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Positive data in myasthenia gravis with Zilucoplan in phase 3 RAISE study

Positive topline results from the RAISE trial evaluating investigational treatment Zilucoplan, a self-administered, subcutaneous ( SC ) peptide inhibitor of complement component 5 ( C5 inhibitor ), versus placebo in adults with generalized myasthenia gravis ( gMG ), were announced.

The primary endpoint of the trial was met; a clinically meaningful and statistically significant improvement from baseline in Myasthenia Gravis-Activities of Daily Living Profile ( MG-ADL ) total score at week 12 was observed for the Zilucoplan treatment group vs placebo.

All key secondary endpoints were also met, including statistically significant improvements from baseline in Quantitative Myasthenia Gravis ( QMG ) score, Myasthenia Gravis Composite ( MGC ) score and MG-QoL15r score at week 12 for the Zilucoplan treatment group vs placebo.

The results have shown Zilucoplan was well-tolerated and no major unexpected safety findings were identified compared to earlier Zilucoplan studies.
The incidence of serious treatment emergent adverse events ( TEAEs ) in the Zilucoplan and placebo treatment arms was similar.

The RAISE study ( Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis ) is a multi-center, phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Zilucoplan in adult patients with generalized myasthenia gravis.

Patients were randomized in a 1:1 ratio to receive daily subcutaneous ( SC ) doses of Zilucoplan or placebo for 12 weeks.
The study was designed to determine if complete complement inhibition can bring clinical benefit to people with gMG and if complement inhibition was effective across a broad spectrum of patients with acetylcholine receptor antibody positive ( AChR Ab+ ) myasthenia gravis regardless of disease duration, prior treatment or response to previous therapies.

The primary endpoint for RAISE study is change from baseline at week 12 in the MG-ADL score, an eight-item patient-reported scale developed to assess myasthenia gravis symptoms and their effects on daily activities.
Secondary endpoints include change in the Quantitative Myasthenia Gravis ( QMG ) score, MGC and MG-QoL15r from baseline to week 12; time to rescue therapy; the percentage with minimum symptom expression ( MSE ) ( defined as MG-ADL of 0 or 1 ), the percentage with a 3-point or more reduction in MG-ADL and the percentage with a 5-point or more reduction in QMG, all measured at week 12.

Zilucoplan targets complement component 5 ( C5 ), a component of the terminal complement activation pathway, and binds to C5 with high affinity and specificity. This prevents its cleavage by C5 convertases into the complement components C5a and C5b.
In addition, Zilucoplan is understood to bind to the domain of C5 that corresponds to C5b and thereby block binding of C5b to complement component C6.
Inhibition of C5 cleavage prevents the downstream assembly and activity of membrane attack complex ( MAC ).
This dual mechanism of action of Zilucoplan has the potential to prevent activation of the terminal complement pathway and downstream assembly and activity of MAC that can damage and destroy the postsynaptic membrane, disrupt ionic channel conductance and impair neuromuscular transmission.

The safety and efficacy of Zilucoplan have not been established and it is not currently approved for use in any indication by any regulatory authority worldwide.

Myasthenia gravis is a rare disease impacting almost 200,000 patients in the U.S., EU and Japan. , People living with generalized myasthenia gravis can experience a variety of symptoms, including drooping eyelids, double vision and difficulty swallowing, chewing and talking, as well as severe life- threatening weakness of the muscles of respiration.

Generalized myasthenia gravis is a chronic and unpredictable auto-immune disease in which pathogenic autoantibodies can inhibit synaptic transmission at the neuro-muscular junction by targeting specific proteins on the post-synaptic membrane. This disrupts the ability of the nerves to stimulate the muscle and results in a weaker contraction.
Generalized myasthenia gravis can occur at any age and in any race, although previous studies have shown that women are more often impacted than men.
Complement activation, a key mediator of antibody function, is recognized as an important driver of pathology in generalized myasthenia gravis. ( Xagena )

Source: UCB, 2022