Opportunities and Challenges in the Treatment of Pediatric-Onset Multiple Sclerosis with Highly Active Disease-Modifying Therapies

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system, with an incidence of 1 in 100,000. Pediatric-onset MS (POMS) accounts for 2% to 10% of cases.^1,2 Although POMS is rarer than adult-onset MS (AOMS), unique aspects of MS in children provide key insights into the pathophysiology of MS across the life span. Relative to AOMS, children and adolescents with POMS experience higher relapse rates with quicker recovery.^1,2 Individuals with POMS can present with a wide spectrum of symptoms before and after diagnosis, including cognitive dysfunction, depression, fatigue, visual disturbances, extremity weakness, coordination issues, and bowel and bladder problems.¹

Early diagnosis and treatment with disease-modifying therapy (DMT) lead to better long-term outcomes.² More than 25 DMT options have been approved by the Food and Drug Administration (FDA) for individuals with AOMS, but only 1 treatment option has been approved for people with MS who are younger than 18.^1,3 This poses a challenge for providing medication options to children with MS but also highlights opportunities for innovative trial designs4 and expansion of therapeutics in POMS. The purpose of this review is to highlight advances and changes in pediatric clinical research and the future of POMS treatment.

Risk Factors

The risk for developing MS is complex and involves a combination of genetic and environmental factors.^2,5 Factors identified in AOMS have largely been replicated in POMS studies. The strongest genetic risk factor is sequence variation in the HLA-DRB1*15:01 gene; other behavioral and physiologic factors such as Epstein-Barr virus infection, cigarette smoking, vitamin D deficiency, and obesity are all associated with increased MS risk.^5-7 In the past several years, environmental factors such as chemical exposures, air quality, and gut microbiota species were also found to be associated with POMS risk.^6,8 Some of these risk factors also have been associated with disease activity.^7,8

Evolution of MS Treatments

Approaches to treatment of POMS historically relied heavily on early FDA-approved DMTs, such as interferon beta (IFNΒ; approved in 1993) and glatiramer acetate (approved in 1996).^6,9 Clinical trials were not completed in children for these original DMTs. However, in observational studies, both classes of injectable medications have demonstrated ability to limit disease activity safely in individuals with POMS.^6,7 Over the past 15 years, higher-efficacy medications have been approved for AOMS treatment, with greater long-term clinical and radiologic efficacy.⁹ The first of these, natalizumab (Tysabri; Biogen, Cambridge, MA), was not studied in children in its original pivotal trials, in part because of little awareness of POMS as a disease entity, as well as safety concerns for the drug itself.^7,9 Subsequent observational studies demonstrated substantial efficacy of this agent in children.⁷

While AOMS research and clinical care were evolving, there was a great need to better understand the disease in children and increase awareness in the medical community.^4,5 Whereas information about POMS incidence and disease features have increased substantially over the past 2 decades,⁵ POMS treatment still largely relies on extrapolation from adult clinical trial data.⁵ This led to a call to action for more clinical trials in POMS⁷ to disseminate higher-quality evidence-based data in children and apply novel clinical trial designs⁴ to reduce disease burden in this vulnerable population. The FDA now requires consideration of children in the development and approval of all new agents for MS.

A 2020 observational real-world research study by the US Network of Pediatric MS Centers examined differences in efficacy of newer DMTs—including fingolimod (Gilenya; Novartis, East Hanover, NJ), dimethyl fumarate ([DMF] Tecfidera; Biogen, Cambridge, MA), teriflunomide (Aubagio; Sanofi Genzyme, Cambridge, MA), natalizumab, rituximab, and ocrelizumab (Ocrevus; Genentech, South San Francisco, CA)—vs the older injectable DMTs IFNΒ and glatiramer acetate.¹⁰ A total of 43% of participants receiving injectable DMTs (n=227) experienced relapse during the study, vs only 19% of participants taking newer DMTs (n=195). In addition, 72% of participants on older injectable DMTs had new or enlarging lesions on MRI compared with 42% of participants taking newer DMTs (Table).¹⁰ These data demonstrate a substantially greater efficacy in the newer DMT group.

Completed Clinical Trials in POMS

Once a DMT has been deemed safe and effective among the adult population, additional clinical research trials are pursued to investigate the benefits and risks of the same treatment in the pediatric population. DMTs approved for use in the AOMS population come in a variety of forms, including intravenous injection, pills or capsules, and subcutaneous injection.^10-12 DMTs considered for pediatric investigative clinical trials should be effective in reducing annual relapse rate, MRI activity, and general disease burden over time in individuals with AOMS with minimal adverse effects.¹

Fingolimod is the only FDA-approved DMT for people with POMS.¹⁰ Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocyte egression from the peripheral lymph nodes, thereby preventing autoreactive lymphocytes from entering the central nervous system.^3,11,12 Results from the PARADIGMS randomized controlled trial (RCT) (Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis, NCT01892722), published in 2019, compared the safety and efficacy of fingolimod vs interferon and determined that fingolimod reduced the annual relapse rate in participants age 10 to 18 years by 85.5% and reduced MRI activity by 52.6% over a 2-year period.^11,12 Whereas fingolimod demonstrated greater efficacy, it also demonstrated greater incidence of serious adverse events and reactions than found in the interferon arm. Approximately 16.8% of individuals in the fingolimod arm experienced at least 1 serious adverse event compared with 6.5% of participants receiving interferon. In addition, of 107 individuals randomized to fingolimod, 6 experienced seizures (5.6%) compared with only 1 of the 108 individuals in the interferon arm (0.9%).^11,12 Another study examining the benefit–risk balance of fingolimod use in individuals with POMS determined that adverse reactions to this drug are common, including liver enzyme elevations, infection risks, cardiac abnormalities such as bradycardia, and macular edema.¹³ Thus, fingolimod is effective in treating individuals with POMS, but people should be carefully screened with baseline cardiac and ophthalmologic evaluations before starting the medication and monitored closely while taking the medication. CONNECT (Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-remitting Muleiple Sclerosis [RRMS], NCT02283853) was a randomized clinical trial comparing the safety and efficacy of DMF vs IFNΒ-1a for use in POMS.¹⁴ Pediatric participants in the IFNΒ-1a arm had a greater number of new or newly enlarging T2 lesions and a higher relapse rate than those in the DMF arm, demonstrating greater efficacy for DMF.¹⁴ Still, safety concerns remain, given the high incidence rate of adverse drug reactions in individuals in both the IFNΒ-1a and DMF arms: 143 out of 150 participants (≈95%) experienced treatment-emergent adverse events, including MS relapse, headache, infection, or gastrointestinal intolerance.¹⁴ Thus, despite the demonstrated efficacy of DMF, safety concerns remain and present a substantial challenge for implementation as a feasible treatment option.

As POMS research continues to develop, some DMT trials have aimed to investigate not only relapse reduction and reduced lesion burden, but also biomarkers of neural injury and degeneration.¹⁵ As an example, the TERIKIDS RCT (Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis, NCT02201108) examined the effect of teriflunomide on plasma neurofilament light chain levels in people with POMS.¹⁵ Participants were randomized to active teriflunomide orally once daily or placebo. Whereas the results for relapse reduction were not significant, teriflunomide significantly lowered plasma neurofilament light chain levels.¹⁵

The paucity of FDA-approved treatment options emphasizes the need for further clinical research trials to test additional DMT for POMS. However, although fingolimod is the only FDA-approved DMT, people with POMS are treated with other high-efficacy DMT off-label.¹⁶

Challenges of POMS Clinical Trials

Several challenges are present when extending an investigational drug trial in an adult population to include the pediatric population. Sample size often differs between POMS and AOMS clinical trials because of the rarity of POMS.¹⁶ Besides the low availability of POMS participants, difficulties exist in consenting and enrolling children and their parents in clinical trials.^7,17 A survey of people with POMS and their parents suggested that this population was hesitant to enroll into investigational drug trials primarily because of concerns related to missed school and work time as well as hesitancy to use an experimental drug in a vulnerable population.^7,17 Despite these mechanistic and systemic challenges, opportunities for positive developments in POMS clinical research remain.

Children have higher relapse rates than adults, which presents opportunities for studying drug efficacy over shorter time periods as well as challenges in maintaining disease quiescence. An observational study comparing the efficacy of treating adults and children with alemtuzumab after natalizumab determined that alemtuzumab is highly effective in treating AOMS but not POMS after natalizumab treatment.⁵ The study examined differences in efficacy when switching from 1 treatment to another, rather than both treatments independently. Whereas individuals with AOMS experienced a lower risk of clinical and radiographic relapses after switching from natalizumab to alemtuzumab, the pediatric population showed a higher risk of relapses.⁵ These results suggest interesting differences in the MS disease course between adult and pediatric populations, although this study was not a RCT.

Additional challenges include considering secondary outcome measures that can best capture DMT efficacy, finding more appealing study designs for people with POMS and their families, and determining new approaches to treating POMS.^4,17 Because research in the POMS population is so valuable and crucial, it is important to understand the methods by which its processes can be improved and the challenges overcome.

Clinical Trial Design and the Future of DMT Development in POMS

Opportunities for people with POMS to access DMTs in clinical trials are improving. Since the first POMS clinical trials and approval of fingolimod in 2018, clinical researchers have modified study designs to appeal more to pediatric participants, with increased safety assessments, reduced time commitments, and access to more treatment options.^4,7 Although several challenges that accompany enrolling in a clinical trial and receiving treatment with investigational DMT remain, the future of POMS clinical research continues to develop in a way that prioritizes feedback from participants and their families and strives to broaden treatment options for the historically overlooked pediatric population.^4,7 Parents and children may be hesitant to participate in an investigational drug trial for newer DMTs.¹⁷ However, a survey of POMS clinical research suggested that individuals and families generally wanted to learn more about the research process and assist in advancing science and knowledge pertaining to the disease.¹⁷ In addition, people with POMS and their families reported that having their clinical, research, and safety data monitored closely by a research team was appealing.^7,17 Clinicians and researchers are continually reviewing the methodology of pediatric clinical research and identifying ways in which the process can be improved.¹⁷

Challenges in recruiting large enough sample sizes call for more novel trial designs. As an example, Bayesian study designs can leverage previous data to help reduce sample sizes. The Bayesian study design is structured to make probable suggestions about a data set by considering historically collected data from a similar population.^4,17 Therefore, data collected from AOMS populations in adult research studies can be used for POMS research.^4,17

There is a great need to gather additional outcome measures other than annualized relapse rate and MRI activity. Although both of these measures have been shown to be indicators of disease activity and burden in people with MS, individuals with MS experience a broad range of disease burden clinically as well as subclinical development of pathologies that lead to progression independent of relapses later in life; therefore, more comprehensive and quantitative outcome measurements and novel biomarkers that account for this would be beneficial.¹⁷

The future of POMS clinical research will include creative trial designs to facilitate the study of drugs in children, novel outcome measures, and a keen eye on outcomes in the immediate future as well as the potentially changing risk for severe disease later in adulthood.^17,18 With newer outcome measures comes the need for greater regulatory support and sponsorship to continue advocating for pediatric-focused research.

Conclusion

Although children with MS and their families encounter obstacles in the search for the most effective treatment opportunities, there has been continuous and exciting growth in improving these opportunities through clinical research. Children with MS have high rates of new lesions and relapses, and a great need for highly efficacious medications. People with POMS have MS for a longer period across the life span, thus research in this population must have a focus on long-term outcomes. The first clinical trials have been completed in this population and an FDA-approved medication is available, but more work is needed to expand approved options. Creative trial designs and strong international collaboration are required to study multiple medications in this smaller MS population. Applying newer, quantitative outcome measures that can capture neural injury will be important in these designs. As more individuals participate in clinical research and science advances, the opportunities to develop a greater knowledge and awareness of POMS will expand.