Therapeutic focus – ALS field entering pivotal stage


The past few months have seen a sudden flurry of activity within the niche but major unmet medical field that is amyotrophic lateral sclerosis (ALS) – last month Actelion paid €10m for an option to acquire the private French group, Trophos, should olesoxime prove successful in a phase III ALS trial which will read out next year; while in May Teva’s ALS candidate, talampanel, failed a phase II study.

The only FDA-approved drug for ALS, riluzole, offers a modest increase in average survival time. Similar to many neurodegenerative disorders, a genuine disease-modifying therapeutic agent is desperately needed for patients with ALS, estimated to affect 50,000 people worldwide. Actelion’s move on Trophos and Teva’s setback throws the spotlight on a rather thin-looking late stage pipeline of ALS candidates, although the next 18 months could yet bring some much needed success stories (see tables below).

Limited options

ALS, also referred to as Lou Gehrig's disease, is a form of motor neuron disease which causes muscle weakness and atrophy throughout the body as upper and lower motor neurons degenerate over time.

Mean survival time with ALS is three to five years, although many people can live ten or more years. In some cases disease progression actually stops or plateaus, although the reasons why are still not understood; gaining further insight into the mechanisms underlying the illness is therefore crucial to developing new therapies.

Riluzole, discovered and initially developed by Rhône-Poulenc, was approved in 1995 and remains the main treatment option for ALS. The drug works by blocking the activity of glutamate, a neurotransmitter believed to play an important role in the development of ALS.

Sold globally as Rilutek by Aventis and now Sanofi-Aventis, sales of the drug peaked in 2006 at $182m. Since then Sanofi has stopped disclosing sales and analysts have dropped product forecasts from their models as it has gone generic.

Thin pipeline

In terms of the overall pipeline, pipeline data from EvaluatePharma reveals just 20 products are in clinical stage development for ALS, a further 29 having hit the rails along the way.

Count of ALS products
Status Count
Marketed  1
Phase III  3
Phase II  5
Phase I  12
Pre-clinical  25
Research project  10
Abandoned - Phase III  5
Abandoned - Phase II  7
Abandoned - other  17
Total 85

With regard to the late stage pipeline, the table below highlights the key products entering a pivotal stage in development.

Hopes rest on olesoxime

Olesoxime, also known as TRO19622, is probably the most promising ALS candidate in the pipeline, hence Actelion’s desire to ring-fence the opportunity but in a smart move which means Trophos still holds most of the risk of failure.

Olesoxime offers potential as a disease-modifying therapy by interacting with the mitochondrial permeability transition pore (mPTP), designed to promote the survival of motor-function nerve cells.

The phase III trial completed enrolment of 500 patients in March. Results are expected by the end of 2011, after which Actelion can exercise its option to acquire Trophos for between €125m to €195m; the price paid will also be dependent on the progress of Trophos’ other pipeline candidates.

Interestingly, following the failure of talampanel to improve a patient’s ALS Functional Rating Scale-Revised (ALSFRS-R), a scale for monitoring progression of disability in ALS patients, the primary endpoint for the olesoxime trial is assessing the overall 18-month survival rate.

Indeed, olesoxime seems to be the only late stage candidate being assessed primarily on survival rate, perhaps a shrewd move to get away from the inherent pitfalls of using rating scales; Teva’s Copaxone also failed a large phase II ALS trial in 2008 based on the same ALSFRS-R scale.

Conversely, the unpredictable nature of disease progression in ALS, could complicate the outcome of the olesoxime trial. Either way, results at the end of next year will be eagerly awaited by companies and patient groups alike.

Other runners

Mitsubishi Tanabe Pharma has completed phase III trials in Japan for ALS of its stroke drug, Radicut (edaravone), although the timing of the release of results remains unclear.

Technically a phase II/III trial of CytRx’s arimoclomol remains ongoing, expected to complete by the end of 2012. However, the FDA placed a clinical hold on the trial last year and the company is currently seeking a partner for the product or may decide to license it or spin its development out to a new entity.

Meanwhile back in phase II, a number of important trials are due to complete this year. According to, trials of Namenda, CK-2017357 and SB-509 in ALS will conclude this year.

CK-2017357 is one of Cytokinetics’ lead pipeline candidates and the company recently reported rapid recruitment in its phase IIa trial which started in April and will complete in August.

Knopp Neurosciences has so far revealed encouraging phase II data for KNS-760704 (dexpramipexole) in ALS and intends to start a phase III trial by the end of 2010, although at this stage it is unclear whether the private company has the funding in place to do so or is seeking a partner.

Partnering opportunities?

Which leads nicely on to the particularly quiet partnering scene for ALS products. Just 18 licensing deals have been signed in the last decade for products in development for ALS and aside from Sanofi’s involvement in Rilutek, big pharma is conspicuous by its absence from the field. Most of the pipeline candidates are being developed by small biotechs and remain unpartnered.

Only GlaxoSmithKline and Roche are involved in developing ALS candidates; 1223249 and RG7010, respectively, are currently undergoing phase I trials. As such, the disease needs some success stories to bring hope to ALS patients and pique the interest of bigger pharma partners.

Approved and late stage pipeline of products for amyotrophic lateral sclerosis (ALS)
Status Product Company Pharmacological Class Lead Indication Summary
Marketed Rilutek (riluzole) Sanofi-Aventis Glutamate release inhibitor ALS [Marketed]
Phase III Olesoxime (TRO19622) Trophos (Actelion) Mitochondrial pore modulator ALS [Phase III]; Chemotherapy-induced side effects [Phase II]; Spinal muscular atrophy [Phase I]
Radicut (edaravone) Mitsubishi Tanabe Pharma Neuroprotectant Stroke, acute [Marketed]; ALS [Phase III]
Arimoclomol CytRx Superoxide dismutase (SOD1) chaperone ALS [Phase III]
Phase II Namenda (memantine) Forest Laboratories (University of Alberta) NMDA antagonist Alzheimer's disease [Marketed]; Dementia, senile [Marketed]; Pain, post-operative [Marketed]; ALS [Phase II]; Autism [Phase II]
CK-2017357 Cytokinetics Musculoskeletal agent ALS [Phase II]; Age-related frailty [Phase II]; Cachexia (wasting) [Phase I]
SB-509 Sangamo BioSciences VEGF activator Diabetic neuropathy [Phase II]; ALS [Phase II]
sNN0029 NeuroNova VEGF activator ALS [Phase II]; Parkinson's disease [Phase II]
KNS-760704 (dexpramipexole) Knopp Neurosciences Dopamine D3 agonist ALS [Phase II]

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