The chronic autoimmune disease, myasthenia gravis, affects the skeletal muscles responsible for eye movements, breathing and motion
The neuromuscular condition causes both muscle weakness and fatigue, with the immune system erroneously attacking muscle receptors by producing anti-receptor antibodies, particularly those that target antiacetylcholine receptor (AChR) and anti-muscle-specific kinase (MuSK).
Blocking or destroying these receptors means that signals cannot be transmitted from nerves to muscles. In generalised myasthenia gravis (gMG), patients gradually start to experience symptoms such as limb weakness, drooping eyelids and double vision, plus problems with breathing, speech, chewing and swallowing. Although the condition can often be managed with existing therapies, alternatives are still required.
Nipocalimab is a potential new treatment, which was developed by Momenta, and is now being developed by Janssen.
It is a high affinity, fully human, aglycosylated, effectorless IgG1 anti-FcRn monoclonal antibody, which interferes with the binding of IgG, enabling it to undergo lysosomal degradation, reducing serum levels of total IgG and the pathogenic autoantibodies.
The hope is that it will improve nerve-to-muscle signals and muscle function, thereby easing the clinical signs and symptoms of gMG.
A randomised, double-blind, placebo-controlled first-in-human study was done in 50 healthy volunteers.1 Multiple weekly doses of 15 or 30 mg/kg gave mean reductions in IgG of about 85% from baseline, which was maintained at 75% from baseline for up to 24 days. It was well tolerated with no serious adverse events.
A randomised, placebo-controlled Phase II study looked at the safety, tolerability and efficacy of nipocalimab in addition to standard of care treatment in 68 patients with moderate to severe gMG, and whose response to ongoing standard of care treatment was inadequate.2
Subjects were given the antibody or one of three doses of the antibody via intravenous infusion every other week for 8 weeks and, after the follow up period, a separate open label extension study was available for enrolment.
It gave substantial, rapid reductions in serum total IgG and anti-AChR IG autoantibodies, which correlated with progress in the condition; a greater proportion of those treated with the antibody had a rapid improvement in symptoms across all doses.
A durable response was reported by 52% of treated patients compared with 15% of the placebo group. There were no discontinuations as a result of adverse events and the incidence of infections and headaches were comparable with the placebo.
The antibody is also being investigated as a potential treatment for warm autoimmune haemolytic anaemia. It is also being studied in haemolytic disease of the foetus and newborns in pregnant women at risk of the disease, having been shown to cross the placenta in a Phase I study in healthy subjects.3