The rebuff of British biopharma Viatris’ drug is yet another bust in the field of multiple sclerosis. The blow came after pharma giant Merck’s drug failed in the clinic in December. As the multiple sclerosis community continues to wait for new treatment options to cure their disease, do ongoing clinical trials hold promise?
Multiple sclerosis is a chronic autoimmune disorder that is caused by the body’s immune system’s attack against myelin, which is made up of protein and fats. Myelin forms a coat around the nerves to protect them from damage. The loss of myelin in multiple sclerosis results in scar tissue to be formed instead, which appear as lesions. hen the nerves aren’t protected, they fail to conduct electrical impulses normally to the brain.
As a result, people diagnosed with multiple sclerosis experience difficulty when walking, numbness, pins and needles, muscle weakness, have issues with balance and coordination, and are affected by blurry vision. Nearly one million people live with the disease in the U.S., according to a study by the National Multiple Sclerosis Society.
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What are the current treatments for multiple sclerosis?
Currently available medicines include disease-modifying drugs like interferons. These injections contain proteins that interfere with the disease and reduce inflammation that causes nerve damage. While they work fairly well to manage symptoms, there is some controversy about how long the effects of the treatment lasts, according to Mayo Clinic. Moreover, a cure is yet to take on the market that addresses the root cause and fully heals patients.
Nevertheless, ongoing drug trials aim to not only expand therapeutic options but also provide treatment for different forms of multiple sclerosis.
Vidofludimus calcium: a potential treatment for multiple sclerosis
Mechanism of action of vidofludimus calcium
Immunic Therapeutics’ vidofludimus calcium is a drug candidate being tested in the clinic in patients with multiple sclerosis. Vidofludimus calcium is designed to activate Nurr1, which is a neuroprotective transcription factor. Switching this factor on can enable neuroprotection in neurons, microglia, and astrocytes, all of which are key cells in the nervous system. Nurr1 activation leads to a reduction in the number of cytokines that cause inflammation, in microglia and astrocytes, whereas in neurons, it improves the transmission of signals to the brain. This way, the drug is able to stop neurodegeneration in its tracks and mitigate symptoms.
Moreover, the drug candidate aims to tackle virus infections like hepatitis C virus infections, SARS-CoV-2 infections, cytomegalovirus, and Epstein–Barr virus (EBV) infection. A study conducted by Nature found that Epstein–Barr is in fact, a leading cause of the disease. While the link was long suspected as the risk of multiple sclerosis has risen in patients who have been infected with EBV, it was confirmed that the risk was greater than 30-times when compared to people who have not been affected by EBV.
So, if vidofludimus calcium were to tackle EBV, this would bring down the risk of developing multiple sclerosis massively.
“A link between Epstein-Barr virus and multiple sclerosis is undisputed by now. It is also suspected that viral reactivation of the EBV virus causes the disease to progress further, leading to constant, chronic inflammatory reactions that have a whole tirade of negative consequences for the body,” said Hella Kohlhof, chief scientific officer of Immunic Therapeutics. “Vidofludimus calcium emerges as a promising intervention, offering a multifaceted approach by not only exerting neuroprotective and anti-inflammatory effects, but also demonstrating antiviral activity. This innovative strategy holds the potential to chart a new and highly promising course in the treatment of MS.”
Ongoing multiple sclerosis trials for vidofludimus calcium
Currently being investigated in a phase 3 trial in patients with relapsing multiple sclerosis, it is also in phase 2 for progressive multiple sclerosis. Interim results of the latter study were encouraging. It measured serum neurofilament light chain (NfL), which is a key indicator of neuron damage, and is used to monitor the progression of the disease.
Treatment with vidofludimus calcium led to a 6.7% reduction of serum NfLs, compared to a 15.8% increase over baseline in placebo, after 24 weeks. And, at 48 weeks, a 10.4% NfL plummet from baseline compared to a 6.4% increase in placebo was observed.
“Our CALLIPER interim data revealed compelling evidence of vidofludimus calcium’s ability to significantly reduce neurofilament light chain (NfL) levels – a hallmark of its potentially unique neuroprotective activity. This distinctive feature, coupled with an unrivaled safety and tolerability profile demonstrated in 1,800 treated individuals to date, positions our oral small molecule drug as a potential game-changer in the multiple sclerosis treatment landscape. We are confident that vidofludimus calcium has the potential to redefine the standard of care in multiple sclerosis and enhance patient outcomes,” said Daniel Vitt, chief executive officer and president of Immunic Therapeutics.
Progress and challenges of BTK inhibitors in multiple sclerosis treatment
What is the mechanism of action of BTK inhibitors?
Over the years, BTK inhibitors are a class of drugs that pharma giants have become partial to, but only for some to take a step back lately. Bruton tyrosine kinase (BTK) inhibitors are typically used to treat cancers that are caused by defective B cells. In multiple sclerosis research, although they seem to be making a therapeutic difference, mitigating side effects has proven to be difficult.
These drugs act as immunomodulatory drugs and their goal is to prevent overactive B cells from attacking myelin. Although similar to disease-modifying therapies (DMTs) like ocrelizumab in this aspect, unlike DMTs, they don’t wipe out all the B cells. BTK inhibitors, which can cross the blood brain barrier, are meant to be more selective, sparing healthy B cells, and toning down certain unpleasant side effects. But as some of these drugs have been linked to liver injury in the clinic, they have sparked safety concerns.
Setbacks in BTK inhibitor clinical trials
French biopharma Sanofi’s tolebrutinib is currently in phase 3 trials to treat patients with relapsing and progressive multiple sclerosis. This is despite the U.S. Food and Drug Administration (FDA) having slapped a partial clinical hold on four multiple sclerosis studies and a myasthenia gravis trial nearly two years ago. Although the multiple sclerosis studies were allowed to resume, the one for myasthenia gravis – another autoimmune disorder that causes muscle weakness – was scrapped.
Last year also saw the FDA pausing Roche’s BTK inhibitor, fenebrutinib in the clinic owing to cases of liver injury. In two patients, elevated amounts of liver enzymes and bilirubin were seen. Bilirubin is found in bile, a fluid in the liver that helps digest food, and in a healthy liver, most of the bilirubin is eliminated from the body. Once fenebrutinib was discontinued, the bilirubin and liver enzyme amounts returned to normal levels.
It was the end of the road for Merck’s and Biogen’s BTK blockers as well. Merck pulled out of the race after the German pharma giant’s evobrutinib failed to beat DMT Aubagio in two phase 3 trials. It was even dubbed one of 2023’s top ten clinical trial flops in a report by Fierce Biotech.
To add to that, Biogen ditched Chinese biotech InnoCare Pharma’s BTK inhibitor orelabrutinib, for which it had paid $125 million to develop.
BTK inhibitors’ promise in multiple sclerosis treatment
However, Biogen is keen on testing its in-house BTK inhibitor BIIB091. The candidate stands out because it is a non-covalent BTK inhibitor – like fenebrutinib – meaning that it can bind reversibly to the BTK target. This could address drug resistance seen in covalent BTK inhibitors.
The candidate is being tested in a randomized, phase 2 study as a monotherapy as well as in combination with diroximel fumarate, a previously-approved DMT that is sold by Biogen under the brand name Vumerity. Currently enrolling patients, the trial will have 275 participants in total. In the second part of the trial, the reduction of gadolinium-enhancing lesions – which is linked to lowering inflammation – will be measured.
And that’s not all. Novartis is also testing its drug, remibrutinib, against Aubagio in a phase 3 study in patients with relapsing multiple sclerosis. Besides multiple sclerosis, the drug is also being investigated as a potential treatment against skin diseases like hidradenitis suppurativa and hives.
Can immunotherapies and stem cells go beyond cancer care to revolutionize multiple sclerosis treatment?
Aside from BTK inhibitors, American biotech Kyverna Therapeutics is advancing its chimeric antigen receptor (CAR) T therapy through to the clinic. CAR-T is mainly used to treat blood cancers, but lately, researchers have been looking to diversify CAR-T’s scope to target autoimmune disorders as well. Kyverna’s drug candidate KYV-101 works like most CAR-T therapies. A patient’s blood is collected and T cells are isolated. These cells are then modified so they can recognize and destroy faulty B cells. The altered cells are infused back into the patient. The CAR-T cells then attack and kill toxic B cells.
The CAR in KYV-101 being evaluated to treat multiple sclerosis and myasthenia gravis, was designed by the National Institutes of Health (NIH) in the U.S. to improve tolerability. The drug nabbed an FDA fast track designation for multiple sclerosis two months ago and is currently in a phase 2 trial.
Moreover, stem cell therapy has changed the way multiple sclerosis could be treated, although safety concerns loom. Haematopoietic stem cell transplantation (HSCT) is a process by which stem cells are retrieved from a patient, during which they undergo chemotherapy to wipe out immune cells. The stem cells are then reintroduced into the patient. It can reset the immune system to stop it from attacking the central nervous system, according to MS Society. However, HSCT has been linked to an increased long-term risk of developing infections as well as cancer and autoimmune conditions, early menopause, and fertility issues. And, in some cases, the chemotherapy in the process can do more harm than good.
But a recent study led by scientists at the University of Cambridge in the U.K., the University of Milan Bicocca, and Hospital Casa Sollievo della Sofferenza in Italy, found that injecting stem cells directly into the brain not only had a long-lasting effect but also appeared to protect the brain from further damage. The scientists speculate that the stem cell transplant may have dampened inflammation, which led to a halt in disease progression. But since this was a small, early-stage trial, more studies need to be held to confirm these seemingly promising results.
Platform trial to accelerate drug development for multiple sclerosis
In the U.K., a multi-stage platform trial titled the Octopus study has been in the works to speed up therapeutic research for progressive multiple sclerosis. Funded by the MS Society and the National Institute for Health and Care Research (NIHR), the trial has begun recruiting patients at the University College London Hospitals NHS Foundation Trust (UCLH), and up to 30 hospitals are set to partake in the study. As platform trials are said to bring treatments to patients three times faster than traditional trials, people with multiple sclerosis will be likely to have more treatment options reach them sooner.
Although, at present, the multiple sclerosis community is reeling from Viatris and Israel-based Mapi Pharma’s failure to impress the FDA with their immunomodulatory drug glatiramer acetate to treat relapsing forms of the disease, there is still hope for more treatment options. Once researchers find ways to better address the effects of BTK inhibitors, they could make a comeback soon. And with Kyverna’s CAR-T and Immunic’s vidofludimus calcium in the clinic, it’s only a matter of time before they meet regulator and patient demands.
New technologies related to multiple sclerosis:
- Diagnosis and Treatment of Multiple Sclerosis – University of Manitoba
- Fluorinated Glucosamine Analogs for the Treatment of Multiple Sclerosis – Innovate Calgary NeuraPillar Myelination Explorer – University College London
- Inhibitory Compounds for Treatment of Neurodegeneration and Tumors – Tuscan Academic Community