This time, I will present some studies on new treatment options for MS that show promising results and were presented at ECTRIMS 2024. Some candidates are not that new, such as high-dose vitamin D, but the key here is the long-term observation of a large number of MS patients under clearly defined conditions. Furthermore, there are engineered extracellular vesicles (EVs), CAR-T cell therapies and CD40L inhibitors such as frexalimab. These therapies represent a shift towards targeted treatments that aim to modulate the immune system in a more precise way, without the severe side effects of current medications. It’s about the research behind these novel approaches, their potential benefits, and the possibility of achieving better outcomes for patients, especially in the progressive stages of the disease. Listen to the episode or read the post to stay up to date on how these innovations could change the future of MS treatment.
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Table of Contents
Why are new therapies important?
Currently, the acute inflammatory process in multiple sclerosis can be treated well with the disease-modifying therapies. However, this is only insufficiently successful for the diffuse inflammation, which takes place in secret and, for example, is at the forefront of primary progressive MS and can lead to deterioration in MS patients, even though they no longer have any new relapses. The highly effective immunotherapies and anti-CD-20 B-cell therapies cause targeted cell death. They can somewhat mitigate diffuse deterioration, but they also have side effects, such as increased susceptibility to bladder infections and respiratory diseases. That is why the search for effective medications with the fewest possible side effects continues.
Engineered small extracellular vesicles targeting regulatory T cells via CD40L signaling in multiple sclerosis
by Prof. Ju-Hong Min et. al
A new option in MS treatment
Living with multiple sclerosis is a big challenge. Fortunately, motivated researchers, doctors and therapists worldwide are working on innovative and better treatment options. This study is looking at a new approach that uses artificially produced extracellular vesicles (EVs) to regulate immune activity in MS.
What are extracellular vesicles (EVs)?
Extracellular vesicles (EVs) are a type of “message in a bottle” or “information package” that cells send to each other. They transport important signals, in the form of molecules such as proteins, lipids and RNA, from one cell to another. What makes EVs special is that they can be taken up and “understood” by almost all cell types because they can naturally dock to specific receptors on the target cells.
Cells use EVs to communicate with each other and coordinate complex processes in the body. This communication system works like a universal language that cells use to exchange information. They travel throughout the body and each target cell “reads” the message and responds accordingly.
What is this study about?
The study focuses on the use of engineered extracellular vesicles (EVs) to target specific immune pathways, in particular the CD40/CTLA-4 signaling pathway, which plays a role in immune regulation. By targeting regulatory T cells (Tregs), the aim is to reduce inflammation and rebalance the immune system in MS.
Why is this important?
The CD40 and CTLA-4 signaling pathways are crucial players in controlling immune activity. Previous therapies that targeted these pathways showed promising results in studies, but they had limitations. The researchers in this study wanted to overcome these challenges by using extracellular vesicles, which can transport therapeutic molecules to provide targeted treatment.
Methods: How the study worked
The researchers developed EVs loaded with CD40 and CTLA-4 signaling molecules. They tested these in both lab models of MS and in human immune cells. The study examined:
- Toxicity: checking if the EVs were safe for cells.
- Immune effects: Measuring changes in the activity of regulatory T cells (Tregs).
- Disease progression: Testing the effects on an animal model of MS (experimental autoimmune encephalomyelitis, EAE).
Key findings
- Increased immune regulation:
- The engineered EVs increased the proportion of regulatory T cells, which help to calm the overactive immune system in MS.
- The treatment reduced inflammatory markers associated with MS.
- Reduced disease activity:
- In animal models, these EVs significantly reduced disease severity.
- Demyelination (damage to the protective layer of nerves) was reduced in spinal cord tissue.
- Safety:
- The engineered EVs were safe for use in cells and showed no toxic effects.
Why this study is relevant
This study provides moderate evidence based on preclinical models (laboratory and animal studies). While it has not yet reached the level of randomized clinical trials (the gold standard in the Cochrane scale), it provides meaningful preliminary data for further investigation. The results suggest a novel and targeted approach to the treatment of MS that could complement or improve current therapies.
What this means
This research offers hope for more precise, less invasive treatments for MS. Although still in the experimental phase, the concept of targeting immune pathways with engineered EVs could lead to therapies with fewer side effects and better outcomes.
Bottom line: one step closer to personalized MS treatment
This study highlights the potential of using cutting-edge science, like engineered EVs, to tackle the complexity of MS. Although more research is needed, this is an exciting step towards personalized, effective treatment options. Keep the hope and faith alive – new solutions are on the horizon!
Overview of CAR-T therapy in autoimmune diseases
Presentation by Prof. Dr. Frauke Zipp
In CAR-T therapy, T cells are taken from a patient and modified to find and destroy B cells that express CD-19. These special cells are then multiplied and returned to the patient.
Because CD-19 is present on a broader developmental cycle of B cells, this therapy is even more deeply depleted. Both B cells in an earlier and in a later stage of development than CD-20 are recognized and destroyed.
Although CAR-T cell therapy is new to neurologists, it has been used in cancer therapy since the 1980s and has led to great success. Remarkable individual cases have already been reported in systemic lupus. Also in myasthenia gravis.
In progressive MS, a reduction of oligoclonal bands could be shown. And the patients showed significantly fewer or no neurotoxic side effects.
There are planned and ongoing studies for relapsing and progressive MS.
CAR-T cell therapy continues to develop. Patients must be monitored closely and studies should only be conducted in experienced clinics in close collaboration with oncologists who have a wealth of experience with this form of therapy.
Future of new therapies in MS: CAR-T, CD40L and others
Presentation by Prof. Dr. Patrick Vermersch
The focus is on neuroinflammation. Therapy must target both parts of the immune system, the innate and the adaptive immune system, to successfully treat MS in both the central nervous system and the periphery, i.e. outside the brain and spinal cord.
CD40-CD40 Ligand
CD40-CD40 ligand interactions appear to be a good approach for targeted treatment of networks because they are expressed on many immune cells.
Frexalimab was compared to a placebo. The patient-reported outcomes (PROs) were positive, less fatigue, even if there was hardly any activity in the form of relapses, the PROs showed differences between the treated group and the placebo group. The treated group suffered less from fatigue.
The exciting thing about the CD40 ligand is also that it increases in progressive forms of MS and that in soluble form it would also be a good biomarker to measure whether a treatment is working, because then the number would have to decrease.
Masitinib
Masitinib inhibits microglia by reducing mast cells. If there are no mast cells present, it is very difficult to trigger MS-like disease in mice, which is a strong indication of the importance of these cells.
There are already small pilot studies showing a significant slowing of disability progression in inactive progressive MS patients, both in SPMS and PPMS. And a significant reduction in the risk of reaching EDSS 7.
CAR-T Therapy
Anti-CAR-T cells show impressive data in B-cell depletion. So far, however, there is no evidence that they affect microglia, which appear to drive progressive MS. Also, there are some serious side effects, so it really should only be used very judiciously. Especially neurotoxicity and cases of PML.
RIPK1
Inhibition of RIPK1 to regulate neuroinflammation and cell death. They focus on microglia and astrocytes which are both important in MS.
CXCR7
Another interesting research is done on CXCR7 antagonist which has both immunomodulator and promyelinationg effects . This chemokine receptor could be a potential target to reduce neuro-inflammation and promote remyelination.
Conclusion
There are many new targets which show convincing data with new candidates. Drugs acting on different pathways with potential synergetic actions:
- Adaptative and innate immunities
- Adaptative immunity and astrocytes
- Neuroinflammation and cell death
- Potential combinations
Phase II and III for these studies are planned or ongoing.
Long-term outcomes of phase-1 study of neural stem cell transplantation in progressive multiple sclerosis
Presentation by Matteo Azzimonti
Introduction
There is growing interest in using neural progenitor/stem cells (NPCs) to treat multiple sclerosis (MS) and other neurodegenerative diseases, due to their role in endogenous tissue repair. The STEMS trial, a phase 1 clinical study, demonstrated the safety and feasibility of transplanting human fetal NPCs (hfNPCs) in MS patients. Results showed that patients who received higher doses of hfNPCs experienced slower brain and gray matter atrophy over time. Additionally, detailed analysis of cerebrospinal fluid (CSF) indicated a shift toward a more anti-inflammatory and neuroprotective profile in the central nervous system (CNS) after transplantation.
Aims:
- Long-term follow-up: The health of STEMS participants is being monitored over an extended period, including clinical evaluations, brain scans (MRI), and tests to assess brain and nervous system function.
- Comparing brain changes: The study aims to compare changes in brain structure between STEMS patients, those with early-stage MS, and healthy controls. This comparison seeks to determine if hfNPCs transplantation can help slow or alter the development of brain damage (neurodegeneration) in patients with primary progressive MS (PMS).
Long-term Follow-up and Clinical Evaluation:
Patients in the STEMS study were assessed 4–6 years after the hfNPCs transplantation. They underwent a range of evaluations, including:
- Clinical assessment: Disability progression was measured using the EDSS score, with other factors like disease relapses and symptoms tracked. Patients’ use of disease-modifying treatments (DMTs) and potential side effects related to the stem cell transplant were also noted. Cognitive function was assessed using the Symbol Digit Modalities Test (SDMT).
- OCT evaluation: The retinal nerve fiber layer (pRNFL) was measured, as changes here can reflect changes in the brain.
- MRI evaluation: Brain scans were conducted to assess:
- Areas of brain damage (T2-hyperintense lesions),
- New damage or areas of activity (Gd-enhancing lesions),
- Overall brain shrinkage (brain volume changes),
- Changes in gray matter (GM) and white matter (WM) to track disease progression.
Results:
- Patient Information: The study involved 12 patients with an average age of around 50 years, including 4 men and 8 women. These patients were followed for a period ranging from 1.8 years up to 6 years.
- Clinical Assessment (EDSS, SDMT, pRNFL):
- EDSS (disability severity score): At the start, the EDSS score was low (0.24), but it increased slightly over time, indicating some increase in disability.
- SDMT (Symbol Digit Modalities Test): The SDMT score was 39 at baseline, showing small improvement during follow-up visits, indicating some positive change in cognitive function.
- pRNFL (peripapillary retinal nerve fiber layer): This measurement remained stable over time, suggesting that the eye’s nerve fibers, and by extension the CNS, did not experience significant further deterioration.
- Key findings:
- No serious side effects or MS relapses were related to the hfNPCs treatment.
- 4 out of 11 patients (36%) began a disease-modifying treatment during the follow-up, with a combination of teriflunomide and ocrelizumab.
- There was no significant correlation between the amount of hfNPCs injected and changes in EDSS, SDMT, or pRNFL scores.
Conclusion:
- The hfNPCs transplantation was safe, with no serious adverse events related to the procedure over 4–6 years.
- Although there was no clear relationship between the treatment dose and changes in disability, cognition, or brain atrophy, slower gray matter loss was noted in the long-term follow-up compared to the 2-year mark.
- At long-term follow-up, patients with primary progressive MS showed rates of gray and white matter loss that were comparable to those seen in healthy, age-matched controls and early MS patients.
- These findings suggest that the neuroprotective effects of hfNPCs transplantation are maintained over time.
- In summary, while the treatment did not completely stop brain atrophy, it slowed down the rate of brain tissue loss, particularly in gray matter, and was safe and well tolerated in the long term.
High-dose cholecalciferol reduces multiple sclerosis disease activity after a clinically isolated syndrome : results of a 24-month placebo-controlled randomized trial (D-lay MS)
Presentation by Prof. Dr. Eric Thouvenot
Aim and Methods:
Vitamin D deficiency is considered a risk factor for multiple sclerosis (MS) and is associated with increased disease activity. This study aimed to explore whether high-dose vitamin D (cholecalciferol) supplementation could reduce disease activity in clinically isolated syndrome (CIS).
The study was a double-blind, randomized, placebo-controlled trial conducted over 24 months with 316 patients diagnosed with CIS. Participants were randomly assigned to receive either 100,000 IU of vitamin D or a placebo every two weeks. Key inclusion criteria included patients aged 18 to 55 years, with a CIS diagnosis within 90 days, serum vitamin D levels below 100 nmol/L, and MRI criteria meeting the Swanton standard or showing at least 2 lesions and oligoclonal bands (OCBs).
Results:
Disease Activity:
- 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group showed disease activity.
- The hazard ratio for disease activity was 0.66 (34% lower risk) in the vitamin D group (p = 0.004).
- Median time to disease activity was 432 days in the vitamin D group, compared to 224 days in the placebo group.
Secondary Outcomes:
- MRI Activity: Significant reduction in contrast-enhancing lesions (CELs) (p = 0.022) and new/enlarged lesions (NELs) (p = 0.003) in the vitamin D group.
- Relapses: No significant difference in relapse rates (p = 0.160).
- No significant differences in EDSS or other functional tests.
Subgroup Analysis:
- In 247 RRMS patients (2017 McDonald criteria), vitamin D reduced MRI activity, CELs, and NELs (all p ≤ 0.032), but there was no difference in disease activity.
Safety:
- 288 patients (95.1%) completed the study.
- 33 serious adverse events (SAEs), none related to the study drug.
- 20 SAEs (12.8%) in the vitamin D group, and 13 SAEs (8.8%) in the placebo group (p = 0.68).
Discussion: High-dose vitamin D was safe and well tolerated. It showed a 34% reduction in disease activity compared to placebo, similar to other therapies for CIS. Further studies are needed to compare high-dose pulse therapy to daily oral supplementation and assess vitamin D’s effectiveness in relapsing-remitting MS (RRMS) under the 2023 criteria.
Conclusion: This was the largest trial of vitamin D in MS, demonstrating that high-dose vitamin D supplementation (100,000 IU every two weeks) effectively reduces disease activity in CIS and early MS. With an excellent safety profile, it supports vitamin D as a key therapeutic option in early MS stages.
Interaction with Prognostic Factors:
- Patients who benefited most from vitamin D supplementation had no spinal cord lesions, severe vitamin D deficiency, and a normal BMI at the start of the study.
Safety and Efficacy of Frexalimab in the Treatment of Relapsing Multiple Sclerosis: 18-month Results from the Phase 2 Open-Label Extension
Presentation by Prof. Dr. Gavin Giovannoni
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses. This pathway is involved in the development of multiple sclerosis (MS).
By inhibiting this pathway, frexalimab could alter the activation of T and B cells as well as the function of innate immune cells such as macrophages, microglia and dendritic cells, without reducing lymphocytes.
Results of frexalimab in phase 2 study:
- Primary objective achieved: Frexalimab showed favorable safety and efficacy in a 12-week phase 2 study in patients with relapsing MS.
- Reduction of lesions: Frexalimab led to an 89% reduction in new gadolinium-positive T1 lesions (primary endpoint) compared to placebo (p = 0.0004) after 12 weeks.
- Long-term effect: A sustained reduction in the number of lesions was observed over 48 weeks of treatment with frexalimab.
- Aim of the study: The study was designed to report the safety and efficacy of frexalimab over 18 months (week 72) in the open-label extension (OLE) phase of the phase 2 study.
Conclusions from the continued study:
- Treatment with frexalimab continued to show sustained disease activity reduction as measured by MRI, with low gadolinium-positive T1 lesions and stable T2 lesions through week 72.
- Clinical endpoints remained stable through week 72:
- The annualized relapse rate (ARR) in the frexalimab group (1200 mg IV every 4 weeks) was very low (0.07, 95% CI: 0.03–0.20), and 94% of patients were relapse-free.
- The EDSS score remained stable from baseline to week 72.
- Frexalimab was well tolerated, with no new safety signals. Lymphocyte counts remained stable through week 72.
- These results reinforce the rational basis for targeting MS by blocking the CD40L pathway and support the further development of frexalimab in phase 3 studies as a potentially highly effective, non-lymphocyte-depleting therapy.
See you soon and try to make the best out of your life,
Nele
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