a fundamental component of the innate immune system and has been demonstrated to be involved in destruction in both peripheral and central motor neuron pathways in ALS,” Read said. “Robust preclinical data support the role for central and peripheral complement activation and deposition in ALS. In animal models, targeting complement delayed disease progression and extended survival.”

Read distinguished the small peptide from the larger monocolonal antibodies that have been used to therapeutically target complement, noting that zilucoplan appears to have greater tissue distri- bution and other properties that make it an optimal C5 inhibitor for evaluation in ALS.

“Importantly, we are working hand in hand with the Healey Center as we work toward trial initiation, and the relationship has been incredibly collaborative and productive,” Read said. “We’ve found a unique partner to allow us to efficiently conduct this trial, while also continuing to allocate our resources to our other ongoing clinical trials for zilucoplan, including a phase 3 trial for generalized myasthenia gravis and phase 2 trial for immune-mediated necrotizing myopathy.”

Qureshi shared this enthusiasm for the prospects of the platform trial. “We are in a new era for ALS therapy development, and we must think differently and boldly about how to find effective treatment for our patients,” he said. “To that end, we are excited to accelerate how therapies are developed for people with ALS, and this [platform] trial will help in that process.”

“I think we will be seeing many more platform trials in neurotherapeutics,” Cudkowicz said. “We are planning a symposium next summer for platform trials in neurology to bring together groups working on this approach, to share lessons and approaches.”

“We are in a new frontier for neurotherapeutics for ALS and other disorders,” she said. “It is a very hopeful time.”

1. Dunn A. First-of-its-kind trial in ALS spurs hope for brutal disease. Biopharmadive. September 25, 2019. biopharmadive.com/news/als-platform-trial-mass-general-healey-center/563595/. Accessed January 6, 2020. 

2. US Food and Drug Administration Center for Drug Evaluation and Research.  Amyotrophic lateral sclerosis: developing drugs for treatment. Guidance for industry. September 2019.  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/amyotrophic-lateral-sclerosis-developing-drugs-treatment-guidance-industry. Accessed November 27, 2019.

3. FDA statement on final guidance to help advance development of novel treatments for ALS [news release]. September 23, 2019. fda.gov/news-events/press-announcements/statement-final-guidance-help-advance-development-novel-treatments-als. Accessed January 6, 2020. 

The Healey ALS Platform Trial learns from successful cancer drug studies to identify and accelerate new treatments for the devastating disease.

Kenneth Bender, PharmD, MA

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