Myasthenia Gravis
Conditions
Interventions
Part A1 (cohort 1 and cohort 3)
single doses of NMD670 (2 active 1 placebo)
Part A1 Food effect cohort (cohort 2)
single doses of NMD670 (3 active and 1
placebo, or 2 active and 2 placebo (2 repeated dose levels in a fasted and fed
state)
Part A2
single dose of 800mg NMD670
Part B
Multiple ascending dose part, dosing of dose levels chosen after PK
evaluation of part A for 10 consequtive days QD, BID or TID
Part C
two single oral doses of NMD670 and 1 dose of placebo
Sponsors
NMD Pharma A/S
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Main inclusion criteria healthy volunteers (Part A and B) 1. Signed informed consent prior to any study-mandated procedure 2. Part A1: Healthy male subjects, 18 to 45 years of age, inclusive at screening. 3. Part A2: Healthy female subjects of non-childbearing potential, 18-65 years of age, inclusive at screening. 4. Part B: Healthy male subjects 18-65 years of age, inclusive at screening. 5. Body mass index (BMI) between 18 and 30 kg/m2, inclusive at screening, and with a minimum weight of 50 kg. 6. All males must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment. 7. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions. Main inclusion criteria myasthenia gravis patients (Part C) 1. Signed informed consent prior to any study-mandated procedure 2. Male and female subjects 18 and above years of age, inclusive at screening. 3. Diagnosis of myasthenia gravis, MGFA class I, II, III or IVa, based on characteristic muscle weakness and a positive AChR or muscle-specific tyrosine kinase (MuSK) antibody test. Subjects with MGFA 0 using pyridostigmine (mestinon) may be included, if muscle weakness is present when refraining from pyridostigmine (as assessed by a medical doctor based on an interview of the patient at screening). 4. Patients using steroids should be using a stable dose of steroids for at least 1 month before dosing, and the dose of steroids should be expected to remain stable for the duration of the study. 5. Body mass index (BMI) between 18 and 34 kg/m2, inclusive at screening, and with a minimum weight of 50 kg. 6. All women of child bearing potential and all males must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment. 7. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions. 8. Must be able to cease the use of pyridostigmine as per study requirements, if applicable.
Exclusion criteria
Exclusion criteria: Main exclusion criteMain exclusion criteria healthy volunteers (Part A and B) 1. Evidence of any active or chronic disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance. 2. Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects. 3. Use of any medications (prescription or over-the-counter [OTC]), within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to 1g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator. 4. Positive test for drugs of abuse at screening or pre-dose. Retesting is allowed at the discretion of the Investigator. 5. Alcohol will not be allowed from at least 24 hours before screening or pre-dose. 6. Smoker of more than 10 cigarettes per day prior to screening or who use tobacco products equivalent to more than 10 cigarettes per day and unable to abstain from smoking whilst in the unit. 7. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). 8. Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease. 9. History of trauma to the lower extremities or other conditions (most importantly neurological or muscle diseases) that, in the opinion of the investigator, could affect the electrophysiological measurements. 10. Excessive exercise within 7 days before study drug administration. 11. Clinically significant abnormalities in coagulation. Main exclusion criteria myasthenia gravis patients (Part C) 1. Evidence of any active or chronic disease or condition apart from myasthenia gravis, that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) and 12-lead electrocardiogram (ECG)). Deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance. 2. Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). 5. Use of any medicati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Tolerability / safety endpoints The following endpoints will be determined at time points indicated in the Schedule of Assessments. * Serious adverse events (SAEs) and adverse events (AEs) will be collected throughout the study at every study visit. * Concomitant medication * Clinical laboratory tests o Haematology o Chemistry o Urinalysis o Coagulation * Vital signs o Pulse Rate (bpm) o Systolic blood pressure (mmHg) o Diastolic blood pressure (mmHg) o Respiratory rate * ECG o Heart Rate (HR) (bpm), PR, QRS, QT, QTcF * 24-hour Holter recording * Handgrip dynamometry o Grip release profile; timeprofile from 100% maximum voluntary contraction (MVC) to 5% of the 100%MVC o 100%MVC (Part C only) | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetic endpoints Blood and urine samples for assay of NMD670 and its acyl glucuronide metabolite will be taken at timepoints indicated in the Visit and Assessment Schedule. PK endpoints for single dose cohorts: * NMD670: Cmax, tmax, AUClast, AUCinf, AUC extrapolated, t*, Lambda_z, CL/F, and Vz/F, Cmax/D, AUCinf/D. * Metabolite Evaluation plasma [Acyl glucuronide of NMD670 (NMD1190), NMD670 R-isomer (NMD1239)]: Cmax, tmax, AUClast, AUCinf, AUC extrapolated, t* * Urine PK endpoints for NMD670: Aelast, Aelast%, CLR. * Urine PK endpoints for Acyl glucuronide of NMD670 (NMD1190) and NMD670 R-isomer (NMD1239): Aelast, Aelast%. PK endpoints for multiple dose cohorts: * NMD670: AUC0-24h, Cmax (per dose), tmax (per dose), t* (following second dose of the day), Lambda_z (following second dose of the day), CL/F (day 9 only), Vz/F (day 9 only), MRT0-24h (day 9 only); Ctrough on intervening days (see Visit and Assessment schedule) and the last day of dosing; Rac(Cmax per dose) and Rac(AUC0-24h), Cmax/D and AUC0-24h/D. * Metabolite Evaluation plasma [Acyl glucuronide of NMD670 (NMD1190), NMD670 R-isomer (NMD1239)]: AUC0-24h, Cmax (per dose), Cmin (per dose), tmax (per dose), t* (following second dose of the day), Lambda_z (following second dose of the day), Ctrough on intervening days (see Visit and Assessment schedule) and the last day of dosing; Rac(Cmax per dose) and Rac(AUC0-24h). Exploratory endpoint: plasma protein binding (PPB), fraction unbound | — |
Countries
Netherlands
Outcome results
None listed