Categories: General

FDA Releases Statement about ALS and GM604

Posted by author Jessica Sullivan

clock April 17, 2015

The following statement was released by the FDA today.


Amyotrophic Lateral Sclerosis (ALS) Statement

FDA recognizes the critical unmet medical need for new, effective treatments for amyotrophic lateral sclerosis (ALS). We are committed to working with drug companies and the ALS community to facilitate development and approval of drugs to treat this devastating disease. FDA is prepared to use all expedited development and approval pathways available to us to further this mutual goal.

FDA knows that ALS patients, their families, and others in the ALS community are concerned about the status of Genervon’s experimental drug, GM604, for the treatment of ALS. However, FDA is prohibited by law, under usual circumstances, from releasing confidential information about experimental drugs, including GM604.

We call upon Genervon to release all the data from their recently completed trial in order to allow a more informed discussion of the trial findings among ALS stakeholders. Such a release should include the pre-specified clinical outcome measures as assessed by change from baseline observations that were taken just prior to randomization to drug or placebo. Such data provide the strongest basis to assess for drug-related changes in efficacy and safety parameters.

FDA will continue to provide detailed advice and support to Genervon as they pursue further study of GM604 to determine if it is safe and effective to treat ALS. We remain committed to working with the ALS community to find effective treatments for this disease.

Helpful Links:

Statement on the FDA's website: Statement on Genervon:

CEO Steve Perrin's Personal Blog, GM604: Is It Ready for FDA Approval?

Washington Post "ALS patients press FDA for quick access to controversial biotech drug" 

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Categories: Featured

100th Patient Enrolled in World's First Precision Medicine Program for ALS

Posted by author Jessica Sullivan

clock April 14, 2015

The ALS Therapy Development Institute announced today that it has enrolled the 100th patient in its Precision Medicine Program (PMP).  This milestone marks a significant step in the program, which after today includes over 500 people interested in participating and 280 prescreened for enrollment.  Nearly 200 additional people living with ALS (PALS) or healthy volunteers have been scheduled for participation before the end of the year. This program is the first of its kind to be created for ALS and includes multiple aspects unique to the field of precision medicine specifically aimed to discover and develop treatments for ALS.

The Institute is providing all participants with access to the data via a secure online portal, where they can monitor their health status by viewing changes in motion tracker and speech recording data, and track the data generated from the biological samples. Data obtained by the Precision Medicine Program will be instrumental for identification of the subtypes of ALS, as well as for the discovery and clinical development of therapies for ALS.

“Each of the people enrolled in this program are true trailblazers in my opinion. Their effort through the Precision Medicine Program adds in a huge way to our already hyper-focused and data-driven efforts to develop ALS treatments. The patients and volunteers in the Precision Medicine Program are standing right there on the edge of scientific discovery together with us at the Institute as we share the goal of urgently finding ways to get at this disease in a meaningful way,” said Steve Perrin, Ph.D., Chief Executive and Scientific Officer of the ALS Therapy Development Institute.

The Institute began planning its Precision Medicine Program in 2013, and announced a call for volunteers this past summer. The Institute’s enrollment was boosted by the social media phenomenon, the ALS Ice Bucket Challenge.  Nearly $4 million was donated directly to the Institute, and every dollar was assigned directly to ALS research, including $1 million to the Precision Medicine Program, allowing it to expand enrollment from 25 to 300 people.

The Institute is currently working to expand the program further to include more patients and volunteers, and expects to make additional announcements regarding that in the coming months.

For more information on the 100th patient, Greta Mae Hart (see photo) and others in the Precision Medicine Program, please visit

About The Precision Medicine Program at the ALS Therapy Development Institute

Precision medicine is an emerging field of biomedical research that aims to leverage patients’ genomic and other molecular or cellular data together with their clinical information to more rapidly identify potential therapies. The Institute’s Precision Medicine Program seeks to gain critical new insight into the mechanisms of ALS through integrative analysis of each participating patient’s genetic data, obtained by full genome sequencing, and their clinical data including a combination of monthly self-reporting questionnaires, motion tracking, and voice recordings. This information will be linked to data obtained by analyzing patient-derived cells that are differentiated from induced pluripotent stem cells (iPSC). These patient-derived cells will facilitate identification and development of better-focused ALS drug discovery screens.

About the ALS Therapy Development Institute

The ALS Therapy Development Institute ( and its scientists actively discover and develop treatments for ALS.  The Institute is the world’s first and largest nonprofit biotech focused 100 percent on ALS research. Led by ALS patients and their families, the charity understands the urgent need to slow and stop this horrible disease.  The ALS Therapy Development Institute, based in Cambridge, MA, has served as one of the leaders in sharing data and information with academic and ALS research organizations, patients and their families. For more information, visit

Media Contact: Mari Cody, ALS Therapy Development Institute, 617-441-7220,

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Categories: Featured , Roundtable

25th Annual Symposium on ALS/MND Research: Day 2

Posted by author Jessica Sullivan

clock January 14, 2015

The second day of the International ALS/MND Research Symposium started off with a talk from Kevin Eggan of Harvard University (pictured). For many, Dr. Eggan is recognized as the first person to create an induced pluripotent stem cell line from a person diagnosed with ALS (the technology and process to create iPS cells was invented previously by Shinya Yamanaka, M.D., Ph.D. of Kyoto University in 2006).  Dr. Eggan’s talk dove deep into asking whether or not these type of stem cells were living up to their potential as drug development tools, and he provided some interesting results from his analysis of the field to date.

According to Dr. Eggan, his lab can coax mature adult fibroblasts to revert to a state of pluripotency using the Yamanaka factors, inserting into the nucleus of those cells several genes which induce their revision into stem cells.  One of the challenges with this method is that these genes randomly insert themselves into the genome of the cell and remain there in perpetuity. However, the cells do become stem cell like.  Newer methods to induce to revert to a stem cell state are being used by other labs, including ALS TDI, which don’t rely on random gene insertion approach. Regardless, the Eggan lab differentiated its iPS cells into motor neurons over a period of 24 days on average, creating a disease-relevant cell line to study. Before subjecting this cell line to experiments, the team spends about 30 days confirming its status and stability.

Of interest to the Eggan lab was to look at whether or not there were differences in the way electrical currents traveled across the ALS motor neurons.  They used sophisticated technology to shoot a current across several different lines created from PALS with different ALS-associated gene mutations, including SOD1.  Interestingly, they found that the SOD1 A4V lines had the greatest number of action potential spikes (a way to measure the amount/speed at which neurons communicate with surrounding cells, such as other neurons or astrocytes) of all the lines they looked at, suggesting that perhaps different forms of familial ALS may have specific cellular phenotypes, which could help explain the different trajectories of disease and be used in drug development experiments.

Speaking of drug development, the Eggan Lab earlier in 2014 announced that it had taken this information on action potential and begun to screen potential drugs which may modify its expression or amplification back to what is seen in non-ALS cell lines. One such drug screened, retigabine, showed the greatest benefit in the lab’s cell based screen.

Retigabine (pictured) is thought to open potassium acid channels and correct the sodium channel regulation in motor neurons.  It is an FDA approved compound for the treatment of certain forms of epilepsy and, together with the Northeast ALS  Consortium, a 120 person clinical trial is being planned at 12 NEALS sites.  Enrolled participants will have the opportunity to be placed into either the treatment group (which will include two different dosing groups) or a placebo control group. No date was given for when patient screenings will begin, site locations, or when exclusion criteria will be available for this trial.  When the trial does begin, it will be the first trial to be launched on the basis of information gathered from iPS lines only in ALS.  It is not known whether iPS cell lines are “better” tools for drug screening than more common models including fruit flies, mice, and other animals. However, this trial will provide an opportunity to begin to answer that question for the first time, at least in ALS research.

There were several other speakers during this first session of the day which focused on in vitro modeling. Two such talks were given regarding the characterization of iPS cells created from C9orf72 patient samples. Roxanne Mutihac, Ph.D. of the Nuffield Department of Clinical Neurosciences at the University of Oxford (pictured), provided data from her research on two C9orf72 iPSc lines she created. In one of her lines, she reported that it maintained a total of 1380 hexanucleotide repeats and in the other, 510 were maintained through the reprogramming process. After confirming that the expansion was stable, she began studying the cells and found a key hallmark of C9orf72 pathology- the presence of toxic RNA foci within the cells. Other interesting findings reported included the phenomenon of high levels of calcium in C9orf72 motor neurons versus cortical neurons, which may suggest a unique trait for further study. Finally, it is worth noting that in the age of oligogenetics in ALS, TDP43 proteins mislocalized in the C9orf72 iPSc lines created in Mutihac’s lab.    

ALS in China, the US Military and Head Injury

An entire session at this year’s International Symposium was devoted to the epidemiology of ALS. It included important reports on the landscape of ALS in China, new data on military incidence of ALS from the US, and a conversation on whether head injuries (ie: concussions) alter the progression of ALS.

China is the world’s most populous country with more than 1.3 billion people. It is an immensely diverse demographic, and results reported at this year’s meeting from Liying Cui, Ph.D. of the Peking Union Medical College in Beijing, suggest that the population of PALS in China may be very different from that found in other nations across the globe. According to Cui, 95% of ALS cases in China are sporadic, and the ALS-associated genes found in Chinese PALS are very different from those found in western countries. However, there are some similar characteristics. The mean age of onset of ALS in China is about 52 years of age in PALS, and the time from symptom onset to diagnosis is generally about 13 months- statistics not wholly unlike what we see in many other countries.

Recently, Cui and her colleagues in 10 different research hospitals created an ALS registry, recruiting and documenting 461 PALS from across China.  According to China ALS Registry data, only 29% of PALS take rilutek versus 39% which opt for traditional herbs to treat the disease. In a separate study of 680 PALS, Cui reported on the site of onset and spread of disease in Chinese PALS.  More than half of all PALS in the study were found to have their first symptoms in upper limbs generally (cervical), with another 1 in 5 cases experiencing the first symptoms in either bulbar or lumbar regions.  According to this new study, 85% of PALS developed symptoms in the upper and lower motor neurons, with 10% lower motor neuron only. The mean survival of PALS in this study was 34 months with bulbar onset ALS (PALS survive only 12 months on average in China). As seen and reported in other epidemiological studies of ALS, Cui suggested that the data confirmed that the number of regions of the spinal cord involved in the first three months of disease onset seem to correlate with the overall pace of the disease.

For many years, ALS was not thought to be related to dementia. However, more recent studies have now shown different cognitive and executive dysfunctions in PALS.  In the US, it is now thought that at least 10% of PALS develop frontotemporal dementia in addition to the progressive neurodegenerative disease. However, according to Cui’s research, the percentage of ALS/FTD in China is only 2% overall. Similarly, it seems ALS-associated genes in China vary greatly from those found in western nations. Less than 1% of FALS cases in China are carriers of the C9orf72 expansion, according to Cui.  More commonly found are SOD1 (26%), TDP43 (5.6%), and FUS (12%).

It is a commonly cited fact in the US that deployed military service members have a greater chance of developing ALS than the civilian population. However, little additional data has been reported since the original work was presented more than a decade ago. Marc Weisskopf, PhD, ScD (pictured) of the School of Public Health at Harvard University provided his analysis of the National Longitudinal Mortality Study, a sampling of households within the US.  In this data, he identified 800 ALS deaths, including 221 military service members through 2002. Nearly two thirds of these PALS served in the Second World War (WWII), with the others serving in the Korean, Vietnam, or other wars except World War I.  Weisskopf’s review of the Mortality Study found there were different rates of ALS within the military over time, with WWII veterans developing ALS at a great rate when compared to veterans from Korea or Vietnam.  He suggests there may be other deployment-related linkages which need to be explored.

Before moving on to head injury and ALS, it is worth noting an important talk from Daniela Mariosa, a Ph.D. student at the Karolinska Institute in Stockholm, Sweden. Mariosa’s research concerned diabetes as a risk factor in the development of ALS, which was originally suggested in a paper from Martin Turner, M.D., Ph.D. last year. Mariosa decided to look at the 1990 Swedish census, in which she identified 5108 newly diagnosed ALS cases. Controlling nearly 5:1 with non-ALS cases in the census, Mariosa found that an insulin-dependent diabetes diagnosis before age 30 increased the likelihood of developing ALS.

There has been great attention paid to the topic of head injury in the US as of late, with the National Football League (NFL) recently settling a class-action lawsuit of former players claiming the injuries they suffered while playing caused them to develop several different neurodegenerative diseases, including ALS. An original research study done by Everett Lehman at the National Institute of Occupational Safety and Health found a greater incidence rate of neurodegeneration in former NFL players as compared to the general population, a summary of which was provided via webinar by the ALS Therapy Development Institute in 2012. Notable former NFL players diagnosed with ALS include Philadelphia Eagles fullback Kevin Turner (Kevin Turner Foundation), New Orleans Saint’s hero Stephen Gleason (Team Gleason) and journey-man linebacker Tim Shaw (pictured, @TShawsTruth). Despite the evidence of some kind of correlation between ALS and the NFL, Lehman and most others have been careful to clearly state their studies are not intended to measure if concussions or other type of injuries play a direct role in ALS onset.

Instead, the goal of their studies was to explore if head injuries affect the progression rate of the disease. Christina Fournier, M.D., an instructor at Emory University, reported on her research into this question. She presented data suggesting no correlation between a head injury (which she defined as causing the loss of consciousness or hospitalization) and the progression rate of ALS.  Using data from Emory University, she found 24 PALS which met her criteria for head injury and compared them to 76 cases which didn’t. Fournier also looked at autopsy samples from PALS with and without head injury, and found no major differences in the frequency of proteinopathies in TDP-43, Tau, and others. In summary, more research is needed before a definitive connection between head injury and ALS can be identified.

Neurofilaments as ALS Biomarker

One of the greatest challenges in ALS drug development is the lack of biomarkers to predict disease progression. Biomarkers are typically defined as a measureable indicator of the presence or severity of a disease in patients.  Most of the time, ALS progression is measured using a patient-reported and rather subjective scale known as the revised ALS Function Rating Scale, a questionnaire used by clinicians to note changes in a PALS’ ability to move, eat, or breathe independently. Earlier in 2014, the ALS Therapy Development Institute called together more than 30 scientists for a biomarker research meeting, co-hosted with The ALS Association and NINDS, to discuss the latest data- some of which was later presented at the International Symposium in December.

According to Robert Bowser, Ph.D. (pictured), one of the foremost leaders in biomarker research in ALS, there is a huge gap between the discovery and validation of biomarkers. A review of the published work in this field conducted by Bowser showed there have been more than 20,000 publications on potential biomarkers in neurodegenerative disorders such as ALS. However, only 318 of those publications specifically aimed to validate a proposed biomarker.  This important gap highlights the difference between basic, observational research and the application of those observations in a drug development or clinical setting.

At this year’s International Symposium, a special session on biomarkers focused on the changes in the presence of neurofilaments in PALS overtime as a valid biomarker of disease progression. Filaments play a major role in the structural health of cells, and a specific class of them known as neurofilaments can be found in motor neurons. As any cell degenerates, its shape, size, and overall structure (cytoskeleton) changes.  Neurofilaments have been looked at in ALS as a potential way to measure the overall health of motor neurons for many years; however since they are primarily found in cells within the spinal cord, assessing neurofilament levels is both costly and difficult. 

Two of the presenters during the biomarker session speaking on neurofilaments in ALS, Martin Turner, Ph.D. of Oxford and Andrea Malaspina, M.D., Ph.D., decided to skip protocol and to present back-to-back and then to take questions together from the audience. Similar in topic, the data they would be presenting resulted from a collaborative effort on their parts.

Malaspina began with an overview of neurofilaments and review of previous research. Neurofilament auto-antibodies increase as ALS progresses and the neurons degenerate.  However, there are many different forms of neurofilament chains. Typically, they are separated based on weight into three different categories or subunits: light, medium, and heavy. The loss of neurofilaments is not unique to ALS, and decreases have been associated with all sorts of disorders of the spinal cord which are associated with degeneration or damage to motor neurons, including spinal cord injuries. According to Malaspina’s research, ALS stands out- at least when it comes to the light subunit of neurofilament (NfL). In his research on plasma and cerebrospinal fluid (CSF) samples, he discovered a correlation between the increase and decrease in the level of NfL present.  This may be an important finding as blood samples are easier to collect and analyze than CSF; both for the patient as well as the researcher.

The collaborative group has been collecting samples and tracking a group of patients for more than three years now. The data suggests that changes in NfL levels measured in the blood do match up to those found in CSF as the disease progresses. Further, Malaspina and team suggest that high blood NfL levels may correlate with survival time with ALS; meaning that the higher the levels, the longer the survival.

Turner followed Malaspina with additional research from the collaborative, which used magnetic resonance imaging (MRI) technology to attempt to corroborate this data. Looking at the white matter in PALS’ brains, Turner and his team determined the fractional anisotrophy in the corticospinal tract, and found that it correlates with disease progression- further suggesting that NfL levels may be a useful biomarker in ALS.

Following the tag-team event, Bowser took to the podium and offered a different view of neurofilament measurement in ALS.  His teams at both the Barrows Institute and his spin-off Iron Horse Diagnostics have been seeking to validate earlier published work suggesting that neurofilament heavy chain (NfH) may be a more appropriate biomarker for ALS, specifically as a diagnostic tool. Bowser has been developing an assay, or test, to measure the presence of NfH in biological samples with the idea that it could be used to speed up the diagnostic process.  On average it takes more than a year to diagnose ALS, generally because it is a process of excluding all other possible disorders.  This presents a major problem for patients, their attending medical teams, as well as researchers seeking to develop treatments; by the time a person is diagnosed, their disease has progressed significantly.

To attempt to address this issue, Bowser conducted, in partnership with NEALS, a prospective validation study of 126 CSF and 204 plasma samples from 23 different states or provinces in US and Canada.  The samples were sent blind to Bowser’s lab, and his team applied their assay to measure the level of NfH in the sample to determine if it was from a PALS or a healthy volunteer.  His team failed to identify only four PALS in the CSF samples (92% specificity) with slightly lower efficacy in the plasma samples. Bowser and his team are focused on improving the assay and have already created a modified version which has greater specificity, especially in identifying NfH levels in plasma.  However, in closing, and during questioning, he suggested that the test isn’t ready for primetime use in the clinic, and that further work needs to be done to take it from an “academic adventure to industry standards.”

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Categories: Meeting Report

25th Annual Symposium on ALS/MND Research: Day 1

Posted by author Jessica Sullivan

clock December 8, 2014

ALS Clinical Trials: What’s Wrong? And updates on NP001, sNN0029, Tirasemtiv and PreFALS

The International Symposium on ALS/MND Research is the preeminent meeting of the global ALS/MND community. It brings together hundreds of neuroscientists, neurologists, and associated health professionals for three days in a different country each year. 

Founded and operated by the MND Association, the 2014 meeting was the 25th annual installment and was held at the Square in the city of Brussels, Belgium, and hosted locally by the ALS Liga Belgie.  It was estimated that approximately 900 people attended the conference.  The meeting is typically split into two simultaneous tracks; one on basic science and the other spanning the issues and developments in clinical trials and related clinical topics, such as respiratory and palliative care topics. Several satellite meetings and poster sessions are also held.

This summary spans some of the talks offered.  Since many of the presentations made were pre-publication, presenters were asked to indicate whether or not outside reporting could be done on their talks.  Happily, most were offered without embargo.

What’s Wrong with ALS Clinical Research?

It is estimated by most that there are at least 400,000 people living with ALS/MND worldwide.  However, there are no currently effective treatments available. This reality inspired the opening plenary talk, from Alfred Sandrock, M.D., Ph.D., Chief Medical Officer at Biogen Idec.  He offered his expert opinion on drug development based on his experience as both a clinician and a scientist. Sandrock summarized that the biggest issues in ALS drug development are the lack of robustly predictive disease models, coupled with the inability to do well designed phase 1 and 2 clinical trials. He reviewed the work on dexpramipexole briefly and referenced a paper from Sean Scott of the ALS Therapy Development Institute which suggested that drugs screened in the SOD1 mouse model have failed to translate to the clinic due to poor preclinical design and the limitation of that model to recapitulate the relevant biology of many of the drugs screened in it to date.  On animal model development and use, Sandrock suggested to the audience that it was paramount to use animal models as tools to investigate specific disease biology and that no model is a perfect model of all aspects of ALS disease onset or progression.

In offering a path forward, Sandrock offered the audience an alternative approach, which may accelerate ALS drug development in certain cases.  This “Approach 2” as he termed it, would use human induced pluripotent stem cells as a basic model of disease, measuring specific genetic and biology to screen potential therapeutics.  As these cells are characterized, they could be used for drug screening directly.  He emphasized, however, the crucial role of developing a dosing strategy and relevant biomarkers and pharmacodynamics for compounds.  These two steps are where different animal models may be able to help greatly, according to Sandrock.

”We really need to look at surrogate endpoints before efficacy screening in people,” said Sandrock in hammering this point home.  One of the more direct recommendations that he offered to the trial designers and operators in the crowd was to do early stage trials correctly, which he suggested meant more than 100 people in each arm and including a placebo controlled arm of a trial.

PreFALS and the 29 Month Journey to Getting into Clinical Trials

Michael Benatar, MD, PhD, of the Miller School of Medicine at the University of Miami (USA), provided the opening talk of this session, in which he reviewed the extensive data from the PreFALS study which he and his collaborators have been conducting for the last several years. Before getting into specific FALS related data, Benatar commented about a significant problem in ALS: a delay in diagnosis and enrolling PALS into clinical research programs.  According to Benatar’s research, it takes on average 12 months to diagnosis a person from the onset of their symptoms, and an additional 17 months from there to successfully enroll that person into a clinical research program.  This delay can cause challenges for drug development.  However, in the PreFALS study, those diagnosed with ALS saw a much quicker enrollment path into clinical research: less than 5 months following their diagnosis on average, according to Benatar.

“On average, general practitioners see one or two cases of ALS during their career.  I don’t think we want to get the word out that every fasciculation should lead to a diagnosis,” said Benatar.  Specific efforts have been set up to attempt to address the diagnosis delay in PALS, including the identification of Red Flags, which can be distributed to general practitioners.  For example, the Red Flags identified and being distributed by the MND Association to general practitioners in the United Kingdom.

All told there have been 226 people screened for the PreFALS study, with 85 enrolled and providing a total of 227 “people years” of data currently. The idea is to enroll people that are asymptomatic for ALS in the study and to identify triggers of the disease by following them for a significant amount of time.  Benatar reported that seven people in the program have “phenoconverted”, meaning that they developed clinical symptoms of ALS/MND. A series of clinical visits and tests are included in the PreFALS study and 2 case studies of phenolconverters were provided for this presentation. The first, a 57 year old female with the SOD1A4V mutation presented with measurable denervation in laboratory tests six weeks prior to presenting symptoms of the disease. Her disease course lasted about 14 months from diagnosis. Denervation was also measured in the second phenoconverter, a 52 year old female, 28 weeks before her symptoms developed. That person had the SOD1-1113T mutation and survived almost 19 months from her diagnosis. The PreFALS data suggests that “disease progression is gradual early on and speeds up later on”, according to Benatar.  However, a recent paper of the PRO-ACT database, first discussed by Sandrock in the opening plenary, showed the first three months of disease progression can predict overall speed of the disease course; meaning that a quick disease onset will likely equate to a more rapidly progressing disease and vice versa for slower onset and progression rate.

VEGF Safe and Tolerable in Early Clinical Trial in Belgium

Philip Van Damme, PhD, of the University of Leuven (Belgium) reported the outcomes from a Phase 1 study of a vascular endothelial growth factor (VEGF) clinical study.  VEGF is thought to play a role in the health of motor neurons, and the company NeuroNova began a clinical trial of their VEGF compound sNN0029 to in 2008.  Earlier preclinical studies were conducted in SOD1 rats and in SOD1 mice, both quite small. But they produced modest improvements in survival overall, which provided the company information to launch their clinical research efforts. 

The clinical trial of sNN0029 included three different doses of the compound as well as placebo arm.  This multi-arm clinical trial is now completed.  In total, there were 19 PALS enrolled in the study, which included two different cohorts; one placebo control (N=10) and the other not (N=8).  In the placebo controlled cohort, four PALS received the high dose (2ug/day) and three received a lower dose (0.8 ug/day), and were compared to three additional PALS given a placebo.  The other cohort looked at a lower dose as well (0.2 ug/day) in 2 PALS, 2 at the middle dose and 4 at the high dose.  Van Damme was clear to the audience that the study was in no way powered to measure efficacy, but that the data suggested clearly that sNN0029 was safe and tolerated in all PALS in the trial.

It is interesting to note that 66% of the trial’s participants were male, and on average the onset age of enrolled PALS was 48 years old.  During the post-presentation discussion, audience members asked Van Damme if he thought that a higher dose of VEGF would be tolerable, which he responded he thought perhaps but that any follow up trial would likely use the doses informed on in the early trial.  A timeline for additional clinical research efforts on sNN0029 was not provided, however Van Damme said that he expects a follow-up will occur when asked casually later in the meeting hall.

LPS Levels May Dictate NP001 Trial Enrollment Going Forward

The compound known as NP001 has been in the news of ALS clinical research for several years now, following the completion of both Phase 1 and Phase 2 clinical research studies on the compound. Presenting updated analysis of the trial data was Michael McGrath, MD, PhD, co-founder of Neuraltus, the virtual biotechnology company which is conducting research of the compound in several different diseases, including ALS.  NP001 (sodium chlorite) targets activated macrophages.  It is now widely accepted that the immune system in ALS patients is highly active, causing several things to go awry in the body as a result of increased inflammation.

“It is highly purified sodium chlorite,” said McGrath in outlining what NP001 is for the audience to begin his talk. Chlorite is a pro-drug that gets converted inside the body, and is being pursued for its ability to down regulate certain aspects of the innate immune system, specifically macrophage that are activated in ALS.  The study included as many as 136 PALS overall, with smaller groups in each category; including a placebo arm and both high and low doses. According to McGrath and team’s analysis of the data, 10% of placebo PALS in the study did not progress at all during the clinical trial, whereas 19% of those on the low dose remained stable, and 27% of those which tolerated and completed the high-dose arm remained unchanged in ALSFRS-R measures. It was a small study and not powered to measure efficacy. However, encouraging data was offered by McGrath related to the target of NP001, activated macrophages.

The amount of these cells present in the blood stream can be measured using a variety of markers, including lipopolysaccharides (LPS).  McGrath reported that PALS in the study with higher levels of LPS reacted more positively to treatment with NP001.  While the numbers of PALS which fell into this category was admittedly small, it could provide a clinical enrollment criteria going into larger and perhaps pivotal clinical trials of NP001, suggested McGrath.

When asked during the follow-up session is he would only enroll PALS with high levels of LPS in these potential future studies, McGrath said that it is something that his scientific advisory board and he are discussing as a reality. It is important to note that no timeline for a follow up clinical trial of this compound was reported at the meeting, however during casual conversations there are talks going on to fund these follow up studies and more information is expected within the next year.

Slow Vital Capacity on Fast Track as Primary Endpoint for Tirasemtiv?

Several other presentations were made during the session, including an overview of the latest data of the tirasemtiv Phase 2 clinical trial. In ALS, the motor axon separates from the muscle, causing the muscle to lose its ability to contract voluntarily. Overtime as the axons separate (a process known as “denervation”) from individual muscles (there are many connections per muscle), the muscle will atrophy.  Tirasemtiv is a fast skeletal muscle troponin activator and, in essence, amplifies the force of the muscle contraction. 

As has been reported in the past, that compound failed to reach statistically significant outcomes on its primary endpoint, ALSFRS-R.  However, the drug’s effect on the clinical measure of slow vital capacity (SVC) was interesting and Cytokinetics is making the case to pursue SVC as a potential primary endpoint in future studies. 

Jinsey Andrews, M.D., provided the overview during the session, in which it was reported that SVC improvement was statistically significant at each time point in the trial (a week 5, 10, and 15).  This was most interesting as the final time point was post-drug, suggesting that tirasemtiv may have had a lasting effect. Andrews suggested that SVC may be a more sensitive measure to the effects of tirasemtiv, because troponins may be better at augmenting muscle contractibility in submaximal ways.  

Additional reports will be provided from the Research Symposia.  However, a review of the meetings official hashtag, #alssymp, is suggested.  An overview of social media at the conference is provided here and compiled by SymPlur.

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Categories: In The Pipeline

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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