studies of amifampridine have not been conducted.
Mutagenesis
Amifampridine was negative for mutagenicity in an in vitro bacterial reverse mutation (Ames)assay and for clastogenicity in in vivo mouse micronucleus and chromosomal aberrationassay.Amifampridine was positive for clastogenicity in an in vitro mouse lymphoma assay in theabsence of metabolic activation.
Impairment of Fertility
Animal Studies to assess the potential adverse effects of amifampridine on fertility have not beenconducted.
14 CLINICAL STUDIES
The efficacy of RUZURGI for the treatment of LEMS was established by Study 1, a randomized,double-blind, placebo-controlled, withdrawal study (NCT: 01511978). Study 1 enrolled patientswith an established diagnosis of LEMS, confirmed by documentation and an independentneurologist review. Patients were required to be on an adequate and stable dosage (30 mg to 100mg daily for at least 3 months) of RUZURGI prior to entering the study.
The primary measure of efficacy was the categorization of the degree of change (e.g., greaterthan 30% deterioration) in the Triple Timed Up and Go test (3TUG) upon withdrawal of activemedication, when compared with the time-matched average of the 3TUG assessments atbaseline.
The 3TUG is a measure of the time it takes a person to rise from a chair, walk 3 meters, andreturn to the chair for 3 consecutive laps without pause. Higher 3TUG scores represent greaterimpairment.
The secondary efficacy endpoint was the self-assessment scale for LEMS-related weakness (WSAS),a scale from -3 to 3 assessing a person’s feeling of weakening or strengthening frombaseline. A higher positive W-SAS score indicates a perceived greater improvement of strength.
A more negative score indicates perceived greater weakening.
After an initial open-label run-in phase, 32 patients were randomized in a double-blind fashion toeither continue treatment with RUZURGI (n = 14) or switch to placebo over a 3-day downwardtitration (n = 18) period. Following the downward titration period, patients remained on blinded RUZURGI or placebo for 16 more hours. Efficacy was assessed 2 hours after the last dose of thedownward titration period. Patients were allowed to use stable dosages of peripherally-acting cholinesterase inhibitors or oral immunosuppressants. Seventy-nine percent of patientsrandomized to RUZURGI were receiving cholinesterase inhibitors, versus 83% in the placebogroup, and 29% of patients randomized to RUZURGI were receiving an immunosuppressanttherapy, versus 39% in the placebo group.
Randomized patients had a median age of 56 years (range: 23 to 83 years), 66% were female,and 91% were White. Ninety-seven percent of patients had a diagnosis of autoimmune LEMS,and 3% of patients had a diagnosis of paraneoplastic LEMS.
All 32 patients completed the study. None of the patients randomized to continue RUZURGIexperienced a greater than 30% deterioration in the final post-dose 3TUG test. In contrast, 72%(13/18) of those randomized to placebo experienced a greater than 30% deterioration in the final3TUG test (p < 0.0001). Patients who were randomized to placebo returned to baseline afterrestarting RUZURGI. Figure 1 shows the time course of the mean percent change from baselineon the 3TUG during the double-blind phase and with reinitiation of RUZURGI.
Figure 1: Mean Percent Change From Baseline in Post-dose 3TUG TimeDuring the Double-blind Phase of the Study and Return to
Baseline Upon Reinitiation of RUZURGI |
