**4.1 Pathophysiology of motor neuron degeneration in ALS**

Pathophysiological mechanisms involved in ALS include (reviewed in Mitsumoto et al., 2006; Wijesekera & Leigh, 2009):


These pathophysiological mechanisms all end in motor neuron degeneration as the final pathway in disease progression (reviewed in Bruijn et al., 2004; Carlesi et al., 2011; Thatte & Dahanukar, 1997).

To address the genetic influence in ALS, two databases have been established. The ALSoD database (alsod.iop.kcl.ac.uk) contains detailed information about genes involved in ALS pathophysiology, and the ALSGene database lists genetic association studies (www.alsgene.org) (Lill et al., 2011).

### **4.2 Pathophysiological considerations in the planning of ALS treatment strategies**

Most pre-clinical trials in ALS research started with the pathophysiological model of the disease. In counteracting the pathophysiology of the disease, motor neuron survival and stabilization of motor neuron function is increased (reviewed in Bedlack et al., 2007; Carlesi et al., 2011; Fornai et al., 2011; Ilieva et al., 2009; Pradat et al., 2010; Silani et al., 2011).

Current strategies for treatment concepts reach for counteracting the individual pathophysiological actors. They including the following groups of agents:

 Anti-excitotoxicitory drugs. Excitotoxicity is mainly modulated by the release of glutamate and contributes to an acute toxicity. Typical molecules involved are the NMDA and AMPA receptors and the glial glutamate transporter Excitatory amino-acid

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials 9

In the typical process of drug development, preclinical data such as biochemical assays, cellular assays, and rodent models for the disease, lead to positive results with regard to predefined outcome parameters, for example, the increase in muscle strength, or survival time. For all of the drugs listed in the next section, promising preclinical data have been provided and published (for review, see (Ludolph & Sperfeld, 2005)). But why did the

Three major points came to my notice, when reviewing the literature: First, the animal models (mouse, rat, drosophila etc.) may either not sufficiently reflect the human pathology, or the animal pathology does not reflect human conditions (discussed in Green, 2002; Kiernan et al., 2011; Scott et al., 2008). Second, "ALS" is a clinical but not a pathophysiological entity. Thus, the inter-personal variability between patients is too big, and the inclusion criteria are too broad. Third, the design of the clinical trials may be insufficient (Aggarwal & Cudkowicz, 2008; Fornai et al., 2011; Kiernan et al., 2011;

majority of the clinical trials fail, when preclinical data have been so promising?

the outcome measures are not well-defined and comparable, or insufficient.

In future clinical trials, these issues should be discussed and included into the design of

Therefore, a round table has been established to agree on minimal criteria for a "good" clinical trial (Miller et al., 1999). Of note, there have been substantial efforts also in other diseases such as stroke research to agree on clinical and pre-clinical guidelines for research, such as the "Stroke Therapy Academic Industry Roundtable (STAIR)" (STAIR - Stroke

In the following paragraphs, I will shortly summarize the consensus guidelines for ALS trial. The prerequisite for any ALS trial should be a substantial diagnosis according to the criteria defined by the World Federation of Neurology (see above). Moreover, the inclusion criteria should be handled strictly, including that both sporadic and familial ALS can be entered into the trial. The age of the patients should be limited between 18 and 85 years of age. Symptoms should show a disease progression within the first six months after onset, but not more than five years. Additionally, also exclusion criteria have been defined, for example, the patients should not show sensory abnormalities, dementia, other neurological diseases, they should not suffer from any uncompensated medical illness, substance abuse, or psychiatric illness. Of

The endpoints of the trial must be defined in advance, for example, survival time, muscle strength, or ventilator dependence are common endpoints. All trials should include a

The quality of life should be assessed in every efficacy trial. The statistical analysis must be sound and planned with sufficient power. Any co-medication must be carefully re-

**5. Clinical trials in ALS** 

Maragakis, 2009), including:

 the number of subjects is too small, the time for follow-up is too short,

the inclusion criteria are too broad,

**5.2 Consensus guidelines for ALS trials** 

Treatment Academic Industry Roundtable, 2006).

note, the patients should not be taking any other investigational drug.

clinical ALS trials (Borasio, 1997).

control group.

considered.

the power of the study is calculated too low,

**5.1 Programmed failure in clinical trials for ALS?** 

transporters type-2 (EAAT2), which is regulating most of the extracellular glutamate concentration.

