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European Researchers Re-purpose Drugs for MS

Existing drugs for cancer and other diseases used in multiple sclerosis trials.

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European Researchers Re-purpose Drugs for MS

Demyelination by MS

Wikipedia

It's becoming more common for researchers and drug companies to turn to already approved or abandoned drugs to serve as "new" treatments for a wide range of diseases. There are many advantages to this approach, including more rapid, less costly development and the opportunity to take advantage of existing research and data.

The National Institutes of Health (NIH) has endorsed this approach. In April 2011, the NIH sought help from pharmaceutical industry leaders in accessing approved and abandoned drugs for trials in patients with rare and neglected diseases.

This strategy is also being used in Europe on at least two drugs that show promise as repurposed drugs for multiple sclerosis (MS). MS is an autoimmune disease that affects about 2.5 million people worldwide, according to the World Health Organization.

By the end of 2013, Spanish researchers will have concluded a phase 2 trial involving 100 Spanish and German patients with relapsing-remitting multiple sclerosis (RRMS) using a drug originally developed for treating pancreatic and heart diseases.

At Sweden's Karolinska Institutet, researchers are testing the cancer drug imatinib ( Gleevec) on animal models to see if it will slow MS progression.

Results of the trials completed to date have been published in peer reviewed medical journals.

Marco Pugliese, general director and a founder of Neurotec Pharma, a University of Barcelona School of Medicine spin-off company, said development of NT-KO-003, a new molecule to be marketed as NeuroAdvan, has progressed at a rapid pace. "By the end of 2010 we already had an efficient preclinical package in an animal model, which is now being tested on human patients," he said. The study phase of the project will be completed in August 2013 with results available by the end of the year, said Pugliese. When the drug is ready to move to phase 3 trials, Neurotec Pharma plans to license the drug to a multinational pharmaceutical company. The company said it has signed confidentiality agreements with pharmas in Europe, the United States and Asia.

Neurotec Pharma, based at Barcelona's Science Park, holds the patent for NeuroAdvan both as a multiple sclerosis treatment and as a treatment for amyotrophic lateral sclerosis (ALS). Neurotec Pharma is also testing the drug's efficiency in treating ALS in animal models.

"We have managed to save research time and costs and reduce patient risk because the compound has already been deemed safe. Furthermore, the doses that we use are much lower than those used to treat these other illnesses," says Pugliese.

Neurotec is collaborating with another Barcelona-based company, Advancell, on the clinical trial. Advancell was the first company to take a drug from a Spanish university to a clinical testing phase. Advancell's acadesine has shown effectiveness in treating leukemia and lymphomas.

Neuroprotector Effect

Unlike most MS treatments that target the patient's immune system in order to protect neurons from being attacked, NT-KO-003 acts as an anti-inflammatory and neuroprotector, said Pugliese

NT-KO-003, a small molecule drug, works by regulating glial reactivity. The molecule acts as a neuroprotector since it reduces the expression of other inflammatory molecules, says Pugliese. "Thanks to its union with certain potassium channels, the drug has a direct neuroprotector effect on the neurons when decreasing the toxicity associated to the increase of intracellular calcium. It also inhibits neural degeneration and regulates mitochondrial membrane potential, thus improving functionality."

If eventually approved in Europe and in the United States as an MS treatment it could offer some advantages for certain patients. The drug doesn't cause the same side effects associated with many conventional therapies, and it can be taken orally as opposed to injected, according to Puliese.

Current investors in the project include the Spanish ministry on the economy and competitiveness, Genoma España, the government of Catalonia, and private firms Inveready Seed Capital and Caixa Capital Risc.

Cancer Drug Being Evaluated as MS Treatment

Imatinib (Gleevec), a drug used for treating certain types of cancer, was found to reduce neurological symptoms and slow the progression of MS in animal models, according to research published in PLOS ONE.

Because the drug is already approved for cancer patients, the researchers at Karolinska Institutet in Sweden expect to launch a human clinical trial in MS patients soon.

“There is a particularly urgent need to find new, efficacious drugs with minimal adverse effects for patients with MS in the relapsing phase of the disease,” said Ingrid Nilsson, an assistant professor with Karolinska Institute’s Department of Medical Chemistry and Biophysics and a member of the research team.

The researchers hypothesized that they could influence the neurological symptoms of MS in rats by sealing the blood-brain barrier. For the study, the rat models' immune defenses were stimulated by an endogenous protein in the nerve tissue that triggered an autoimmune reaction, causing white blood cells to attack the protein in the CNS. The rats were then treated with imatinib.

Nilsson said imatinib slowed the disease progression and eliminated neurological symptoms by preventing white blood cells from entering the nerve tissue. In addition, the treatment suppressed the autoimmune reaction and reduced the number of white blood cells leaking through the blood-brain barrier.

“The treatment proved effective even when administered to animals that had already developed symptoms, which is very important in terms of its use in patients with multiple sclerosis,” according to Nilsson.

Trial funders included the Swedish Brain Foundation/the Hållsten Research Foundation, VINNOVA (an agency of the Swedish government) and the Swedish Association of Persons with Neurological Disabilities.

Resources:

Z. Adzemovic M, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I (2013) Imatinib Ameliorates Neuroinflammation in a Rat Model of Multiple Sclerosis by Enhancing Blood-Brain Barrier Integrity and by Modulating the Peripheral Immune Response. PLoS ONE 8(2): e56586. doi:10.1371/journal.pone.0056586

Mancuso R, Oliván S, Mancera P, Pastén-Zamorano A, Manzano R, Casas C, Osta R, Navarro X. "Effect of genetic background on onset and disease progression in the SOD1-G93A model of amyotrophic lateral sclerosis". Amyotroph Lateral Scler. 13(3):302-10; May 2012

Virgili N, Espinosa-Parrilla JF, Mancera P, Pastén-Zamorano A, Gimeno-Bayon J, Rodríguez MJ, Mahy N, Pugliese M. "Oral administration of NT-KO-003 ameliorates disease progression in a murine model of multiple sclerosis". J Neuroinflammation. 2;8:149; Nov. 2011. doi: 10.1186/1742-2094-8-149

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