Categories: In The Pipeline

Mexiletine - channeling ALS?

clock February 5, 2013

cortical hyperexcitability sodium channel ALS MND

 

Calming ALS nerves Mexiletine may help protect the motor nerves from further damage by reducing the overactivity of sodium channels (blue) snaking through the CNS. Courtesy of Wellcome Images.

New medicines can take more than a decade to go from the laboratory to the clinic. But with many of their ALS patients facing 2-5 years to live, clinicians are rethinking the way that potential medicines are being pushed forward in the clinic. Adaptive clinical trial designs according to some experts might enable drugs to be evaluated more rapidly. And, futility studies may allow ineffective and unsafe medicines to be more quickly discarded.

Some researchers, however, hope to bring potentially life-changing treatments to people with ALS even faster by dusting off existing FDA-approved drugs from pharmacy shelves which target emerging key mechanisms of the disease.

One of these medicines, mexiletine, may help reduce the overactivity (hyperexcitability) of certain neurons in people with ALS, a potentially early step in the disease.  The drug, suspect researchers, may therefore reduce further injury to the motor nerves – slowing the progression of the disease.

”Mexiletine could be of benefit in ALS,” says University of Washington School of Medicine neuromuscular disease specialist Michael Weiss MD, principal investigator of the study.  “Hyperexcitability could be a very early event in the neurodegenerative process.”

The phase II clinical trial is scheduled to begin sometime in early 2013.

cortical hyperexcitability sodium channel ALS MND

Check out our podcast with UW neurologist Michael Weiss MD to learn more about mexiletine and its potential benefits for people with ALS.

Clinicians first looked to mexiletine in the early 1990s to reduce muscle stiffness in people with a rare group of muscle diseases called myotonias.  The drug, originally developed to regulate heart rhythms, is thought to shut the gate of inappropriately activated sodium channels - helping muscles relax more easily.

Mexiletine, recently put to the test in people with non-dystrophic myotonias, appears to reduce key signs of “myotonia” including muscle stiffness and muscle pain.  The drug is quickly becoming routine practice for myotonia in people with these muscle diseases.

“We showed that mexiletine worked.  It’s a really big deal,” says University of Kansas Medical Center neuromuscular disease specialist Richard Barohn MD, leader of the study.

Mexiletine is now being evaluated as a potential treatment for muscle cramps in a growing number of conditions– including in people with ALS.

“We think the large [part of the] problem with muscle cramps is these persistent sodium channels,” explains University of California - Davis School of Medicine neurologist Bjorn Oskarsson MD, principal investigator of the study.  “The axons are not working right.”

Out of hyperdrive?

University of Massachusetts neurologist Robert Brown MD however suspects that mexiletine might do much more for people with ALS.  The drug might reduce the overactivity of sodium channels on certain neurons in the brain and spinal cord – a potential cause or contributor to the damage that fuels the progression of ALS. The daily treatment of mexiletine according to Brown significantly extends the survival of a mouse model of the disease.

 

Quiet down Mexiletine might reduce the flow of sodium ions (green) through neuronal channels (above) in the brain and spinal cord - helping to protect the motor nerves. Video: Courtesy of Vladimir Yarov-Yarovoy PhD, University of California – Davis School of Medicine.

This overactivity, know as hyperexcitability, is suspected to be an early step in the disease according to studies led by King's College London's Kerry Mills PhD FRCP and Neuroscience Research Australia’s Steve Vucic PhD.  Sodium channels that decorate certain neurons of the motor regions of the brain appear to be overactive in people with ALS. And, these changes may occur before the onset of symptoms according to a small study of people at high risk of developing the familial form of the disease.

Mexiletine therefore might not only protect the motor nerves from further damage; the drug might slow ALS even earlier in the disease course.

Now, US neurologists are gearing up to put mexiletine to the test in people with ALS to determine whether the drug can indeed slow down the disease. 

The 16 week phase II clinical trial will take place at 10 Northeast ALS Consortium (NEALS) sites in the US including the University of Washington School of Medicine, University of Kansas Medical Center and Penn State University School of Medicine.

The main goal is to evaluate the safety and tolerability of mexiletine in people with ALS.  Other measures include functional abilities (ALS FRS) and the frequency and severity of muscle cramps. 60 people with ALS are expected to participate.

“Mexiletine is a drug we know a fair amount about,” says University of Washington neuromuscular disease specialist Michael Weiss MD.  “It’s a pretty safe medicine.  It’s been FDA-approved for almost two decades.”

Patient Resources

A safety and tolerability study of mexiletine in patients with sporadic ALS.  Contact | ALS TDI | Website 

Mexiletine for the treatment of muscle cramps in ALS.  Contact | ALS TDI | Website 

References

Vucic, S and Kiernan, M.C. (2010) Upregulation of persistent sodium conductances in familial ALS. Journal of Neurology, Neurosurgery and Psychiatry 81(2), 222-227. Abstract | Full Text (Subscription Required)

Vucic, S., Nicholson, G.A. and Kiernan, M.C. (2008) Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131, 1540-1550.  Abstract | Full Text

Mills, K.R. and Nithi, K.A. (1997) Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis.  Muscle and Nerve 20(9), 1137-1141. Abstract | Full Text (Subscription Required)

KwieciƄski, H., Ryniewicz, B. and Ostrzycki, A. (1992)  Treatment of myotonia with antiarrhythmic drugs. Acta Neurologica Scandinavica 86(4), 371-375. Abstract | Full Text (Subscription Required)

Further reading

Vucic, S., Ziemann, U., Eisen, A., Hallett, M. and Kiernan, M.C. (2012) Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. Journal of Neurology, Neurosurgery and Psychiatry doi:10.1136/jnnp2012-304019 Abstract | Full Text  (Subscription Required)

Statland, J.M. et al. (2012) Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. Journal of the American Medical Association 308(13), 1357-1365. AbstractFull Text (Subscription Required)

Kanai, K., Kuwabara, S., Arai, K., Sung, J.Y., Ogawara, K. and Hattori, T. (2003) Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain 126, 965-973.  Abstract | Full Text

 

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Categories: In The Pipeline

Nuedexta, getting more than emotional?

clock August 10, 2012

Nuedexta dextromethorphan quinidine speech swallowing ALS

 

A dynamic duo? Nuedexta contains dextromethorphan (DM) (above) and a small amount of quinidine to slow DM breakdown.

One of the biggest fears for people with ALS is losing the ability to be speak. For many, this is a challenge that might be faced late into the disease. But for people with the bulbar-onset form of ALS, trouble speaking is amongst the first signs of the disease.

Now, US researchers are gearing up to evaluate a medicine that may help people with ALS retain some of this so-called bulbar control.  The drug, called Nuedexta, is currently used in the US to help people, including those with ALS, to control their emotions.

Nuedexta is one of at least three medicines currently or soon to be evaluated that may improve the quality of life for people with ALS.

“If you can improve the quality of life,” says Center for Neurologic Study (CNS) neurologist Richard Alan Smith MD, leader of the study, “This represents real progress in tackling the disease and providing support for patients.” 

The clinical trial is one of a number of studies within the growing “TREAT ALS” portfolio, an ALS Association initiative that helps push emerging ALS medicines into the clinic.

signma 1 receptor brainstem medulla motor neuron speech swallowing ALS

 

To speak, perchance to dream. Scientists suspect that DM may stimulate receptors that decorate motor neurons in the brainstem to help people speak and swallow. Adapted from Longone, P. et al. (2011).

CNS scientists first suspected in the 1990s that dextromethorphan (DM), a neuroprotective substance, might be helpful to people with ALS by slowing down the progression of the disease.  But when people with ALS starting take the drug in a small phase I safety study, the team noticed something else.  DM helped people with ALS control their emotions.  

Subsequent phase II and phase III clinical trials in the early and mid 2000s found that the number of uncontrollable crying and laughing outbursts dropped about 50%.

The condition, known as pseudobulbar affect (PBA), occurs in about 20% - 50% of people with ALS.  PBA is suspected to occur due to structural damage sustained by certain parts of the brain which control emotions.

The medicine, reformulated and named Nuedexta, was FDA-approved for use to treat PBA in October 2010.

Speak Up

Nuedexta, however, may help people with ALS do more than keep their emotions in check. 

A growing number of people with ALS taking Nuedexta for PBA according to anecdotal observations also appear to show signs of improvements in the rate and quality of their speech and their abilities to swallow.

“Nuedexta can help reduce PBA.  We know that,” says Duke University School of Medicine neuorologist Rick Bedlack MD PhD MS. "But what’s shocking is that the drug can, at least temporarily, improve [bulbar] dysfunction when upper motor neurons go bad.” 

The drug, acting on receptors decorating motor neurons in the brainstem, may also be helping people with ALS maintain bulbar control.

Nuedexta dextromethorphan quinidine speech swallowing ALS

 

Measuring stick The CNS-bulbar function scale, a self-reported measure (above) co-developed by Patientslikeme, will be primarily used to estimate Nuedexta's ability to help people with ALS speak and swallow. Courtesy of Paul Wicks PhD. Reproduced with permission.

Now, the US team is gearing up to put Nuedexta to the test in people with ALS that are having trouble speaking and swallowing.  The placebo-controlled randomized crossover clinical trial is to be conducted at 7 Northeast ALS Consortium (NEALS) sites in the US including Massachusetts General Hospital.  All participants are to be treated with Nuedexta and placebo successively for 30 days separated by a 10-15 day washout period.  Primary outcomes include: self-reported and clinician-assessed improvements in speech quality and swallowing abilities.  Other measures include: ALS-FRS. 60 people with ALS are expected to participate.

The trial is scheduled to begin in the spring of 2013.

This is the first medicine to be tested specifically to help people with ALS speak and swallow.

“We can compensate for [abilities] people are losing but we have been unable to take these problems and make them better,” says Bedlack.  “Now, for the first time, we are starting to see things like that.”

Patient Resources 

Clinical Trial of Nuedexta in Subjects with ALS Contact | ALS TDI Website 

References

Pioro, E.P., et al. (2010) Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.  Annals of Neurology 68(5), 693-702.  Abstract | Full Text 

Brooks, B.R., et al. (2004) Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology, 63(8), 1364-1370.  Abstract | Full Text (Subscription Required)

Al-Saif, A., Al-Mohanna, F. and Bohlega S. (2011) A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Annals of Neurology, 70(6), 913-919.  Abstract | Full Text  (Subscription Required)

Mavlyutov, T.A., Epstein, M.L., Andersen, K.A., Ziskind-Conhaim, L. and Ruoho, A.E. (2010) The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. Neuroscience 167(2), 247-255. Abstract | Full Text  

Further Reading

Rosen, H. (2008) Dextromethorphan/quinidine sulfate for pseudobulbar affect.  Drugs of Today 44(9), 661-668. Abstract | Full Text

 

Update (3/10/13) : Clinical trial launch date rescheduled. Patient resources added.

Update (9/10/12) : Researchers recently revised the CNS-BFS scale.  The figure has been updated accordingly.

 

 

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Categories: In The Pipeline , Watchlist

Neuralstem: surging immunosuppression?

clock April 12, 2012

human neural stem cells

 

Transplant stat.  Emory University School of Medicine neurosurgeon Nicholas Boulis MD injected between 0.5 and 1 million neural stem cells (above) in the lumbar section of ALS patients' spinal cords. Image: Corey Seehus, Brain Cells Inc for the 2010 GE Healthcare Image Competition.

Researchers estimate that more than 70% of motor neurons could be lost in people with ALS just one year after being diagnosed with the disease. To stem the tide of neurodegeneration, scientists are working hard to develop neuroprotective therapies to help keep their muscles moving.

One such potential treatment strategy, being developed by Maryland’s Neuralstem Inc., hopes to deploy neuronal bodyguards into the spinal cord that crank out protective substances which may shield the motor nerves from further destruction. The experimental stem cell transplantation procedure, performed during surgery, involves the direct injection of healthy neural stem cells into the spinal cord. The transplanted stem cells according to preclinical studies may give rise to populations of so-called interneurons that might plug directly into ALS-ravaged motor neurons, providing them life support.

In 2010, US physicians launched a phase I clinical trial to evaluate the safety of Neuralstem’s stem cell transplantation procedure. Patients received stem cell injections in the lumbar (leg-moving) region of the spinal cord. 12 people with ALS participated. 

Now, the team reports the first results from the phase I clinical trial.

The stem cell transplantation procedure appears to be safe and does not appear to aggravate the disease.  But, the immunosuppressants prescribed to prevent rejection of these transplanted stem cells were not well-tolerated by trial participants.

The results are published in the journal Stem Cells.

Emory University School of Medicine neurosurgeon Nicholas Boulis MD injected up to 1 million neural stem cells into the spinal cords of 12 ALS patients post-laminectomy.  Patients received anti-rejection medicines routinely used in whole organ transplants before and after surgery.

The team found that the procedure appeared to be safe and 6 to 18 months later did not rapidly worsen patients’ condition according to ALS-FRS, forced vital capacity and other functional measures. 

But researchers discovered that ALS patients could not tolerate the immunosuppressants (mycophenolate mofetil and tacrolimus) prescribed post-surgery.  Most trial participants had to drop or reduce the dosage of at least one of the two anti-rejection medicines due to chronic bloating, diarrhea and vomiting.  And, 2 out of 12 patients had to be taken off both drugs altogether due to the inability to control these symptoms through other medications.

adult mesenchymal stem cells from bone marrow

 

Under adult supervision. Scientists are creating potentially neuroprotective astrocyte-like cells from adult (mesenchymal) stem cells obtained from the patient's own bone marrow in hopes to slow down the disease. Image: Stem Cell Institute, Panama.

The jury is still out however whether a personalized stem cell therapy such as Brainstorm Cell Therapeutics’ NurOwn is a better way to go – particularly for people with inherited forms of ALS. The treatment strategy, which uses the patients’ own bone marrow to generate neurotrophin-producing cells, eliminates the need for immunosuppressants. But these transplanted cells according to some experts contain potentially ALS-triggering mutations which might also further contribute to the disease.

Neuralstem’s phase I clinical trial remains ongoing. Six people with ALS are expected to be implanted with stem cells in the cervical (diaphragm-moving) region of the spinal cord sometime this spring or summer. The trial is expected to be completed in October 2012.

Brainstorm Cell Therapeutics’ NurOwn phase I/II clinical trial is currently ongoing in Israel. Researchers are expected to launch a phase I/II ALS clinical trial in the US sometime in 2012.

References

Glass, J.D., Boulis, N.M., Johe, K., Rutkove, S.B., Federici, T., Polak, R., Kelly, C. and Feldman, E.L.(2012) Lumbar intraspinal injection of neural stem cells in patients with ALS: results of a phase I trial in 12 patients. Stem Cells, doi:10.1022/ stem.1079. Abstract | Full Text (Subscription Required)

Xu, L., Ryugo, D.K., Pongastaporn, T., Johe, K. and Koliatsos, V.E. (2009) Human neural stem grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. Journal of Comparative Neurology 514(4), 297-309. Abstract Full Text

Xu, L., Yan, J., Chen, D. Welsh, A.M., Hazel, T., Johe, K., Hatfield, G. and Koliatsos, V.E. (2006) Human neural stem cell grafts amerliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82(7), 865-875. Abstract Full Text (Subscription Required)

Further reading

Boulis, N.M., Federici, T., Glass, J.D., Lunn, J.S., Sakowski, S.A. and Feldman, E.L. (2012) Translational stem cell therapy for amyotrophic lateral sclerosis. Nature Reviews Neurology 8(3), 172-176. Abstract Full Text (Subscription Required) 

Maragakis N.J. (2010). Stem cells for the neurologist. Amyotrophic Lateral Sclerosis, 11(5), 417-423.  AbstractFull Text (Subscription Required)

Patient Resources

Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in ALS Patients. ALSTDI | Website | Contact 

Note: We will update this information when details in regards to Brainstorm's US trial become available.

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Categories: In The Pipeline

Empower Gathers Steam

clock November 23, 2011

 

Mirror mirror on the lab bench. Researchers found that the so-called enantiomer (mirror image) of the Parkinson’s drug pramipexol (red), dexpramipexole (blue), is well tolerated. Scientists suspect that this is because the drug is unable to overstimulate the dopamine receptors in the brain reducing unwanted side effects such as severe nausea, sleeplessness and hallucinations.

Knopp Biosciences’ experimental drug dexpramipexole may slow the progression of amyotrophic lateral sclerosis (ALS) according to a new study published this week.

The placebo-controlled phase II clinical trial, led by Massachusetts General Hospital neurologist Merit Cudkowicz MD MSc, found that in just 12 weeks, people taking 300mg of the drug daily progressed 31% slower than those on placebo. 102 ALS patients participated.

This is the largest reduction in motor function decline observed in people with ALS in a clinical trial at the phase II stage.

“These results came out more positive that we could have expected,” says senior author and Knopp Biosciences’ Chief Scientific Adviser Valentin Gribkoff PhD. 

The drug, now licensed to Biogen Idec, is being tested at the phase III stage in about 800 patients at 81 sites worldwide.

Researchers at the University of Virginia first looked toward the highly related drug pramipexole (Miraprex) to treat ALS in 2003 because of its ability to protect neurons from degenerating in people with Parkinson’s disease.  The scientists later switched to dexpramipexole suspecting that the drug might be safer and exhibit fewer side effects.

The phase II trial took place in two parts.  The first 12 weeks, patients were given daily 50, 150, 300mg or placebo and after 4 weeks of ”washout”, 24 weeks of either 50mg or 300mg. 

Dexpramipexole appeared to be safe and well-tolerated according to the phase II results.  The reduction in decline of motor function was dose-dependent and highest at the 300 mg dose.  And after 24 weeks, the risk of death dropped significantly between those on 300mg and 50mg of drug.

“If this is to hold true in a larger study, these are all clinically significant levels of benefit,” says Gribkoff.

Power Up

Scientists suspect that neuroprotective agents such as dexpramipexole may help ALS patients retain muscle function by keeping the energy flowing in degenerating motor nerves, slowing the progression of the disease.  Other drugs that may strengthen mitochondria include Trophos’ olesoxime which is currently being evaluated at the phase III stage in Europe.

The FDA fast-tracked dexpramipexole in 2009 due to the need for a more effective treatment for ALS.  The initial results for the phase III trial are expected sometime in 2013.

To learn more about the role of mitochondria in ALS, read ALS, More Than A Power Play. 

Reference

Cudkowicz, M. et al. (2011) The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis.  Nature Medicine. doi: 10.1038/nm 2579  Abstract Full Text (Subscription Required)

Further Reading

Gribkoff, V.K. and Bozik, M.E. (2008) KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride monohydrate] for the Treatment of Amyotrophic Lateral Sclerosis CNS Neuroscience and Therapeutics, 14, 215-226.  Abstract Full Text (Subscription Required)


CORRECTION:  Patients were administered during the first 12 weeks a total of 50mg, 150mg, 300mg dexpramipexole or placebo and after 4 weeks "washout" for 24 weeks, a total of 50mg or 300mg of the drug.

 

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