Amifampridines are the Most Effective Drugs for Treating Lambert-Eaton Myasthenic Syndrome With a Focus on Pediatric Lambert-Eaton Myasthenic Syndrome

Abstract

In 1983, the first successful trial of 3,4-diaminopyridine (3,4-DAP) in Lambert-Eaton myasthenic syndrome (LEMS) was reported. Efficacy of amifampridine (3,4-DAP and 3,4-diaminopyridine phosphate [3,4-DAPP]) for symptomatic treatment in LEMS was proven by seven randomized studies in 3,4-DAP and two randomized studies in 3,4-DAPP. US Food Drug Administration approved 3,4-DAPP usage for adult LEMS in 2018 and for pediatric LEMS in 2022. Nineteen pediatric LEMS cases were identified in the literature. Compared with adult LEMS, the rate of malignancy is low as expected and the rate of dysautonomia is also low in pediatric LEMS. Unexpected finding is two cases of pediatric LEMS following antecedent infection. Amifampridine can be safely used as long the daily dose is less than 80 mg a day for adult LEMS patients and less than 30 mg a day for pediatric LEMS patients. Amifampridines can be supplemented with a liberal amount of pyridostigmine for long term usage. Amifampridine was used as symptomatic treatment in eight (42%) of 19 pediatric LEMS patients: 3,4-DAP in six and 3,4-DAPP in two patients. The most common practice of 3,4-DAP was a combination with pyridostigmine in four patients. With 3,4-DAP, normal activity was reported in 3 cases and mild to moderate-improvement in other 3 cases. In two patients with 3,4-DAPP, significant improvement in one and no improvement in one. Amifampridines are proven to be effective and safe drugs for the symptomatic treatment without serious side reaction in adults as well as in children as long as the dosage is properly adhered.

Graphical Abstract

INTRODUCTION

Amifampridines were first introduced as an alternative to 4-aminopyridine in 1983 for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS).¹ The US Food Drug Administration (FDA) finally approved the use of 3,4-diaminopyridine phosphate (3,4-DAPP) for adult LEMS in 2018 on the basis of the effectiveness demonstrated in two double-blind 3,4-DAPP studies of adult LEMS performed by Catalyst Pharmaceuticals (CP).²,³,⁴ This long delay was due to the associated randomized, placebo-controlled trials. The FDA approved the use of 3,4-diaminopyridine (3,4-DAP) for pediatric LEMS in 2019 on the basis of the effectiveness demonstrated in one double-blind study of 3,4-DAP in adults performed by Jacobus Pharmaceutical Company (JPC).²,⁵ In 2022, the FDA reversed its decision about the JPC 3,4-DAP approval in pediatric LEMS, and instead approved the use of 3,4-DAPP for symptomatic treatment.⁶

This review summarizes the effectiveness and safety profile of amifampridines for the symptomatic treatment of LEMS, with a focus on pediatric LEMS.

LAMBERT-EATON MYASTHENIC SYNDROME

General information

LEMS is a rare presynaptic neuromuscular junctional disorder induced by antibodies to the voltage-gated calcium channel (VGCC) producing fatigue and muscle weakness.⁷ LEMS is less common than myasthenia gravis (MG). Wirtz et al.⁸ investigated the epidemiology of MG and LEMS in the northern part of South Holland (The Netherlands), and estimated that LEMS was 46 times less prevalent than MG.

In LEMS, by blocking VGCC by VGCC antibody, Ca⁺⁺ uptake in the pre-synapses is decreased. This decreases the release of acetylcholine (ACh) from the synaptic vesicles, inducing muscle weakness.⁹ LEMS is frequently associated with small-cell lung cancer (SCLC), which was reportedly observed in 75% of LEMS cases during the 1960s and in 50% of LEMS cases during the 2000s.⁷,¹⁰,¹¹,¹²

LEMS is considered a disease of the elderly, with the most-common age at the onset of symptoms being around 60 years.¹² This is due to paraneoplastic LEMS, which develops typically in middle-aged-to-elderly individuals, and was originally more common in males. The age and sex distributions in autoimmune LEMS are similar to those reported for MG. Autoimmune LEMS is seen at all ages, with a peak age at onset of around 35 years and a second larger peak at an age of 60 years. Most patients with autoimmune LEMS are female.

There are no obvious clinical and electrophysiological differences that distinguish paraneoplastic LEMS from autoimmune LEMS. Rapid disease progression and cerebellar degeneration were found to be suggestive of paraneoplastic LEMS.⁸ According to our experience, cancer is less likely to be associated with LEMS if the patient is a young female and if LEMS symptoms have been present for longer than 3 years. The discovery of LEMS usually precedes that of cancer by several months to 2 years.⁸ With modern diagnostic techniques, cancer has been detected within 3 months of an LEMS diagnosis in about 92% of LEMS patients and within 1 year of an LEMS diagnosis in 96% of LEMS patients.⁸ Thus, it is important to perform a workup for occult cancer, especially SCLC, at the time of LEMS diagnosis and serially thereafter for up to 2 years. High-resolution chest computed tomography and fludeoxyglucose-positron emission tomography can be used to detect SCLC and extrapulmonary cancer.

Symptoms and findings

The most-common symptoms of LEMS are proximal muscle weakness, especially in the legs, and easy fatigability.⁷,¹²,¹³ Due to its similar symptomatology, MG is the most commonly misdiagnosed entity in patients with LEMS. However, oculobulbar symptoms, which are common initial symptoms in MG, are rare in LEMS. The tensilon test is positive in 90%–95% of MG cases but only 33% of LEMS cases.¹⁴

The triad of findings In LEMS comprises proximal muscle weakness, weak or absent reflexes, and dysautonomia.¹²,¹³ In MG, reflexes are normal and dysautonomic symptoms are absent. The common dysautonomic symptoms in LEMS are dryness of mouth, orthostatic hypotension, and erectile dysfunction. Thus, it is important to ask about dysautonomic symptoms in patients with suspected LEMS. The pathognomonic simple bedside diagnostic test for LEMS is documentation of postexercise facilitation (PEF) in the muscle strength or reflexes.¹⁵ After brief muscle exercise (e.g., for 10 s), an improvement of the muscle strength or reflexes can be documented in LEMS. Unfortunately PEF was observed only in one-third of LEMS patients.¹⁵

Diagnosis

The repetitive nerve stimulation (RNS) test is the key diagnostic test in LEMS (Fig. 1). Unlike in MG, abnormality is found universally in all muscles in LEMS.¹³,¹⁶ The abductor digiti minimi muscle testing is the most commonly preferred and usually sufficient to diagnose LEMS. The triad of findings in the RNS test are a low cpompound muscle action potential (CMAP) amplitude, a decremental response to low-rate stimulation, and an incremental response after brief exercise or high-rate stimulation (HRS). For ensuring an adequate technical test, brief 10 s exercise and a 2.5 min wait period between the tests are recommended.¹⁷,¹⁸

Fig. 1. Improvement in the repetitive nerve stimulation (RNS) test in the abductor digiti quinti muscle with 3,4-diaminopyridine (3,4-DAP) compared with placebo. In placebo, the RNS test showed a pattern typical of presynaptic neuromuscular block except for the response to 2 Hz stimulation, with a low CMAP, postexercise facilitation, and increased response to high-rate (50 Hz) stimulation. An increased response to low-rate (2 Hz) stimulation is atypical of a presynaptic block. With 3,4-DAP, the RNS test normalized. This figure is cited with author’s permission from page 84 in Oh and Sieb. US Neurol 2014;10:83-89.⁵³ CMAP, cpompound muscle action potential.

For the diagnostic marker of LEMS, an incremental response ≥100% was used in the past.⁷ Our study showed that a CMAP increase of ≥60% provided a sensitivity of 96% and a specificity of 98% in diagnosing LEMS.¹³ Lipka et al.’s¹⁹ study confirmed this finding.

The VGCC antibody test was found to be positive in 91% of LEMS patients.⁹ However, in view of the low specificity of 3%, LEMS should not be diagnosed based on a positive VGCC antibody test alone.²⁰

Treatment

Treatments for LEMS consist of immunotherapy, cancer therapy, and symptomatic treatment. Being an immune-mediated disease, immunotherapy should be the mainstay therapy for LEMS. However, most experts recommend immunosuppressive treatment in patients who are unresponsive to symptomatic treatment. Among various immunotherapies, intravenous immunoglobulin (IVIg) was the only treatment showing a better outcome than placebo.²¹ Various immunosuppressive therapies such as prednisolone, azathioprine, cyclosporin, and plasma exchange have shown some efficacy in treating LEMS. Aggressive therapy for cancer is also essential because LEMS symptoms improve and paraneoplastic LEMS patients who receive aggressive treatment live longer than SCLC patients who do not receive such treatment.²²,²³

Symptomatic treatment

For symptomatic treatment, voltage-gated potassium channel (VGKC) blocking agents have been the drugs of choice.²,²⁴ By blocking VGKCs and inhibiting repolarization at nerve endings, such agents induce the opening of slow VGCCs and increase Ca⁺⁺ influx into nerve terminals, subsequently leading to exocytosis of ACh-containing synaptic vesicles and hence increased ACh at synapses.²⁴

Guanidine HCl is one of four available VGKC blocking agents, and was the first drug used for LEMS and has been studied in case series. Administering guanidine HCl to 47 LEMS patients resulted in clinical improvement in most cases and electrophysiological improvement in all cases.²⁵ Rare instances of bone-marrow suppression and renal insufficiency, which seemed to be related to the dose, resulted in guanidine HCl being withdrawn from general use for LEMS from the early 1990s. However, Oh et al.²⁵ reported in 1997 that a combination of low-dosage guanidine (1 g/day) and a liberal dose of pyridostigmine in nine LEMS patients produced improvements in muscle strength and CMAP amplitudes without any serious side effects.

An open-label trial of another VGKC blocking agent (4-aminopyridine) involving nine LEMS patients in 1977 demonstrated clinical and electrophysiological improvements.²⁶ However, seizure occurred in two patients.

PEDIATRIC LEMS

In 1974, Dahl and Sato²⁷ reported the first pediatric case of LEMS in a 13-year-old male who had experienced fatigable limb weakness for 9 months. Examinations showed proximal muscle weakness with an improvement in strength after repeated exercise, but with normal reflexes. The RNS test showed a 5-mV CMAP, 45% decrement at 3-Hz stimulation and 85% increment at 50-Hz HRS. The edrophonium test was positive. Neostigmine at 180 mg/day improved the muscle strength to normal. Guanidine at 2.5 g/day maintained normal daily activity. The patients was treated with guanidine and neostigmine for 4 years with an excellent outcome.

Following that first case, the reported number of pediatric LEMS ranged from 10 to 12 in 2013 and 2014.²⁸,²⁹ In 2023, PubMed search found 66 articles under search words: children, Lambert Eaton Myasthenic Syndrome. Excluding four patients aged 4–16 years with autosomal dominant LEMS due to synaptotagmin 2 mutation because this disorder is hereditary,³⁰ we identified 23 cases of acquired pediatric LEMS in the literature (Table 1).²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶ Four of these 23 cases were excluded because they did not meet the second criterion of a CMAP increase of ≥60% either after brief exercise or HRS in the RNS test.¹³ The RNS test was not performed in three cases and was normal in one case.³²,³⁴ The VGCC antibody test was not used as a diagnostic criterion for LEMS due to its high false-positive rate.²⁰ Another four excluded cases included one case of Wilms tumor and three cases of neuroblastoma.³²,³³,³⁴ The case reported by Moor and Gardin³¹ was included even though the degree of PEF was not reported. This selection procedure finally yielded 19 cases of pediatric LEMS that met our diagnostic criteria for LEMS.¹³

Table 1. Comparison of adult vs. pediatric Lambert-Eaton myasthenic syndrome (LEMS).

Variable		Adult LEMS (n=44)*	Pediatric LEMS (n=19)
Sex and age
	Male:female	24:20	10:9
	Age range (yr)	26–75	3–16
	Mean age (yr)	55.5	7.0
	<40 years: ≥40 years	5:39
	<10 years: ≥10 years		8:11
Symptoms/findings
	Acute onset after infection	0	2
	Oculobulbar symptoms	25 (56)	8 (42)
	Limb weakness	43 (98)	19 (100)
	Decreased or absent reflexes	43 (98)	13 (68)
	Dysautonomia	20 (45)	2†
	Positivity in edrophonium/prostigmin test	14/24 (58)	2/2 (100)
Antibody test positivity
	VGCC antibody	17/24 (71)	10/11 (91)
	AChR antibody	3/26 (12)	2/9 (18)
Malignancy		24 (55)	3 (16)‡
	SCLC	21 (48)

Data are n or n (%) values except where indicated otherwise.

^*Data from Oh SJ. Muscle Nerve 2016:53:20-26⁵⁹; ^†Dry mouth; ^‡Leukemia (n=2), neuroblastoma (n=1).

AChR, acetylcholine receptor; SCLC, small-cell lung cancer; VGCC, voltage-gated calcium channel.

There were 10 male and 9 female patients whose ages ranged from 3 to 16 years: 12 patients aged 6–10 years, 5 patients aged 11–17 years, and 2 patients aged 0–5 years. The disease duration before the evaluation ranged from 1 day to 4 years: from 1 day to 6 months in nine patients, 7–12 months in five patients, 1–4 years for three patients, and for an unknown period in two patients. One patient with floppy infant syndrome was evaluated at 4 years of age.³⁵

Two patients developed limb weakness after viral illness or 5 days of diarrhea, with gait difficulty lasting for 1 day in one patient and for 5 months in the other patient.²⁹,³⁶ All patients had limb weakness, and 11 (56%) had oculobulbar symptoms. One patient had respiratory insufficiency.³⁷ Two patients showed an improvement in muscle strength after a short period of muscle exercise.²⁷,⁴⁴ Reflexes were absent in 13 cases, reduced in 1, normal in 3, and not mentioned for 2. One patient showed an improvement in reflexes after a short period of muscle exercise.⁴⁴

Dryness of mouth was reported in two patients.³⁶,³⁹ Two patients had autoimmune disease: one with scleroderma and one with thyrotoxicosis.⁴⁰,⁴¹ Malignancy was detected in three (16%) patients: Burkitt lymphoma with acute lymphocytic leukemia 3 months before LEMS diagnosis, neuroblastoma at the time of LEMS diagnosis, and leukemia at 1 month after LEMS diagnosis.²⁸,⁴²,⁴³ Thus, there are three distinct features in pediatric LEMS compared with adult LEMS: low malignancy rate (16%), low rate of dysautonomia, and high rate of antecedent infection (11%) (Table 1).²⁹,³⁶ Adult LEMS was reported to be associated with SCLC in 50%–70% of cases, while, in pediatric LEMS, the malignancy rate was found to be low (16%) and the association was with blood cancer.¹⁰,¹¹ Postinfectious LEMS was not reported in adult LEMS. A 70-year-old patient with Fisher syndrome and LEMS for 6 weeks did not have any preceding infection but had elevated cerebro-spinal fluid protein and positivity for GQ1b and P/Q-type VGCC antibodies.⁴⁷

In pediatric LEMS patients, VGCC antibody was positive in 10 (92%) of 11 tested pediatric LEMS patients, while AChR antibody was positive in 1 of 8 tested patients and MuSK antibody was negative in 2 tested patients. The RNS test was performed in hand muscles in 15 pediatric LEMS patients, in foot muscles in 3 patients, and in unspecified muscles in 3 patients. The CMAP was low or low-to-normal in all of the reported 17 patients. An increase in CMAP of >60% was documented in 18 patients either in the postexercise test (8 patients) or for HRS at 20–50 Hz (11 patients). In one case, an increase in CMAP was present but its amount was not specified.³¹

The treatment method was not reported for one patient with thyrotoxicosis and multiple autoautoantibodies.⁴⁰ LEMS was cured in one patient following surgical removal of neuroblastoma after seven plasma exchanges.²⁸ Death was reported at 2–3 months after an LEMS diagnosis in two patients: one with lymphoma and the other with leukemia.⁴²,⁴³

Immunotherapy was the main stay of treatment in 12 (71%) of 17 pediatric LEMS patients. Immunotherapy was the only treatment in one patient: plasma exchange followed by IVIg for 2 years and with cyclosporin alone for 8 years, which resulted in improvement leading to being symptoms free during the 7-year follow-up.²⁹ Plasma exchanges and neuroblastoma removal resulted in complete recovery after 3 years in one patient.²⁸ Plasma exchange, IVIg, prednisone, and cyclosporine were tried in each of four patients. Azathioprine was used in two patients. Symptomatic treatment was added to immunotherapy in 10 (59%) patients: amifampridines in 6, AChE inhibitor in 3, aminopyridine in 1, and guanidine in 1.

For symptomatic treatment, AChE inhibitor (pyridostigmine) was the most commonly used symptomatic treatment in 11 (58%) patients in pediatric LEMS. AChE inhibitor was combined with immunotherapy in three patients, which produced no response in one patient and improvement in two patients. AChE inhibitor was used with VGKC blocking agents with improvement in seven patients: aminopyridine in one patient, guanidine in three patients, and amifampridines in four patients. No improvement was found with neostigmine in one patient with leukemia.

Guanidine HCl, the first VGKC blocking agent introduced for use in LEMS, was used with an excellent improvement in three cases, including one case with neostigmine in one.²⁷,³⁵,³⁷ Immunotherapy was not added in any of these patients. Improvement in the RNS test was documented in one case.³⁵

4-Aminopyridine, the second VGKC blocking agent introduced for use in LEMS, was added to pyridostigmine in the second year in one patient, which led to an improvement of strength in the limb muscle.⁴⁴ However, the patient required IVIg treatment and mycophenolate monfetil in the subsequent follow-up.

AMIFAMPRIDINES AS THE MAIN DRUG FOR THE SYMPTOMATIC TREATMENT IN LEMS

3,4-DAP and 3,4-DAPP are the third VGKC blocking agents introduced for use in LEMS. 3,4-DAP has greater potency in neuromuscular transmission and a lower convulsant effect than 4-aminopyridine, and its first administration in three LEMS patients in 1983 resulted in clinical and electrophysiological improvements (Table 2).¹ Since then, 128 patients have been treated with 3,4-DAP in open-label trials, resulting in improvement in muscle strength or the ability to perform the activities of daily living in 123 (96%) patients.² Six randomized, placebo-controlled trials involving 48 patients showed a significant improvement of the primary endpoint (quantitative myasthenia gravis [QMG] score and CMAP amplitude) for 3,4-DAP over placebo.²,⁴⁸ However, seizure occurred in four patients: one patient had brain metastasis, and the other three had taken 3,4-DAP at ≥80 mg/day. A toxic level of aminophylline was found in one of these three patients. Since then, 80 mg of 3,4-DAP has been set as the maximum daily dose.

Table 2. Summary of amifampridine trials in adult and pediatric LEMS patients.

			Patients	Duration	Daily dose	Improvement results
3,4-DAP
	Adult patients
		Open-label study	128 Patients	3 months to 10 years	30–80 mg	Muscle strength and daily activity in 123 (98%) patients
		Randomized study	6 Studies 48 patients	1 day to 6 months	10–100 mg	Muscle strength, QMG score, CMAP (p<0.02)
		Sponsored randomized study*	1 Study 18 patients	7 days	30–100 mg	3 TUG. W-SAS (p<0.0001)
	Pediatric patients
		Open-label study	6 Patients	4–12 years	20–30 mg	Improvement in 6 patients
3,4-DAPP
	Adult patients
		Open-label study	8 Patients	Up to 5 years	40–80 mg	Daily function in 6 patients, ocular symptoms in 1 patients, QMG score in 2 patients
		Sponsored randomized study†	2 Studies 70 patients	7–14 days	15–80 mg	QMG score, SGI, CGI, TWF-25FW (p<0.002)
	Pediatric patients
		Open-label study	2 Patients	2 years	30 mg	Good quality of life in 1 patient

^*Sponsored by drug company⁵⁴; ^†Sponsored by drug company³,⁴.

3,4-DAP, 3,4-diaminopyridine; 3,4-DAPP, 3,4-diaminopyridine phosphate; CGI, Clinical Global Impression of Improvement; CMAP, compound muscle action potential; LEMS, Lambert-Eaton myasthenic syndrome; QMG, quantitative myasthenia gravis; SGI, Subject Global Impression of improvement; TUG, turn-up-gait; TWF-25FW, timed 25-foot walk test; W-SAS: LEM-related weakness self-assessment scale.

3,4-DAPP is 3,4-DAP with added phosphate. Compared with 3,4-DAP, 3,4-DAPP is more stable and can be stored at room temperature.² Around 2010, 3,4-DAPP was approved for use in LEMS by the European Medicine Agency without any further study under the “exceptional circumstance” criterion on the basis of previous trials with 3,4-DAP.⁴⁹ This approval resulted in the price of 3,4-DAPP increasing dramatically, such as by 50-fold in the UK which received widespread publicity.

Two recent randomized, placebo-controlled, multicenter trials involving 64 patients compared 3,4-DAPP with placebo for treating LEMS by using the QMG score and the subjective global score of improvement as the primary endpoints, and the clinical global impression of improvement and walking tests (timed 25-foot walk and three times up-and-go test) as the secondary endpoints.³,⁴ There were significant improvements in all of the primary and secondary endpoints for 3,4-DAPP relative to placebo. The FDA approved 3,4-DAPP (Firdapse, CP) for LEMS in 2018. However, the price of 3,4-DAPP has remained high, such as at USD 180 for a 10-mg Firdapse tablet.²

The recommended maximum dosage of amifampridines (3,4-DAP and 3,4-DAPP) is 80 mg/day, divided into three or four times daily due to their shorter half-life.² 3,4-DAP has a longer time to peak than 3,4-DAPP and thus can be given only twice daily.² The two most-common side effects are tolerable paresthesia around the mouth and fingers and gastrointestinal distress. No other major side effect has been reported, including prolongation of the QT wave interval in the electrocardiography (which is a potential side effect). For long-term administration, amifampridines can be supplemented with a liberal amount of pyridostigmine.

PHARMAOKINETIC PROFILE OF AMIFAMPRIDINES

Clinical improvement was seen in LEMS patients within 5 min of an intravenous administration of 3,4-DAP at 8–9 mg.⁵⁰ 3,4-DAPP taken orally is rapidly absorbed and has a relatively short half-life (2.5 h). The effect peaks at 1.5 h after oral administration, with treatment effects maintained for 3–8 h. Food intake does not significantly alter the pharmacokinetics of 3,4-DAP.⁵¹ The oral dose needs to be approximately three times that given intravenously to achieve the same efficacy.⁵⁰

3,4-DAP free base is predominantly metabolized to its pharmacologically inactive metabolite, 3-N-acetyl-3,4 diaminopyridine (3-Ac-DAP), by aryl N-acetyl transferases, with approximately 80% of the orally administrated drug being excreted through renal elimination as 3-Ac-DAP.² Compared with subjects with normal renal function, amifampridine exposure was two- to three-fold higher in those with moderate or severe renal impairment.² A bioequivalence study comparing the 3,4-DAP base and its phosphate salt form (3,4-DAPP) showed a higher Cmax and a shorter time to the peak concentration for the salt form.²

SAFETY PROFILE OF AMIFAMPRIDINES

Serious complications

Seizure is the most serious complication of 3,4-DAP. Seizure was reported in four LEMS and three multiple sclerosis patients.² One LEMS patient had brain metastasis and two of the multiple sclerosis patients had a previous history of seizure. Three LEMS patients were taking 3,4-DAP at 100 mg/day and one patient was on 60 mg/day. There was no seizure in two patients when the 3,4-DAP daily dose was reduced to 40 mg or 70 mg. One of these three patients had a toxic level of theophylline, and did not experience seizures after theophylline was discontinued. As a result of these findings, amifampridines are not recommended in any patient with brain disease or with any drug known to increase the risk of seizure (including theophylline), and the maximum recommended daily dose of 3,4-DAP is 80 mg.

There is a theoretical risk of 3,4-DAP causing prolongation of QT interval and hence a predisposition to cardiac arrhythmia. So far no clinically serious cardiovascular complication has been reported when administering therapeutic doses of 3,4-DAP. However, two cases of palpitation without any QT prolongation were reported with 3,4-DAPP.²

Two cases of liver toxicity were reported

One case of elevated liver enzymes without any clinical manifestation during 3,4-DAPP treatment, and one case of biopsy-confirmed drug-induced hepatotoxicity with spontaneous recovery during 3,4-DAP treatment.²

Long-term safety data for amifampridines

No serious irreversible side effect was found with 3,4-DAP or 3,4-DAPP treatment in 4 studies involving 37 patients with follow-up data covering more than 3 years.² The final report of the European LEMS registry of 3,4-DAPP based on 50 patients with 3,4-DAPP, 21 patients with 3,4-DAP, and 25 with other treatments for follow-up periods of up to 9 years documented 9 treatment-related serious side effects in 8 participants and identified no new safety signals. But multiple confounding factors were identified for each serious adverse event, limiting interpretation of the contribution of treatment.⁵²

REGULATORY STATUS OF AMIFAMPRIDINES

The FDA granted an orphan drug designation to 3,4-DAP to JPC in 1990. Under this program, two randomized studies and a few open-label studies on 3,4-DAP were published.⁵³ JPC provided 3,4-DAP free of charge to patients under the Independent New Drug program for many years. In 2013, 3,4-DAP was granted a “breakthrough therapy designation” in the US,⁵³ which permitted a fast-track New Drug Application process.

After the Dapper study provided significant evidence of the efficacy of 3,4-DAP in maintaining muscle strength in adults with LEMS in 2018, 3,4-DAP (Ruzurgi) was approved for pediatric LEMS patients younger than 17 years to JPC in 2019.⁵⁴

Following the successful completion of the first phase III study of Firdapse (3,4-DAPP) in 2016 and the second phase III study in November 2018 by CP, the FDA approved the use of 10-mg tablets for treating adult LEMS.³,⁴ The price of Firdapse remains high, at more than twice that of 3,4-DAP (USD 80 per tablet).

CP filed a suit against the FDA in June 2019 regarding its approval of Ruzurgi, alleging that the FDA violated the company’s statutory rights to Orphan Drug Exclusivity for Firdapse for the treatment of LEMS for 7 years.⁵⁵ In February 2022, the court released an opinion that Ruzurgi approval for pediatric LEMS was no longer valid.⁵⁵,⁵⁶ In October 2022, CP received FDA approval for the expanded pediatric indication for Firdapse.⁵⁵,⁵⁷

AMIFAMPRIDINE TREATMENT IN PEDIATRIC LEMS

Usage of amifampridines in pediatric LEMS

Amifampridines were used for symptomatic treatment in 8 (42%) of 19 pediatric LEMS patients: 3,4-DAP in 6 patients and 3,4-DAPP in 2.

The first pediatric LEMS patients was treated in 1991 with 3,4-DAP, plasma exchange, prednisone, and azathioprine, which improved muscle strength and increased the CMAP.³⁸ The highest daily dose administered was 30 mg (Table 3).³⁸,³⁹ The most-common practice was to combine 3,4-DAP with pyridostigmine (in four patients). Treatment with 3,4-DAP alone was applied for 11 years in one patient.³⁶ 3,4-DAP was used in combination of immunosuppresssive agents in five patients: cyclosporin in three, azathioprine in two, and prednisone in one. Normal activity was reported in three cases, while the improvement was mild to moderate in the other three cases.

Table 3. Recommended oral dosages of 3,4-DAP and 3,4-DAPP for the treatment of LEMS.

Body weight		Initial dosage	Titration regimen	Maximum single dose	Maximum total daily dose
3,4-DAPP (Firdapse)
	≥45 kg*	10–15 mg/day, in 3 or 4 divided doses	Increase total daily dose by 5 mg every 3–4 days	20 mg	80 mg, given in divided doses
	<45 kg	5–15 mg/day, in 3 or 4 divided doses	Increase total daily dose by 2.5 mg every 3–4 days	10 mg	40 mg, given in divided doses
3,4-DAP (Ruzurgi)†
	≥45 kg	15–30 mg/day, in 2 or 3 divided doses	Increase daily in 5- to 10-mg increments, divided in up to 5 daily doses	30 mg	100 mg
	<45 kg	7–15 mg/day in 2 or 3 divided doses	Increase daily in 2.5- to 5-mg increments, divided in up to 5 daily doses	15 mg	50 mg

^*Same as adult (any weight); ^†Recommended previously by Ruzurgi.

3,4-DAP, 3,4-diaminopyridine; 3,4-DAPP, 3,4-diaminopyridine phosphate; LEMS, Lambert-Eaton myasthenic syndrome.

The first pediatric LEMS patient was treated in 2013 with 3,4-DAPP at 30 mg/day for 2 years, resulting in a good quality of life at the time of the report.³⁹ This patient had taken 3,4-DAP for 11 years, and experienced significant improvement prior to starting on 3,4-DAPP. 3,4-DAPP was not effective in the second pediatric LEMS patient.

Safety of amifampridines in pediatric LEMS

Our review of seven pediatric LEMS patients taking 3,4-DAP or 3,4-DAPP did not identify any major side effect. The longest trials of these medications lasted 17 years.

JPC reported side effects similar to those seen in adult patients in 15 LEMS and non-LEMS patients aged 6–17 years in expanded access programs, with 9 receiving 3,4-DAP for at least 1 year.⁵⁶ CP also reported that side effects in pediatric patients were similar to those seen in adult patients in 21 pediatric LEMS patients receiving 3,4-DAPP for at least 1 year.⁵⁷ However, clinically significant weight loss was reported in two pediatric patients on a daily dose of at least 60 mg.³ In 57 patients with congenital myasthenic syndrome 3,4-DAP was given at 15–80 mg/day without any serious side effects.²

EXPERT OPINIONS

3,4-DAP

Since the first use of 3,4-DAP in LEMS was reported in 1983, clinical improvement has been documented in 123 (96%) of 128 cases in open-label studies (Table 2).¹,² Usually this was achieved with 3,4-DAP dosages of 30–80 mg/day, often with the addition of pyridostigmine at 30–240 mg/day. Six randomized studies of 48 patients found a significant difference in favor of 3,4-DAP relative to placebo in the primary endpoints score and the CMAP amplitude.²

3,4-DAPP

Open-label studies have reportedly only involved eight cases, including one of ocular LEMS.¹,²,⁵⁸ 3,4-DAPP at 40–60 mg/day improved daily function in six of seven treated patients and in more than two QMG scores in three treated patients. One ocular LEMS patient experienced the complete relief of eye symptoms with 3,4-DAPP at 80 mg/day combined with pyridostigmine at <240 mg/day.⁵⁸ Two randomized, multicenter trials compared 3,4-DAPP with placebo for treating 64 cases of LEMS.²,³ All of the primary and secondary endpoints showed statistically significant improvements with 3,4-DAPP relative to placebo.

The maximum daily dose of amifampridines (3,4-DAP and 3,4-DAPP) is recommended to be 80 mg for adults, divided into three or four times daily due to their shorter half-life (Table 2). 3,4-DAP can be given twice daily due to its slower release compared with 3,4-DAPP.² Side effects are minimal and tolerable. A liberal amount of pyridostigmine may be used supplement amifampridines for long-term administration.

Amifampridines have been demonstrated to be effective and safe drugs for symptomatic treatment without serious side effects in both adults and children as long as the appropriate dosage is administered. Thus, these should be the drugs of choice for symptomatic treatment in pediatric LEMS.

The main problem with amifampridines currently is their high price. Amifampridines are the best-studied and most-effective symptomatic drugs for LEMS, and hence should be available to all LEMS patients at a reasonable price.

CONCLUSION

Forty years after the first trial of 3,4-DAP in LEMS, amifampridines were approved by the FDA in 2022 for the symptomatic treatment of LEMS for adults as well as children. Many open-label studies and all of the double-blind control studies of the amifampridines 3,4-DAP and 3,4 DAPP have shown that these are effective and safe drugs for the symptomatic treatment of LEMS. Thus, amifampridines should be the drugs of choice for the symptomatic treatment for pediatric LEMS.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.