New research in MS was presented at AAN 2023, the annual meeting of the American Academy of Neurology. The
features below highlight some of the studies presented during the conference.
Gold Nanocrystals May Be Effective as Adjunctive MS Therapy
“We still do not have a therapy that promotes remyelination,and we certainly do not have a
proven neuroprotective therapy for MS,” said Michael Barnett, PhD, MBBS (Hons), in his presentation,
noting that this unmet need exists despite the availability of many highly effective
disease-modifying therapies. CNM-Au8 is hypothesized to restore neuronal health and function
by supporting brain energy metabolism. In preclinical models, this resulted in neuroprotection and
remyelination.
The phase 2/3 trial VISIONARY-MS, a multicenter, randomized, double-blind study, evaluated
CNM-Au8 versus placebo over 48 weeks in participants with stable relapsing MS. Patients
were randomized 1:1:1 to CNM-Au8 15 mg/day, 30 mg/day, or placebo. Of the 150 planned participants,
73 were randomized. Participants were aged 18 to 55, had relapsing MS for less than 15
years, were clinically stable over the prior 6 months, and had chronic optic neuropathy, with a best
corrected-low contrast letter acuity (BC-LCLA) using 2.5% low-contrast Sloan letter chart of
20/40 or worse in the affected eye. The primary endpoint was a change in BC-LCLA score in
the most affected eye to week 48.
The secondary endpoint was a global neurologic improvement,
measured by the change in the modified MS Functional Composite to week 48. Both the primary and secondary
clinical endpoints significantly improved. The BC-LCLA change in the affected eye was significantly
different as early as week 24. At week 48, the LS mean difference was 3.13 (95% CI, -0.08 to 6.33). In the CNMAu8
group, global neurologic improvement at week 48 was also more favorable than in the control
group, with an LS-mean difference of 0.28 (95% CI, 0.05-0.51; P=0.0197). The positive result of
the latter endpoint was mainly driven by changes in LCLA in both eyes, in the Symbol Digit Modalities
Test, and the 9-hole peg test of the dominant hand. CNM-Au8 also improved independent
quantitative biomarkers of enhanced axonal integrity, namely multifocal visual evoked potential amplitude
and fractional anisotropy, and was safe and well-tolerated. Treatment-emergent adverse events
were mild to moderate and transient.
MS Therapies Not Associated With Pregnancy Complications
N adine Bast, a pharmacist at St. Josef Hospital in Bochum, Germany, presented an analysis
of registry data that concluded that most disease-modifying therapies (DMTs) for MS are not
associated with an increased risk for complications during pregnancy. Although a few therapies were
associated with slightly elevated rates of congenital abnormalities attributable to prenatal exposure,
the small sample sizes in this particular cohort limited the strength of the conclusions, underscoring
a need for future prospective research.
Although MS does not negatively influence most pregnancy outcomes, less is known regarding the
effects of prenatal exposure to novel DMTs. Fetal safety is typically protected over maternal safety
on most drug labels, which may mean that patients have to make tough choices about treatment
during their pregnancy without much evidence-based information to support their decision.
The objective of this study was to examine associations between neonate health outcomes and
prenatal exposure to DMTs in birth cohorts in mothers with MS.
To address the impact of DMT use on pregnancy outcomes, Bast and colleagues analyzed 3,387
pregnancies from the German MS and Pregnancy Registry, of whom 2,639 were DMT-exposed at
some point during the pregnancy. The other 748 fetuses were unexposed to DMTs and served as
the comparator. The researchers then split the cohort based on the types of therapy, with the larger
group (n=1,671 pregnancies) having been exposed to older DMTs, such as glatiramer, teriflunomide,
dimethyl fumarate, and interferon therapies. Bast explained, “These classes of DMT are thought to
be less effective at delaying disease progression but are also less likely to cause side effects than newer
therapies. The remaining 968 patients were treated with newer, relatively more effective therapies,
including S1P modulators—mostly fingolimod—and CD20 antibodies, as well as cladribine, alemtuzumab,
and natalizumab.”
There were differences at baseline between the groups, with more than 700 women taking interferon
therapies while pregnant, compared with fewer than 20 participants on some of the other agents,
which complicated statistical analyses. The researchers also found that maternal age at conception as
well as alcohol or tobacco use also differed significantly. However, critical pregnancy complications,
including miscarriage, ectopic pregnancy, and stillbirth, did not vary significantly between those taking
any DMT and patients not receiving DMTs.
Bast said, “When looking at health outcomes of the infants, rates of chromosomal abnormalities
or death shortly after birth were very low across all groups and did not differ between DMT-exposed
or unexposed patients. Furthermore, rates of major congenital abnormalities between DMT-exposed
and unexposed babies did not vary significantly, although there were some notable numerical
increases among babies exposed to some of the drugs (6%), when compared with the control nonexposed
infants (3.5%).”
While the findings indicate that additional research is needed, the numbers were not “statistically alarming,”
according to Bast.
“Our data, however, do point to prenatal exposure to DMTs, both in older as well as newer classes
of DMTs, resulting in significantly lower birth weights independent of gestational age than unexposed
babies,” she added.
In her conclusion, Bast noted the small sample size of the cohort, which limited the study’s statistical
power. “Future research on DMT use in pregnancy should focus on these medications, as well as additional
types of S1P modulators and anti-CD20 therapies. We also have to keep in mind that patients
who are prescribed higher efficacy DMTs might have more aggressive disease management
to control their severe underlying disease, which could confound the results. All the groups, including
unexposed babies, had higher rates of being abnormally small for their gestational age than would
be expected in the general population.”
Stem Cell Therapy Improves Outcomes in Progressive MS
a randomized, double-blind, placebo-controlled phase 2 trial of patients with primary progressive
disease or secondary progressive disease. They had significant disability but could still walk
(Expanded Disability Status Scale [EDSS], 3.0–6.5).
Saud A. Sadiq, MD, FAAN, founder/director of the International MS Management Practice and director
and chief research scientist at the Tisch MS Research Center of New York, and colleagues randomly
assigned patients to six intrathecal in- jections of 10 million MSC-NPs (n=24) or saline (n=27)
spaced 2 months apart. Due to the compas- sionate crossover design, participants crossed over into
the opposite group in year 2. The primary out- come was EDSS Plus, which means improvement in
either EDSS, the timed 25-foot walk (T25FW) test, or the 9-hole peg test.
Of nine serious adverse events, none were related to MSC-NP treatment. There were no cases of men-
ingitis or malignancies associated with the interven- tion. Mild headaches and fever were
relatively more frequent following MSC-NP treatment.
In the MSC-NP group, EDSS Plus improvedin 33% of participants and in 37% of the place- bo group. After
2 years, 47 participants received a placebo as well as MSC-NP. In this group, EDSS improved in 20 of 47
patients (43%), 16 patients (34%) remained stable, and 11 (23%) declined. Regarding secondary endpoints,
in patients with EDSS scores of 6.0 to 6.5, the MSC-NP group performed significantly better than the
placebo group on the T25FW (P=0.030), which was confirmed by the 6-minute walk test (P=0.036). In patients with less
advanced grey matter atrophy, grey matter was relatively better preserved in the treatment group
(P=0.021). In addition, in patients with impaired bladder function, 11 of 16 (69%) in the treatment
group had improved post-void residual volume versus 4 of 11 (36%) in the placebo
group.
