Nasal Foralumab Shows Attenuation of Microglial Activation, Clinical Stabilization in Non-Active Secondary Progressive MS With PIRA

Tarun Singhal, MD, MBBS

Significant findings from an open-label expanded-access program revealed that treatment with investigational foralumab (Tiziana Life Sciences) resulted in damped microglial activation and clinical stability in patients with non-active secondary progressive multiple sclerosis (na-SPMS) who had progression independent of relapses (PIRA). Investigators are planning a double-blind, placebo-controlled, dose-ranging study of the agent in this population using (F-18)PBR06-PET, the main tool used to measure microglial activation, as a primary end point.

At both the 3 and 6 month time points, 5 of 6 foralumab-treated patients (83%; 95% CI, 44%-97%) demonstrated a qualitative reduction in (F-18)PBR06-PET in multiple brain regions. Presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, patients in the small-scale study also had stable Expanded Disability Status Scale (EDSS) scores and improvements in Modified Fatigue Impact Scale (MFIS) as a result of foralumab treatment.

Following promising preclinical studies, lead author Tarun Singhal, MD, MBBS, director of the PET Imaging Program in Neurologic Diseases at Brigham and Women’s Hospital, and colleagues, aimed to assess the effect of nasal foralumab in patients with na-SPMS with PIRA. Foralumab, a fully-human anti-CD3 monoclonal antibody, has a mechanistic function that binds to the T cell receptor and dampens inflammation by modulating T cell function, thereby suppressing effector features in multiple immune cell subsets.

"PIRA is a condition that poses a major unmet need for patients with multiple sclerosis," Singhal said in a statement.¹ "Currently, there are no disease-modifying therapies approved for this category of progressive MS patients. This study provides initial evidence that this fully human anti-CD3 has the potential to benefit this type of MS, which is the most difficult form to treat."

In the study, a voxel-by-voxel z-score mapping approaches was used and sum of z-scores in voxels with z-values of more than 2 were calculated. In addition to the 6 patients, the study also included 2 patients with na-SPMS with PIRA who underwent a test and a retest (F-18)PBR06-PET scan. In the foralumab-treated group, white matter z-scores were reduced by 26%-36% at 3 and 6 months, which was at least 4-5-times higher compared to the 6% variability observed in the test-retest group (PET effect size estimate at 3 months, 1.4).

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"We do not have any recognized approaches to try to alter microglial activation at present, which everyone agrees at this point in time is relevant throughout the life of a patient with MS. Even ocrelizumab [Ocrevus] for primary progressive MS has modest impact, so the potential here is great, and the proof of principle that you can alter the microglia is a real punchline," John Corboy, MD, FAAN, an endowed chair in neurology and director of the Rocky Mountain Multiple Sclerosis Center at the University of Colorado Anschultz Medical hospital, said in a statement.¹

Using the same group of patients from the expanded access program, findings presented at MSMilan 2023, the joint ECTRIMS-ACTRIMS meeting, showed that treatment with foralumab resulted in improvements in clinical measures of fatigue and physical function. The analysis included the 6 patients, 4 of which were on therapy for at least 12 months and 2 who completed 6 months of treatment. At the conclusion of the analysis, all 6 patients reported improvement in at least 1 clinical measure of EDSS, pyramidal score, or MFIS at 6 months.³

Additional data showed no new T2 or gadolinium-enhancing lesions on post-treatment 3T MRIs. The therapy was shown to be safe and well tolerated with runny nose and nasal congestion, both self-limited, as the only treatment-related adverse events (AEs). Two patients had serious AEs deemed unrelated to the study drug (Patient EA1 and EA2 – COVID diagnosis; EA1 – 2 episodes UTI/cystitis associated with benign prostatic hyperplasia).

Months following MSMilan 2023, Tiziana announced the FDA cleared an investigational new drug application (IND) submission to evaluate foralumab as a treatment for Alzheimer disease. Formerly known as NI-0401, foralumab has been shown to reduce release of key cytokines in healthy volunteers and in patients with Crohn disease. The belief is that its ability to attack neuroinflammation may make it a promising therapy for AD.⁴

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REFERENCES
1. Intranasal anti-CD3 foralumab in multiple sclerosis patients with PIRA highlighted in Neurology Today. News release. Tiziana Life Sciences. April 19, 2024. Accessed April 19, 2024. https://www.tizianalifesciences.com/news-item?s=2024-04-19-tiziana-life-sciences-announces-study-results-from-intranasal-anti-cd3-foralumab-in-multiple-sclerosis-patients-with-pira-highlighted-in-neurology-todayr
2. Singhal T, Zurawski Jm Cicero S, et al. Treatment of PIRA with nasal foralumab dampens microglial activation and stabilizes clinical progression in non-active secondary progressive MS. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. ABSTRACT 006130
3. Chitnis T, Singhal T, Zurawski J, et al. Treatment of six non-active secondary progressive MS with nasal anti-CD3 monoclonal antibody (foralumab): safey, biomarker, and disability outcomes. Presented at: MSMilan; October 11-13, 2023; Milan, Italy. POSTER 281
4. Tiziana Life Sciences Announces FDA IND Clearance of Intranasal Foralumab for the Treatment of Alzheimer’s Disease. News Release. Published August 15, 2023. Accessed April 19, 2024. https://www.tizianalifesciences.com/news-item?s=2023-08-15-tiziana-life-sciences-announces-fda-ind-clearance-of-intranasal-foralumab-for-the-treatment-of-alzheimers-disease