Research - Motor Neurone Disease

Motor neuron disease encompasses a group of progressive, degenerative neurological disorders affecting our motor neurones. The most common of these, amyotrophic lateral sclerosis, is characterised degeneration of both upper and lower motor neurones, generating its classical combination of clinical signs. In contrast, the less common progressive lateral sclerosis only affects the upper motor neurones, and progressive muscular atrophy only affect the lower motor neurones. Onset is typically heralded by weakening of a limb, though subtypes that initially affect the bulbar or respiratory muscles exist.

As with many other neurodegenerative conditions, there has been a disappointing lack of translational research – whilst much is being learnt, little is making the jump from an interesting finding to effective treatment. Recent publications in Lancet Neurology follow this similar pattern – some significant progress, and a negative trial of treatment.

MND and Fronto-temporal dementia - known link and new information on underlying genetics

It has long been recognised that there is a clinical overlap with MND and fronto-temporal dementia (Kiernan 2011). With detailed cognitive assessments, 20-50% of patients with ALS meet criteria for probably or define FTD; less commonly, patients presenting with FTD go on to develop ALS. Imaging studies have confirmed fronto-temporal atrophy in patients with ALS, and post-mortum samples have shown that almost all cases of ALS contain TDP-43 positive ubiquitinated cytoplasmic inclusions – they are also found in 50% of FTD cases. More recently, familial clustering of ALS and FTD have been explored:

Such familial clustering was first attributed to loci on chromosome 9, with genome wide association studies similarly identifying the region to be a significant genetic risk factor.  Further work has now identified a hexanucleotide repeat expansion in the gene C9ORF72 to be causal. The GGGGCC expansion is though to be responsible for 5-14% of sporadic and familial ALS cases, and is the second most common mutation in FTD cases. (Andersen 2013)

Recent research has now gone further into exploring the role of this repeat expansion (Blitterswijk 2013). By investigating the size of the expansion in post-mortum samples of the central nervous system of patients with ALS, FTD or a combination of both conditions, a number of findings have been produced. Firstly, as has been noted in other neurological conditions due to repeat expansions, the length of the repeat is variable – it is at its longest in the frontal lobes, whilst shorter expansions are found in the cerebellum. A longer expansion was correlated with older age of FTD onset, perhaps suggesting that the expansion increases with age within the patient. Only in the cerebellum, where the smaller expansions were found, was the size of the expansion negatively correlated with survival from disease onset.

Whilst all of the above represents a significant advance in our understanding of ALS/FTD genetics, many questions remain as to the significance of this new information, and how it may impact patient care in the future. It has been suggests that the repeat expansion may result in neurotoxicity via various mechanisms, but whilst the work represents the essential early steps, we are still a very long way from translating this into therapeutic options.

Another disappointing trial - dexpramiprexole produces no improvements in ALS

Jumping forward to the other end of the research escalator, results of the stage 3 randomised, placebo controlled trial of dexpramipexole, an agent thought to enhance mitochondrial function, have also been recently published (Cudkowicz. 2013)

Mitochondria have been implicated in the pathogenesis of ALS via multiple strands of evidence. Reported functional abnormalities include increased levels of mutated mitochondrial DNA, reduced overall levels of mitochondrial DNA, and changes in the activity of the mitochondrial complexes involved in the electron transport chain (Kiernan 2011). Structural abnormalities of mitochondria have also been noted in ALS patients, potentially indicating mitochondrial dysfunction (Sasaki 2007). Such malfunctioning mitochondria can result in neurotoxicity via reduced ATP levels starving the ion transport systems, with the resulting depolarisation activating excitotoxicity mechanisms.

Following favourable results with dexpramiprexole in in vitro assays of mitochondrial function and in vivo models of ALS, a phase 2 study was undertaken (Cudkowicz 2011). This met the primary end point of safety, but also showed a significant improvement of 300mg daily dexpramipexole over 50mg daily, using the ALS functional rating scale. After this promising start, however, the phase 3 trial has failed to show any benefit over placebo (Cudkowicz. 2013). With 943 patients enrolled, no differences were seen between treatment and placebo groups in the end points of the combined assessment of function and survival, changes in ALS functional rating scale, or time to death.

With these disappointing results, dexpramiprexole joins lithium, talampanel and ceftriaxone in the pile of initially promising drugs that have failed stage 3 trials in ALS. The cause of such disappointments is likely multifactorial (Gordon 2013).

Firstly, one has to question the models of ALS that are currently used at the earliest stages of drug development. We still do not understand the underlying mechanisms of ALS, and have no guarantee that the existing models accurately replicate the disease in man. Indeed, the SOD1 transgenic mouse model is frequently used, but SOD1 mutations can account for no more than 5-10% of ALS (Kiernan 2011) – are the results in such mice valid?

Secondly, the phase 2 trial results must be questioned. The apparent efficacy of dexpramipexole represents type 1 error. The key role of phase 2 trials is to establish the safety of the medications and clarify dose selection – establishing the maximum tolerable dose increases the chance of efficacy in future trials (Gordon 2013). Their small sample sizes inherently lead to unreliable results when it comes to efficacy.

Perhaps the current lack of effective treatments in ALS is self-reinforcing. When potential agents are discovered, one naturally is eager to rush to stage 3 trials, where we hope to show efficacy and hence provide patients with the much-needed treatments. Instead, perhaps focussing back on the animal models, questioning their relevance, and spending more time on carefully selecting potential candidate drugs and their optimal dosing, will in the future reduce the significant expenditure and disappointment which currently characterises drug development in ALS. To this end, the progress already discussed in the role of C9ORF72 in the genetics of ALS do at least provide glimmers of future hope; if they can be translated into improved models of the disease, drug development will naturally benefit.

Bibliography

1.     Andersen, P. "ALS and FTD: two sides of the same coin?" Lancet Neurology (Elsevier) 12, no. 11 (October 2013): 937-938.

2.     Blitterswijk. "Association between repeat sizes and clinical and pathological characteristics in carriers of the C9ORF72 repeat expansion (Xpansize-72): a cross-sectional cohort study." Lancet Neurology (Elsevier) 12, no. 10 (October 2013): 978-988.

3.     Cudkowicz. "The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis." Nat Med., no. 17 (Nov 2011): 1652-1656.

4.     Cudkowicz. "Dexpramipexole versus placebo for patient with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial." Lancet Neurology 12, no. 11 (November 2013): 1059-1067.

5.     Gordon, P. "The murky path to drug discovery in ALS becomes clearer." Lancet Neurology (Elsevier Ltd) 12, no. 11 (November 2013): 1037-1038.

6.     Kiernan. "Amyotrophic lateral sclerosis." Lancet (Elsevier) 377 (March 2011): 942-955.

7.     Sasaki. "Mitochondrial alterations in the spinal cords of patients with sporadic amyotrophic lateral sclerosis." J Neuropathol Exp Neurol 66, no. 1 (January 2007): 10-16.