Tiziana Life Sciences has reported positive Phase 2a results for its investigational intranasal antibody foralumab, demonstrating a statistically significant reduction in a brain inflammation imaging marker among patients with non-active secondary progressive multiple sclerosis. The randomized INFORM-MS study met its primary neuroinflammation and safety endpoints, with the 50 µg treatment group showing a significant improvement in microglial activation measurements compared with placebo after 12 weeks. Patients receiving either the 50 µg or 100 µg dose also experienced improvements in fatigue scores, supporting further investigation of a treatment approach designed to modify immune activity through nasal administration.
The findings represent encouraging clinical progress for a form of multiple sclerosis characterized by worsening disability despite the absence of recent relapses or new inflammatory activity on conventional magnetic resonance imaging. However, the study enrolled only 48 participants, its higher-dose group did not demonstrate a statistically significant imaging benefit, and no improvement was observed on the Expanded Disability Status Scale during the three-month treatment period. Tiziana now intends to complete its analysis and seek guidance from the U.S. Food and Drug Administration on further clinical development.
How did nasal foralumab perform in the Phase 2a INFORM-MS trial for progressive multiple sclerosis?
The Phase 2a INFORM-MS study enrolled 48 patients with non-active secondary progressive multiple sclerosis across eight clinical sites in the United States. Participants were randomly assigned to receive placebo, 50 µg intranasal foralumab or 100 µg intranasal foralumab in a double-blind, placebo-controlled design.
The placebo group included 18 patients, while 19 received the 50 µg dose and 11 received the 100 µg dose. Treatment continued for 12 weeks through four consecutive three-week dosing cycles, allowing investigators to evaluate biological activity, safety and changes in selected clinical measures.
The study’s primary objectives focused on safety and tolerability alongside changes in microglial activation measured through translocator protein positron emission tomography, commonly called TSPO PET imaging. This technique provides an indirect measure of inflammatory activity involving immune cells within the central nervous system.
Among 40 participants with evaluable PET scans, the 50 µg group demonstrated a statistically significant treatment difference compared with placebo. The adjusted difference in the globally normalized white-matter PET signal was minus 0.0231, with a 95% confidence interval extending from minus 0.0416 to minus 0.0046 and a p-value of 0.0168.
The result remained statistically significant in an alternative analysis that did not adjust for baseline disability and walking-speed measurements. This additional finding provides some support for the consistency of the lower-dose imaging response across statistical approaches.
However, the 100 µg treatment group did not achieve a statistically significant improvement in the PET endpoint. The difference between dose groups raises questions about the optimal dosing schedule, biological variability and the relationship between drug exposure and treatment activity.
Why does reduced microglial activation matter in non-active secondary progressive multiple sclerosis?
Non-active secondary progressive multiple sclerosis is a form of the disease in which neurological disability continues to worsen without the obvious inflammatory relapses that characterize more active disease.
Patients may experience increasing difficulty walking, reduced coordination, cognitive problems and persistent fatigue. These changes can substantially affect daily activities and independence even when conventional magnetic resonance imaging shows limited new inflammatory activity.
Microglia are immune-related cells within the central nervous system that help maintain brain health and respond to injury. However, sustained microglial activation has been associated with inflammatory processes that may contribute to progressive neurological damage.
Tiziana’s approach is based on the possibility that modifying immune activity could reduce persistent inflammation within the brain and spinal cord. The company believes intranasal foralumab may influence regulatory T cells and associated inflammatory signaling.
The INFORM-MS imaging findings offer controlled clinical evidence that the treatment can affect a biological marker associated with neuroinflammation. The significance is heightened by similarities between these observations and findings previously reported through the company’s expanded-access program.
Nevertheless, TSPO PET is an indirect marker of cellular activity rather than a direct measurement of neuronal preservation. A reduction in PET signal does not independently establish that patients will experience slower disability progression or improved long-term neurological function. Larger studies will therefore need to determine whether changes in microglial activity translate into meaningful clinical outcomes.
What did the INFORM-MS results show about fatigue improvement after 12 weeks?
Fatigue was an important secondary outcome because it is among the most disabling symptoms experienced by people with progressive multiple sclerosis. Investigators assessed fatigue using the Modified Fatigue Impact Scale, which measures how fatigue affects physical, cognitive and psychosocial functioning. Lower scores indicate less fatigue-related impairment.
After 12 weeks, patients receiving 50 µg foralumab showed a mean reduction of 6.17 points from baseline, while the 100 µg group experienced a 7.18-point reduction. The placebo group demonstrated a smaller mean improvement of 3.12 points.
Both active-treatment groups achieved statistically significant improvements when compared with their own baseline scores. The reported p-values were 0.035 for the 50 µg group and 0.040 for the 100 µg group.
The company described these changes as clinically meaningful based on published criteria for interpreting fatigue scores. The reductions exceeded four points in both treatment groups, a threshold previously associated with potentially important symptom improvement.
However, the trial was not statistically powered to establish definitive differences in clinical outcomes such as fatigue. The reported statistical significance was based on comparisons within each treatment group rather than formal evidence that either foralumab dose significantly outperformed placebo.
This distinction is important because patients receiving placebo also experienced improvement. The observed numerical differences support further study but cannot establish that foralumab provides a confirmed fatigue benefit.
The trial also found no change in the Expanded Disability Status Scale during the three-month observation period. Consequently, the results should not be interpreted as evidence that the treatment has already slowed or reversed neurological disability.
How does intranasal foralumab target immune pathways involved in progressive multiple sclerosis?
Foralumab is a fully human monoclonal antibody that targets CD3, a component of the receptor complex involved in T-cell activation. The antibody is administered through the nose rather than intravenously, an approach designed to influence immune regulation through mucosal pathways. Tiziana believes nasal delivery may stimulate regulatory T cells capable of modifying inflammatory responses associated with neurological disease.
Regulatory T cells help maintain immune tolerance and prevent excessive immune activation. Their activity is being investigated as a potential therapeutic target in conditions where abnormal inflammation contributes to ongoing tissue damage.
The nasal formulation represents a distinctive approach because therapeutic antibodies are more commonly delivered through injections or intravenous infusions. If proven effective, intranasal delivery could potentially offer practical advantages involving convenience and treatment administration.
However, convenience alone would not establish therapeutic value, and the extent to which nasal delivery produces reliable clinical benefits remains under investigation.
The treatment’s development draws on research conducted by Howard Weiner and colleagues at Harvard Medical School and Brigham and Women’s Hospital. Earlier findings suggested that intranasal foralumab could influence immune pathways associated with neuroinflammatory activity.
Tiziana has also administered foralumab to 14 patients with non-active secondary progressive multiple sclerosis through an expanded-access program. The company reported improvement or stability during six months of treatment, although the uncontrolled nature of the program prevents firm conclusions about effectiveness.
The randomized INFORM-MS findings provide more rigorous biological evidence than expanded-access observations. Nevertheless, both datasets remain insufficient to establish that foralumab can alter the long-term course of progressive multiple sclerosis.
What did the Phase 2a trial reveal about foralumab safety and tolerability?
Tiziana reported that the investigational nasal antibody was generally well tolerated at both doses evaluated in INFORM-MS. All 48 participants completed treatment, and investigators reported no deaths, discontinuations caused by adverse events or serious adverse events considered related to the study drug.
Treatment-emergent adverse events occurred in 23 of the 30 participants receiving foralumab, representing 76.7% of the combined active-treatment population. The corresponding rate was 83.3% among placebo recipients, with 15 of 18 reporting at least one event.
The most frequently reported events occurring in at least 10% of patients in either active-treatment group included headache, falls, nasal congestion and rhinorrhea.
These findings offer preliminary reassurance about short-term tolerability, particularly because the treatment is intended for a neurological condition that may require prolonged management.
However, the study’s 12-week duration and limited enrollment restrict conclusions about uncommon adverse events, cumulative immune effects and safety during long-term administration.
The occurrence of falls also requires careful interpretation in a population where neurological disability can affect balance and mobility. The reported adverse-event frequencies do not independently establish whether specific symptoms were caused by treatment or underlying disease. Longer follow-up and larger controlled trials will be necessary before foralumab’s safety profile can be adequately characterized.
Why are the mixed dose-response findings important for future foralumab clinical trials?
The difference between the two foralumab dose groups represents an important consideration for the next stage of development. The 50 µg dose achieved statistical significance on the primary imaging measure, while the 100 µg dose did not demonstrate a significant difference from placebo. Both doses showed numerical improvements in fatigue, although those clinical observations were exploratory.
This pattern does not establish that the lower dose is universally more effective. The higher-dose group included only 11 patients, creating substantial uncertainty around treatment-effect estimates.
Differences in baseline characteristics, measurement variability or the biological response to immune modulation could potentially contribute to the observed findings. The available topline announcement does not provide enough information to determine which explanation is most likely.
The company will need to evaluate the complete dataset before selecting an appropriate regimen for future studies. Additional analyses may clarify whether particular patient characteristics influence the imaging response.
Future trials must also determine how PET imaging changes relate to validated clinical outcomes, especially sustained disability progression. A treatment that modifies neuroinflammation without demonstrating a meaningful effect on patients’ functioning would face important clinical and regulatory limitations.
What comes next for Tiziana Life Sciences and nasal foralumab development?
Tiziana Life Sciences plans to complete its analysis of INFORM-MS and present detailed findings at an upcoming scientific meeting. The company also intends to engage with the FDA to discuss the results and the potential design of subsequent clinical studies in non-active secondary progressive multiple sclerosis.
Those discussions could help determine appropriate endpoints, patient selection criteria, treatment duration and dosing strategies. However, the company has not announced FDA agreement on a registrational development pathway or a confirmed date for its next pivotal trial.
Beyond multiple sclerosis, intranasal foralumab is being investigated in additional Phase 2 programs involving Alzheimer’s disease, amyotrophic lateral sclerosis and multiple system atrophy.
These studies reflect the company’s broader interest in immune mechanisms associated with neurological degeneration. Nevertheless, positive imaging results in multiple sclerosis do not establish effectiveness in other diseases.
The INFORM-MS findings provide encouraging support for continued investigation of nasal anti-CD3 therapy, particularly because the study demonstrated an effect on a prespecified neuroinflammation endpoint in a placebo-controlled setting.
For patients with non-active secondary progressive multiple sclerosis, the possibility of reducing chronic brain inflammation is scientifically important. However, the clinical significance of that biological effect remains uncertain until larger and longer studies demonstrate meaningful improvements in disability, symptoms or disease progression.
