Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole

Figures & data

Table 1 Genes mutated in familial ALS

Locus	Gene	Inheritance	Phenotype
ALS1	SOD1	AD, AR	ALS, PMA
ALS2	ALS2	AR	Juvenile ALS, Juvenile PLS
ALS3	Not defined	AD	ALS
ALS4	SETX	AD	ALS, dHMN
ALS5	SPG11	AR	Juvenile ALS
ALS6	FUS	AD, AR, De Novo	ALS, ALS-FTD
ALS7	Not defined	AD	ALS
ALS8	VAPB	AD	ALS, PMA
ALS9	ANG	AD	ALS, ALS-FTD, PBP
ALS10	TARDBP	AD	ALS, ALS-FTD
ALS11	FIG4	AD	ALS, PLS
ALS12	OPTN	AD, AR	ALS
ALS13	ATXN2	AD	ALS
	C9orf72	AD	ALS, FTD, ALS-FTD

Abbreviations: ALS, amyotrophic lateral sclerosis; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; FTD, frontotemporal dementia; dHMN, distal hereditary motor neuropathy; PBP, progressive bulbar palsy; AD, autosomal dominant; AR, autosomal recessive.

Table 2 Recent clinical trials in ALS

Drug	Trial design	Mechanism	Sample	Endpoint	Outcome
Glatiramer	Phase III	Immune modulator	360	ALSFRS-R	Negative
Lithium	Phase II	Antiglutamatergic, Protein clearance	Up to 171	Survival/ALSFRS-R	Negative
Ceftriaxone	Phase II–III	Antiglutamatergic	600	Survival/ALSFRS-R	Ongoing
Memantine	Phase II	Antiglutamatergic	63	ALSFRS-R	Negative
Arimoclomol	Phase II	Heat shock protein inducer	84	Safety	Adequate safety
Talampanel	Phase II	Antiglutamatergic	59	Arm strength	Nonsignificant improvement
CoQ10	Phase II dose selection/futility	Antioxidant/mitochondrial cofactor	185	ALSFRS-R	Negative
Minocycline	Phase III	Anti-inflammatory/antiapoptotic	412	ALSFRS-R	Negative
Xaliproden	Phase III	Antiapoptotic	Up to 1210	Survival Breathing capacity	Negative
Gabapentin	Phase III	Antiglutamatergic	204	Arm strength	Negative
Celecoxib	Phase III	Anti-inflammatory	300	Arm strength	Negative
Riluzole	Phase III	Antiglutamatergic, unknown	Up to 959	Survival	Positive

Abbreviation: ALSFRS-R, revised version of the Amyotrophic Lateral Sclerosis Functional Rating Scale.

Table 3 Trials of dexpramipexole in ALS

Design	Sample size	Primary endpoints	Secondary endpoints	Outcome
Phase I randomized controlled trials (single dose, then multidose)	54	Safety and pharmacokinetics		Safe, well-tolerated, linear PK
Open-label trial of 30 mg/day for 6 months	30	Safety	Change in slope of ALSFRS-R pre to post-treatment	Safe and well tolerated at this dose; no significant change in ALSFRS-R
Open-label dose escalation trial up to 300 mg/day	10	Safety		Safe and well tolerated at high doses
Open-label extension of 30 mg vs 60 mg/day	10 (?)	Safety	Difference in decline of ALSFRS-R	Safe and well tolerated; no significant difference in slopes of ALSFRS-R
Phase II randomized controlled trial of three doses for 12 weeks	102	Safety and pharmacokinetics		Safe and well tolerated; linear pharmacokinetics
Phase II trial of 50 or 300 mg/day	92	Safety	ALSFRS-R and survival	Safe; improvement in a joint ALSFRS-R-mortality outcome
Phase III trial of 300 mg/day	800	ALSFRS-R – Survival joint endpoint	Other functional measures and safety	Ongoing

Abbreviation: ALSFRS-R, revised version of the Amyotrophic Lateral Sclerosis Functional Rating Scale.