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Lambert-Eaton Myasthenic Syndrome

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Channel Blockers

All Drugs and Chemicals

Amifampridine

Potassium Channel Blockers

Dosage form: tablets containing the equivalent of 10 mg amifampridine per tablet.

Amifampridine Phosphate given based on Investigator assessment of optimal neuromuscular benefit. In adult patients \> 16 years of age, Doses ranged from 30 mg to 80 mg, divided into doses taken 3 to 4 times per day and in pediatric patients age \< 16 years the maximum daily dose was 60 mg/day. No single dose to exceed 20 mg.

Amifampridine Phosphate

Perry Shieh, MD, PhD

Primary:

The primary objective of this study under the original protocol was to provide neuromuscular specialists and neurologists access to amifampridine phosphate therapy for their patients with LEMS, CMS or downbeat nystagmus until the product became commercially available.

Secondary:

The secondary objective of this study under the original protocol was to provide additional long-term safety data on amifampridine phosphate in patients.

Primary The primary objective of this study after its fifth amendment was to provide access to amifampridine phosphate therapy to pediatric patients with LEMS, and pediatric and adult patients with CMS until the product became commercially available for these indications or development of the product for the indication was terminated.

Secondary:

The secondary objective of this study after its fifth amendment was to assess the long-term safety of amifampridine phosphate in pediatric patients with LEMS, and pediatric and adult patients with CMS.

This multicenter, expanded access study was designed to allow EAP-001 Investigators, neuromuscular specialists, and neurologists access to amifampridine phosphate therapy for their patients with LEMS, CMS, or downbeat nystagmus until such time the product became commercially available for these specific indications or development of the product for the indication was terminated. Given that these are chronic conditions, this study obtained some long-term safety data by evaluating Adverse Events, physical exams, vital signs, standard safety laboratory tests (chemistry, hematology, and urinalysis), pregnancy testing (if applicable) and abnormal ECG findings, where each of these data/measures were performed as part of a routine standard of care treatment provided by the Principal Investigator or the patient's personal physician(s) (i.e., could be performed by a different physician not involved in the treatment of neuromuscular disease).

Planned -100 sites in US and up to 200 patients. Actual- 50 sites activated and 200 patients enrolled.

Patients were seen at screening/baseline, Day 1 and at least once per year at the PIs discretion. With the COVID-19 Pandemic, telehealth visits were allowed and assessments that could be completed via remote telehealth visits were performed via phone or videoconference. Follow-up visits included Physical exams, vital signs, standard safety laboratory tests (chemistry, hematology, and urinalysis), pregnancy testing (if applicable) and ECGs.

Patients were titrated to an optimal individualized dose of amifampridine phosphate based on Principal Investigator assessment of optimal neuromuscular benefit. In patients already taking amifampridine base, amifampridine phosphate was started at an equivalent or lower dose of amifampridine phosphate, at the Principal Investigator's discretion. Therapeutic doses were to range from 10 to 80 mg, divided into doses taken two (2) to four (4) times per day, with a maximum single dose of 20 mg. For upward titration, amifampridine phosphate could be increased by 10 mg increments every four (4) to five (5) days to a maximum of 80 mg per day (ages \>16 years), and to a maximum of 60 mg (ages 2 to 16 years) based on optimal neuromuscular benefit and at the discretion of the Principal Investigator. If needed, titration could occur in 5 mg/dose and per day increments. Drug was shipped to the clinic for the first dose ( Day 1) and subsequent shipments were sent to the patients home by a specialty pharmacy.

In addition to amifampridine phosphate, patients received best supportive care (BSC) treatment as determined by the Principal Investigator using concomitant medications permitted by protocol, including selected oral immunosuppressant's (i.e., prednisone or other corticosteroids, azathioprine, mycophenolate) and peripherally acting cholinesterase inhibitors (e.g., pyridostigmine). Changes to BSC could be made at the Principal Investigator's discretion, as long as prohibited concomitant medications were not used.

Firdapse® was approved for adult patients with LEMS in November 2018 and approved for pediatric patients with LEMS ages 6 years and older in September 2022. The indications for CMS and DBN were not pursued.

Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome

An Open-Label, Expanded Access Protocol for Firdapse® (Amifampridine Phosphate; 3,4-Diaminopyridine Phosphate) Treatment in Pediatric Patients With Lambert-Eaton Myasthenic Syndrome (LEMS), and in Pediatric and Adult Patients With Congenital Myasthenic Syndromes (CMSs)

Catalyst Pharmaceuticals, Inc.

amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days

placebo by mouth 3 to 4 times per day for 4 days

Placebo Oral Tablet

This study evaluates the effect of withdrawing amifampridine phosphate treatment from patients with LEMS. One half of the patients will continue to receive amifampridine phosphate and the other half will receive placebo, during this double-blind study.

This was a randomized (1:1), double-blind, placebo-controlled, parallel-group, withdrawal study designed to evaluate the efficacy and safety of amifampridine phosphate in patients diagnosed with LEMS. The study was planned to include approximately 28 male and female patients.

Prior to the study, patients were receiving unblinded treatment in the expanded access program (EAP-001). Patients had to be on a stable dose and frequency of amifampridine phosphate for at least 1 week prior to randomization into LMS-003. Screening and randomization (Day 0) may have been into a single visit.

Patients who met eligibility criteria were randomized 1:1 to amifampridine phosphate (at the patient's optimal dose) or placebo on Day 0.

Baseline assessments were obtained on Study Day 0, while the patient has been on open-label amifampridine phosphate and in relationship to the usual dosing schedule. Patients took blinded study medication on Day 1 through Day 3. On Day 4, a dose of blinded study medication was administered by the site study personnel. This was the same medication that the patient took on Day 1 through Day 3. The assessments listed below were performed following either the second, third, or fourth dose of medication taken on Day 4, and this should be the same dose after which Day 0 assessments were performed. For example, if the patient took their second dose of amifampridine in the clinic on Day 0 and had assessments started 40 minutes later, then on Day 4, that patient should be assessed after taking their second dose of investigational product (IP).

Beginning with the next dose after all Day 0 baseline assessments were completed, the patient received IP through Day 4, with a clinic visit on the last day (Day 4) for assessments.

The planned duration of participation for each patient was up to 12 days, including screening (up to 7 days), Day 0 assessments and randomization, and IP administration (Day 1 through Day 4).

Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)

A Phase 3, Double-Blind, Placebo-controlled, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate in Patients With Lambert-Eaton Myasthenic Syndrome

The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.

The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.

The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.

The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.

Treatment-emergent AEs (TEAEs) were summarized using system organ class and PT by treatment and overall for all patients in the safety population.

amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days

Amifampridine Phosphate

placebo by mouth 3 to 4 times per day for 4 days

Placebo Oral Tablet

Placebo (for Amifampridine Phosphate)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Weight

Gary Ingenito

Baseline

Day 4

Change from baseline

Quantitative Myasthenia Gravis (QMG) Score

Change from baseline to Day 4

Subject Global Impression (SGI) Score

Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline

The number and proportion of patients with a ≥20% increase in 3TUG average time

Triple Timed Up and Go Walk Test (3TUG)

Overall Study

Subjects continued taking their usual individualized regimen of 3,4-DAP base, 30 to 100 mg daily divided into at least 3 doses.

Subjects were tapered over 3 days from their usual individualized regimen of 3,4-DAP base (30 to 100 mg daily divided into at least 3 doses) to placebo with up to an additional 16 hours of placebo before resuming their usual pre-study regimen of 3,4-DAP base

Subjects were maintained on their usual personal dose and schedule of 3,4-DAP base

Continuous 3,4-DAP

Subjects were tapered over 3 days from their usual regimen of 3,4-DAP base to placebo with up to an additional 16 hours of placebo before resuming their usual pre-study regimen of 3,4-DAP base

Taper 3,4-DAP to Placebo

Kathy L Aleš, MD

Hypothesis: 3,4-Diaminopyridine base (3,4-DAP) improves Lambert-Eaton Myasthenic Syndrome (LEMS)-related weakness.

The objectives of the study were to confirm the safety and to test the efficacy of 3,4-DAP in the treatment of LEMS-related weakness.

This was a phase 2 randomized double-blind placebo-controlled withdrawal study in subjects with known clinically active LEMS who had been on a chronic stable dose of compassionate distribution Jacobus 3,4-DAP provided through FDA-approved individual investigator-held INDs.

This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study to assess the safety and efficacy of 3,4-DAP in subjects on a stable regimen of all LEMS-related treatments, including 3,4-DAP, for a minimum of 3 months prior to study entry. Subjects who met all study entry criteria were randomized in a 1:1 ratio to continue their current treatment regimen (Group A, continuous 3,4-DAP) or tapered withdrawal from 3,4-DAP (Group B, taper to placebo).

Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome

Inpatient Double-Blind Placebo-Controlled Withdrawal Study of 3,4-Diaminopyridine Base (3,4-DAP) in Subjects With Known Lambert-Eaton Myasthenic Syndrome

The 3TUG time obtained 2 hours after the last dose of the withdrawal period (i.e., at time of theoretical "peak drug effect") was compared to the average time-matched 3TUG tests performed during 2 days of baseline observation prior to randomization.

The study endpoint was a change of more than 30% in the final post-dose 3TUG during the withdrawal period and was based on blinded readings of video recordings of 3TUG tests.

The last post-dose self-assessment of LEMS-related weakness from the withdrawal period with categories of much much weaker (-3), much weaker (-2), somewhat weaker (-1), about the same (0), somewhat stronger (1), much stronger (2), and much much stronger (3).

Jacobus Pharmaceutical

The return of Lambert-Eaton Myasthenic Syndrome (LEMS)-related signs and symptoms in a withdrawal design was anticipated and therefore adverse events were categorized as (1) treatment emergent adverse events, (2) treatment emergent adverse events excluding LEMS-related signs and symptoms, and (3) LEMS-related signs and symptoms adverse events

Subjects were administered their usual dosage on their regular personalized schedule

Continuous 3,4-Diaminopyridine (3,4-DAP)

Subjects were administered decreasing amounts of 3,4-DAP on their regular personalized schedule

3,4-DAP Taper to Placebo

Race (NIH/OMB)

Height

Body Mass Index (BMI)

Age at diagnosis

Time between symptom onset and diagnosis

Duration of diagnosis prior to randomization

Positive P/Q type voltage-gated calcium channel (VGCC) antibodies at screening

Compound Muscle Action Potential (CMAP) consistent with Lambert-Eaton Myasthenia (LEM) at screening

Total Daily Dose of 3,4-DAP at randomization

Number of 3,4-DAP individual daily doses at randomization

Dr. Kathy Aleš, Medical Director

Subjects were continued on their usual pre-randomization 3,4-DAP dosing regimen.

Subjects were tapered off of their pre-randomization 3,4-DAP dosing regimen over 3 days with up to an additional 16 hours of placebo.

Number of Participants With 30% or More Deterioration in Triple Timed Up & Go (3TUG) Test, Compared to Time-matched Baseline

Subjects were administered their usual dosage on their regular personalized schedule.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome	NCT02189720	Congenital Myas... Lambert-Eaton M... Nystagmus, Acqu...	Amifampridine P...	2 Years -	Catalyst Pharmaceuticals, Inc.
Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome	NCT02189720	Congenital Myas... Lambert-Eaton M... Nystagmus, Acqu...	Amifampridine P...	2 Years -	Catalyst Pharmaceuticals, Inc.
Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)	NCT02970162	Lambert-Eaton M...	Amifampridine P... Placebo Oral Ta...	18 Years -	Catalyst Pharmaceuticals, Inc.
Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome	NCT01511978	Lambert-Eaton M... Eaton-Lambert M...	Continuous 3,4-... Taper 3,4-DAP t...	18 Years -	Jacobus Pharmaceutical
Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)	NCT02970162	Lambert-Eaton M...	Amifampridine P... Placebo Oral Ta...	18 Years -	Catalyst Pharmaceuticals, Inc.

Spots Global Cancer Trial Database for lems

Every month we try and update this database with for lems cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for lems

Every month we try and update this database with for lems cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for lems cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.