INFORM-MS delivers the first randomized placebo-controlled signal for intranasal foralumab in non-active secondary progressive MS, meeting dual primaries with TSPO-PET microglial reduction at p=0.0168 for the 50 ug arm and favorable tolerability for 50 ug and 100 ug plus MFIS fatigue improvement at 12 weeks, extending a 10-patient open-label experience with EDSS stabilization, MFIS gain in 6 of 10 and TSPO-PET reduction at p<0.05. [1][2] The weight rests on randomized Phase 2a NCT06292923 with enrollment 54, above single-arm Phase 2 open-label NCT06890923 with enrollment 55 and Phase 1 healthy-volunteer NCT06879067 with enrollment 27, while oral foralumab programs in Crohn's, NASH/T2DM and COVID-19 stand withdrawn at enrollment 0. [3][2] Indication-only peers underline isolation: MIS416 in single-arm Phase 2 dose-escalation, MOR103 in randomized Phase 1b, and BIIB033 anti-LINGO-1 in randomized Phase 1 share no anti-CD3 Treg mechanism and carry no pivotal weight. [4] No ICER, HTA decision or pricing is established, though TSPO plus serum metabolomics reaching AUC 0.98 versus 0.78 alone frames future stratification. [5] Regulators will likely treat TSPO-PET as supportive Phase 2 biomarker requiring confirmed disability trials, leaving registrational success moderate-low without larger durable EDSS/MSFC data. [3]
Phase 2a INFORM-MS met TSPO-PET p=0.0168 and MFIS at 12 weeks with enrollment 54, but no Phase 3 or confirmed disability data. [3][6]
| Indication | Non-Active Secondary Progressive Multiple Sclerosis |
| Drug | Foralumab |
| Mechanism of Action | anti-CD3 monoclonal antibody |
| Company | Tiziana Life Sciences |
| Trial Phase | Phase 2a |
| Trial Acronym | INFORM-MS |
| Category | Clinical Trial Event |
| Sub Category | Topline Results Positive |
| Therapeutic Area | Neuroscience |
| Primary Endpoints | Statistically significant reduction in microglial activation as measured by TSPO PET imaging (p=0.0168 for 50 ug arm vs placebo), Safety/tolerability |
| Secondary Endpoints | Modified Fatigue Impact Scale (MFIS), Expanded Disability Status Scale (EDSS) |
| Dosage | 50 ug nasal foralumab, 100 ug nasal foralumab |
| Patient Population | Non-active secondary progressive multiple sclerosis (na-SPMS) patients |
| Patient Enrollment | 48 participants (18 placebo, 19 foralumab 50 μg, 11 foralumab 100 μg) |
| Treatment Duration | 12 weeks |
| Statistical Significance (Microglial Activation) | p=0.0168 (50 ug arm vs placebo) |
| Statistical Significance (MFIS 50 ug) | p=0.035 (vs baseline) |
| Statistical Significance (MFIS 100 ug) | p=0.040 (vs baseline) |
| Regulatory Engagement | U.S. Food and Drug Administration (FDA) |
Intranasal Foralumab Meets Dual Primary Endpoints in na-SPMS Trial
Tiziana Life Sciences announced positive topline results from its Phase 2a INFORM-MS trial evaluating intranasal foralumab in patients with non-active secondary progressive multiple sclerosis (na-SPMS). The randomized, double-blind, placebo-controlled study successfully met its dual primary endpoints, demonstrating a statistically significant reduction in neuroinflammation, specifically microglial activation measured by TSPO PET imaging (p=0.0168 for the 50 ug dose arm), and confirming a favorable safety and tolerability profile for both 50 ug and 100 ug doses. Additionally, the trial showed clinically significant improvements in fatigue, as measured by the Modified Fatigue Impact Scale (MFIS), in both treatment arms after 12 weeks.
- The INFORM-MS trial achieved its primary efficacy endpoint, showing a statistically significant reduction in neuroinflammation. Patients treated with 50 µg nasal foralumab exhibited a significant decrease in microglial activation, as measured by [¹⁸F]PBR06 TSPO PET imaging, compared to placebo (p=0.0168). This finding corroborates previous observations from an expanded access program, providing robust evidence of foralumab's biological activity in reducing neuroinflammation in na-SPMS patients.
- Beyond imaging, intranasal foralumab also demonstrated clinically significant improvements in patient-reported fatigue. Both the 50 µg and 100 µg dose arms showed a clinically meaningful reduction of more than 4 points in Modified Fatigue Impact Scale (MFIS) total scores from baseline to Week 12. These improvements were statistically significant within each treatment group (p=0.035 for 50 µg and p=0.040 for 100 µg), addressing a key unmet need for na-SPMS patients.
- The trial confirmed intranasal foralumab's favorable safety and tolerability profile across both dose levels. All 48 participants completed treatment, with no deaths, discontinuations due to adverse events, or study-drug related serious adverse events reported. The most common treatment-emergent adverse events were mild. Tiziana plans to conduct a full analysis of the data, present detailed results at a scientific congress, and engage with the U.S. FDA to discuss the path forward for further clinical development in na-SPMS.
The Critical Need for New Therapies in na-SPMS
Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. Many pharmacological agents can reduce relapsing-remitting episodes, but are ineffective on secondary progressive MS, causing symptoms to worsen over time.
In SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability.
Cyclophosphamide has limited, if any efficacy in primary progressive MS, or stages of secondary progressive MS with slow clinical deterioration, in the absence of relapses or inflammatory changes (gadolinium enhancement) on magnetic resonance imaging.
Natalizumab did not achieve a statistically significant primary composite disability outcome in a trial of 887 patients with secondary progressive MS, but it did demonstrate a benefit on a prespecified component of the 9-Hole Peg Test.
After 3 years, confirmed disability progression (CDP)-free survival was high in relapsing-remitting MS (> 97%) and lower in secondary progressive MS (48.9%) and PPMS (57.2%) in patients treated with ocrelizumab for ≥ 1 year.
Combination of high GFAP and low NfL levels could distinguish non-active pwPMS with particularly high progression risk, with risk further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53-12.13], p = 0.006).
Key Efficacy and Safety Findings from INFORM-MS
Recent studies in secondary progressive multiple sclerosis have evaluated natalizumab, ibudilast, and sphingosine 1-phosphate receptor modulators. These trials enrolled patients with secondary progressive multiple sclerosis for 2 years or more and assessed disability progression, brain atrophy, and biomarker responses.
ASCEND – natalizumab: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0.86; 95% CI 0.66-1.13; p=0.287). No treatment effect was observed on the EDSS (OR 1.06, 95% CI 0.74-1.53; nominal p=0.753) or the T25FW (0.98, 0.74-1.30; nominal p=0.914), however, natalizumab treatment reduced 9HPT progression (OR 0.56, 95% CI 0.40-0.80; nominal p=0.001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events, two deaths occurred in part 1, neither of which was considered related to study treatment, and no progressive multifocal leukoencephalopathy occurred.
SPRINT-MS (NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942) – ibudilast (≤100 mg daily) or placebo for 96 weeks: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.
EXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692) – siponimod and fingolimod, respectively: Baseline pNfL levels were higher in SPMS (geomean 32.1 pg/mL) than in PPMS (22.0 pg/mL; p < 0.0001). Independent of treatment, high vs low baseline pNfL levels were associated with significantly higher risks of confirmed 3-month (SPMS [32%], hazard ratio [95% CI] 1.32 [1.09-1.61]; PPMS [49%], 1.49 [1.05-2.12]) and 6-month disability progression (SPMS [26%], 1.26 [1.01-1.57]; PPMS [48%], 1.48 [1.01-2.17]). pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo-treated patients and higher in those having experienced disability progression.
Frequently Asked Questions
References
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