Update of Therapeutic Clinical Trials for Amyotrophic Lateral Sclerosis

Nam-Hee Kim; Min Oh Lee

doi:10.14253/kjcn.2015.17.1.1

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Kim and Lee: Update of Therapeutic Clinical Trials for Amyotrophic Lateral Sclerosis

Original Article

Korean J Community Nutr 2015;17(1):1-16.

Published online: 18 December 2015

DOI: https://doi.org/10.14253/kjcn.2015.17.1.1

Update of Therapeutic Clinical Trials for Amyotrophic Lateral Sclerosis

Nam-Hee Kim, Min Oh Lee

Department of Neurology, Dongguk University Ilsan Hospital, Goyang, Korea

Address for correspondence; Nam-Hee Kim Department of Neurology, Dongguk University Ilsan Hospital, 27 Dongguk-ro, Ilsandong-gu, Goyang 410-773, Korea Tel: +82-31-961-7214 Fax: +82-31-961-7212 E-mail: nheekim8@hanmail.net

Received 12 December 2014 Revised 10 February 2015 Accepted 29 May 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive death of motor neurons in the cortex, brainstem, and spinal cord. Until now, many treatment strategies have been tested in ALS, but so far only Riluzole has shown efficacy of slightly slowing disease progression. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. Other motor neuron disease such as spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA) are also progressive neurodegenerative disease with loss of motor neuron as ALS. This common thread of motor neuron loss has provided a target for the development of therapies for these motor neuron diseases. A better understanding of these pathogenic mechanisms and the potential pathological relationship between the various cellular processes have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS. (Korean J Clin Neurophysiol 2015;17:1-16)

Keywords: Amyotrophic lateral sclerosis, Clinical trial, Treatment

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Fig. 1.

Update of therapeutic clinical trials for ALS. CoQ10; conenzyme Q10, TUDCA; tauroursodeoxycholic acid, G-CSF; granulocyte colony stimulating factor, BDNF; brain-derived neurotrophic factor, IGF-1; insulin-like growth factor-1, CNTF; ciliary neurotrophic factor, PBA; 4-phenylbutyrate, SC; stem cell.

Table 1.

Summary of pathomechanism-based clinical trials for ALS

	Proposed mechanism	Phase	Number of pts (active/total)	Start/End	Dose	Results and cements	Report
Glutamate target
Riluzole	Inhibition of presynaptic glutamate release, inhibit NMDA receptor, enhanced extracellular glutamate uptake	3	77/155	2001/2004	50 mg bid	Efﬁcacy in survival (3 months) Bulbar—onset: improved 1yr survival rates 73% VS 35% for placebo, Limb-onset: 74% VS 64% for placebo	Bensimon, 1994, NE] M
Ceftriaxone	Decreases synaptic glutamate by transcriptional activate of EAAT2 expression	1,2	340/513	2006/2012	4 g qu	Safety, Dose determine (4 g) Closed in 2012 due to no efﬁcacy	Cudkowicz, 2013, PloS One
Gabapentin	Inhibit AMPA receptor	3	102/204		3,600 mg qd	No efﬁcacy, Signiﬁcantly more rapid decline of PVC Mild side effects	Miller, 2001, Neurology
Topiramate	Diminish neuronal glutamate release and antagonize kainate activation of AMPA receptor	2	197/295		800 mg qd	No efﬁcacy Faster rate of muscle strength decline Multiple Side effects	Cudkowicz, 2013, Neurology
Lamotrigine	Inhibit glutamate release and inactivates VGCC	2	19/38		300 mg qd	No efﬁcacy	Ryberg, 2003, Acta Neurol Scand
Arundic acid (ONO-2506)	Opposing astrocyte activation through Inhibitory action on S 100B synthesis	2	420	2006/2008 (safety 2013)	1,200 mg qd	Safety, No efﬁcacy?	No report
Memantine	NMDA receptor antagonist	2, 3 Ongoing 2	63 90	2005/2009~2017	20 mg qd	Safety, No efﬁcacy Effect on ALSFRS/ cognitive function (c FTTN	De Carvalho, 2010, Amyotroph Lateral Scler,
Talampanel	AMPA receptor antagonist Anti-inﬂammatorv	3		2008/2010		No efﬁcacy	Closed 2010 No report
LDN/OSU-0212320 (pyridazine derivative)	Decrease synaptic glutamate by increasing EAAT2 protein through translational activation	Animal study only				Efﬁcacy in delayed motor decline and prolonged survival
Methylcobalamin (E0302)	Decrease glutamate toxicity, Increasing myelination	2 Ongoing 3		2008/2014 (2016)	50 mg im 2/Wk	Prolong survival time or period to become respirator-bound	Izumi, 2007, Brain Nerve, Eisai
Mexiletine	Sodium channel blocker, blocking excitotoxicity	2	60	2013/2014	300 mg or 900 mg qd	Safety: N/A	Washington Univ
Sodium valproate	Reduce glutamate toxicity (HDAC inhibitor transcriptional regulation)	1,3	163	2005/2007	1,500 mg qd	Safety, No efﬁcacy	Piepers, 2009, Ann Neurol.
Oxidative stress
Vitamin E (alpha-tocopherol)	Mitigation of free radical oxidative injury	2/3	144/289		PO, 500 mg bid	Safety, No efﬁcacy Riluzole + Vitamin E remained longer in the milder states of ALS health state scale	Desnuelle, 2001, Motor Neuron Disord.
Aeolus (AEOL-10 1 50) Manganese porphyrin-labeld	Catalytically neutralizes hydrogen peroxide, superoxide, peroxynitrite and also inhibits lipid peroxvdation	1	12/18		SC Multiple dose	Safety Efﬁcacy: N/A	Orell, 2006, Curr Opin Investig Drugs
Edaravone (MC-186)	Free radical scavenger	2	20 (206)	2006/2008	IV, 60mg	Safety, may delay progression Safety or Efﬁcacy: N/A	Yoshino) 2006, Amyotroph Lateral Seer. Mitsubishi Tanabe pharm.
Edaravone (MC-186)	Free radical scavenger	3	128	2011/2015	IV, 60mg	Safety, may delay progression Safety or Efﬁcacy: N/A
Acetylcysteine	Free radial scavenging	2	55/110		SC, 50 mg/kg/d	No efﬁcacy Rash, pain at injection site	Louwerse, 1995, Arch Neurol.
Inosine	Increase of urate serving as a maj or defense against oxidative stress	1		2014/2016	Oral, up to 3g	Safety or Effect on biomarkers: N/A	Sabrina, MGH, US
Mitochondrial target
Minocycline	Inhibition of cytochrome c and caspase-3 activation	3	206/412	2003/2007	PO, up to 401 mg/d	No efﬁcacy, ALSFRS-R deterioration was faster Safety (side effects)	Gordon, 2007, Lancet Neurol.
Creatine	Stabilize mitochondrial transition pore and support mitochondrial ATP production (presumptively abating dysfunction occurring early in ALS)	2	50/104	2002/2006	PO, 5 g qd	Safety, No efﬁcacy but trend Effect on muscle strength: N/A	Shefner, 2004, Neurology
		3	107	2003/2005
		3	156	2013
CoQ10	Antioxidant and mitochondrial cofactor	2	75/150	2005/2008	PO, 2700 mg/d	Safety, No efﬁcacy	Kaufmann, 2009, Ann Neurol.
Dexpramipexole (KNS-760704)	Mitochondrial antioxidant effect	2/3	804/943	2011/2013	PO, multiple dose	2: Dose—dependent trend in slowing rate of disease progression by ALSFRS, trend toward survival beneﬁt in 300 mg vs 50 mg Nausea, joint pain, neutropenia	Rudnicki, 2013, Amyotroph Lateral Scler. Cudkowicz, 2013, Lancet Neurol.
Rasagiline (Azilect)	Anti-apoptotic compound, neuroprotective thru mitochondria	2, 2,2	30 80, 250	2011/2013 2012/2016, 2015	PO, 2 mg qd		Yunxia Wang, US
Olesoxime (TR019622)	Modulates mitochondrial permeability transition pore complex and reduces mitochondrial cytochrome c release after induction of neuronal apoptosis	2,3	NE/512	2009/2011	PO, 330 mg qd	Safety, No efficacy	Lenglet, 2014?Eur J Neurol.
TUDCA (tauroursodeoxyc holic acid)	Anti-apoptotic activity thru mitochondria	2	26	2008/2012	?	Safety or efficacy: N/A Safety, No efficacy	Italy, Istituto Nazionale Min, 2012, J KMS
TUDCA (tauroursodeoxyc holic acid)	Anti-apoptotic activity thru mitochondria	3	63	2005/2007	3.5 g qd	Safety or efficacy: N/A Safety, No efficacy	Italy, Istituto Nazionale Min, 2012, J KMS
Acetyl-L-carnitine (ALC)	Mitochondrial antioxidant effect	2	42/82			Safety, Better ALSFRS-R and FVC, Better survival	Beghi, 2013, Amyotroph Lateral Scler FTD
Melatonin	Antagonism of both caspase-med and caspase-independent mitochondrial induced cell death	1,2	31/31		Rectal, 300 mg qd	No efficacy, Normalize marker of oxidative stress Safety	Weishaupt, 2006, J Pineal Res.
Mitogard	Cyclosporine A protects mitochondria from rupture.	2		2011	Intrathecal	Safety or Efficacy: N/A	NINDS
Neuroinflammation
Celecoxib	Counteract elevated COX-2 which potentiate neuronal susceptibility to glutamate toxicity	2	201/300	2006/2011	800 mg qd	No effect Safety	Cudkowicz, 2006, Ann Neurol.
Thalidomide	Penetrate BBB and produce anti-inflammatory effect thru modulation of cytokines (TNF-a)	2	23/23	2005/2007	400 mg qd	No efficacy Rash, sedation, bradycardia, sudden death	Stommel, 2009, Amyotroph Lateral Scler.
Glatiramer acetate	Stimulation of Th2 receptor	2	184/366	2006/2008	40 mg/d	No efficacy Injection site reactions	Meininger, 2009, Amyotroph Lateral Scler.
Fingolimod (TDI- 132, Gilenya)	Reduce circulating lymphocytes	2	30	2013/2014	0.5 mg	Safety: N/A	Berry, US, MGH
NP001 (Neuraltus)	Control activation of macrophage and reduce motor neuron loss	2 3 (plan)	105	2011/2012		Safety, Non-significantly delay progression	ANA abstract. 2013 Neuraltus pharm US
Pioglitazone	Stimulating PPAR-gamma transcription factor, anti-inflammatory and anti-oxidant	2	219	2008/2011	45 mg qd	Safety, No efficacy	Duuis, 2012?PLoS
Masitinib	Inhibition of mast cell degranulation, reducing neuroinflammation	3		2012			Madrid, Spain
Neurotrophic factor
G-CSF	Neurotropic and anti-apoptotic effect	2	17/39	2006/2007	SC,5ug/kg bid *4 day, every 3 month for 1 year	No efficacy, Successful mobilization of autologous BM cells, Safety (mild flu-like, nausea, asthenia)	Nefussy, 2010, Amyotroph Lateral Scler.
Haptocyte growth factor (HGF, VM202)	Promoting survival of motor neuron	1,2	18	2014/2015	IM	Safety: N/A	US, ViroMed
Insulin-like growth factor (IGF-1)	Via tyrosine kinase transmembrane receptor mechanism exerting anti-apoptotic effect and support neuronal regeneration	3	167/330	-/2005	SC, 0.05 mg/kg bid	No efficacy Safety (headache, hepatotoxicity, VA change)	Sorenson, 2008, Neurology
GDNF	Protective factor of spinal motor neuron				intrathecal	No efficacy
BDNF	Agonize low affinity nerve growth factor receptor	3	748/1135		SC, 35 or 100 No ug/kg	efficacy, Benefit in patients with early impaired respiratory and bowel function Diarrhea, increased bowel move, injection site reaction	BDNF study group, 1999, Neurology
CNTF	Neuroactive cytokine	2,3	730		SC 30 ug or 15 ug/kg	Safety, No efficacy,	1996, Neurology
VEGF (sNN0029, recombinant VEGF 165)	Anti-apoptosis	1,2	18	2009/2014	Intraventricul Safety: N/A ar using SynchroMed pump		NeuroNova, Belgium
SB-509	Increase production of VEGF-A	2	45	2008/2010	IM	Safety or efficacy: N/A	US
Xaliproden (SE57746A)	Promote neuroprotection and secretion of several endogenous motor neuron growth factors	3	804/1210		PO, 1 or 2 mg qd	No efficacy Weight gain, nausea, vomit, insomnia	Meininger, 2004, Amyotroph Lateral Scler
GM604	Human motor neurotropic factor	2	12	2013/2015	IV 6 dose over 2 weeks	Ongoing	Genervon bio- pharmaceuticals, MGH, US
Apoptosis taiget
Indinavir	Anti-apoptosis	Pilot	23/46		PO, 800 mg qd	Toxicity (nephrolithiasis, GI problem) No efficacy	Scelsa, 2005, Neurology
TCH346 (CGP3466)	i Binding to GAPDH and blocking apoptotic pathway in which GAPDH involved	2/3	442/591	2003/2004	PO, multiple dose	No efficacy	Miller, 2007, Neurology
Pentoxyfilline	Anti-apoptotic effect thru inhibition of PDE4B (overexpressed in preclinical model with motor neuron degeneration	3	199/201		PO,1.2gqd	No efficacy 43% increased risk of death Side effect: nausea, dysphagia, flushing	Meininger, 2006, Neurology
Protein target
17-AAG (17-allyla- mino-17- demethox- ygeldanamycin)	Inhibit Hsp 90 and activate autophagy					Effect on animal model
4-phenybutyrate (PBA, NaPB, Sodium PB)	Pan-HDAC inhibitor	1,2	40	2005/2006	PO	Safety, No efficacy	Cudkowicz, 2009, Amyotroph Lateral Scler.
Arimoclomol (BRX-345)	Inducing heat shock protein expression under cell stress	2/3	80	2008/2016	200 mg tid	Safety In SOD1 positive FALS	Cudkowicz, 2008, Muscle Nerve
Tamoxifen	Anti-oxidant, inhibit protein kinase C, activate autophagy and remove TDP-43 aggregation	2	100	2001/2005	Escalating dose 40 mg qd	Safety, May prolong survival Safety?	Wisconsin univ, US
Tamoxifen		1,2	20	2014/2016	Escalating dose 40 mg qd	Safety, May prolong survival Safety?	Wisconsin univ, US
Lithium	Enhance macro autophagy with increased clearance of mSODl	2,3	40/84	2009/2009	PO, serum level of 0.4-0.8 meq/1	No efficacy, Safety	Aggarwal, 2010, Lancet Neurol. UKMND-LiCALS study group, 2013, Lancet Neurol.
Lithium	Enhance macro autophagy with increased clearance of mSODl	2,3 3	40/84 107/214	2009/2009 2009/2011	PO, serum level of 0.4-0.8 meq/1	No efficacy, Safety
L-serine	L-serine could prevent the BMAA neurotoxin from being mis-incorporated into proteins, thereby preventing cell death	1,2	20	2013/2014	PO, Up to 15 gbid	Safety: N/A	Levine, Phoenix neurological associates, US
Muscle target
CK-2017357 (Tirasemtiv)	Selectively activates fast skeletal muscle troponin complex by increasing the sensitivity to calcium augments m force	2	67/67	2010/2012	PO, 250 or 500 mg for 3 dosing periods	Two doses had a dose-dependent improvement in fatigue, strength and pulmonary function Safety	Shefiier, 2012, Amyotroph Lateral Sclero.
Ozanezumab (anti-Nogo-A, GSK1223249)	Suppress Neurite outgrowth inhibitor (Nogo-A) overexpressed in ALS skeletal m	1 76,294 2 (ongoing)	76,294	2012/2014	IV	Safety, No efficacy Safety or efficacy: N/A	Meininger, 2014, PLoS One

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