Categories: Featured , In The Pipeline

120 PALS to Enroll in Retigabine Trial

clock April 21, 2015

A group of collaborators announced their intent to launch a clinical trial in 12 academic sites on the anti-epileptic drug, Retigabine (aka Ezogabine), in people diagnosed with ALS. The sites will be chosen by the Northeast ALS Consortium, and include sites in California (3), Massachusetts (2), Michigan, North Carolina, Maryland, Georgia, New York, Florida and Arizona. Screening for enrollment should be expected to begin sometime before the end of 2015. The primary goal of this research project is to study the effect of retigabine on upper and lower motor neuron physiology in ALS patients, however researchers have outlined a number of secondary outcome measures as well such as safety etc.

At the end of 2014, during a scientific meeting in Brussels, Kevin Eggan, Ph.D., who led the team doing the preclinical research behind the selection of this drug, reported that the trial will enroll up to 120 people between the 12 sites and that approximately 1/3 of PALS will be given placebo in the trial. According to Brian Wainger, M.D., PALS enrolled and selected for the active compound arm will be split into two cohorts, one receiving 600 mg and the other 900 mg of Retigabine. 

In a webinar held shortly after the announcement, Wainger told PALS to expect to be in the study for at least 10 weeks. To be considered for enrollment, PALS must meet certain enrollment criteria such as having a possible, probable or definite ALS diagnosis and symptom onset occurring no more than then 36 months ago.  There are several specific exclusion items, most important perhaps to PALS with bulbar onset is that to enroll in the study a PALS must be able to swallow the retigabine pills throughout the study. Other examples of exclusion include the presence of a feeding tube or treatment for a serious cardiac issue at time of screening. Full study information is available in the global ALS clinical trial database.

As mentioned in that report from December, researchers at Eggan’s lab intend to collect skin samples from enrolled PALS from which they can create patient derived stem cells, sometimes referred to as induced pluripotent stem cells or more simply, iPSc.  Researchers plan to then test those iPS lines to determine if they could be used in future trials to determine whether or not a specific PALS would potentially benefit from this drug. The group working on this clinical trial include Harvard Stem Cell Institute, where Dr. Eggan is based, Massachusetts General Hospital Neurological Clinical Research Institute, GlaxoSmithKline, and the ALS Association. 

This trial, along with all others, regardless of who funds them or where they are located, are listed and tracked by staff at the ALS Therapy Development Institute. You can view that global database and subscribe to receive email updates on trial launches, etc, by clicking here.

Bottom Line:

The Retigabine trial is NOT currently enrolling PALS. The ALS Therapy Development Institute has spoken about this drug and the trial multiple times, and we encourage people to review comments from our science team members, Drs. Lincecum and Perrin and others in recent webianrs on the Brussels meeting and Clinical Trials in general. In addition, there is an active discussion thread on this proposed clinical trial on the ALS Forum, in which our CEO, Dr. Steve Perrin provides his individual comments on the drug and trial.

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Categories: Featured , In The Pipeline

TW001 Gets Orphan Drug Designation in US and EU

clock April 3, 2015

Recently, Treeway B.V., announced that the active component, edaravone, found in one of the company’s lead therapeutic compounds, TW001, has received orphan drug status from regulatory agencies in both the United States (FDA) and European Union (EMA). These special designations provide the company specific developmental protections and other opportunities for the compound. Orphan drug status designation is not the same as these regulatory agencies approving TW001 for the use in treating ALS. 

The active compound in TW001 is edaravone, which is used in some countries as a treatment following stroke.  In Japan, the pharmaceutical company, Mitsubishi Tanabe, operated a Phase 3 clinical trial of the compound, under the code name MCI-186, in ALS patients over the last several years. Results from the study have not been published, but are expected. 

According to Treeway, they have reengineered edaravone so that it can be delivered in pill form (TW001) rather than via intravenous infusion (MCI-186) as was done in the original trial by Mitsubishi Tanabe. Treeway believes that constant exposure to edaravone in PALS will be required to determine its efficacy and that the oral formulation will enable such an experiment to be conducted best.

According to Treeway, they have patented their oral formulation of edaravone (TW001), and will conduct a phase 1 clinical trial to ensure the optimal exposure levels needed. At the time of this post, the status or results from the phase 1 safety and dose optimization trial was not known.

However, Treeway has announced they anticipate launching a phase 3 clinical trial in PALS by the end of 2015.  With the results of the phase 1 study pending, it should be assumed that they will be needed to inform the design and execution of such an additional clinical study on TW001. All clinical trials occurring globally are listed and updated regularly by staff at the ALS Therapy Development Institute, and as new information becomes available, we will add information about any TW001 clinical trial to the database when they are announced.

What is Edaravone?

In Treeway’s filing with the European Medicines Agency, they describe the following rationale for how they expect TW001 to work: Damage to nerve cells in ALS appears to have several causes, but there is evidence that it may involve damage to nerves caused by toxic molecules containing oxygen. In some patients this is associated with a defect in the gene responsible for producing the enzyme called superoxide dismutase (SOD), which causes the enzyme to clump together inside nerve cells. This leads to inflammation and kills the affected nerve cells. Edaravone is expected to act as an antioxidant, a molecule that can prevent damage to nerve cells caused by oxygen-containing molecules, and also blocks the clumping together of SOD in the nerves and so reduces inflammation.


TW001 is not approved for the treatment of ALS at this time. To our best knowledge, TW001 is not currently available to PALS in clinical trials or otherwise. Limited information about edaravone efficacy in ALS, via the phase 3 clinical trial in Japan, or this reformulation of the compound, makes commenting on the formulations difficult at this point in time.  Additionally, the planned phase 1 study should inform regarding any additional differences in dosing strategies between the oral and IV formulations. The ALS Therapy Development Institute looks forward to seeing data from Mitsubishi Tanabe’s clinical trial, Treeway’s phase 1 study on dose optimization and their trial design for the phase 3 program. We encourage both companies to continue to make public information about their clinical development programs for ALS as they move their proposed treatments through that process in the US, EU and elsewhere. 

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Categories: Featured , In The Pipeline

Ibudilast Clinical Trial Halfway Enrolled

clock February 27, 2015


Last week, MediciNova announced that they have enrolled 30 PALS in their Phase 2 clinical trial of MN-166, also known as Ibudilast. The trial is enrolling people diagnosed with ALS at a single site in Charlotte, North Carolina, USA.  These types of announcements are common in clinical research programs.  MediciNova and the study’s principal investigator, Benjamin Brooks, M.D., are seeking a total of 60 PALS for participation. At the pace currently, it is estimated the trial may become fully enrolled by the end of 2015 and results from the study should be available by the middle of 2016.

Ibudilast (MN-166) is thought to help motor neurons stay alive by modifying the presence of amino acids, called cytokines, which cause motor neurons and supporting cells to become puffy or inflamed. Tamping down the expression of certain pro-inflammatory cytokines is an approach of great interest in the ALS research field. For more information on this clinical trial, including links to relevant research papers and comments from people in the clinical trial itself, click here. 

The ALS Therapy Development Institute encourages PALS and their families to become informed about the current ALS clinical trials and research. We provided an overview of 14 different clinical trials during a recent webinar with our CEO, Dr. Steve Perrin earlier this month. You can access that webinar by clicking here.

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NurOwn Phase 2 Clinical Trial Update

clock February 3, 2015

It was recently announced via press release by BrainStorm Cellular Therapeutics that their proposed treatment for ALS, NurOwn, will continue to be investigated in ALS in the United States through a Phase 2 clinical trial. According to the latest update provided by BrainStorm on the status of the clinical trial, the ALS Therapy Development Institute lists this trial as “currently recruiting” in its global ALS clinical trial database.

The announcement comes as a result of the trial’s Data and Safety Monitoring Board (DSMB) recommendation for the continuation of the study.  This is not uncommon, highlighted by a similar announcement from AB Science regarding their compound masitinib.  It is one of the jobs of a DSMB to review data continuously throughout the trial they are charged with monitoring, and to make a recommendation for its continuation or cancellation based on that data. This announcement should not be interpreted as any indication this treatment is effecting ALS disease progression in either a positive or negative way. It should only be considered a sign that the DSMB believes that the trial should continue forward.  It should be expected that a final report of the trial’s results will be known only after the trial is completed, which shouldn’t be expected for another year based on the timelines outlined by BrainStorm previously.

What is NurOwn?

NurOwn may help keep motor neurons healthy in people with ALS by boosting production of GDNF, a neuroprotective substance which promotes their survival and growth. In this potential treatment strategy, adult stem cells from the patient's own bone marrow are reprogrammed into GDNF-secreting astrocyte-like cells and reintroduced. NurOwn can likely be administered without anti-rejection medicines. Earlier clinical trials have taken place on this approach in Israel.  Investigators are exploring both intra-muscular and intra-spinal administration of their stem cells in people diagnosed with ALS in a Phase 2 clinical trial currently enrolling in the United States. 

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International Alliance of ALS/MND Associations Annual Meeting Report

Posted by author Jessica Sullivan

clock December 3, 2014

The 22nd annual meeting of the International Alliance of ALS/MND Associations was held over two days, December 2 and 3, in Brussels, Belgium.  It is the mission of the Alliance to bring together the representative organizations of people living with ALS (also known as MND) from different countries across the globe.  At this year’s meeting there were 20 different countries from 6 continents present.

In 2014, the worldwide social phenomenon known as the ALS Ice Bucket Challenge created global awareness of ALS/MND and boosted the budgets of many of the member organizations. All told, according to the General Manager of the Alliance, Rachel Patterson, members reported receiving a total of $164 million (USD) through the ALS Ice Bucket Challenge.  As a result, the first topic of discussion at this year’s meeting was how this action began, how it spread, and what potential next steps the Alliance and its members may take to leverage the challenge in the future.

Robert Goldstein of the ALS Therapy Development Institute provided the opening plenary at the meeting on this topic and described its success as the result of being an organic, patient-created, and online community-led action. ALS was not the first cause to utilize an “Ice Bucket Challenge”.  However, it gained momentum after two young men, Pete Frates and Pat Quinn (both of the USA), and their friends started challenging other friends to accept or to donate to ALS research.  The challenge required a person to record a video online, usually posted via Facebook, of them pouring a bucket of water with ice in it over their head and then calling out others in their network to do the same. According to Goldstein, more than 30 million Facebook users posted, liked, or shared Challenge videos.  He then provided some thoughts to organizations seeking to conduct the Challenge again in the future, suggestions for success, and challenges to avoid.  His main recommendation was that the campaign is most likely to be successful if it remains an organic movement, not one led by a specific ALS organization. He closed by providing a brief overview of where his Institute would be investing the $3.5 million it raised as a result of the ALS Ice Bucket Challenge, and suggested that getting information out to those that gave this year about how their donations were being used would be one of the most important things that each member organization could do.

Different Countries, Different Fundraising Strategies

Three additional talks were given regarding fundraising activities and ideas; from Rod Harris (MND Victoria, Australia), Jens Spanfelt (Muskelvinfonden, Denmark) and Pablo Aquino ( ELA Argentina).  According to Harris, his organization receives many different offers from people to fundraise for it, including ones which require up-front expenses. Harris described the importance of being careful of these offers and shared a story of his organization taking a chance on one such idea which then took his organization two years to see a return. 

“We don’t accept every opportunity to raise funds. Sometimes we have to say ‘no.’  The last time we invested up front, it took us two years to recoup the expense and turn a very small profit,” said Harris.

He suggested that members focus on creating strategic fundraising programs which support individual fundraisers with their efforts, providing tool-kits and guidance.  Harris also noted that an organization should look at its responsibility to create sustainable fundraising by availing itself of various forms of investments with their capital.  MND Victoria reported having more than $4.5 million (AUD) in its various investments upon which it receives an 8% return annually. This allows his organization to serve the more than 360 people living with MND in Victoria, Australia.

The Muscular Dystrophy Association of Denmark, Muskelsvinfonden, has a unique fundraising event which raises a total of half its annual fundraising budget called Green Concert.  The annual music festival is held in eight different cities in the country each year and is organized in partnership with the brewer, Turborg. Jens Spanfelt suggested to the Alliance membership present that one of the keys to success of the event was the more than 700 person-strong volunteer base which operates it.  With a population of 5.6 million people, the country of Denmark reports having about 350 people living with ALS in its country at a given time.

“After so many years doing this, there is now really no one in Denmark that doesn’t know about the Green Concert and Muskelsvinfonden.  Pretty much everyone has either attended or volunteered,” remarked Spanfelt about the impact on the Green Concert beyond fundraising.

Awareness, Advocacy, and Service Challenges

Many people and media are asking what is being done with the funds raised by organizations as a result of the ALS Ice Bucket Challenge. In Argentina, they are using the $150,000 (USD) to begin the creation of the first specialized ALS center for the Spanish speaking population in South and Central America. 

One of the questions that a lot of people ask ALS organizations is whether or not they give support grants to people living with ALS.  Christian Lunetta, MD, of AISLA Onlus in Italy shared during the Awareness and Advocacy portion that his organization saw an influx of €2 million from the Ice Bucket Challenge and that they will be spending those funds on three aims, the first of which is to provide economic support for patients and their families.  These grants will cover the cost of direct, disease-related healthcare needs; such as a home care provider, or to rent or buy specific equipment such as assistive communication or breathing devices. Another aim of the AISLA investment will go to establishing the first ALS biobank in Italy, which will be free of charge to researchers and will gather DNA samples from PALS for study.

The decision-making process of where to invest funds was a key theme of the Alliance meeting.  According to Sally Light, CEO of the MND Association, one approach is combining information from surveys from clients served with input from board members. Her organization put out a call for feedback to its PALS and received 2000 responses; 88% of replies said they felt the windfall of funds from the Ice Bucket Challenge (the MND Association received £7 million (GBP)) should be spent on ALS research.  The next most popular suggestions from the survey were providing care and educating health professionals, among others.

The Japanese ALS Association (JALSA) gave a talk on their decision-making process, which also included outreach to its donors and PALS.  In total, according to representative Yumiko Kawaguchi, their organization raised the equivalent of $318,000 (USD).  Similar to others, the feedback they received was to invest the dollars primarily in external ALS research. Kawaguchi reported some of the challenges and limitations related to the Challenge, including that it was really hard for people to say “no” to participation. In addition, some celebrities used the Challenge to raise their own profile, and in general she thought that the Challenge didn’t achieve education, only simply awareness.

Striving to reach and provide care and other services to all people living with ALS is a goal of many of the organizations present at the Alliance’s meeting.  However, as organizations develop programming to reach out to people living with ALS/MND, there are many considerations which will impact their ability to achieve this important goal; such as cultural, language, and other differences between people within their country’s borders.  According to Erfat Carmi, CEO of IsrALS (Israel), there are nearly 600 PALS in Israel, but her organization is only able to reach 446 PALS.  Only 4% of those receiving services were ethnic Arabs. 

Carmi set out to figure out how her organization could reach the large Arab population in Israel in order to find and support PALS within that community.  Over the past several years, accomplishing this goal has been a major focus.  According to Carmi, in order to reach Arab PALS, her organization needed to address several important barriers.  On the day of her presentation, IsrALS launched a version of its website and corresponding social media channels written entirely in Arabic.  They have over the last couple of years also engaged an Arab social worker who can “literally walk from town to town” within the Arab community.  As a result of this effort, IsrALS is now serving twice as many Arab PALS as it was before it began its new outreach effort. Reaching PALS and keeping them involved in the care services that organizations offer differs greatly between the countries presenting at this year’s Alliance meeting. Two extremes were highlighted during presentations from the Russian ALS Charity and the ALS Association of the USA.

Gleb Levitsky, MD, a neurologist and the head of the Russian ALS Charity Foundation reported results of a survey of PALS served, which showed that upwards of 80% of them attend a visit with a neurologist only once, typically to receive the diagnosis.  Oppositely, 12% of PALS said they are receiving a very high level of care and attention in Russia.  Some of this polarization of care is due to a “fatalistic” belief among many Russian PALS, according to Levitsky. Due to the low level of compliance, Gevitsky doesn’t believe in the establishment of an ALS clinic in Moscow. However, his research suggests that the most appropriate model for PALS support in his country is a “combination approach”, which he described as the provision of services free from foundations like his together with services which PALS will have to pay for at local or regional medical centers and providers.

While in Russia there is a single organization serving PALS, there are many in the United States, including the ALS Association. Nicole Yarab, Director of Certified Center Programs at the ALS Association, provided a window into their services.  According to Yarab, the ALS Association employs 374 people across its 38 chapters in the United States, including 115 staff dedicated to care services.  The National Office, where Yarab is located, employs 50 people, 6 of which are devoted to care services. In 2013, the Association provided services to upwards of 15,000 people living with ALS in the USA.  About half of those people, 7,328 according to Yarab, visited one of the Association’s 43 “centers of excellence” at least once.

Additional talks were provided by several other speakers not reported on here, including a hefty discussion on the role of and appropriate ways to set up a national registry with great discussions from representatives of MND Scotland and MND Australia.  Many of the discussions centered on the barriers of getting PALS enrolled.  In Scotland, they found early on that relying on neurologists to report PALS was less than effective.  However, applying a comprehensive approach of auditing medical records and reaching out to PALS directly, MND Scotland found that between 1998 and 2004 the incidence rate of ALS in its country rose by a staggering 27% (from 2.3 to 3.0 per 100,000 people). While the reason behind this is not entirely known, the revamped registry effort has helped MND Scotland, according to Chief Executive Craig Stockton.  Of PALS which opt-in to the registry, 95% say that they will participate in research trials, which though limited in opportunity in Scotland, is a key focus of their organization.

One of the most important programs of the Alliance is its partnership and mentoring effort, which combines its more experienced member organizations with emerging ones in different countries.  One of the most experienced leaders in the program, Kathy Mitchell, provided an overview of how best to accomplish this and described a recent trip to Argentina to work with the ALS organization there on training programs for local nurses and other health professionals.  Over the past several years the Alliance has also been encouraging its member organizations to arrange regional meetings, two of which have now been established; including a new one for the Asia Pacific region to be held in Taiwan in April 2015, and the model for the regional meetings, the Nordic ALS/MND Alliance meeting, will be held in Latvia in August 2015.

Additional reports will be forthcoming from the 22nd Annual Meeting of the International Alliance of ALS/MND Associations as well as the 25th annual ALS/MND research symposium to be held December 5-7 in Brussels. You can also follow us on Twitter @ALSTDI or #alssymp for live updates. 

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Tirasemtiv: a question of tolerance?

clock May 2, 2014


Breathe easier? Tirasemtiv may improve breathing in some people with ALS according to initial phase IIB results. But the drug did not appear to slow progression of the disease, the primary endpoint of the study. Courtesy of Nature Publishing Group.

Cytokinetics’ tirasemtiv may help some people with ALS breathe better according to initial phase IIB clinical trial results presented this week at the 2014 meeting of the American Academy of Neurology in Philadelphia.

The randomized placebo-controlled study found that people with ALS taking tirasemtiv for 12 weeks appeared to experience one third the reduction of breathing (slow vital) capacity (P < 0.0006) compared to those taking the placebo.

No significant improvement, however, was detected in other respiratory measures including an emerging indicator of strength of the diaphragm muscles (SNIP) – at least in people with lung disease indications.

The clinical trial, led by State University of New York neurologist Jeremy Shefner MD PhD, took place at 75 sites in 8 countries worldwide. 711 people with ALS participated. 473 people with ALS completed the study.

”This is the most positive ALS trial since riluzole,” says Shefner.

Cytokinetics introduced tirasemtiv in April 2008 in hopes to improve muscle function in people with neuromuscular diseases. 

The drug, originally known as CK-2017357 (CK-357), aims to make the most of deteriorating neuromuscular junctions (muscle-motor nerve connections) by amplifying the signals generated by motor neurons that ‘tell’ the muscles to move. 


Sensitivity training? Tirasemtiv aims to keep muscles moving longer by increasing their sensitivity to weakening electrical impulses emitted by diseased motor nerves. 

Tirasemtiv entered clinical testing in 2009. The potential muscle booster is currently being evaluated as a treatment of a growing number of neuromuscular diseases including myasthenia gravis.

The drug, according to phase IIB results, also appears to significantly improve the strength of certain skeletal muscles in the elbows, wrists, knees and ankles.

People with ALS taking tirasemtiv appeared to experience one third the reduction in muscle strength (P < 0.0158) vs those on placebo according to a so-called muscle megascore.

“Tirasemtiv may actually make patients stronger,” says participating investigator Bob Miller MD of California Pacific Medical Center (CPMC) in San Francisco. “Not just slow the decline.”

Tirasemtiv is the first drug to show a potential benefit at the phase II stage on respiratory and muscle function in people with ALS.

“We have for the first time evidence that a drug may improve breathing and muscle strength,” says participating investigator Merit Cudkowicz MD MSc of Massachusetts General Hospital (MGH).

A GI Bill?

Key challenges remain.

Tirasemtiv appears to be relatively safe. But according to phase IIB results, the drug is not well tolerated by many people with ALS.

More than 100 people with ALS dropped out in the first week of the study due to the inability to tolerate 250 mg of tirasemtiv – 50% of the study dose. And, nearly three times the number of participants dropped out of the clinical trial vs those on placebo.

Common side effects included nausea, dizziness, headaches and fatigue. People with ALS unable to tolerate tirasemtiv lost “slightly more” than twice the weight of those taking placebo.

hand held dynamometry muscle megascore HHD ALS clinical trial


Gathering strength Tirasemtiv may help keep certain skeletal muscles stronger longer according to phase IIB results. But the drug did not improve muscle fatigue - at least in the hands.

”I think further development of tirasemtiv depends on whether the tolerability of tirasemtiv can be improved,” says Shefner.

Mixed signals

In 2010, Cytokinetics began testing the potential muscle booster tirasemtiv in people with ALS in hopes to improve respiratory strength.  Reduce fatigue. And, to help people with ALS do more everyday tasks.

But although some people taking tirasemtiv appeared to breathe better (as determined by breathing capacity) and certain muscles appeared stronger (as determined by muscle mega score), no significant improvement was detected in disease progression estimated by the ALS revised functional rating scale (ALSFRS-R), the primary endpoint of the phase IIB clinical trial.

“The ALSFRS-R is a great global measure of functional impairment in ALS.” says CPMC’s Bob Miller MD.  “But, to me it is a very high bar.  No drug as of yet has shown in a clinical trial an impact on that scale.”

Side effects including nausea, fatigue and loss of appetite may make it more difficult to assess the functional abilities of people with ALS taking tirasemtiv according to MGH’s Merit Cudkowicz MD.

“I think this may be more of a tolerability issue.  The ALSFRS-R is very dependent on how patients feel,” says Cudkowicz.

And, a significant loss of weight may also be confounding efficacy analysis says SUNY neurologist Jeremy Shefner MD PhD.


The sniff test Sniff inspiratory pressure (SNIP) is an emerging measure that is being increasingly used to measure diaphragm strength in people living with chronic lung diseases. The measure according to CPMC's Bob Miller MD is relatively new to the ALS field and much less understood in terms of disease course than vital capacity.

More studies will be needed to determine whether tirasemtiv has the potential to slow progression of the disease.

People taking tirasemtiv did however appear to show potential improvements in strength of some skeletal muscles – at least determined by SVC and muscle megascore.

These so-called secondary outcomes, however, were also planned to be measured says Cytokinetics Chief Medical Officer Andrew Wolff MD.  And, were part of the study protocol – the phase IIB clinical trial design.

“These are pre-specified secondary endpoints, they are not measures we looked at in a post-hoc manner,” says Wolff.

Promoting Tolerance?

Side effects of tirasemtiv, however, remain a considerable obstacle.

Only 50% of people with ALS taking tirasemtiv could tolerate 500 mg daily of tirasemtiv for 12 weeks according to principal investigator Jeremy Shefner MD PhD. 1 out of 4 participants taking tirasemtiv could tolerate only 250 mg daily – 50% of the study dose.

“We want to understand issues related to tolerability - how that can be improved,” says Cytokinetics’ CEO Robert Blum. “We need to delve more deeply into the [phase IIB clinical trial] data to know what we may do next.”

But MGH’s Merit Cudkowicz MD remains undaunted.

“We learned the side effect profile [of tirasemtiv] in the study,” says Cudkowicz. “They are all manageable.”

high fat  calorie dense ketogenic diet ALS clinical trial


Nutrition facts A calorie dense diet may help people with ALS increase their calorie intake according to a clinical trial led by MGH neurologist Anne-Marie Wills MD MPH.

Medicines are available to reduce key gastrointenstinal (GI) side effects of tirasemtiv including nausea according to Cudkowicz. And, nutritional-based interventions could help people with ALS taking tirasemtiv maintain their weight.

The drug could also be introduced more slowly to people with ALS by ramping up the dose of tirasemtiv during a longer period of time says SUNY neurologist Jeremy Shefner MD PhD.

”I continue to feel that there is something here. And, so do my patients,” says CPMC’s Bob Miller MD.


To learn more about tirasemtiv and ALS, check out CK-357, helping PALS live strong? To find out more about the clinical trial including phase IIA results, read Tirasemtiv phase IIB powers up.  To learn about other emerging strategies to help people with ALS breathe better, check out Clearing the air on the DPS?

Patient Resources

Study of Safety, Tolerability & Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS) (Completed)  Contact  |  ALS TDI |   Website


Hansen, R. et al. (2014) Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle and Nerve,  doi: 10.1002/mus.24239.  Abstract  |  Full Text  (Subscription Required)

Shefner, J. et al. (2013)  A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(7-8), 574-581.  Abstract  |  Full Text  (Subscription Required)

Shefner, J.M., Wolff, A.A. and Meng, L. (2013) The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS.  Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(7-8), 582-585.  Abstract  |  Full Text    (Subscription Required)

Russell, A.J. et al. (2012)  Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nature Medicine 18(3), 452-455.  Abstract  |  Full Text




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ALS clinical trial nears T off

clock March 10, 2014

regulatory T cell FOXp3 antigen presenting cell dendritic cell ALS MND


Par-foxP3? Regulatory T cells (red) may help protect motor neurons in people with ALS in part by reducing the production of inflammatory substances by key immune cells (blue) including effector T cells that infilitrate the CNS. Image: John R James PhD and Ron Vale PhD. Courtesy of Howard Hughes Medical Institute. All rights reserved. 

More than 200,000 people are diagnosed with ALS every year around the globe. About 10% of people with ALS will live at least 5 – 10 years. But many more survive only 2 -3 years with the disease.

Researchers are working hard to understand why certain people may live longer with ALS in hopes to design therapies that slow progression of the disease. 

An emerging competitive advantage in the ALS fight is a high number of regulatory T cells, key immune cells that help keep inflammation in check.  

People who survive at least 6 years after diagnosis according to Methodist Neurological Institute’s Stan Appel MD PhD appear to have three times the number of regulatory T cells in circulation compared to those that live at most 2-3 years. What’s more, the larger the number of regulatory T cells that are on ‘the course’ in people with ALS, the slower the progression of their disease. 

The results suggest that increasing populations of regulatory T cells may help more people with ALS be on their 'A' game. But how to boost these cells in people with ALS remains unclear.

A growing group of clinicians in France suspect that low dose interleukin 2 (IL-2) may help expand regulatory T cells in people with ALS.  And, thereby slow the progression of their disease. 

The treatment strategy, originally developed to fight transplant rejection, is one of the first potential ALS treatments to be tested in the clinic that aims to supe up regulatory T cells in people with the disease.

A phase I/II clinical trial is scheduled to begin in April of 2014.

regulatory T cell FOXp3 ALS MND


Bump and run? The surface of regulatory T cells are highly decorated with high affinity receptors that tightly bind IL-2 - enabling them to be potentially selectively expanded by lose doses of IL-2. Image: NIAID.

In the mid 2000s, Dana Farber Cancer Institute’s Jerome Ritz MD turned to IL-2 in hopes to promote tolerance in stem cell transplant recipients at high risk of developing grafts versus hosts disease (GVHD).

The growth substance, at low doses, according to studies led by Ritz, appears to stimulate the expansion of regulatory T cells. But leave troublesome effector T cells, lacking high affinity IL-2 receptors, untouched.

The treatment strategy, according to a growing number of phase I and phase II clinical studies, appears to double numbers of circulating regulatory T cells - at least in people at high risk of GVHD. And, boost levels of FOXP3 – a key regulatory substance critical to help these cells keep inflammation in check.

The approach is being developed to help combat transplant rejection in people with certain blood diseases. And, people battling complications of certain viral infections.

Now, Assistance Publique – Hôpitaux de Paris’ Gilbert Bensimon MD PhD is gearing up to put low dose IL-2 to the test in people with ALS in hopes to increase numbers of regulatory T cells and thereby slow progression of their disease.

A phase I/II randomized placebo-controlled clinical trial is to take place in France. Participating sites include Centre Hospitalier Régional Universitaire de Nîmes and Centre Hospitalier Régional Universitaire de Montpellier.

The 6 month study aims to evaluate the safety and tolerability of low doses of IL-2 in people with ALS.  And, determine the ability of the drug to boost regulatory T cells in people with the disease.

24 people with ALS are expected to participate.

The first results are expected sometime in 2015.


To learn more about the role of regulatory T cells in ALS, check out Regulating ALS. To find out about other emerging treatment strategies to boost them in people with ALS, check out ALS, extracellular matrix reloaded? and Emerging potential of HDACIs in ALS.

Patient Resources

Immunomodulation in ALS (IMODALS): A phase I/II of safety and activity of low dose interleukin in ALS.  Contact | ALS TDI | Website 


Kennedy-Nasser, A. et al. (2014) Ultra low-dose IL-2 for graft-versus-host disease prophylaxis after allogeneic HSCT mediates expansion of regulatory T cells without diminishing anti-viral and anti-leukemic Activity.  Clinical Cancer Research  doi:10.1158/1078-0432.CCR-13-3205 Abstract | Full Text  (Subscription Required)

Matsuoka, K. et al. (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease.  Science Translational Medicine 5(179), 179ra43.  Abstract  |  Full Text  (Subscription Required)

Henkel, J.S, Beers, D.R., Wen, S., Rivera, A.L., Toennis, K.M., Appel, JE, Zhao, W., Moore, D.H., Powell, S.Z. and Appel, S.H.  (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival.  EMBO Molecular Medicine 5(1), 64-79.  Abstract  |  Full Text

Beers, D.R., Henkel, J.S., Zhao, W., Wang, J., Huang, A., Wen, S., Liao, B. and Appel, S.H. (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.  Brain 134(5), 1293-1314.  Abstract  |  Full Text

Saadoun, D., Rosenzwajg, M., Joly, F., Six, A., Carrat, F., Thibault, V., Sene, D., Cacoub, P. and Klatzmann, D. New England Journal of Medicine 365(22), 2067-2077.  Abstract  Full Text

Koreth, J. et al. (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease.  New England Journal of Medicine 365(22), 2055-2066.  Abstract  |  Full Text

Zorn, E. et al. (2006) IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo.  Blood 108(5), 1571-1579.  Abstract  |  Full Text

Further Reading

Bluestone, J.A. (2011) The yin and yang of interleukin-2-mediated immunotherapy. New England Journal of Medicine 365(22), 2129-2131.  Abstract  |  Full Text (Subscription Required)



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Categories: In The Pipeline

A new player in the ALS Q

clock October 31, 2013

astrocyte als neuroinflammation neuroprotection stem cell


ALS Detox? Healthy astrocytes may help keep motor neurons alive in people with ALS by detoxifying the nervous system. Image: Andrew Swift for Duke University School of Medicine.

More than 50% of motor neurons are lost by some estimates in people with ALS before the first signs of disease. To turn the tide of destruction, clinicians hope to keep existing motor neurons healthy in their patients by increasing supplies of neuroprotective substances.  But whether these strategies are helpful to people with ALS remains hotly debated.

A growing number of neurologists suspect that the introduction of healthy astrocytes might provide ‘life support’  to existing motor neurons in people with ALS.  And, protect them from destruction.

The stem cell-based strategy, known as astrocyte replacement, involves the injection of astrocyte precursors directly into the spinal cord. The transplantation-based approach according to preclinical studies may work in part by reducing the build up of potentially toxic levels of glutamate in the brain and spinal cord.

One of these potential treatments, known as Q cells, is approaching the clinic. The strategy, developed by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD, is emerging as one of a growing number of potential personalized medicines that may benefit people with certain forms of sporadic and inherited disease.

At the 2013 Northeast ALS Consortium Meeting, ALS Today talked to Nicholas Maragakis MD to learn more about astrocyte replacement and its potential for people with ALS going forward.


To learn more about astrocyte replacement strategies being developed for people with ALS, check out our report from the 2013 meeting of the International Society for Stem Cell Research (ISSCR), ALS Stem to Stern.

Further reading

Haidet-Phillips, A.M., Gross, S.K., Williams, T., Tuteja, A., Sherman, A., Ko, M., Jeong, Y.H., Wong, P.C. and Maragakis NJ (2013) Altered astrocytic expression of TDP-43 does not influence motor neuron survival.  Experimental Neurology doi: 10.1016/j.expneurol.2013.10.004.  Abstract |  Full Text  (Subscription Required)

Serio, A. et al. (2013) Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy.  Proceedings of the National Academy of Sciences 110(12): 4697-4702.   Abstract  |  Full Text



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Categories: In The Pipeline

What's in the ALS pipeline - 2013?

clock September 16, 2013

More than 30 potential ALS medicines have been tested in the clinic.  Only riluzole, however, is FDA-approved to treat ALS.  And, increases survival 2-3 months.

Researchers are working hard to develop a more effective treatment for ALS.  In 2012 and 2013 alone, more than 20 new strategies entered the clinic.

Ahead of the 2013 Northeast ALS (NEALS) Consortium meeting and the International Symposium on ALS/MND, ALS Today takes a second look at potential therapies for ALS being investigated in the clinic in this interactive timeline.  Click on the pipeline to learn more about medicines being developed for the disease.

motor neuron astrocyte als mnd


Toxic avenger? Astrocytes (green) are unable to soak up enough glutamate from diseased motor neurons (red) according to some studies, making them vulnerable to degeneration (glutamate- induced excitotoxicity). Image: Ludo Van Den Bosch PhD and Maarten Dewil MD PhD for the Proceedings of the National Academy of Sciences.

A long and winding road

In the 1980s, the first treatment of ALS emerged. Sanofi-Aventis’ riluzole, entering clinics in 1990, aims to help protect motor neurons by reducing glutamate buildup. The drug hit pharmacy shelves in 1995.

In 1993, scientists identified superoxide dismutase 1 (SOD1) as the first ALS-linked gene. And, began to develop treatment strategies to remove ‘free radicals’ in the brain and spinal cord. Mitsubishi Tanabe Pharma’s edavarone (Radicut), introduced in ALS clinics in 2001, aims to reduce the stress level of the motor neurons by lowering production of these toxic substances.

With the advent of the first mouse model of ALS, researchers discovered that the buildup of misfolded proteins may contribute to ALS. And, treatment strategies that aimed to sweep out aggregates out of motor nerves emerged. Chaperonin-targeted therapies including Cytrx’s arimoclomol aim to help proteins to properly fold.  And, ISIS’ SOD1RX aims to reduce their synthesis by sopping up the RNAs via antisense-steeped sponges.

By the late 1990s, ALS emerged as an energy crisis. And, clinicians began to look toward treatment strategies that could help keep the power on in the muscles and motor nerves. The metabolic supplement creatine, introduced in 2000, aims to boost energy production. And, putative mitochondrial-targeted therapies including Knopp’s dexpramipexole (licensed to Biogen Idec), Trophos’ olesoxime and Teva’s rasagiline (Azilect) hope to keep power production at full throttle by bolstering them.  

But specific targets of ALS remained elusive.  And,  many research teams turned to more general strategies in hopes to develop treatments for the disease. Repurposed HDAC-targeted medicines aim to keep motor neurons healthy by throwing key genetic switches – turning up production of neuroprotective substances.  And, stem cell strategies including Brainstorm’s NurOwn and Neuralstem’s NSI-266 hope to increase levels of these substances by delivering them directly to the nervous system. 

mitochondria dysfunction ALS


Power up? Mitochondrial-targeted medicines aim to slow progression of ALS by boosting power production in the motor nerves. Dexpramipexole and olesoxime however appeared to be ineffective in phase III trials. Image: Xiaowei Zhuang MD PhD, Harvard University.

In the mid 2000s, clinicians targeted the immune system in hopes to reduce neuroinflammation - slowing the progression of the disease. Anti-inflammatories including Sobi’s anakinra (Kineret) and Roche’s tocilizumab (Actemra) aim to soak up key substances that might damage the motor nerves in people with ALS. And more recently, immunomodulators including Novartis’ fingolimod (Gilenya) and Neuraltus’ NP001 may quiet down microglia by keeping out emerging instigators of inflammation including macrophages and certain T cells (Teffs).

Meanwhile, other research teams peered into the muscles of people with ALS in hopes to develop treatments for the disease. GlaxoSmithKline’s ozanezumab (anti-NogoA), entering clinics in 2009, aims to help keep the motor nerves connected. Cytokinetics’ tirasemtiv (CK-357) might help keep muscles moving by making the most of existing motor neuron-muscle connections.  And, Synapse Biomedical's NeuRx diaphragm pacing system, introduced in 2007, hopes to help keep people breathing by conditioning the respiratory muscles.

Many of these potential medicines are being tested in the clinic today.  Learn more about them by clicking on our interactive timeline.

Images:  Courtesy of Children's Hospital of Philadelphia, Montreal Neurological Institute, National Institute of Neurological Disorders and Stroke, Paul Derry, Rockefeller University Press, Wikimedia Commons.

Patient Resources

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

A Study of Creatine Monohydrate in Patients With ALS  Contact   |   ALS TDI    |    Website

A Phase 3 Study of MCI-186 for Treatment of ALS    ALS TDI    |    Website

A Phase II/III Randomized, Placebo-controlled Trial of Arimoclomol in SOD1 Positive FALS  Contact   |   ALS TDI    |    Website

A Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of ALS   ALS TDI    |    Website

A Study of Safety, Tolerability & Efficacy of CK-2017357 in ALS   ALS TDI    |    Website

A Study of Rasagiline in Patients With ALS   Contact   |   ALS TDI    |    Website

SOD1 Inhibition by Pyrimethamine in Familial ALS    Contact  |   ALS TDI   |   Website

A Trial of Safety and Efficacy of Rasagiline in Patients With ALS   Contact   |   ALS TDI    |    Website

Safety and Tolerability of Anakinra in Combination With Riluzol in ALS  Contact   |   ALS TDI    |    Website

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

A Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in ALS    ALS TDI    |    Website

Dose Escalation and Safety Study of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis    Contact   |   ALS TDI    |    Website

An Evaluation of masitinib in ALS   Contact   |   ALS TDI    |    Website

Mexiletine in Sporadic ALS   Contact   |   ALS TDI    |    Website

Mexiletine for the Treatment of Muscle Cramps in ALS Contact   |   ALS TDI    |    Website

Gilenya in Amyotrophic Lateral Sclerosis   Contact   |   ALS TDI    |    Website     

A Study to Explore the Safety and Tolerability of Acthar in Patients With ALS  Contact   |   ALS TDI    |    Website   

A GM604 Phase 2A Randomized Double-blind Placebo Controlled Pilot Trial in ALS  Contact   |   ALS TDI    |    Website   

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Taming the Charley Horse

clock March 14, 2013

mexiletine muscle cramps ALS


Muscles cramping your style? A group of US neuromuscular disease specialists are evaluating mexiletine as a potential treatment option for muscle cramps. Image: Pacific Northwest Health & Safety Center, University of Washington.

More than 50% of people with ALS experience pain. Their discomfort, however, is underreported, undertreated and often ignored by health teams.  Few pain relievers except Advil® and Aleve® are typically prescribed to people with ALS – particularly at early stages of the disease.

No pain medication is considered standard clinical practice for people with ALS. 

A growing number of neurologists are working hard to identify more effective pain relievers in hopes to improve the quality of life of their ALS patients.  One such medicine, mexiletine, is emerging as potential treatment option for muscle cramps – a key cause of physical discomfort in people with the disease.

A phase IV clinical trial is scheduled to begin in April 2013.

“We know the drug. It’s pretty safe and available,” explains University of California-Davis (UCD) School of Medicine‘s Bjorn Oskarsson MD, principle investigator of the study.  “And, we don’t have a good alternative today.”

For decades, people with a number of neurological and neuromuscular diseases reached for quinine (the key ingredient in tonic water) – particularly before going to bed. But these tablets are no longer recommended by the FDA for routine use due to concerns of potentially fatal blood and heart complications.

In recent years, University of California-Davis School of Medicine's Bjorn Oskarsson MD turned to mexiletine as a potential alternative to treat muscle cramps in people with ALS. The drug quiets down overactive neuronal sodium channels – the prime suspect behind cramps in people with the disease.


Symptoms reducer? A growing number of medicines are being explored to improve the quality of life for people with ALS.

Mexiletine is one of growing number of medicines that aims to improve quality of life for people with ALS.

“If we can find treatments to help with the symptoms,” says University of Missouri School of Medicine’s Richard Barohn MD, “I think that’s a great thing.”

Now, US physicians are gearing up to put mexiletine to the test in people with ALS. The phase IV randomized placebo-controlled study is to take place in California. Participating Pacific ALS Consortium (PAC-10) sites include University of California Davis School of Medicine in Sacramento. 30 people with ALS are expected to participate.

The clinical trial is 1 of 2 studies in the US that aims to determine whether the FDA-approved heart medicine can relieve muscle cramps in people with ALS.

"We have a really good safety profile regarding this medicine," says neuromuscular disease specialist Michael Weiss MD, principal investigator of the concurrent Northeast ALS Consortium clinical trial.

Mexiletine is 1 of at least 5 existing medicines being evaluated to relieve key symptoms of the disease. “We’re not curing ALS,” says Oskarsson.  “This is the kind of treatment that might help people live better with their ALS.”

To learn more about mexiletine and its potential benefits for people with ALS, check out our interactive feature Mexiletine: channeling ALS?

Patient Resources

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

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


Rivera, I., Ajroud-Driss, S., Casey, P., Heller, S., Allen, J., Siddique, T. and Sufit, R. (2013) Prevalence and characteristics of pain in early and late stages of ALS.  Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Journal doi:10.3109/21678421.2012.751614.  Abstract  |  Full Text (Subscription Required)

Chiò, A., Canosa, A., Gallo, S., Moglia, C., Ilardi, A., Cammarosano, S., Papurello, D. and Calvo, A (2012) Pain in amyotrophic lateral sclerosis: a population-based controlled study. European Journal of Neurology 19(4),  551-555.  Abstract  | Full Text (Subscription Required)

Baldinger, R., Katzberg, H.D. and Weber M (2012) Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease.  Cochrane Database of Systematic Reviews, doi: 10.1002/14651858.CD004157.pub2.  Abstract  |  Full Text (Subscription Required)

Brettschneider, J., Kurent, J., Ludolph, A. and Mitchell, J.D. (2010) Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews, doi: 10.1002/14651858.CD005226.pub2.  Abstract  |  Full Text (Subscription Required)

Further Reading

Handy CR, Krudy C, Boulis N, Federici T. (2011) Pain in amyotrophic lateral sclerosis: a neglected aspect of disease.  Neurology Research International 2011, 403808.  Abstract  |  Full Text



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