Amyotrophic lateral sclerosis: clinical perspectives

Figures & data

Table 1 Summary of human clinical trial results of agents delaying disease progression in ALS animal models

Compound	Proposed mechanism	Results from preclinical studies	Results from human clinical trials	Improvement inhuman survival
Anakinra	Interleukin-1 receptor antagonist	Prolongs survival of SOD1^G^Citation93^A mice^Citation117	Phase trial of anakinra in combination with riluzole is currently under way (NCT01277315)	To be determined
Arimoclomol (BRX-345)	Amplifies heat shock protein expression under cell stress	Delayed denervation and nerve sprouting, reversed muscle fiber transformation, and increased Hsp70 expression in SOD1^G^Citation93^A mice in early^Citation118 and late stages of the disease^Citation119	Well tolerated in Phase study,^Citation120 Phase II/III study under way (NCT00706147)	To be determined
Brain-derived neurotrophic factor	Growth factor	Promotes survival in spinal motoneurons after axotomy^Citation121 or ventral root avulsion;^Citation122 improves motor dysfunction in wobbler mouse motor neuron disease;^Citation123 protects neuron from in vivo excitotoxicity^Citation124	No survival benefit^Citation125	No benefit
Ciliary growth factor	Growth factor	Prevents degeneration of motoneurons after axotomy;^Citation126 prevents degeneration of motor neurons in the pmn/pmn mouse model (model of progressive motor neuropathy)	No survival benefit and side effects at higher doses^Citation127	No benefit
Ceftriaxone	Direct decrease of glutamate production and indirect increase of glutamate breakdown (upregulates mRNA for glutamate transporter on astrocytes)	Delays loss of neurons and muscle strength, increased survival in SOD1^G^Citation93^A mouse model^Citation128	No change in decline of ALSFRS-R^Citation129	No benefit
Celecoxib	Reduction of astrocytic glutamate release, reduced production of free radicals, anti-inflammatory	Delays onset of weakness and weight loss and increases survival in SOD1^G^Citation93^A mice^Citation130	No change in the rate of upper extremity motor function decline^Citation131	No benefit
Coenzyme Q	Mitochondrial cofactor, free radical scavenger	mproves survival in SOD1^G^Citation93^A mice^Citation132	No change in decline of ALSFRS-R^Citation133	No benefit
Creatine	Antioxidation	Dose-dependent improvement in motor performance and extended survival in SOD1^G^Citation93^A mice^Citation134	No change in decline of ALSFRS-R or on quality of life^Citation135	No benefit
Cyclosporine	nhibits mitochondrial permeability transition pore	Reduces neuronal death and prolongs survival of late-stage SOD1^G^Citation93^A mice after intrathecal administration^Citation136	No change in the rate of disease progression^Citation137	No benefit
Dexpramipexole	Preservation of mitochondria function by reducing apoptosis	No published ALS animal data prior to clinical studies, later found to have no effect in SOD1^G^Citation93^A mice^Citation138	No change in the decline of ALSFRS-R^Citation139	No benefit
daravone	Antioxidant, scavenger of free radicals	Slows motor decline and decreases SOD1 deposits in SOD1^G^Citation93^A mice^Citation140	No effect on disease progression^Citation141	No benefit
Fingolimod	Sphingosine-1-phosphate receptor modulator, which leads to sequestration of lymphocytes in lymph nodes, thus preventing them from contributing to an autoimmune reaction	No data from animal studies in motor neuron disease available	Phase trial is currently under way (NCT01786174)	To be determined
Gabapentin	Reduces glutamate synthesis at high doses	Prevents neuronal death^Citation142 and prolongs survival in SOD1^G^Citation93^A mice^Citation134	No change in the rate of decline of the arm muscle strength and more rapid decline of forced vital capacity^Citation144	No benefit
Glatiramer acetate	T-cell modifier	nitial studies showed delayed disease progression in low-copy but not high-copy SOD1^G^Citation93^A mice,^Citation145 follow-up studies showed no effect in SOD1^G^Citation93^A or SOD1^G^Citation37^R mice^Citation146	No change in decline of ALSFRS-R^Citation147	No benefit
Insulin-like growth factor 1 (GF-1)	Growth factor	Increases motor performance, delays onset of disease, and increases survival in SOD1^G^Citation93^A mice^Citation148	Initial study showed reduction in functional impairment,^Citation149 but two large follow-up studies did not show benefit^Citation150,Citation151	No benefit
Intravenous immunoglobulin	Anti-inflammatory	No data from animal studies in motor neuron disease available	No change in decline of muscle strength or bulbar function^Citation152	No benefit
Lamotrigine	Inhibition of glutamate release	Rescues motor neurons from death from cell death induced by axotomy,^Citation153 not tested in animal models of ALS	No improvement in ALSFRS-R or other clinical scales^Citation154,Citation155	No benefit
Lithium	Mechanism incompletely understood, may include reduction in glutamate and increase in serotonin	Delays disease onset and prolongs life span of SOD1^G^Citation93^A mice^Citation156	A nonplacebo control study showed delay of disease progression,^Citation63 but controlled follow-up trials showed no change^Citation157,Citation158	No benefit
Methionine	Antioxidation	Delays disease onset and prevents loss of motor neurons in SOD1^G^Citation93^A mice^Citation159	No change in rate of disease progression^Citation160	No benefit
Minocycline	Inhibition of microglial activation	Delays disease onset and prolongs survival in a dose-dependent manner in SOD1^G^Citation93^A mice^Citation161	Accelerated decline in ALSFRS-R^Citation162	No benefit
N-acetylcysteine	Ant-oxidation	Improves survival and preserves motor function in SOD1^G^Citation93^A mice^Citation163	No change in rate of disease progression^Citation160	No benefit
NP001	Reduction in macrophage activation	Prolongs survival in most accepted animal models of ALS (unpublished data)^Citation164	Reduction in expression of monocyte CD16 in Phase study.^Citation165 Phase study ongoing (NCT01281631)	To be determined
Olesoxime (TRO19622)	Inhibits release of apoptotic factors	Delays muscle denervation and motor neuron death in SOD1^G^Citation93^A mice^Citation166	No effect on survival^Citation167	No benefit
Plasmapheresis	Anti-inflammatory	Not tested in animal models of ALS	No change in decline of muscle strength or functional ability^Citation168	No benefit
Pyrimethamine	Reduction of SOD1	Reduced SOD1 in cell culture and SOD1^G^Citation93^A mice^Citation169	Reduction of SOD1 in CSF (Phase study)^Citation170	Undetermined
Rasagiline	Irreversible inhibitor of monoamine oxidase	Dose-dependent therapeutic effect on motor function and survival alone and in combination with riluzole in SOD1^G^Citation93^A mice^Citation171	Phase trial is currently under way (NCT01879241)	To be determined
Talampanel (LY300164)	AMPA receptor	Other AMPA antagonists (NBQX,^Citation172 ZK 187638^Citation173) were shown to preserve motor function and prolong survival in SOD1^G^Citation93^A mice. Talampanel itself increases intracellular calcium in motor neurons of SOD1^G^Citation93^A mice but does not preserve motor function or prolong survival^Citation174	Slows decline in muscular strength and in ALSFRS-R but not statistically significant^Citation175	No benefit
Tamoxifen	Decreases glutamate binding to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (NMDA) receptors	Extends survival in a virally induced mouse model of ALS^Citation176	Phase trial shows safety and tolerability (unpublished data), two Phase trials completed (NCT01257581; NCT00214110), awaiting final results; one Phase I/II trial is still ongoing (NCT02166944)	To be determined
Tirasemtiv (CK-2017357)	Activation of musculature by increasing its calcium sensitivity	Improves muscle function in SOD1^G^Citation93^A mice^Citation177	Dose-dependent improvement in strength and endurance,^Citation178 Phase trial completed (NCT01709149), awaiting final results	To be determined
Topiramate	Antagonism of glutamate receptors	Protects against motor neuron degeneration in organotypic spinal cord cultures but not in the SOD1^G^Citation93^A mouse model^Citation179	No survival benefit, additionally high-dose treatment was associated with a faster rate of decline in muscle strength and with an increased risk for adverse events^Citation180	No benefit
Vascular endothelial growth factor	Growth factor	Improves motor performance and prolongs survival of SOD1^G93A mice and rats, when administered via intrathecal^Citation181 or intraperitoneal^Citation182 injection or viral^Citation183 delivery	A Phase trial showed safety and tolerability of intracerebroventricular administration (NCT00800501), a second Phase trial to assess the safety of a continuous intracerebroventricular infusion is under way (NCT01999803). A Phase trial is also currently under way (NCT01384162)^Citation184	To be determined
Vitamin	Antioxidation	Delays onset of disease and slows progression but does not improve survival in SOD1^G93A mice^Citation143	No change in rate of deterioration of function (Norris limb scale) at low^Citation185 or high^Citation186 dose when taken in addition to riluzole. Possible protective benefit, as long-term users have lower risk of developing ALS^Citation187	No benefit

Notes: Phase I clinical trial: Screening for safety in a small group of patients. Phase II clinical trial: Establishing the efficacy of the drug, usually against a placebo in a larger group of patients. Phase III clinical trial: Final confirmation of safety and efficacy in comparison to commonly used treatment.

Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS functioning rating scale–revised; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; SOD1, superoxide dismutase-1.

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