ALS is a neurodegenerative disease characterised by progressive muscular paralysis. It is a devastating disease leading to muscle weakness, difficulty in swallowing, speech and eventually paralysis and death. Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. However, cases of the disease do occur in persons in their twenties and thirties. Overall, there is a slight male prevalence (M:F ratio~1.5:1).
Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to muscle weakness and wasting, where the symptoms may start in the upper and lower limbs. Gradually, spasticity may develop, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with difficulties in speech and swallowing, but limbs symptoms can develop almost simultaneously with bulbar symptoms and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases.
Most research on prevalence and incidence numbers of ALS has been performed in Europe. It appears that the diversity of ALS epidemiology is related to the population demographics. Also, ALS is more common among the elderly, thus in light of the global trend of increasing life expectance the incidence may increase. Other factors that have been considered to be related to the occurrence of ALS are environmental risk factors, geographical differences and genomic epidemiology.
A review of published incidence and prevalence literature in Europe and the US revealed that the median incidence rate in Europe is 2.7/100.000 person years resulting in 15.355 estimated cases. Median prevalence is 5.4/100.000 person years corresponding to 39.863 cases (Chi, et al., 2013). In the US these numbers are similar as the incidence is 10.131 cases annually and the prevalence is 36.480 cases (Borlongan, et al., 2013). Thus, in the Western world approximately 75.000 patients are currently eligible for new drug therapy.
Given its prevalence ALS is an orphan or rare disease, which from a regulatory perspective are defined as those diseases where there are less than 200,000 patients in the US or that affect no more than five in 10,000 of the general population in the EU. Nowadays, a number of unique clinical, regulatory and commercial challenges are associated with the development of therapies for the treatment of rare diseases.
There are limited pharmacotherapeutic options in the treatment of ALS; the mainstay of management is symptomatic treatment. ALS patients who receive care at a multidisciplinary clinic may have a better prognosis than patients attending a general neurology clinic. Median survival is up to 7.5 months longer for the patient group treated at a multidisciplinary clinic and was up to two months more for patients with bulbar dysfunction. Overall, the data suggest that active management enhances survival (Gordon, 2013).
Currently, only one drug therapy has been approved for the treatment of ALS. Riluzole (Rilutek) is a neuroprotective drug that blocks glutamatergic neurotransmission in the central nervous system, thereby preventing apoptosis (programmed cell death) of the motor neuron. The beneficial effects of riluzole in the treatment of ALS are, however, rather modest and this therapy only prolongs life with 3 months.
All other pharmacotherapeutic treatment options which are commonly used in the clinical management of ALS are palliative treatments aiming at reducing signs and symptoms associated with the disease but which on their own are not specifically indicated for ALS (e.g. treatment of muscle spasms, pain, insomnia, dysphagia and emotional instability; see below). In addition, supportive non-pharmacotherapeutic treatments may be required, like mechanical ventilation for the management of respiratory insufficiency. However, none of these therapies prolong life and they should be considered as symptom suppression only.
Although many drugs have been tested in ALS patients over the last 20 years (see Figure 1), none of them have shown adequate clinical efficacy. Reasons for these failures can be diverse, including insufficient exposure at the site of action (pharmacokinetics), insufficient drug efficacy or non-validated drug targets (pharmacodynamics) or poorly designed proof-of-concept trials. Demonstrating efficacy in ALS patients is difficult as there are no reliable biomarkers predictive of efficacy, the manifestation of the disease across the population is highly variable and efficacy is measured by means of subjective questionnaires.