@tatiana987 Trial protocols and inclusion/exclusion lists for the ORION program generally excluded people with “severe concomitant non-cardiovascular disease” and had other exclusions that tend to screen out unstable or severe systemic illnesses. The formal protocols include neurological exams and other screening steps. That means people with active, unstable, or severe autoimmune diseases (including many people with MS) were often excluded or under-represented. The phase-3 publications and protocol appendices list these exclusions.

I could not find any completed, large clinical trial that specifically enrolled people with MS to evaluate inclisiran safety in that population. That leaves limited direct evidence for MS patients.

Remaining unknowns:

Mechanism: inclisiran is an siRNA that acts in the liver to reduce PCSK9 production (it’s not a broadly immunosuppressive drug). That mechanism reduces the biological plausibility of causing systemic autoimmune flares, but it doesn’t eliminate possibility of immune reactions (e.g., injection hypersensitivity, rare immune events) or very rare long-term effects that only show up in larger or longer datasets.

Because MS and other autoimmune conditions were under-represented, the issue cannot be highly confident about the absence of very rare autoimmune flares or interactions with disease-modifying therapies for MS — the trials were not designed to answer that question.

Practical implications / reasonable next steps

If someone has MS (or another autoimmune disease), it’s reasonable to:

1. Discuss with both the prescribing cardiologist and the patient’s neurologist before starting Leqvio, especially if the MS is active or they’re on immunomodulatory/immunosuppressive therapy.

2. Be alert for new/worsening neurological symptoms or other autoimmune symptoms after dosing and report them promptly.

3. Know that dermatologic/injection-site reactions and arthralgia are the most common side effects; serious allergic reactions are rare but listed in the label.

There is reassuring multi-year safety data for inclisiran from pooled analyses and open-label extensions (follow-up into the multi-year range, with some groups reported beyond 3–6 years and >12,000 patient-years reported in pooled analyses). The safety profile has been consistent (injection-site reactions, arthralgia, some respiratory infections; rare hypersensitivity). However, people with autoimmune diseases such as MS were largely not included in the pivotal trials, so direct trial evidence in that population is limited; therefore extra caution, close monitoring, and consultation with the neurologist are sensible if considering Leqvio for someone with MS.