Myasthenia gravis (MG) is a rare, debilitating, acquired autoimmune disease of the neuromuscular junction (NMJ), caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies (Abs) to proteins involved in signaling at the NMJ. The main proteins affected are acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). Myasthenia gravis is clinically characterized by weakness and fatigability of skeletal muscles, with disease severity varying widely among affected patients. MuSK-MG, in particular, is a subclass of the disease, characterized by a predominance in females, an earlier onset than other MG subclasses, prominent bulbar involvement, more severe clinical condition, and significant resistance to treatment.1-3
MuSK-MG is estimated to affect up to 8% of all patients with MG and its presentation can be grouped from mild to severe3,4:
- Mild: Patients may have increased generalized muscle weakness; otherwise, it’s indistinguishable from AChR-MG
- Moderate: Patients have increased neck, shoulder, and respiratory muscle weakness
- Severe: Patients have prevalent bulbar weakness and frequent myasthenic crisis
Although many patients with MuSK-MG are treated with anticholinesterase inhibitors or immunosuppressants, they do not respond well to such treatments. Hence, MuSK-MG patients may continue to have marked generalized weakness and bulbar signs. In these patients, the search for alternative treatment strategies targeting different pathophysiologic aspects of the disease is a medical need.1,2
Amifampridine Phosphate in MuSK-MG
Catalyst is enrolling patients into a phase 3 trial examining amifampridine phosphate, a neuronal potassium channel blocker, for the treatment of MuSK-positive myasthenia gravis (MuSK-MG).
- Change in MG-ADL score* from baseline (day 0) to day 10
- Change in QMG score† from baseline (day 0) to day 10
Patient safety is monitored throughout the trial and the open-label extension period
QMG=Quantitative Myasthenia Gravis; AChR=acetylcholine receptor; MG= myasthenia gravis; MG-ADL= myasthenia gravis activities of daily living scal
- The myasthenia gravis activities of daily living (MG-ADL) profile is an 8 item patient-reported scale developed to assess MG symptoms and their effects on daily activities; it has been validated and shown to correlate with the QMG score. The MG-ADL correlates strongly with newer, validated MG outcome measures (MGC and MGQOL15). A 2-point improvement in the MG-ADL indicates clinical improvement.
- The QMG test is a physician-rated test using 13 assessments, including facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each of the 13 items is scored from 0 (none) to 3 (severe). The total score can range from 0 to 39. Increased QMG total score correlates to worsening symptoms of LEMS.
- Pasnoor M, Wolfe GI, Nations S, et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve. 2010;41(3):370-374.
- El-Salem K, Yassin A, Al-Hayk K. et al. Treatment of MuSK-associated myasthenia gravis. Curr Treat Options Neurol. 2014;16: 283.
- Koneczny I, Cossins J, Vincent A. The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014;224(1):29-35.
- Sieb J.P. Myasthenia gravis: an update for the clinician. Clin Exp Immunol. 2014;175(3):408–418