- The Annual Symposium on ALS/MND brings together researchers and clinicians who specialize in ALS from around the world.
- Experts in all aspects of ALS and newcomers to the ALS field exchanged ideas about ALS biology, clinical care, diagnosing and measuring ALS, clinical trial design and trial results, and strategies for therapeutic development at this three-day meeting in Orlando, Fla.
- Links to additional information are provided.
New insights and perspectives on the biology of amyotrophic lateral sclerosis (ALS), best practices in the care of individuals with the disease, and future directions for development of ALS therapies were the central themes of the 21st International Symposium on ALS/MND (Motor Neuron Disease) that took place in Orlando, Fla., Dec. 11-13, 2010.
The United Kingdom-based Motor Neurone Disease Association organizes the annual symposium as a place where ALS-focused clinicians and scientists from around the world can gather and exchange ideas.
About 800 people attended this year's meeting, including dozens of MDA-affiliated physicians and MDA-supported research grantees (several of whom presented their work), as well as representatives of MDA's research, health care services and public health education programs.
Below is an overview of the topics addressed at the symposium; some topics will be addressed in more detail in future print and online MDA/ALS Newsmagazine articles.
Clinical aspects of ALS
At least two somewhat surprising aspects of the clinical picture in ALS emerged.
One was that pain, caused by abnormal joint mobility or cramps, is a frequent part of the disease.
A second was that mild, subtle cognitive and behavioral impairments are often present in ALS and may have a negative impact on social interactions and communication.
Questions about when to start noninvasive ventilation to support failing respiratory muscles, when to insert a feeding tube to provide nutritional support, and whether some types of exercise may be beneficial in ALS, remain open.
Among the themes explored in ALS biology were the multiple pathways influenced by the TDP43 protein, now known to be abnormally located and aggregated (stuck together) in many cases of ALS, and to be abnormal because of a genetic TDP43 mutation in some cases.
TDP43 biology is proving to be a fruitful area for uncovering possible disease mechanisms and targets at which to aim experimental therapies.
Another theme explored was the major contribution made by glial cells to the ALS disease process. Glial cells in the central nervous system (the site of ALS-related damage) include astrocytes, microglia and oligodendrocytes. None of these are nerve cells (neurons), but they provide vital functions to support neurons.
There's increasing evidence that motor neurons are not the only cells affected in ALS. Glial cells are also part of the problem and, if treated or replaced, could become part of the solution.
It's been known for decades that two sets of motor neurons — those that control the movements of the eyes and those that control the external sphincter muscles of the anus and urethra — are spared in ALS. Another theme explored at the symposium was that learning why these particular motor neurons are resistant to the ALS disease process could shed valuable light on disease mechanisms and might provide new therapeutic directions.
Tracking, measuring and diagnosing ALS
Several lectures focused on new ways to diagnose or track and measure the progress of ALS, particularly in the context of clinical trials, where it's crucial to determine the effect of an experimental treatment as accurately and quickly as possible.
New developments include:
- a portable device called ATLIS (accurate test of limb isometric strength), which is an adjustable tilting chair in a frame that can accurately measure strength changes in a cost-effective manner;
- new applications of ultrasound imaging and magnetic resonance imaging (MRI);
- a new type of electrophysiological measurement called a "combined motor action potential scan progression score," which its developers say is objective, informative, easy to interpret and appears to show disease progression more accurately than current related techniques; and
- the possibility of diagnosing ALS and predicting its progression by measuring the levels of proteins called neurofilament heavy chain, cystatin C and complement C3 in the spinal fluid and blood.
Clinical trial design
A major area of interest for conferees was the design of clinical trials of experimental treatments for ALS. Among the interesting ideas proposed:
- trials should be thought of as "diagnostic" tests, not for the presence of disease but for the effects of a treatment;
- questions to be asked in trials must be clearly defined, and the trial must be designed to answer those questions;
- the main question to be answered by phase 2 trials should be whether or not to move to a phase 3 trial;
- "futility" trials, whose end point is that the drug is very unlikely to have any benefit, are useful in some situations; and
- trials that are too small or otherwise poorly designed can actually slow the research process.
Clinical trial results
Some results of recent clinical trials were announced at the MNDA symposium.
CK-2017357, an experimental drug designed to enhance muscle contraction, has shown "evidence of effect" in a phase 2a trial in ALS. The drug is in development by the South San Francisco company Cytokinetics . The results were announced for the first time at the Orlando meeting and were summarized on the company's website Dec. 13, 2010. (See Cytokinetics Announces Successful Completion of Phase IIA "Evidence of Effect" Clinical Trial of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis.)
KNS-760704, also known as dexpramipexole, has shown promise in a phase 2 study and likely will be taken into a phase 3 study in 2011. The experimental drug, in development by Pittsburgh-based Knopp Neurosciences, is designed to improve energy production and provide protection to neurons under stress. Initial data for this phase 2 study were announced in December 2009, and additional data were announced in April 2010. (See Knopp Neurosciences Presents Further Encouraging Trends in its Phase 2 Study of KNS-760704 (Dexpramipexole) in ALS.)
Talampanel, an investigational drug designed to interfere with signaling by the potentially toxic chemical glutamate, failed to slow disease progression in a phase 2 trial in ALS. The drug was being tested by the Israeli company Teva Pharmaceuticals, which originally announced the negative findings May 17, 2010. (See Teva Provices Update on Talampanel for the Treatment of Amyotrophic Lateral Sclerosis.)
A trial in ALS of pioglitazone, a drug marketed as Actos in the United States, United Kingdom and Germany for the treatment of type 2 diabetes, was stopped early when it became clear that participants taking a placebo were doing better than those taking the drug. Pioglitazone makes tissues more sensitive to insulin and had shown promise in animal models of ALS. The drug was being tested in a multicenter trial in Germany. (See Study of Pioglitazone in Patients With Amyotrophic Lateral Sclerosis.) The investigators are further analyzing the results and hope to figure out why the drug was not effective and was perhaps harmful in ALS.
Several investigators presented their work in development of new experimental therapies for ALS.
Among the intriguing reports of therapeutic strategies in development:
- the ongoing design of artificial viruses at the University of Sheffield in the United Kingdom that are designed to deliver therapeutic genes safely and effectively to the central nervous system;
- the creation of "induced pluripotent stem cells" from ALS patients' skin cells at the South San Francisco biotech iPierian, as model systems in which to study the disease and the effects of various therapies; and
- a plan to transplant stem-cell-derived astrocytes into people with ALS, by approximately the year 2014, as a joint venture of the University of California-San Diego, the Salk Institute and the Carlsbad, Calif., company Life Technologies. (See UC San Diego, Salk Institute for Biological Studies and Life Technologies Team to Conduct Cell Transplant Research for ALS.)
For more information
Want to know more about what happened at the 21st MNDA International Symposium? See the meeting's Highlights and Insights Blog and Abstract Book 2010.
The 22nd MNDA International Symposium will be held in Australia.
Editor's note: This article was updated Dec. 22, 2010, to correct the dates when data were released about the experimental ALS drug KNS-760704.