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http://www.alscenter.org/news/briefs/061212.cfm

December 12, 2006

CLINICAL TRIALS: STATE OF THE PIPELINE

Here, as a service, we summarize a recent article from the Nov. 6 issue of Neurology on the twenty drugs that ALS researchers in the know have earmarked for further testing in the therapeutic pipeline. Packard researcher Bryan Traynor, M.D., is the first author. Merit Cudkowicz, M.D., who advises Packard clinician-scientists on setting up trials, is senior author.

Scientists know a number of processes weave together to cause and maintain the motor nerve death that results from ALS. The six major ones—they include excitotoxicity, inflammation, mitochondrial dysfunction—all involve chains of reactions in cells that are part of normal cell activity but that go awry in disease.

So in identifying drugs for Phase III trials—the major national studies that reveal if a something truly is a useful therapy—the authors were especially interested in those that could correct or improve flaws in any of the notorious six.

Safety and side effects, of course, were also a consideration. And drugs that performed well in the best animal models of ALS or that showed signs of neuroprotection in earlier, smaller patient studies were added.

The list of 113 drugs circulated through the ALS research community and was narrowed to 24. After a clinical pharmacologist took a closer look at safety and the way the drugs were metabolized in the body, the list was down to 20.

Here is a sample of the drugs that made the list. The remainder are listed below.

* AEOL 10150 (Aeolus Science Inc.) targets damage from toxic free radicals present in ALS. The drug is a potent antioxidant shown to improve survival in SOD1 mouse models 196 percent.

* Arimoclomol (Cytrx Corp.) increases production of protective heat shock proteins known to protect cells from sudden stressors. Arimoclomol prolonged the life of SOD1 mouse models by 22 percent. It was also well tolerated in a small trial of healthy volunteers. A phase II trial is now enrolling patients (www.clinicaltrials.gov NCT00244244).

* Ceftriaxone (Roche Laboratories) helps protect against excitotoxicity—damage that’s related to overactivity of receptors for the nerve transmitter glutamate. The drug indirectly increases removal of toxic glutamate from motor neuron synapses. It also enters the central nervous system well and stays at active levels in the body a relatively long time. A combined phase II and III study will begin enrolling in the near future.

* Coenzyme Q10 (generic) strengthens the activity of mitochondria, the cell’s major power source and a particularly vulnerable cell organ in ALS. The drug enters the central nervous system particularly well and large doses are safe and well tolerated by ALS patients. A phase II study is enrolling patients (www.clinicaltrials.gov NCT00243932).

* Memantine (Forest Laboratories, Inc.) Motor neurons carry higher numbers of a type of receptor for the neurotransmitter glutamate than do other neurons. Called AMPA receptors, the relatively plentiful proteins may explain why motor neurons are vulnerable to damage from the overabundance of glutamate—the phenomenon called excitotoxicity. Because of its AMPA-blocking ability and subsequent protection of neurons, memantine is licensed for Alzheimer’s disease. Patients tolerate it well, but no data exists for its use in ALS.

* IGF-1 (Cephalon) Agents called neurotrophic factors allow nerve cells to differentiate and also selectively help maintain adult nerve cells. In a U.S. phase III trial, one of them, insulin-like growth factor 1, slowed the decline of abilities in ALS patients by 26 percent. By contrast, a European phase III trial was negative. The uncertainty has prompted a third phase III trial. IGF-1’s large size may complicate its crossing into the central nervous system. Earlier studies show it’s well tolerated. (www.clinicaltrials.gov NCT00035815)

* ONO-2506 (Ono Pharmaceutical Co. Ltd.) works on key support cells for motor neurons, the astrocytes, that have a role in ALS. The agent is the mirror image of the prescribed antiepileptic drug, valproate that restores normal astrocyte behavior after brain damage. ONO-2506 has anti-inflammatory and antiexcitatory properties that may prove useful. Data from a phase II trial are being analyzed. A phase III trial of the parent drug, valproate, has begun enrolling subjects in Europe. (NCT00136110)

* Sodium phenylbutyrate (Scandinavian formulas) is an FDA-approved drug for hyperammonia, the result of a metabolic disorder. It’s of interest in ALS, however, because of its ability to increase activity of useful genes. It extends survival of model SOD1 mice by roughly 22 percent. A human safety study of 40 ALS patients is in progress.

* Thalidomide (Celgene) Mice without the VEGF (for vascular endothelial growth factor) gene develop ALS symptoms. Also, abnormalities in this gene in people are known to increase the risk of true ALS. Because one of the VEGF gene’s natural functions is to increase in growth and permeability of blood vessels, testing a drug that blocks those phenomena, especially given the intriguing ties to ALS, could be revealing. A phase II trial is currently recruiting patients. (NCT00140452 www.clinicaltrials.gov)

Other agents on the suggested trials list are: Celastrol, Copaxone, IGF1 via adeno-associated virus, Minocycline, Naadalase inhibitor, NBQX, Nimesulide, Nimodipine, Riluzole, Scriptaid, Talampanel, TCH346, Trehalose, Vitamin E.

You can access the entire Neurology article online at: http://www.ncbi.nlm.nih.gov

For information about clinical trials at the Johns Hopkins ALS Clinic, please visit http://www.alscenter.org/clinical_trials/
or contact
Lora Clawson, MSN, CRNP
Director of ALS Clinical Services
410-955-8511
lclawson@jhmi.edu

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