The preceding discussion highlights just some of the exciting advances that have occurred in the last decade in our understanding of ALS. A tremendous and long overdue explosion of interest in the design of novel treatments of ALS has also accompanied this unparalleled growth of knowledge. This includes an understanding of the factors that are required to keep motor neurons surviving, or to enhance their ability to repair themselves. Although there have been a number of failed trials in the treatment of ALS over the last two decades, several medications have shown promise. The following represents a summary of these medications.

Neurotrophic Factors
Neurotrophic factors are naturally occurring proteins required for the development, maintenance and maturation of neurons. As discussed earlier, there is evidence to suggest that these agents will retard the rate of neuron loss in models of spontaneous motor neuron degeneration. In models of neuronal injury, these agents have the capability of enhancing the rate of recovery. It has been postulated, therefore, that this class of agents may promote neuronal recovery and enhance survival in ALS. Several agents have been, or are currently, under consideration.

R-metHuBDNF
(recombinant brain-derived neurotrophic factor)
While the initial study of BDNF (r-metHuBDNF) administered subcutaneously failed to slow the progression of ALS, this may have been related to an inability of the drug to cross the blood-brain barrier. Two trials are attempting to overcome this barrier. The first involves the intrathecal administration of BDNF.

Using an implantable pump BDNF can be administered directly to the cerebrospinal fluid. This route of administration allows for smaller, better tolerated, amounts of BDNF to be given directly to the site where it is needed the most. Stable levels of the drug can be established. The implantation of the pump is safe and well tolerated. The objective of the current study is to demonstrate a 25% reduction in the rate of progression in pulmonary decline. The second trial involves the administration of high-dose r-metHuBDNF subcutaneously. Enrolment commenced in the 1st quarter of 1999 and is restricted to American sites.

GDNF
(glial derived neurotrophic factor)
This is another naturally occurring trophic factor that has been shown to be protective and survival promoting to motor neurons. This trial again involves the direct administration of the medication to the CSF. But in contrast to that of the intrathecal BDNF trial, this involves implantation of a catheter directly into the ventricles of the brain, thereafter followed by administration of the drug through an access port. The current study involves a small number of patients in a phase I study designed to establish the safety of the drug and of the route of administration. Enrolment is complete.

Myotrophin
The final decision regarding the use of myotrophin (insulin-like growth factor; rhIGF-1) by the Food and Drug Administration has not been rendered. On May 12th, 1998, the FDA issued an “approvable” letter to Cephalon, the parent company, indicating the additional steps that were required by Cephalon in order for myotrophin to gain approval. To date, these “approvable” criteria have not been met. Although rhIGF-1 may slow progression of functional impairment and the decline in health-related quality of life in ALS patients, only one of two valid randomized clinical trials of rhIGF-1 demonstrated results favouring improvement in mortality, rate of clinical decline, and quality of life. In the North American trial, the numbers needed to treat (NNT) to progress less than 20 points on ALS disability scale over 9 months using 0.1 mg/day rhIGF-1 subcutaneously was 6, and to survive 30 months using 0.05 or 0.1mg/day subcutaneously was 8. This suggests that this trophic factor may have a significant beneficial effect in ALS. However, only 53% of patients completed the North American study protocol and the results were highly variable. In contrast, the European protocol failed to show a significant difference in either measure. These last two issues are at the heart of the controversy surrounding this drug.

SR57746A
A phase III study of SR 57746A, sponsored by Sanofi Pharmaceuticals, is nearing completion. This oral therapeutic may work at a number of different levels, by increasing the synthesis of a number of neurotrophic factors. It is anticipated that the study will be completed by December 1999, with the analysis being completed by the summer of the year 2000. There is no information available at this time.

Small molecule neurotrophic agents
Amgen and Guilford Pharmaceuticals are in the process of developing a new class of neurotrophic agents defined as small molecule neurotrophic agents. These are orally active neurotrophic agents that will cross the blood–brain barrier, and they possess activity similar to nerve growth factor (NGF), BDNF and GDNF. They are expected to have a direct effect on injured neurons, and promote repair. Trials to date have been restricted to preclinical trials.

Riluzole
Although not yet approved for release in Canada, Riluzole has been approved for release in the United States and several other countries as a treatment for ALS. Riluzole appears to improve survival although the degree of improvement is small. In the pivotal phase III study, the improvement in survival ranged from 4.9% (50 mg dose) to 7.4% (200 mg daily dose), with little difference between the 100 mg and 200 mg dosage. The number needed to treat value (NNT representing the number of patients needing treatment before a statistically significant benefit is observed) ranged from 20 to 14, respectively, although the 95% confidence intervals were very broad (approaching infinity). This suggested a wide range of responses. In a retrospective study, utilizing novel staging techniques of ALS, there is a suggestion of a prolongation of time spent within a stage of ALS at which functional benefit would have been gained. This remains to be further studied through prospective studies. Recently, it has been demonstrated by Canadian investigators, that the use of Riluzole may retard the rate of neuronal loss as measured by magnetic resonance (MR) spectroscopy analysis.

Novel anti-glutamergic agents
Two American universities are currently participating in a small 50-patient study of a glutamate antagonist (LY300164) versus placebo in the treatment of ALS. No results are as yet available from this.

Gabapentin (Neurontin)
It is anticipated that the results of the current phase III, placebo-controlled study of Neurontin, currently being conducted by the Western ALS Research Consortium (WALS), will be completed and an analysis will be presented at the 1999 International ALS/MND symposium. The focus of the study is to attempt to confirm a previously observed (but not statistically significant) reduction in the rate of arm muscle weakening in people with ALS.

Creatine therapy
Although the exact mechanism by which this agent may work is not entirely clear, it is likely that Creatine will function predominantly as an antioxidant, and in the presence of steroids, may also increase muscle bulk. Based on a study demonstrating a delay in the onset of disease in mutant SOD1 mice, a placebo-controlled trial of Creatine is currently being formulated.

Gene Therapy
There are currently no studies evaluating the efficacy of gene therapy in ALS. However, purine analogues have the ability to modify gene expression of proteins that are involved in nerve regeneration. A novel class of such agents has been developed by NeoTherapeutics. These agents are currently in preclinical studies. In addition, the use of adenovirus vectors to deliver the genes encoding neurotrophic factors directly to injured motor neurons is being explored actively. In a naturally occurring mouse model of motor neuron disease, the initial studies demonstrated a 50% increase in life span.

Being told that you have ALS is a shock for which most people are totally unprepared. When a healthy person starts to have problems with muscle weakness, and ultimately learns that he or she may have a terminal disease, shock is normally part of the first reaction as are many other feelings such as anger, frustration, disbelief, and denial. These emotions are normal for both the individual and their family.

Everyone must find his or her own way of dealing with grief. Communication is especially important. Sharing emotions and feelings normally helps, as does having empathy and respect for the way others are handling this shock.

Denial, in various forms, is a common reaction to the diagnosis of a terminal disease. If a person wishes to deny his or her condition, respect his or her opinion and be ready to help when he or she wants help. Often it is the family that suffers as a result of an individual's denial. Denial can be an effort to keep control of managing one's life. On the other hand, “meeting the challenge” can lead to managing life within the realities of the disease, and taking action can minimize the effect of the symptoms.

Anger may also be part of your response. You may feel angry with medical personnel because they cannot find a cure. You may also be angry with members of your family because they are not ill and cannot really understand what it is like to face ALS. You may later respond by feeling withdrawn and depressed, as you face up to all of the changes that will occur in your life.