Multiple sclerosis (MS) has long been known as an unpredictable, debilitating, and hard-to-pin-down autoimmune disease of the central nervous system. MS affects approximately 2.8 million people worldwide—80% of whom are women. Furthermore, the treatment of MS has frustrated doctors and patients alike for years due to its varied forms of expression in the body, as well as the myriad potential side effects of treatment.
Luckily, there is potentially good news coming out of a recent MS clinical trial. Immunic, Inc. announced positive interim data from their phase 2 CALLIPER trial of Vidofludimus calcium for Progressive Multiple Sclerosis (PMS).
What is MS?
There are three main types of MS:
- primary progressive MS (PPMS);
- relapsing-remitting MS (RRMS); and,
- secondary progressive MS (SPMS).
They are classified according to their activity and progression. The most common type of MS, RRMS, presents as an exacerbation of neurological symptoms followed by periods of remission. SPMS occurs secondarily with gradually worsening symptoms and is classified as active or nonactive based on disease relapse or evidence of new brain lesions on MRI. The distinction of whether progression is involved (referring to the pattern of disability accumulated over time) further expands the complexity of MS classification.
What are treatment options for MS?
The drug ocrezilumab (Ocrevus) has long been used to treat PPMS and RRMS. However, anti-inflammatory drugs have a limited effect on PPMS unless initiated early when central nervous system inflammation is present and there are currently no reliable nor effective treatment options for SPMS.
With the EMPhASIS Trial, investigators discovered that vidofludimus calcium has neuroprotective capabilities. The ongoing research focuses on a potential treatment for relapsing and progressive MS where few therapeutic options are available. Nurr1, a potent nuclear receptor-related 1 activator, is predominantly expressed in neurons and has neuroprotective and anti-inflammatory activity. It has subsequently become an appealing target to treat neurodegenerative pathologies, including Alzheimer’s disease, Parkinson’s disease, and MS.
According to Immunic’s Co-Founder and Chief Medical Officer, Andreas Muehler, MD, most of the drug development in MS focused on anti-inflammatory drugs, which he says do not show promising efficacy. The CALLIPER study intended to look at a population of MS that doesn’t have focal inflammatory disease as a predominant mechanism or is in a phase where the focal inflammatory disease has subsided and progressive mechanisms have taken over. A progressive mechanism implies the occurrence of active signs and symptoms of a disease.
Immunic’s bid to treat MS
Immunic has a well-established pipeline of small molecule therapeutics for chronic inflammatory and autoimmune diseases. One such investigational drug intended as an oral, next-generation treatment option is the Nurr1 activator, vidofludimus calcium.
According to Dr. Muehler, recent data shows biomarker evidence that the activity of vidofludimus calcium extends beyond its known anti-inflammatory and anti-viral effects as a neuroprotective agent, accomplishing the goal Immunic initially intended.
As the nonactive secondary progressive form of MS has the highest unmet medical need, Immunic chose this group as the majority (two-thirds) of the population to test along with a smaller portion (one-third) of patients with PPMS. The interim analysis, per Dr. Muehler, looked at 2 biomarkers: serum neurofilament light chain (NfL) and glial fibrillar acidic protein (GFAP) levels at 24 and 48 weeks. NfL and GFAP are found in the central and peripheral nervous systems.
When neurons are destroyed, their proteins break down into neurofilaments and are released into cerebral spinal fluid and blood. Obtaining serum NfL as a biomarker has reliably shown to capture disease activity and predict future disability in patients with MS. Though GFAP is a newer biomarker, and has a delayed response behind NfL, it signifies disease severity within the frontotemporal lobe.
With the interim results, at both time periods, serum NfL responses were observed for vidofludimus calcium in the PMS population with a reduction from baseline in serum NfL compared to an increase over baseline in the placebo. The data was promising enough to support vidofludimus calcium’s activity as a Nurr-1 activator and beyond that as an anti-inflammatory drug.
The data obtained at this early stage in the trial is encouraging to the investigators in the drug’s safety profile and improvement in NfL over placebo. The findings were better than what have previously been seen with other therapeutic approaches, and according to Dr. Muehler, there was a decrease in neurofilament level in nonactive SPMS where other studies showed no effect.
Correlation in data with their phase 2 EMPhASIS trial in relapsing-remitting MS (RRMS) is contributing to the support from the investigators as they have seen how well the patients are doing.
In all subpopulations and subgroup analysis completed, there is a consistent picture of vidofludimus calcium working in populations where inflammatory disease is absent. It is encouraging for Immunic to see its neuroprotective actions as this may be a huge leap forward in terms of treatment for progressive forms of multiple sclerosis.
The CALLIPER trial includes 467 patients at more than 70 sites throughout North America, Western, Central, and Eastern Europe. The primary endpoint is the rate of percent brain volume change as seen on MRI up to 120 weeks. The secondary endpoints include the rate of change in whole brain atrophy and specifications on the expanded disability status scale (EDSS).
Even with the promising results seen with serum biomarkers, Immunic anticipates converting this emerging data into brain atrophy and disability in context of vidofludimus calcium in the next 6 months. The data from the phase 2 CALLIPER trial is expected in April 2025.