Current and emerging treatments for amyotrophic lateral sclerosis

Figures & data

Table 1 List of drugs tested in ALS, with hypothetical mechanisms of action and currently available results

Compound	Mechanism of action	Principal results
Riluzole	Antiglutamatergic	Preclinical studies with positive results^Citation8,Citation9 In three clinical trials was associated with increase in survival of about two months^Citation6 Results from population-based studies indicated an increase in survival rates at 12 months by 10% and in median survival by 4–6 months^Citation10,Citation11 A trend for stronger benefice amongst bulbar-onset ALS and patients aged >70 years was also observed^Citation10,Citation11 The favorable effect was transient, as it was lost in prolonged follow-up (after 18 months)^Citation10,Citation11
Memantine	Antiglutamatergic	Neuroprotective in in vitro and in vivo studies^Citation14 Positive preclinical studies on SOD1 transgenic mice^Citation16,Citation17 No data on humans
L-Arginine	Antiglutamatergic	Positive preclinical studies on SOD1 transgenic mice^Citation19 Lower plasma L-arginine levels in ALS patients^Citation20 No clinical trials on ALS patients
Ceftriaxone	Antiglutamatergic	Positive preclinical studies on SOD1 transgenic mice^Citation21,Citation22 No clinical trials on ALS patients Limited data on humans
Cobalamin	Antiglutamatergic	Two trials on SOD1 transgenic mice gave positive results^Citation26,Citation27 A small double-blind trial found that short term (four weeks) high-dosage (0.5 mg/day) was effective in improving compound motor action potential, used as indicator of lower motoneuron number^Citation28 Patients with a good response to treatment presented slower disease progression (disease duration: 23.1 vs 18.8 months; P = 0.02)^Citation28 The clinical benefit was however transient, as it was followed by deterioration after 1–3 months^Citation28
Talampanel	Antiglutamatergic	Prolongs survival in SOD1 transgenic mice^Citation8 In a phase II study on 60 patients with ALS showed safe and well tolerated results^Citation8,Citation23 No data on efficacy
N-acetylated alpha-linked acidic dipeptidase	Antiglutamatergic	Positive results from in vivo studies on motor neurons^Citation31 and in vivo studies on SOD1 transgenic mice^Citation30 No data on safety and efficacy in ALS patients
Topiramate	Antiglutamatergic	Preclinical studies with conflicting results: effective in vitro, but not in vivo^Citation32 A randomized clinical trial showed no benefits. Patients receiving the drug had more pulmonary emboli, deep vein thrombosis, and renal calculi^Citation33
Gabapentin	Antiglutamatergic	Preclinical results with gabapentin suggested that this agent may prolong motor neuron survival^Citation34 A phase II randomized trial found a slowing of the rate of strength decline^Citation35 A phase III clinical trial found no benefit on survival^Citation36
Lamotrigine	Antiglutamatergic	Animal model with axotomy gave positive results^Citation38 Two small sample randomized clinical trials found no beneficial effects on survival and markers of motor performances^Citation39,Citation40
r-IGF-1	Neuroprotective	In vitro and in vivo studies gave positive results^Citation41 A first clinical trial found beneficial effect,^Citation42 while two further clinical trials gave negative results^Citation43,Citation44
Mechano-growth factor	Neuroprotective	A variant of IGF-1 was more effective on survival of SOD1 transgenic mice, compared to IGF-1^Citation47 No data on humans
Ciliary neurotrophic factor	Neuroprotective	Preclinical study with positive results^Citation48 Two clinical trials revealed it was ineffective in ALS patients^Citation50,Citation51 A trend for higher serious adverse events was noted^Citation50,Citation51
EPO	Neuroprotective Anti-inflammatory Antiapoptotic	Neuroprotective effects in in vivo and in vitro studies^Citation53,Citation54 Safe and well tolerated in a phase II clinical trial^Citation55 No data on efficacy in humans
VEGF	Neuroprotective (against excitotoxicity)	VEGF polymorphisms have been associated with an increased risk for ALS^Citation23 Preclinical studies found efficacy on SOD1 transgenic mice^Citation56,Citation57 No data regarding safety, tolerability or efficacy in humans. The compound requires intrathecal delivery^Citation23 A phase II clinical trial is underway^Citation24
rh-GSF	Neuroprotective Antiapoptotic	Preclinical studies on ALS animal models gave positive results^Citation60 Safe and well tolerated in two small sample open-label pilot studies^Citation6,Citation62 One study found a trend of slowing disease progression^Citation62
rh-HGF	Neuroprotective Antiapoptotic Antiglutamatergic	Prolonged survival in different studies on SOD1 animal models^Citation63^–^Citation65 Safety or efficacy data in patients with ALS are lacking and the compound requires intrathecal delivery
BDNF	Neuroprotective	Positive results in preclinical studies on ALS animal models^Citation68,Citation69 A trend for prolonged survival after the subcutaneous infusion of BDNF was found in a phase I/II study^Citation70 A large phase III placebo-controlled clinical trial found no beneficial effect from subcutaneous administration of BDNF^Citation71 Intrathecal infusion was safe and well tolerated in 25 ALS patients^Citation66
GDNF	Neuroprotective	Treatment with GDNF mediated by either an adeno-associated virus vector^Citation72^–^Citation74 or by mesenchimal stem cells^Citation75,Citation76 was effective in preclinical in vitro and in vivo studies No data on ALS patients
Xaliproden	Neuroprotective	Modest effects on vital capacity but not on survival in phase II and III clinical trials^Citation79,Citation80
Coenzyme Q	Antioxidant Mitochondrial cofactor	Prolongs survival in SOD1 transgenic mice^Citation81 Safe and well tolerated in a recent phase II clinical trial^Citation82 Not effective in a phase II futility trial^Citation83
Creatine	Antioxidant Mitochondrial cofactor	Preclinical studies with positive results^Citation23,Citation84 Several phase II clinical trials on ALS patients using doses up to 10 g/day gave negative results^Citation85^–^Citation87 Treatment with 20 g/day increases maximal isometric power in ALS patients^Citation88 Clinical trials using high dosage or a combination with celecoxib are ongoing^Citation24
Vitamin E	Antioxidant	Effective in ALS animal models^Citation9 High intake of vitamin E was associated with a 50%–60% decreased risk of developing ALS, in a recent retrospective case-control study^Citation93 Safe, well tolerated, but not effective in two double blind, placebo-controlled, clinical trials as add-on to riluzole^Citation91,Citation92
Edavarore	Antioxidant (Free-radicals scavenger)	Preclinical studies with positive results^Citation94 Was safe and well tolerated and there was a suggestion of slowed disease progression in an open-label phase II study^Citation95
R(+) Pramipexole	Antioxidant Antiapoptotic	Prolonged survival in an animal study on SOD1 transgenic mice^Citation96 A nonsignificant reduction in disease progression was observed in a recent phase II clinical study^Citation97
AEOL-10150	Antioxidant	Effective in prolonging survival in animal study on SOD1 transgenic mice^Citation99^–^Citation101 In a recent open-label study on patients with ALS was safe and well tolerate^Citation102
Ammonium tetrathiomolybdate	Antioxidant (copper-chelating drug)	Positive preclinical studies on SOD1 transgenic mice^Citation104 No data on humans
N-acetylcysteine	Antioxidant	Prolonged survival and delayed onset of motor impairment in ALS animal study^Citation105 Not effective in a double-blind placebo-controlled clinical trial^Citation106
TRO19622	Antioxidant	Positive results from in vitro and in vivo studies^Citation107 No data on ALS patients
Tamoxifen	Antioxidant	A phase II clinical trial indicated a trend for survival benefit with administration of tamoxifen at the dose of ≥20 mg/day^Citation108
Minocycline	Antiapoptotic Anti-inflammatory	Extends survival in mouse models of some neurological conditions^Citation109^–^Citation111 Safe and well tolerated in phase-II clinical trials^Citation112 A recent multicenter, randomized placebo-controlled phase III trial found that minocycline in escalating doses of up to 400 mg/day for nine months has a harmful effect on patients with ALS^Citation113
TCH-346	Antiapoptotic	A small sample double-blind placebo controlled clinical trial conducted find no beneficial effects^Citation114
zVAD-fmk	Antiapoptotic	Significantly delayed disease onset and prolonged survival in SOD1 transgenic mice^Citation116 Data on ALS patients are still not available
Pentoxifylline	Antiapoptotic	A large phase II randomized clinical trial found that the drug is not effective in ALS and should be avoided in patients treated with riluzole^Citation117
Celecoxib	Anti-inflammatory (cyclo-oxygenase-2 inhibitor)	Positive preclinical studies on SOD1 transgenic mice^Citation119,Citation120 A double-blind, placebo-controlled, clinical trial demonstrated that celecoxib (800 mg/day) was safe but did not have a beneficial effect on patients with ALS^Citation121 A clinical trial evaluating the association with creatine at high dose is underway^Citation24
Glatiramer acetate	Anti-inflammatory Antiglutamatergic growth factor-stimulating effects	Conflicting results from preclinical studies: some studies found that it prolonged survival in SOD1 mutant mice,^Citation124 while others did not^Citation125 Was safe and well tolerated in a phase II trial^Citation126 A double-blind, randomized, placebo-controlled, multicenter trial confirmed safety and tolerability but did not show any beneficial effect^Citation127
AM-1241	Anti-inflammatory (via cannabinoid receptors)	Delayed the disease progression in animal studies^Citation128,Citation129 No data on humans are available
Celastrol	Anti-inflammatory Antioxidant Interfere with protein aggregation (by heat-shock protein induction)	Significantly improved weight loss, motor performance and delayed the onset of ALS in SOD1 transgenic mice^Citation130 No data on humans are available
Thalidomide	Anti-inflammatory	Enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in animal studies^Citation131 A small open-label study find no improvement in progression of the disease and a high risk for side effects^Citation132
Nordihydroguaiaretic acid	Anti-inflammatory Antiglutamatergic	Extends survival and slows disease progression in animal studies^Citation135 No data are available on humans
Pioglitazone	Anti-inflammatory	Significantly improved muscle strength and body weight, delayed disease onset, and prolonged survival in SOD1 transgenic mice^Citation136^–^Citation138 No data are available on humans
RO-28-2653	Anti-inflammatory (inhibits matrix metalloproteases)	Prolongs survival in ALS SOD1 transgenic mice^Citation139 No data on humans are available
ONO-2506	Anti-inflammatory Restores astrocytes Antiglutammatergic	Limited data on preclinical studies and on humans^Citation140 Trials have been however recently completed
Lithium	Inductor of autophagy Antioxidant	Effective in preclinical studies on SOD1 transgenic mice^Citation141 In a small sample open label study delayed disease progression in 44 patients affected by ALS^Citation141 Two large clinical trials are ongoing^Citation24
Sodium phenylbutyrate	Inhibit protein aggregation (histone deacetylase inhibitor)	Promotes cell survival, alone or in combination with riluzole in animal studies^Citation144,Citation145 Safe and well tolerated in a recent open-label study^Citation146
Valproate	Inhibit protein aggregation (histone deacetylase inhibitor)	Preclinical studies on SOD1 mutant mice gave discordant results;^Citation149^–^Citation152 some studies found that it prolongs survival,^Citation149,Citation150 while others did not^Citation151,Citation152 Safe but not effective in a recent sequential clinical trial^Citation153
Scriptaid	Inhibit protein aggregation (histone deacetylase inhibitor)	Preliminary positive results in cultural cells transfected with SOD1^Citation154 No data on animal models and humans are available
Ariclomol	Inhibit protein aggregation (by heat-shock protein induction)	Effective in preclinical studies^Citation155,Citation156 Safe and well tolerated in a phase II clinical trial^Citation157 No data on efficacy onALS patients

Abbreviations: ALS, amyotrophic lateral sclerosis; r-IGF-1, recombinant insulin-like growth factor; EPO, recombinant human erythropoietin; VEGF, vascular endothelial growth factor; rh-GSF, recombinant human granulocyte-macrophage colony-stimulating factor; rh-HGF, recombinant human hepatocyte growth factor; BDNF, brain-derived neurotropic factor; GDNF, glial cell-derived neurotropic factor; SOD1, superoxide dismutase-1.

Table 2 List of compounds undergoing clinical trials for ALS¹⁶³

Compound	Phase	Mechanism of action
Ariclomol	II/III	Heat-shock protein induction
Ceftriaxone	II/III	Antiglutamatergic
Cobalamin	II/III	Antiglutamatergic
Creatine	II/III	Antioxidant
Celecoxib		Anti-inflammatory
Edavarore	II/III	Free-radicals scavenger Reduces mutant SOD1 deposition
Lithium	a) II/III b) II/III	Inductor of autophagy
Memantine	II/III	Antiglutamatergic
Pioglitazone	II	Anti-inflammatory
R(+) pramipexole	II	Antioxidant Antiapoptotic
Talampanel	II	Antiglutamatergic
Thalidomide	a) I b) II	Anti-inflammatory
Valproate	II/III	Inhibits protein aggregation by acting as a histone deacetylase inhibitor
VEGF	II	Protects motor neurons against excitotoxicity

Abbreviations: ALS, amyotrophic lateral sclerosis; SOD1, superoxide dismutase-1; VEGF, vascular endothelial growth factor.

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