New immune biomarkers uncovered with foralumab treatment
Intranasal treatment modulates immune cells in nonactive SPMS
Intranasal foralumab can modulate a number of immune cell types in people with nonactive secondary progressive multiple sclerosis (SPMS), a study showed, revealing new immune biomarkers that show how the therapy exerts its effects in people with the condition.
After three months of treatment, gene activity data showed that immune cells including naive B-cells, inflammatory T-cells, regulatory T-cells, and monocytes were affected by foralumab, developer Tiziana Life Sciences said.
“We are excited to announce this breakthrough in understanding how nasal foralumab induces immune modulation in Secondary Progressive MS patients,” Tanuja Chitnis, MD, principal investigator and professor of neurology at Harvard Medical School, said in a company press release.
The company didn’t say whether levels increased or decreased, but noted that the immune changes were associated with a reduction in microglial brain inflammation, or a reduction in the activity of brain resident immune cells called microglia, which has been observed in these same patients in PET scans.
The findings shed additional light on the immune mechanisms through which the therapy exerts its effects in people with nonactive SPMS.
‘Pivotal step’ for treatment
“These findings highlight the potential of nasal foralumab in modulating critical immune pathways and offer new insights into its clinical effects,” said Chitnis. “This discovery represents a pivotal step toward personalized treatment strategies for MS. We look forward to submitting these data to a peer reviewed journal.”
Foralumab works by targeting the CD3 protein at the surface of immune T-cells, which reduces the activity of harmful inflammatory T-cells while increasing the activity of beneficial anti-inflammatory T-cells, known as regulatory T-cells, or Tregs.
The drug’s anti-inflammatory effect is expected to reduce multiple sclerosis (MS) inflammation, which could slow disease progression in people with nonactive SPMS.
Foralumab was first tested in people with nonactive SPMS as part of an expanded access program. Data from the first 10 patients, all of whom had received treatment for more than six months, showed that 80% had a reduction in microglial activity in PET scans — an indication that brain inflammation was reduced — and 70% had less fatigue after six months.
None of the patients experienced a worsening in disability levels over that period, which led the U.S. Food and Drug Administration (FDA) to allow 20 more patients into the expanded access program.
Before and during treatment with foralumab, researchers collected blood samples from all patients in the expanded access program. These were used to detect gene expression changes — measures of which genes are active and to what extent — during treatment to identify potential biomarkers of response to foralumab.
The analysis found gene activity changes that suggesting that the therapy modifies a range of immune cells, including inflammatory T-cells and B-cells, which are involved in MS inflammation, as well as Tregs, which can dampen the excess activity of other immune cells but are generally faulty in MS.
Monocytes, white blood cells that help to fight infections but can also contribute to MS, were also altered with foralumab.
“The observed clinical stabilization and microglial PET findings are supported by these new biomarker discoveries, providing compelling evidence of nasal foralumab’s biological effects,” said Howard Weiner, MD, a neurologist and chairman of Tiziana’s scientific advisory board. “The identification of these biomarkers not only strengthens our understanding of the treatment’s mechanism but also establishes a framework for monitoring its efficacy in future trials and may establish a framework for monitoring a patient’s response to foralumab treatment.”
Foralumab is also being assessed in a Phase 2a clinical trial (NCT06292923) that’s enrolling 54 people with nonactive SPMS who experienced at least two years of continuous disease progression despite treatment with available therapies.
Participants will receive two doses of intranasal foralumab (50 or 100 micrograms), or a placebo, for three months. Treatment will be given in three-week cycles consisting of sprays into each nostril three times a week for two weeks, followed by a week without treatment.
As primary goals, researchers will measure the treatment’s safety and confirm its ability to reduce microglial activity in PET scans over three months. Disability progression, a composite measure of walking ability, dexterity, cognition, and vision, and changes in fatigue will also be assessed.
“Foralumab, the first fully human anti-CD3 monoclonal antibody, is in a Phase 2 trial as a groundbreaking immunomodulatory therapy with applications in autoimmune and neurodegenerative diseases. These findings further confirm its potential and set the stage for broader clinical exploration,” said Ivor Elrifi, PhD, CEO of Tiziana.
Last year, the FDA granted foralumab fast track designation, a status that aims to accelerate the development and regulatory review of experimental medicines that have the potential to fill unmet needs of patients with serious disorders.
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