Zilucoplan

The mechanism

How it works.

In the common, antibody-positive form of myasthenia gravis, the immune system makes antibodies against the acetylcholine receptors at the junction where nerves tell muscles to contract. Those antibodies switch on the complement system, whose final step builds a 'membrane attack complex' that punches holes in the junction and destroys the receptors, so signals fail and muscles tire. Zilucoplan is a small ring-shaped peptide that grabs complement protein C5 and stops it from being split into the pieces that form that attack complex. With the final complement step blocked, the nerve-muscle junction is protected. Because it is a small peptide rather than a large antibody, it can be self-injected under the skin each day; and because it works on the same complement pathway as drugs like the C3 blocker pegcetacoplan, it carries the same need to guard against complement-related infections.

What's next

What we're watching.

Long-term safety and effectiveness, head-to-head comparisons with antibody C5 inhibitors and FcRn blockers, and its place in the myasthenia treatment sequence.

Context

Why this is discussed.

Zilucoplan is a rare thing: a small, self-injectable peptide that does a job usually done by big antibody drugs, blocking complement C5 to protect the nerve-muscle connection in myasthenia gravis. It gives people with antibody-positive disease a daily at-home injection option.

The evidence base

15 cited references.

Keep reading

Related published memos.