Last year saw plenty of news from clinical trials in amyotrophic lateral sclerosis (ALS). Some of it was disappointing, but some gives cause for cautious optimism, in part simply because there are so many trials. “This is the most exciting time in ALS research,” said Swati Aggarwal at Massachusetts General Hospital (MGH) in Boston. Her group and others are testing drugs they hope will stock a medicine cabinet that currently contains but one option: riluzole, which prolongs life by a few months but does little to alleviate symptoms. New candidates—including small molecules, biologics, nucleic acids, and stem cells—span a range of targets, from misfolded proteins, excitotoxicity, and mitochondria, all in the hopes of saving motor neurons.

Here, the Alzforum presents a selection of some of the top ALS trial news of 2009—and looks ahead to 2010 and beyond.

Lay Lithium to Rest?
In February of 2008, Italian researchers reported dramatic effects from a small patient cohort taking lithium—notably, not one of the 16 patients in the treatment group died during the 15-month trial (see ARF related news story on Fornai et al., 2008 and Shin et al., 2007). The Italian group started the human trial after finding that lithium, an old but still widely used anti-mania drug, increased lifespan in ALS model mice. The researchers suggested that lithium promoted autophagy, a process by which cells destroy damaged organelles. Many people with ALS immediately acquired prescriptions, since lithium was already FDA-approved for other conditions such as bipolar disorder. But there were several characteristics of the study that other scientists found “a bit odd,” Aggarwal said. It was not double-blinded, and the participants had already had ALS for three to five years when they enrolled. Given that the disease normally causes death within three years, the participant pool was skewed toward those with an unusually slow disease course.

Aggarwal and others scrambled to put together a larger lithium trial, which commenced in January of 2009. By then they already had reason to doubt the dramatic effects of the Italian study, because many people with ALS had been taking lithium for months without miraculous results. The new trial, sponsored by MGH and coordinated by the National Institute of Neurological Disorders and Stroke (NINDS), the ALS Association, the ALS Society of Canada, and others, included plans for an interim review once the eighty-fourth patient enrolled. By the time that happened in late summer, it was clear that lithium was no blockbuster. NINDS deemed the trial “futile” and halted it in September.

The MGH study did exactly what it was designed to, said Jeffrey Rothstein of Johns Hopkins University in Baltimore, Maryland. “You don’t waste your time on a drug that has no value.” Aggarwal cautioned, however, that the study only tried one dose of lithium, and cannot completely discount any effect of the drug. But she said more preclinical testing is necessary before another human trial.

Other lithium trials are ongoing, including one sponsored by the Forbes Norris Muscular Dystrophy Association/ALS Research Center, and another in Paris, France. And on the ALS forum PatientsLikeMe, people with the disease report they are currently taking lithium; 264 dropped the medication, 126 of those because it did not seem to work.

End Excessive Excitation
Other drug candidates still very much in the running are aimed at dampening the glutamate-based excitotoxicity that may damage motor neurons in people with ALS. In December, Rothstein published the results of a Phase 2 trial—which was actually completed several years ago—of talampanel, a glutamate receptor agonist (Pascuzzi et al., 2009). This small trial—40 people took the drug, 19 placebo—yielded some positive results. Using the ALS Functional Rating Scale (ALSFRS), a standard measure of a person’s ability to perform basic activities like speaking and dressing oneself, the researchers found a 30 percent slower rate of decline in people taking talampanel, although the trial was too small to yield statistically significant data.

Despite this tantalizing result, a larger trial did not begin right away because talampanel changed hands repeatedly—Eli Lilly sold it to IVAX, which was bought by Teva Pharmaceuticals. Teva started a second Phase 2-level trial, with more than 500 participants, in September of 2008; results are expected later in 2010.

Another drug aimed at glutamate toxicity is ceftriaxone. Ceftriaxone is an antibiotic used to treat Lyme disease; a NINDS-led group of researchers picked it out of a screen of 1,040 FDA-approved compounds that might be neuroprotective in models of neurodegenerative disease. Members of this antibiotic family increase expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) and glutamate uptake in cultured human astrocytes (Lee et al., 2008). The science behind the drug is sound, Aggarwal said. Ceftriaxone triples EAAT2 activity in mouse brains and increased lifespan, strength, and neuron survival in ALS model mice (see ARF related news story on Rothstein et al., 2005). Ceftriaxone is an approved drug, but it is not yet clear whether it is safe to take long-term. A Phase 1 trial and compassionate use study have been completed; a multicenter study sponsored by MGH and NINDS, aiming for 600 subjects, started enrolling in May 2009.

Blocking excitatory transmitters is also the rationale for Zenvia, which may soon hit the market as a prescription to relieve the symptoms of pseudobulbar affect. These are unpredictable emotional outbursts, with uncontrollable laughing and crying, that affect half of people with ALS as well as people with multiple sclerosis, Parkinson disease, and dementia including Alzheimer disease.

Zenvia is a formulation of dextromethorphan, which suppresses glutamate release, and quinidine, which prevents the body from breaking down dextromethorphan. A 2004 paper found that the pair reduced symptoms in people with ALS (Brooks et al., 2004). In fact, doctors have used the combination off-label for a long time, Aggarwal said: “It just has this phenomenal effect.” In December, Avanir Pharmaceuticals announced positive results from a multisite Phase 3 trial that included 180 people with ALS; people taking Zenvia reported fewer pseudobulbar episodes. Aggarwal expects that with the new data, the FDA will be able to approve Zenvia for people with ALS.

Protect Those Neurons
One logical place to start with treatments for neurodegenerative disease is to look for neuroprotective compounds. Growth factors are a likely candidate. Sangamo Biosciences’ SB-509 is a nucleic acid encoding the gene for a transcriptional activator of vascular endothelial growth factor A (VEGF-A), which improves prognosis in ALS model mice (see ARF related news story on Azzouz et al., 2004). Based in Richmond, California, Sangamo announced preliminary results from a Phase 2 trial in December 2009 in a presentation at the International Symposium on ALS and Motor Neuron Disease in Berlin, Germany. The interim data included results from 22 of the participants in the 45-subject trial, all of whom received the DNA injections. People in the trial had improved muscle function in manual muscle tests, compared to matched historic controls. The researchers used data from past subjects who had not received this treatment, rather than people on placebo; the stated purpose was so they could give more people the therapy.

Also targeting neuroprotective pathways is CytRx Corporation’s arimoclomol. Arimoclomol is a small molecule believed to induce production of molecular chaperones that mend misfolded proteins, for example, superoxide dismutase 1 (SOD1), which accumulates in some forms of ALS. The drug helps damaged nerves regenerate in animal studies, and it improved muscle function and survival in an animal model of motor neuron disease (reviewed in Lanka et al., 2009). Arimoclomol might potentially be useful for Alzheimer’s, Parkinson’s and Huntington’s, as well, since those conditions are also linked to protein aggregates. Arimoclomol is under trial in an 80-patient combined Phase 2/3 study sponsored by Emory University in Atlanta, Georgia, for people whose ALS is caused by SOD1 mutations.

Beyond that, Los Angeles-based CytRx also wanted to try the drug in the vast majority of patients who do not carry such mutations. The FDA put this plan on hold in January of 2008 because it thought a higher dose of the drug would be appropriate, and requested further preclinical and toxicology experiments to make sure the higher dose would be safe. The hold was lifted in December of 2009, and a small study of 15 patients is planned.

For its part, the ALS Therapy Development Institute of Cambridge, Massachusetts, is looking to the immune system to protect motor neurons with a monoclonal antibody called ALSTDI-00846. Research suggests innate immune cells such as microglia and macrophages are involved in the disease, although it remains unclear whether their action promotes or slows disease—it may be a bit of both (see ARF related news story on Gowing et al., 2008 and ARF related news story on Chiu et al., 2009). The institute used data on gene expression in people with ALS to choose biological pathways to target, and their analysis led them to a T cell receptor known as CD40L. ALSTDI-00846 blocks this receptor, suppressing immune activation. Antibody treatment increases body weight, slows loss of neurological function, and extends lifespan in ALS model mice. CD40L antibodies have been considered for other conditions, such as lupus, so some safety data are already available. Therefore, TDI hopes to jump straight to Phase 2 by the end of 2010, and is negotiating with potential partners in the pharmaceutical industry.

Modulate the Mitochondria
Mutant SOD1 appears to target mitochondria (see ARF related news story on Pasinelli et al., 2004 and Liu et al., 2004), making these cell-sustaining organelles another potential site for drug action. In this regard, Knopp Neurosciences’ KNS-760704 was another topic of discussion in Berlin. This Pittsburgh-based company presented results of a Phase 2 trial of 102 subjects, showing the drug is safe and tolerable for up to nine months in people with ALS. In this trial, people on the drug received one of three dosages, and those on the higher dose had higher survival rates than those on placebo or lower doses. “That’s very promising,” said Lucie Bruijn of the ALS Association. Knopp plans to start a Phase 3 trial this year.

Another mitochondrial modulator is called olesoxime. Made by the French biotechnology company Trophos, in Marseille, olesoxime popped up in a cell-based screen for small molecules that promote motor neuron survival in culture (Bordet et al., 2007). In SOD1 model mice, the compound delayed disease onset and extended survival. The company announced positive results from safety trials last May, and expects to have data from a multicenter, 500-person study on efficacy by 2011. Olesoxime is reported to interact with the mitochondrial permeability transition pore, possibly preventing it from opening; this might help prevent apoptosis.

Silence SOD1 Gene, Seed Stem Cells
In addition to the conventional small molecule drugs, more avant-garde techniques are moving toward their crucible, i.e., the clinical trial. For example, ISIS 333611 from Isis Pharmaceuticals in Carlsbad, California, is an antisense oligomer directed at SOD1. The hope is that it would dial down the gene’s expression, as it does in a rat disease model, and slow disease in people with SOD1 mutations. “It is the first approach that is really hitting a known target for the disease,” Bruijn said. Aggarwal, who is participating in the multicenter Phase 1 safety trial, said she expects to start enrolling participants this February. The trial plans to enroll 32 subjects, and results won’t be in before 2011.

And lastly, scientists are giving stem cells a shot. “I think we are at a stage where we can cautiously move forward to test some stem cell therapies,” Bruijn said. First in line is Neuralstem, Inc. of Rockville, Maryland. In ALS model rats, this company’s neural stem cells differentiate into motor neurons, form synapses, and slow disease onset and progression (Xu et al., 2006). The company began a Phase 1 trial, planning on a dozen participants, last fall at Emory University in Atlanta, Georgia (see ARF related news story). At this point, researchers are simply testing a method to safely deliver the cells to the spinal cord in a few people.

Researchers have also tested stem cells from blood (Martinez et al., 2009) and bone marrow (Mazzini et al., 2009; Mazzini et al., 2009). Just this month, TCA Cellular Therapy, a company based in Covington, Louisiana, received FDA approval to run a Phase 1 trial using stem cells from the person’s own bone marrow.

Physicians are careful to counsel that new drugs may not pass muster. “It means nothing until you publish a Phase 3,” Rothstein said. The ALS Association, Northeast Amyotrophic Lateral Sclerosis Consortium, and the ALS Hope Foundation each maintain lists of clinical trials. In addition, Prize4Life maintains a searchable ALS Drug Development Database.—Amber Dance.


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News Citations

  1. Study Looks to Lithium for Treating ALS—Patients Follow Suit
  2. Lactam Antibiotics Can Prevent Glutamate Neurotoxicity
  3. Viral VEGF Treats Mouse ALS
  4. Microglia in ALS: Helpful, Harmful, or Neutral?
  5. Peripheral Innate Immunity—Not So Peripheral to ALS?
  6. Motoneuron Mitochondria: Preferred Destination For Mutant SOD1
  7. Québec: Stem Cells in ALS Update

Paper Citations

  1. . Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7. PubMed.
  2. . Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis. Mol Pharmacol. 2007 Apr;71(4):965-75. PubMed.
  3. . A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010 May 3;11(3):266-71. PubMed.
  4. . Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem. 2008 May 9;283(19):13116-23. Epub 2008 Mar 7 PubMed.
  5. . Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005 Jan 6;433(7021):73-7. PubMed.
  6. . Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology. 2004 Oct 26;63(8):1364-70. PubMed.
  7. . VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature. 2004 May 27;429(6990):413-7. PubMed.
  8. . Arimoclomol: a potential therapy under development for ALS. Expert Opin Investig Drugs. 2009 Dec;18(12):1907-18. PubMed.
  9. . Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci. 2008 Oct 8;28(41):10234-44. PubMed.
  10. . Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20960-5. PubMed.
  11. . Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004 Jul 8;43(1):19-30. PubMed.
  12. . Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 2004 Jul 8;43(1):5-17. PubMed.
  13. . Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007 Aug;322(2):709-20. PubMed.
  14. . Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation. 2006 Oct 15;82(7):865-75. PubMed.
  15. . Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy. 2009;11(1):26-34. PubMed.
  16. . Stem cells in amyotrophic lateral sclerosis: state of the art. Expert Opin Biol Ther. 2009 Oct;9(10):1245-58. PubMed.

External Citations

  1. new trial
  2. Forbes Norris Muscular Dystrophy Association/ALS Research Center
  3. another in Paris, France
  4. PatientsLikeMe
  5. second Phase 2-level trial
  6. Phase 1 trial and compassionate use study
  7. multicenter study
  8. multisite Phase 3 trial
  9. Phase 2 trial
  10. Phase 2/3 study
  11. Phase 2 trial
  12. Phase 1 safety trial
  13. ALS Association
  14. Northeast Amyotrophic Lateral Sclerosis Consortium
  15. ALS Hope Foundation
  16. ALS Drug Development Database

Further Reading


  1. . Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest. 2006 Aug;116(8):2290-6. PubMed.
  2. . Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol. 2009 Aug;66(2):235-44. PubMed.
  3. . Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve. 2009 Aug;40(2):173-94. PubMed.
  4. . The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice. Exp Neurol. 2009 Aug;218(2):333-46. PubMed.
  5. . Current clinical trials in amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2007 Aug;16(8):1197-207. PubMed.
  6. . Selecting promising ALS therapies in clinical trials. Neurology. 2006 Nov 28;67(10):1748-51. PubMed.
  7. . Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment. Expert Rev Mol Med. 2006;8(11):1-22. PubMed.
  8. . Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 2006 Jul 11;67(1):20-7. PubMed.
  9. . Amyotrophic lateral sclerosis: recent advances and future therapies. Curr Opin Neurol. 2005 Dec;18(6):712-9. PubMed.