Temelimab (formerly known as GNbAC1) is an antibody-based therapy that is being investigated as a potential treatment for relapsing forms of multiple sclerosis (MS).
It aims to lessen the damaging immune response that underlies MS.
GeNeuro, the company developing temelimab, also is testing it for amyotrophic lateral sclerosis and neuropsychiatric symptoms in long-COVID patients.
MS is a progressive neurodegenerative disease that develops when the body’s immune system mistakenly launches an attack that damages the myelin sheath — a fatty substance that wraps around nerve fibers to protect them from damage and to improve the transmission of nerve signals.
The loss of this protective coating can lead to permanent nerve damage and a range of disease symptoms.
Multiple genetic and environmental factors are believed to contribute to the damaging inflammation in MS. One potential factor is the activation of viral genes that have been incorporated into the human genome due to viral infections occurring over several million years. It is estimated that about 8% of the human genome is made up of these viral genes.
A particular virus called human endogenous retrovirus (pHERV-W) is normally inactive, or latent, in the human genome. But some infectious agents can activate this retrovirus and induce the production of pHERV-W Env, a protein of the viral envelope.
This protein is mainly produced in certain cells of the immune system, and leads to more pro-inflammatory behavior. It also results in a reduced ability to repair the damaged myelin.
Consistently, studies by researchers at GeNeuro and other institutions have found this protein in regions of myelin damage, and have also deemed it a major factor that triggers and worsens disease progression in MS patients.
Temelimab is a selective monoclonal antibody designed to target and neutralize the pHERV-W Env protein. Doing so is expected to lower the damaging immune response in MS and potentially enable a more efficient regeneration of the myelin sheath.
In MS clinical trials, temelimab has been given via an intravenous (into-the-vein) infusion. It has been adminstered once per month at doses ranging from 2 to 54 milligrams per kilogram of body weight (mg/kg).
According to GeNeuro, further analyses are needed to determine an optimal dose for future clinical testing.
GeNeuro initially launched two Phase 1 trials — NCT01699555 in 2011 and NCT02452996 in 2015 — testing a single infusion of temelimab in healthy volunteers. Findings showed doses ranging from 0.0025 to 36 mg/kg were safe and well-tolerated.
A small Phase 2a clinical study (NCT01639300) then confirmed the treatment’s tolerability in 10 MS patients who received monthly temelimab infusions (at doses of 2 or 6 mg/kg) for 48 weeks, or nearly one year. This prompted the company to launch another Phase 2b trial investigating the therapy in a larger group of patients.
The Europe-based CHANGE-MS trial (NCT02782858) enrolled 270 adults, ages 18 to 55, with active relapsing-remitting MS. Participants were randomly assigned to receive one of three temelimab doses (6, 12, or 18 mg/kg), or a placebo, for 24 weeks. Injections were given over the course of two hours, in monthly intervals.
After 24 weeks, participants on temelimab continued receiving their assigned dose for another six months. Meanwhile, those originally assigned a placebo were again randomized to one of the three temelimab groups.
The trial’s main goal was to determine if temelimab treatment could reduce the development of brain lesions with active inflammation on MRI scans from weeks 12 to 24.
This goal was not met. But temelimab was very well-tolerated and secondary measures indicated some promising neuroprotective effects with the highest, 18 mg/kg dose.
The proportion of patients without inflammatory lesions from week 12 to 48 was significantly higher among patients continuously receiving the highest dose of temelimab than in those originally assigned a placebo (46.8% vs. 27.7%). Brain volume loss over the 48 weeks also was significantly slowed (by 27%) with the high dose, and patients showed signs of myelin preservation.
The number of T1 hypointense lesions — black holes on MRI scans indicating permanent tissue damage in the brain — was 63% lower in the high-dose group, compared with a placebo. The results, however, showed no differences in relapse rate or in disability progression between the groups.
After completing the 48 weeks in CHANGE-MS, a total of 220 patients chose to join an open-label extension (OLE) study called ANGEL-MS (NCT03239860).
During this OLE, they continued to receive the same temelimab dose for 48 weeks. This totaled up to 96 weeks of treatment for those assigned temelimab from the start.
The trial was prematurely terminated after one year because Servier, which was developing temelimab in collaboration with GeNeuro, decided to end the partnership and withdraw its funding. However, 154 patients received temelimab for at least 96 weeks.
The findings continued to support the benefits observed in the randomized trial. In the combined period of CHANGE-MS and ANGEL-MS, patients who were continuously on the 18 mg/kg dose experienced a 42% reduction in brain volume loss compared with the group that had originally received a placebo. These participants also saw an increase in myelin content by more than 1.5% relative to the original placebo group.
Although earlier preliminary evidence had suggested that the 18 mg/kg dose led to a slower disease progression, no significant differences were observed between groups with regard to relapse rates or disability progression in the final published analyses.
Because only the highest tested dose demonstrated some clinical efficacy, and that dose still failed to reach the primary goal of reducing active inflammatory lesions, GeNeuro began testing still greater doses of the therapy.
The company first conducted a Phase 1 trial (NCT03574428) in 24 healthy men. These participants were randomly assigned to one of four doses of temelimab — 36, 60, 85, or 110 mg/kg — or a placebo, given as a single infusion.
Results showed that these higher doses continued to be well-tolerated, with no patients experiencing serious adverse events or developing antibodies against temelimab.
A Phase 2a trial, called ProTEct-MS (NCT04480307), conducted in Sweden, then evaluated three doses of temelimab against a placebo. A total of 41 patients with relapsing forms of MS were given doses of 18, 36, or 54 mg/kg.
All participants were experiencing disease progression without relapses after at least one year of rituximab, an antibody-based therapy that is commonly used off-label in MS. Patients were then assigned to receive either monthly temelimab, or a placebo, for 48 weeks, or nearly one year.
Top-line data, recently published, showed that all three doses were generally safe and well-tolerated, with no reports of serious side effects nor discontinuations related to treatment. With those results, the trial met its main goal.
Temelimab treatment also was associated with trends toward a preservation of brain volume and myelin integrity. However, the small sample size prevented the detection of statistically significant changes. Still, the magnitude of these effects was similar to that observed in the CHANGE-MS and ANGEL-MS trials.
An open-label extension of ProTEct-MS, which enrolled its first participant in September 2021, is still ongoing. It is designed to gain more insights into the long-term neuroprotective effects of temelimab at higher doses.
The most common side effects of temelimab reported in MS clinical trials include:
Infusion-related reactions did not differ between treatment groups in clinical trials; all reactions were mild or moderate in severity.
In the CHANGE-MS and ANGEL-MS trials, three serious adverse events — breast cancer, toxic hepatitis, and bloody urine — were determined to be related to treatment, which each occurring in one patient.
Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
Temelimab is an experimental antibody therapy that is not yet approved for the treatment of multiple sclerosis (MS). It is designed to block the effects of a viral protein, pHERV-W, which is known to contribute to the damaging immune response in MS. Clinical trials in relapsing forms of the disease have shown a slower brain tissue loss and preserved myelin after temelimab treatment.
It is still too early to know if or when the medication might be approved by the U.S. Food and Drug Administration. Temelimab has shown promising neuroprotective effects in Phase 2 trials involving people with relapsing forms of multiple sclerosis. But an optimal dose for future clinical trials has not yet been determined, and additional studies will be needed before any application for approval can be submitted.
Clinical trials of temelimab have not included people who were pregnant or breastfeeding, and all who had the ability to reproduce were required to use effective methods of contraception. It is not known whether the therapy is safe for such patients.
In the CHANGE-MS clinical trial, a 18 mg/kg dose of temelimab resulted in significant reductions in brain volume loss and in preserved myelin integrity after one year of treatment. However, multiple sclerosis manifests differently in all patients and responses to treatment may vary.
Hair loss and weight gain were not reported as side effects of temelimab in multiple sclerosis clinical trials. Patients who experience unexpected side effects after starting any new treatment are advised to speak with their healthcare providers.
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