Multiple sclerosis has a long way to explore, and disease modification therapy will still seek ECTRIMS 2022

Wonderful content, summarized in one article
.

On October 26-28, 2022, the 38th European Council for the Research and Treatment of Multiple Sclerosis (ECTRIMS 2022) was held
in Amsterdam, the Netherlands, in a combination of online and offline formats.
In this session, there were many bright spots
in the field of neuroimmunity, especially in the treatment of multiple sclerosis (MS).
Now the editor is sorted out below, let's take a look!

Teriflunomide has a good long-term safety profile and does not affect the activity of the new crown vaccine

In the past 20 years, disease-modifying therapy (DMT) has gradually become a long-term integrated management strategy for MS treatment, aiming to reduce the frequency of MS recurrence, reduce the degree of exacerbation, delay the natural course of the disease, relieve clinical symptoms and improve patient outcomes
.
Among them, teriflunomide is the first oral DMT immunomodulator approved for marketing in China, and it is a first-line treatment drug unanimously recommended by domestic and foreign guidelines ^[1].

In this ECTRIMS meeting, a number of teriflunomide-related studies were published, which further provided a reference
for the use of teriflunomide in clinical practice.

▌Long-term "safety", teriflunomide treatment of MS has good safety

Personal data of 81,620 patients in databases such as the MS Registry in Denmark and Belgium were analyzed, of which 22,324 (27%) were treated with teriflunomide, with a median duration of treatment of 3.
5 years
.

Results showed that the use of teriflunomide was not associated with
the risk of all-cause mortality, severe infections, pneumonia, shingles reactivation, pancreatitis, peripheral neuropathy, cardiovascular disease, and cancer disease.
In addition, no cases of progressive multifocal leukoencephalopathy have been identified in patients treated with teriflunomide ^[2].

▌The epidemic spreads, and teriflunomide does not affect the activity of COVID-19 mRNA vaccine, giving patients peace of mind

The coronavirus pandemic is still spreading around the world, and the National MS Association and other expert organizations recommend that all MS patients should be vaccinated
.
Whether DMT drugs affect the immune activity of vaccines is a concern
for many MS patients.

A prospective study evaluating the effects
of teriflunomide on humoral and cellular immune responses to mRNA vaccines.
The results showed that peak IgG titers were similar
between untreated and MS patients treated with teriflunomide at 1 and 3 months after the second vaccination.
In patients with untreated MS, specific SARS-COV-2 memory B cells were detected in 41.
9% and 32.
3% of patients 1 month and 3 months after vaccination, respectively, compared with 40.
0% and 43.
3%
in the teriflunomide treatment group.
Specific SARS-COV-2 memory T cells were 48.
4 percent and 46.
7 percent at one month and 41.
9 percent and 56.
7 percent at three months, respectively, in untreated and teriflunomide-treated MS patients^[3].

This study shows that COVID-19 mRNA vaccines in MS patients treated with teriflunomide produce potent humoral and cellular immune responses
.

▌Teriflunomide has potential antiviral effects and provides more benefits for patients

Teriflunomide is a reversible dihydroorotate dehydrogenase inhibitor and immunomodulator, which can reversibly inhibit the activity of dihydroorotic acid dehydrogenase, a key mitochondrial enzyme synthesized de novo by pyrimidine, prevent neonatal pyrimidine synthesis, and thus inhibit the proliferation of activated T and B cells^[1].

Pyrimidine and nucleotides are also required for viral replication, so teriflunomide may have potential antiviral activity
by reducing the important nucleotide resources required for viral replication.

A longitudinal cohort study presented at this ECTRIMS meeting evaluated the levels of Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) antibody titers and their clinical significance
in patients receiving teriflunomide.
The results showed that after 6 months of teriflunomide treatment, the titers of HHV-6 IgG, HHV-6 IgM and EBNA-1 IgG in 60%, 74% and 73.
3% of MS patients were reduced
, respectively.
Of the 80 MS patients treated with teriflunomide for 24 months, 61.
9 percent of MS patients with elevated EBNA-1 IgG titers after six months of treatment had elevated and/or relapsed Extended Disability Status Scale (EDSS) scores, compared with 37.
3 percent of MS patients without elevated EBNA-1 IgG titers [^4].

Penetrating the blood-brain barrier, BTK inhibitors can be expected in the future

As a key pathogenic agent of inflammatory demyelinating diseases of the central nervous system (such as MS), B cells have received extensive attention
from researchers and clinicians in recent years.
Bruton tyrosine kinase (BTK) is a key kinase in the B-cell antigen receptor signaling pathway, which is involved in the regulation of B cell proliferation, differentiation and apoptosis, and has become an important target for the treatment of MS and other diseases^[5].

Tolebrutinib is a potent selective, orally active and blood-brain barrier permeable BTK inhibitor
.
At this ECTRIMS conference, a number of research data were published, providing strong evidence-based medical evidence
for the treatment of MS by Tolebrutinib.

▌Delay disability progression and regulate the expression of activated microglia-related genes

The pathological features of experimental autoimmune encephalomyelitis (EAE) are highly similar to MS and are ideal experimental models
for studying the pathogenesis of MS.
An animal study presented at this conference evaluated the potential of Tolebrutinib BTK inhibitors to regulate disease progression and gene expression associated with disease-associated microglia in the EAE model ^[6].

The results showed that BTK inhibitors significantly reduced the disease score of EAE mice from day 2 to the control group and maintained until the end of the study (day 10).

After BTK inhibitor treatment, a significant decrease
in the serum of neurofilament protein heavy chain (NfH) was also observed.
In addition, BTK inhibitors have been found to regulate pathways associated with MS pathology and the expression
of mRNA in disease-associated microglia and/or genes associated with BTK signaling.

Figure 1: BTK inhibitors significantly reduced disease scores and serum NfH levels in EAE mice

▌ Not afraid of the test, the efficacy and safety of treatment for up to 2 years are still good

A phase 2b study published in the top journal The Lancet Neurology in 2021 showed that 12 weeks of tolebrutinib treatment resulted in a dose-dependent reduction in the number of new gadolinium-enhancing lesions in MS patients with a favorable safety ^{profile [7].}

。 At the ECTRIMS meeting, a number of extended analysis data for the above phase 2b study were published, the study was divided into 2 phases, stage A patients received 5mg, 15mg, 30mg, 60mg Tolebrutinib treatment, and the therapeutic dose of all patients in stage B was adjusted to 60mg, the results showed:

(1) At week 96, the number of new gadolinium enhancement and T2 lesions and the volume change of T2 lesions in the 60/60mg group remained at a low level
.
Meanwhile, a decrease in the number of new gadolinium-enhancing lesions at weeks 48 to 96 in other low-dose groups was observed^[8].

Figure 2: Changes in new gadolinium-enhancing lesions during the study period

(2) Compared with baseline, the annual recurrence rate (ARR) in the 60 mg dose group remained low (0.
17 vs.
1.
23) at week 96, and 80.
6% of patients remained relapse-free
.
In addition, the average EDSS score of patients remained stable over the 96-week study ^{period [9].}

Figure 3: Annual recurrence rate and frequency of patients at week 96 (top) and average EDSS score for patients during the study period (bottom)

In terms of safety, no dose-related treatment-related adverse events and serious adverse events were observed in phase A of the extended study, and no new safety events were observed after the dose was adjusted to 60 mg in all patients in phase B ^[9].

(3) It is worth mentioning that the investigators also observed the efficacy and safety of Tolebrutinib treatment for 96 weeks in patients with highly active disease (HAD), and consistent with the above results, the number of new gadolinium-enhanced lesions and EDSS scores remained low during the 96-week study; At week 96, the ARR of patients in the 60/60 mg group decreased from 1.
36 to 0.
10, and up to 92.
9 percent remained relapse-free ^[10].

Figure 4: ARR (Figure 4A) and frequency of recurrence (Figure 4B) of patients with HAD at 96 weeks

▌ Unrelated to the rebound of the disease, Tolebrutinib provides better protection for patients

Rebound activity, which refers to a relapse of neurological symptoms and brain injury, has been reported
in patients who have discontinued some disease-modifying therapies.
In this meeting, a 16-week, double-blind, phase 2b study was conducted in a cross-over study design (cohort 1 patients were treated with different doses of Tolebrutinib for 12 weeks, followed by placebo elution for 4 weeks; The order of drug and placebo use in cohort 2 patients is reversed from cohort 1), to assess whether tolebrutinib induces rebound activity in the disease ^[11].

Results showed that in cohort 1, the proportion of patients without new gadolinium-enhanced T1 lesions after 12 weeks of tolebrutinib treatment (83.
3%) was similar
to the proportion after 4 weeks of discontinuation (85.
2%).
In addition, the average number of gadolinium-enhanced lesions after 12 weeks of Tolebrutinib treatment and 4 weeks of placebo elution was 0.
37 and 0.
44
, respectively.

Figure 5: Change in the number of new gadolinium-enhanced T1 lesions (left) and new/enlarged T2 lesions (right).

This preliminary result indicates that discontinuation of Tolebrutinib does not induce rebound activity in the disease, and can be further verified
by long-term observational studies in the future.

Expert reviews

MS is a rare disease characterized by inflammatory demyelinating lesions of the central nervous system, and it is also one of
the most common disabling neurological diseases in young adults in the world.
Fortunately, although it is a rare disease, a number of DMT drugs have been approved for marketing in recent years and have entered the national medical insurance, greatly reducing the burden of
disease on patients.

Among them, teriflunomide is a classic oral DMT drug, which has accumulated rich experience
in clinical practice.
The study presented at the ECTRIMS conference showed that teriflunomide has a good safety profile for long-term treatment, and its ability to block neonatal pyrimidine synthesis reduces the nucleotides required for viral replication, resulting in potential antiviral activity that provides an additional benefit
of antiviral in MS patients.
In addition, the new crown pneumonia epidemic is still spreading around the world, and vaccination is an important way to
prevent infection.
Studies have shown that teriflunomide does not affect the humoral and immune activity of the new crown vaccine, and MS patients can be vaccinated
with peace of mind.

In recent years, with the in-depth study of the pathological mechanism of MS, more and more new therapeutic drugs have begun to emerge
.
The BTK inhibitor Tolebrutinib can penetrate the blood-brain barrier, take into account the inflammation suppression of the peripheral and central nervous system, and is a promising MS treatment
.
The results of multiple studies published in the ECTRIMS meeting show that Tolebrutinib has good efficacy and safety for 2 years of treatment in both general and highly active MS patients, and does not induce rebound activity
.
It is expected that Tolebrutinib will be approved for marketing as soon as possible in the future, providing a "new weapon"
for the treatment of MS patients and clinicians around the world.