The ALS Association

Orlando Symposium Presents Trial Results, Genetic Testing Guidelines and Basic Science Advances

December 11-13, 2015

The 26th International Symposium on ALS/Motor Neuron Disease brought together approximately 800 clinicians, scientists, and others searching for a cure for ALS in a three day meeting in Orlando, Florida, to present research, network, and form new collaborations in the hunt for new ALS treatments. The meeting was organized by the Motor Neuron Disease Association (MNDA), United Kingdom and hosted by The ALS Association. Association President & CEO Barbara Newhouse greeted attendees by saying, “I hope that together we are able to find treatments that can change ALS to a chronic condition, and ultimately to a curable disease.”

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

The meeting featured hundreds of poster presentations and dozens of platform speakers, on topics ranging from basic science inquiries into disease mechanisms to results of the latest clinical trials. Highlights from the meeting are summarized below. Posters and abstracts of presentations are archived at the MNDA site.

Contents:
Clinical Trials and Symptom Assessment
Trial Development and Biomarkers
Genetic Testing
Basic Science Developments
Presentations by Current and Former Milton Safenowitz Fellows
Concluding Session

 Clinical Trials and Symptom Assessment

Nuedexta is Promising for Speech and Swallowing

Nuedexta may improve speaking and swallowing in people with ALS, regardless of whether they have pseudobulbar affect. Nuedexta is an FDA-approved treatment for pseudobulbar affect (inappropriate laughing or crying), which some people living with ALS develop. It is a combination of dextromethorphan and quinidine. The quinidine inhibits a liver enzyme that would otherwise rapidly break down the dextromethorphan in most patients.

Dr. Richard Smith presented results of a trial, supported by The ALS Association, which enrolled 60 patients with bulbar (speech and swallowing) symptoms, only half of whom had pseudobulbar affect. They received treatment for 30 days with drug or placebo, followed by a 10-15 day washout period (a time allowed for all administered drug to be eliminated from the body) and then crossed over to the other treatment arm.

The main outcome was a patient-centered scale, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS), which asks patients to rate their function on several subscales of speech, swallowing and sialorrhea (excess saliva). The scale has high sensitivity and specificity for this application.

Treatment had a large and highly statistically significant effect on the three subscales and on the scale as a whole. It also led to a smaller but still significant effect on the ALS Function Rating Scale Revised (ALSFRS-R), the standard scale utilized to evaluate the impact of ALS on activities of daily living. Emotional lability was also improved in those with pseudobulbar affect.

About 27% of patients were non-responders. Genotyping has not yet been done on the group to try to understand the differential response. Dizziness occurred in 7 patients on drug, versus 1 on placebo. Nausea was seen in 4 patients on the drug vs. 0 in placebo.

"Treatment resulted in robust enhancement of speech and swallowing, independent of pseudobulbar affect," Dr. Smith said.

Whether people with ALS would continue to benefit from treatment beyond the month demonstrated in the trial has not been tested, Dr. Smith said, although he reported his experience with one patient who was treated long-term and continued to benefit until death.

Mixed Results, and Concern, with Diaphragm Pacing

Results were presented from two trials of the diaphragm pacing system (DPS), the treatment in which electrodes are implanted into the diaphragm to support the main muscle of breathing with electrical stimulation. From a Food and Drug Administration (FDA) post-approval, multi-center trial in the United States, Dr. Robert Miller presented data showing efficacy and safety that was consistent with the data reviewed by the FDA when it approved the treatment. However, in a trial from the United Kingdom, Dr. Christopher McDermott presented data indicating that those who received DPS had shorter survival than those who did not. Researchers are puzzled by the inconsistency and plan to analyze both trials in more detail to determine the reason for the discrepancy.

Dr. Miller’s trial enrolled 60 people with ALS, 70% of whom were using non-invasive ventilation (NIV), 27% a cough-assist device, and 15% a PEG feeding tube. Based on breathing strength criteria, 54 of the 60 were implanted with the DPS device. Twenty-four individuals had died at the time of the report, with a median survival of 21 months. Overall survival was better than that seen in two control groups from two different ALS treatment trials, suggesting that treatment with DPS had improved survival compared to no treatment.

Dr. McDermott’s trial, called DiPALS, randomized 74 people with ALS to DPS plus NIV or NIV alone. Mean survival was 11.1 months in the group receiving diaphragm pacing, versus 22.8 months in the control group. The effect was not due to morbidity from surgery, which was safe and well tolerated. The study was stopped early by a data safety monitoring committee as data accumulated showed that survival of treated patients was less than that of the untreated control group. The results were echoed by a French study that also reported harm from the treatment, Dr. McDermott said, and which was also stopped early. Researchers at the session discussed possible differences between the studies presented that may account for the differences in survival, but there was little consensus about what those factors might be. Further analysis of the data from the trial, including differences between the individuals enrolled, may bring some clarity to this unanswered question.

Electron Beam Radiation Therapy for Excess Saliva

Electron beam radiation therapy (EBRT) is safe and effective for excessive saliva production, according to a study of 36 patients with sialorrhea, presented by Dr. Edward Kasarskis. EBRT is distinct from X-ray radiation. It is widely considered safe for the precise destruction of very small regions of tissue. The target here was the parotid glands, where most of the saliva is produced.

Treated patients had reduced saliva production that had a positive impact on daily living. The effect was long lasting, for at least 2 years. There were no side effects to report, except transient skin redness in one patient. The treatment does not address other bulbar symptoms, Dr. Kasarskis noted.

Muscle Cramps are a Common Source of Pain

Dr. Bjorn Oskarsson reported results from an online survey of people with ALS, sent to registrants of the National ALS Registry from ATSDR. 92% of respondents reported cramps, similar to previous work, suggesting that the sample, while not statistically controlled, was representative.

Cramps were the first symptom for 20% of respondents, who reported an average of 5 cramping episodes per day. There was no correlation between cramp frequency or severity and disease duration or ALSFRS. For 62%, muscle cramps were their only source of ALS-related pain. Almost half of respondents took no medication for their cramps. The most commonly used medication was baclofen.

Edaravone Shows Benefit in Very Early ALS

Edaravone, a drug approved in Japan for ALS, reduced decline in the ALSFRS score in a double-blind trial over 6 months in very early ALS patients (those with forced vital capacity (FVC) of ≥80% of predicted). Those receiving placebo experienced a decline of 7.5 points, versus 5 points in those receiving active treatment (p=0.0013). Previous trials have established no benefit from treatment in more advanced ALS. No data were presented on effects past 6 months. Edaravone is a free radical scavenger originally approved in Japan for acute stroke treatment. It has been granted Orphan Drug status by the FDA.

Other Trial News

Dr. Brooks: Six-month safety data from the ibudilast study indicate it is feasible to include advanced ALS patients in drug trials.

Dr. Kaji: High-dose intramuscular cobalamin provides no benefit in large trials, but subgroup analysis suggests a possible benefit in ALS patients at the earliest stages.

 Trial Development and Biomarkers

Short-term Plateaus Can Be Common in ALS Progression

In ALS progression, short-term plateaus are common, as determined by studying longitudinal data from the PRO-ACT database. 17% of patients had at least one 2-month period of no decline. 7% had at least one 18-month period of no decline.

Reversals are rare, but nonetheless about 1% had an improvement of at least 4 points on the ALSFRS lasting 12 months.

“In light of this data, we are skeptical of uncontrolled responder analyses that assume that stable disease over short periods is an indication of treatment benefit,” said Dr. Bedlack.

He is now beginning a closer analysis of patients who experience a reversal, in order to determine what factors may account for it. This may include misdiagnosis of a reversible condition, such as an autoimmune disease that eventually resolves.

ATLIS Strength Assessment Tool May Speed Trials

A new strength measurement tool called Accurate Test of Isometric Limb Strength (ATLIS) is superior to either ALSFRS or vital capacity (VC) in tracking clinical decline, according to Pat Andres, a neurological nurse at Massachusetts General Hospital and developer of the system. The ATLIS system measures isometric strength in 12 muscle groups while the patient is seated, without involvement of the clinician, avoiding the significant ceiling effects seen with hand-held dynamometry.

A study comparing ATLIS to ALSFRS and VC in 100 patients at 5 NEALS sites indicated that ATLIS was far better at reflecting steady decline over time, versus the fluctuations from visit to visit seen in the other two. “ATLIS provides a more reliable estimate of change over time than either ALSFRS or VC,” said Ms. Andres.

Use of the system would reduce the size of short-term clinical trials by a third, allowing smaller and faster phase II trials. It would also more easily reveal whether a treatment has a true effect on disease progression, which is critical for the decision to move to a larger and longer phase III trial.

Development of ATLIS was supported by The ALS Association.

News on Biomarker Development

Dr. Atassi: PET imaging tracer may help distinguish ALS from primary lateral sclerosis (PLS). A new ALS Association-funded study is underway to explore this further.

Dr. Chio: PET imaging with “independent component analysis” can distinguish ALS from controls with almost complete accuracy. Future studies of ALS-mimicking diseases will be needed for determining the role of PET in ALS diagnosis.

Dr. Jenkins: Whole-body muscle MRI may provide a good biomarker for following disease progression. Signal appears to increase with disease; rigorous longitudinal studies are in progress.

 Genetic Testing

The growth in number of ALS genes and the beginning of gene-based therapeutic approaches in ALS, has increased the importance of genetic testing for people living with ALS and their families. But there are still many uncertainties in the interpretation of a genetic test. The implications of a positive or even a negative test result are complex.

Key points from the genetic testing forum:

  • There are more than two dozen genes implicated in ALS.
  • Most genes are autosomal dominant, meaning that a single copy of a disease-associated mutation is enough to cause disease. People may also display incomplete penetrance, meaning clinical symptoms are not always present in individuals who have the disease-causing mutation.
  • There may be variable phenotypes (an individual’s observable traits) and other phenomena that make discovery and interpretation of the family genetic history challenging.
  • Confirming the correct diagnosis of ALS in the index case is crucial. It is important to rule out disease mimics before testing.
  • The pedigree, a genetic representation of a family tree that diagrams the inheritance of genes, is essential for determining familial vs sporadic ALS. Testing in familial ALS is common; there is much less agreement on testing sporadic ALS. (An audience member noted that genetic testing is offered to all sporadic patients in Belgium and 95% undergo testing).
  • Testing should not be rushed. Patients/families need time to work through the implications of testing before testing is performed. The time between clinical confirmation of diagnosis and genetic testing may be 3-6 months, with counseling in between.
  • Genetic counseling with a highly informed counselor or other specialist is a must. Counseling should not be performed by a neurologist with little exposure to ALS.
  • Pre-test counseling should include discussion of the uncertainty of implications of a positive test, given the variation in phenotypes from a given gene. This is especially true for C9orf72, with incomplete penetrance and variable (and unpredictable) phenotype.
  • Potential positive outcomes of genetic testing are that patients are able to “move on” with knowledge instead of uncertainty and family planning is possible.
  • Potential negative outcomes are survivor guilt from a negative test and life insurance denial.

Key points regarding presymptomatic testing:

  • Presymptomatic testing for confirmed gene carrier families is challenging, but can be done safely.
  • Pre-decision counseling is useful in that it allows the family member to decide whether to test or not.
  • One should screen for psychosocial readiness to cope with results, one way or another.
  • Remote counseling may be a very good option, rather than in-person counseling, even for delivering results, since the person receives the result in a more supportive setting (at home), rather than being faced with “a four-hour drive home alone.”
  • Dr. Benatar presented an update on the pre-fALS study, which investigates those with a positive gene test who have not yet developed ALS. The study shows 9 phenoconverters so far out of 105 enrolled individuals, with a maximum of 8 years follow-up.

 Basic Science Developments

Dr. Roselli: He has developed a novel model of ALS by introducing modified ion channels into motor neurons or astrocytes or interneurons, either excitatory or inhibitory, which respond only to a synthetic ligand, allowing precise control of excitation in a living mouse. He has found reduction of pathologic markers (SOD1 accumulation, ER stress markers) with excitation and an increase in markers with inhibition. Astrocyte activation also is protective through an identified pathway. The model should be very useful for testing precisely how excitation and inhibition affect motor neurons at different stages of disease. This study also suggests that excitation of motor neurons in SOD1 mice may be protective, rather than harmful, as commonly thought. The novel model system may allow a more precise understanding of early events in motor neuron death.

Dr. Smith: A mutation in a calcium binding protein is responsible for some cases of both familial and sporadic ALS, based on results from exome sequencing of over 500 cases. The mutation was first identified in multiple generations of three British families. Potentially disease-causing variants in the same gene were found in about 1.2% of familial ALS and 1.5% of sporadic ALS cases, indicating the gene may be a significant genetic contributor to the disease overall. It is not yet clear how the mutation affects the protein’s function, although the mutation appears to promote protein aggregation and inhibits binding to another protein.

Dr. Banack: Feeding the bacterial neurotoxin BMAA to vervet monkeys leads to protein aggregates and ALS-like symptoms, suggesting the toxin may contribute to disease found in humans exposed to the toxin. BMAA is suspected of causing Guam Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and investigations are ongoing to determine whether it plays any role in sporadic ALS elsewhere.

Dr. Biferi: Reducing expression of mutant SOD1 in mice can be accomplished efficiently by delivering a SOD1 antisense sequence via the gene therapy vector adeno-associated virus (AAV). Treatment prolonged mouse survival by 58%, a greater increase in survival than accomplished so far by any other technique in this model. AAV is generally thought to be a very safe vector for gene therapy and antisense reduction of SOD1 is believed to be a viable strategy for reducing the burden of the mutant protein in those with ALS due to a SOD1 mutation.

Dr. Walker: A new mouse model, in which a mutant TDP-43 gene can be turned on and off, is proving valuable for studying the sequence and time course of events in the ALS disease process. Most exciting is the demonstration that turning the gene off allows motor neurons to recover and mice to regain lost function.

 Presentations by Current and Former Milton Safenowitz Fellows

Many Milton Safenowitz Postdoctoral Fellows presented updates on their research at the meeting. In addition, presentations by former Fellows who remain deeply engaged in ALS research highlighted the value of the Fellowship in supporting young researchers at the start of their careers.

The Association offers The Milton Safenowitz Postdoctoral Fellowships for ALS Research Award. Founded by the Safenowitz family through The ALS Association Greater New York Chapter and in memory of Mr. Safenowitz, who died of ALS in 1998, these awards are to encourage and facilitate promising young scientists to enter the ALS field. Fellows work with a senior mentor and receive extensive exposure to the ALS research community through meetings and presentations. Grants are $100,000 over two years.

Jacob Ayers, Ph.D. (2012 Fellow): Mutant SOD1 protein spreads toxic aggregation to neighboring and distant parts of the mouse nervous system, mimicking human disease. Understanding this phenomenon is important for understanding the spread of disease after onset, and this model may be useful for testing therapeutics to slow spread.

Clotilde Lagier-Tourenne, Ph.D. (2009 Fellow): The burden of dipeptide repeat proteins formed from the mutant C9orf72 gene is greatest in the areas least affected by ALS, suggesting that aggregation of the proteins are unlikely to be contributing to disease pathology.

Yang Li, Ph.D. (2013 Fellow) (presented by her principal investigator Dr. Bowser): RBM45 protein, linked to ALS, binds to itself as well as ALS proteins TDP-43 and FUS, contributing to aggregation and pathology.

Russell McLaughlin, Ph.D. (2013 Fellow): Dr. McLaughlin presented data demonstrating the genetic overlap between ALS and schizophrenia that supports common neurodegenerative pathways in each disease. Dr. McLaughlin explained what receiving the fellowship meant to him. “When I was awarded the Milton Safenowitz Postdoctoral Fellowship for ALS research, it provided me the wonderful opportunity to develop my ideas that I had begun during my Ph.D. research into my scientific career. These ideas will hopefully help us understand the genetic basis of ALS further, which will one day lead to a cure,” Dr. McLaughlin said.

Helene Tran, Ph.D. (2012 Fellow): In her C9orf72 fly model, RNA aggregates appear to protect against harm from dipeptide repeats, made from the mutant C9orf72 RNA. This work was recently published in the September 23, 2015 issue of Neuron. When asked what she thought of the meeting, Dr. Tran stated, “This is a great conference that brings together ALS scientists and clinicians to collaborate. I have learned so much about ALS pathogenesis and potential therapies in a short period of time.”

Marka Van Blitterswijk, Ph.D. (2013 Fellow): The goal of Dr. Van Blitterswijk’s research is to understand how the C9orf72 mutation causes such a wide range of clinical and pathological variability, and to identify ALS biomarkers to track disease progression and confirm that a drug is hitting its target and is working. She has found that higher levels of the normal C9orf72 variant 1 protein may have beneficial effects in ALS, indicating the challenge of therapies designed to suppress production of both mutant and normal proteins. When asked how the Milton Safenowitz Fellowship impacted her research career, Dr. Van Blitterswijk stated, “The fellowship is a great opportunity to support young investigators early in their career and to encourage fellows like myself to stay in ALS research.” It also gave her the unique experience of attending ALS meetings, including The ALS Association’s National ALS Advocacy Day and an ALS Research Symposium held by The ALS Association Greater Chicago Chapter, where she not only shared her research but also interacted with many people living with ALS and their families. She stated, “I do research for ALS patients and their families. It really motivates me to work even harder on my projects.”

Qiang Zhu, Ph.D. (2013 Fellow): A 50% loss of expression of normal C9orf72 is not sufficient to cause ALS, while complete loss is associated with lymphomas, suggesting that ALS is not due to absence of the normal protein, but instead due to a toxic gain of function by the mutant gene.

Shuying Sun, Ph.D. (2011 Fellow): Motor neurons develop SOD1-mutation-induced gene expression changes early in the disease, followed by changes in their support cells, such as astrocytes, followed next by changes in oligodendrocytes. The temporal pattern of these changes may provide clues about how each cell type influences the other, leading to better targeting of therapy at different stages of disease.

 Concluding Session

Dr. Clive Svendsen led the closing session with a focus on stem cells in ALS research and gave a broad overview highlighting the incredible progress in the use of stem cell technology and induced pluripotent stem cells (iPSCs) as tools for drug discovery and precision medicine. The ability to manipulate these cells to generate any cells in the body and efforts to create systems in a dish that replicate the human biology is extremely exciting. ALS as a field has in many ways set the stage for other neurodegenerative diseases. Although stem cell transplants, as a therapeutic approach remains challenging, it is encouraging to see two new trials in planning for 2016 based on some of the early successes in safety in the Neuralstem trial. Q therapeutics and Dr. Svendsen team will initiate trials in the new year, each using different stem cells and approaches, both with the goal of improving the milieu surrounding the motor neurons to improve their chances of survival.

Bernard Miller, a person living with ALS gave an inspirational presentation to close the three days of intensive presentations. Bernard and his colleagues were the brains behind ProjectMinE, an initiative to sequence more than 15,000 people with ALS and 7,500 controls to identify genes that are unique to the ALS population. This effort in close collaboration with Answer ALS and Genomic Translation for ALS Clinical care (GTAC), together with the sequencing and data analysis support from the New York Genome Center will bring us closer to understanding the disease and designing therapies that are best matched to those living with ALS. In addition, Bernard established Treeway, a biotechnology company developing therapies for ALS.

“It is extremely exciting to see so many of The ALS Association funded studies presented at the international meeting and most importantly how so many of these large initiatives are working collaboratively to maximize the speed and impact these studies will have to bring us closer to treatments for people living with ALS. These unique collaborations, their global nature and scale are unprecedented in the neurodegenerative disease space. In many ways, the ALS field has lead the way in technologies and therapy development as illustrated by antisense technology now also in clinical trials for Huntington’s disease and Spinal Muscular Atrophy,” commented Lucie Bruijn, Ph.D., MBA, Chief Scientist, The ALS Association.

Our Chief Scientist, Dr. Lucie Bruijn, led an “Ask the Experts” Panel during the ALS/MND International Alliance Meeting. A recording of this event is located here. She also gave highlights and a clear overview of the 26th International Symposium on ALS/MND in a video located here.

The ALS Association’s current call for new Investigator-Initiated Awards and Milton Safenowitz

Postdoctoral Fellowship Awards is located here.

About The ALS Association

The ALS Association is the only national non-profit organization fighting Lou Gehrig’s Disease on every front. By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure. For more information about The ALS Association, visit our website at www.alsa.org.

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