Therapeutic focus – A year of high expectations for Lou Gehrig's

The coming year will see the release of clinical data on some of the most promising candidates for amyotrophic lateral sclerosis, a disease that in Rilutek currently claims just one approved drug.

“A new class of compounds are now in clinical trials – and new ones are entering trials this year and next – that are so much better than the clinical candidates we had a decade ago,” says Dr Steve Perrin, president and CEO of the ALS Therapy Development Institute, a non-profit organisation based in Massachusetts. The litany of trial failures and the fact that Rilutek offers only a two to three-month survival benefit make this an area in which disease-modifying products are badly needed (see table below).

Some of the most promising trends in prolonging survival and slowing disease progression in phase II were shown by Biogen Idec’s dexpramipexole, and strongly positive phase III data in the new year would provide an unexpected boost. And while smaller companies including Cytokinetics and Neuraltus Pharmaceuticals are not without their problems, positive developments could see big pharma come knocking.

Limited options

ALS, also known as Lou Gehrig’s disease, causes degeneration of the upper and lower motor neurons, leading to muscle wasting and weakness. Symptoms include muscle cramps, twitching, speech problems, overactive reflexes and spasticity, and ALS is usually fatal, owing to respiratory failure, within three years of onset.

“In Europe the vast majority of ALS patients are on Rilutek [riluzole], but in the US probably only about 50% of patients are actually on Rilutek for any length of time,” says Dr Perrin. “The number of patients on the drug is actually pretty low and that’s because of the side effects and cost, and because it doesn’t have a major impact.”

Rilutek showed no statistically significant difference in mortality in studies, and failed to show a beneficial effect on muscle strength or neurological function, as well as causing adverse events including weakness and decreased lung function. The drug targets irregular glutamate metabolism; elevated synaptic glutamate can cause nerve damage and death and is believed to have a role in ALS.

The ultimate goal of treatment would be to slow disease progression and improve survival. Biogen Idec's dexpramipexole is perhaps the most promising late-stage drug – data from its phase III Empower trial are expected early next year (Event – Amyotrophic lateral sclerosis success could empower Biogen, October 10, 2012).

In a two-part phase II study oral dexpramipexole was well tolerated, with a clinically significant dose-dependent effect on function and mortality, and favourable efficacy with the 300mg highest dose. In the first part of the study while the overall effect on function across all dose groups was not significant. Empower is testing 150mg twice daily for up to 18 months.

Largest trial

“It’s the largest phase III trial we have had in ALS for a long time, with about 900 patients enrolled worldwide,” says Dr Perrin. “The community are all really excited about it; we are all crossing our fingers that this drug will show some type of effect that will slow down disease progression and improve survival. Do I think it will be as good as the phase IIb data? Probably not as it’s a much bigger trial, which means there will be more heterogeneity in that patient population.”

In phase II the mean slope of decline for patients receiving 300mg was reduced by 39% compared with placebo, and Dr Perrin hopes that Empower will show a benefit “in the teens or low 20s”.

Also in phase III are two drugs marketed for other indications under development by the Japanese companies Mitsubishi Tanabe Pharma and Eisai. The acute stroke drug Radicut is in a 128-patient ALS study, while methlycobalamin, marketed for vitamin deficiency and peripheral neuropathy, is in two phase II/III trials. However, none of these is likely to yield data before 2015.

In the nearer term Dr Perrin sees potential in Cytokinetics, which he says has focused its business on ALS. The California-based biotech recently started a 400-patient phase IIb trial of tirasemtiv, which activates skeletal muscle troponin by increasing its sensitivity to calcium, delaying the onset and reducing the degree of muscle fatigue.

Previous phase II studies have shown good tolerability, with clinically relevant trends in ALSFRS-R, a functional rating scale, and in maximum voluntary ventilation. “The mechanism of action is pretty sound. Muscle function is a prominent problem in ALS; you lose muscle function relatively quickly,” says Dr Perrin.

Less lucky

Another mid-stage Californian biotech, Neuraltus, has not been so lucky with its macrophage regulator, NP001, which is supposed to modulate the immune system and slow down monocyte attack on the peripheral nerves.

The hope lies in a post hoc analysis comparing results to concurrent and matched historical controls that did reach significance. The company itself admits that post hoc analyses must be considered cautiously, but is nevertheless planning a phase III programme expected to begin in the second half of 2013. It is doubtful that the phase II data will attract a partner.

Meanwhile NeuroNova is conducting a phase I/II open-label trial of sNN0029, which contains VEGF, a growth factor important for the survival of motor neurons. This study, set to complete late next year, is a continuation of a previous three-month trial in 18 patients, and sNN0029 is administered directly into the cerebrospinal fluid using an implanted catheter.

NeuroNova retains the rights to sNN0029 in Europe, with the project licensed to Roche in the US, Canada and Mexico. Phase I/II results are also expected next year from two companies using stem cells: New York-based BrainStorm Cell Therapeutics and South Korea’s Corestem.

Dr Perrin’s ALS Therapy Development Institute is itself conducting trials with big pharma, and is sponsoring a trial to test Novartis' recently launched oral multiple sclerosis drug fingolimod. A phase IIa study will aim to determine the safety of 60 days on the drug in 30 ALS patients.

“Based on that we are going to run a pretty large phase IIb study with 250 patients,” notes Dr Perrin. “One dose, a drug and placebo – so pretty good-sized cohorts where we can measure slowing down disease progression as a primary endpoint. We are going to start doing that next year.”

The institute is also working with Biogen and UCB, finalising the preclinical data package for an anti-CD40L antibody, with hopes to move into phase II next year.

Disease markers

Dr Perrin also believes that developing a biomarker for disease progression is crucial, as some ALS patients only survive six months after disease onset while others can live for up to 10 years.

“If you think about how that creates problems in clinical trial design it’s pretty formidable,” he says. “You have a mix of patients enrolling in the trial [and] you have no idea what their disease trajectory is.”

As with other neurological diseases the difficulty with molecular biomarkers is their invasive extraction from the cerebrospinal fluid, Dr Perrin notes. However, imaging techniques such as PET and MRI hold potential to stratify patients, for instance by so-called white matter lesions.

Most of the big clinical centres are investigating imaging technologies as part of their patient evaluations. And while this biomarker development continues the opportunity for new clinical compounds to improve therapeutic options is nearing validation.

“I am really excited about where we are today compared to a decade ago,” says Dr Perrin. “I am really hopeful that we are going to see something in the ALS field that we saw happen with multiple sclerosis ... where we now have about nine drugs that are FDA approved. Ultimately, are any of these [ALS] therapies going to be cures? Probably not. Could many of them be disease modifying? Yes.”

But industry needs to move more quickly, he cautions. “From a patient perspective it’s never fast enough.”

Selected ALS pipeline
Status Project Company Pharmacology class Trial ID
Phase III Dexpramipexole Biogen Idec/Knopp Biosciences Neuroprotectant NCT01281189
Radicut (edaravone) Mitsubishi Tanabe Pharma Free radical scavenger NCT01492686
Nabolin (methylcobalamin) Eisai Vitamin B12 NCT00445172
Phase II Iplex (mecasermin) Roche/Ipsen/Insmed IGF-1 -
sNN0029 Roche VEGF NCT01384162
Tirasemtiv Cytokinetics Troponin activator NCT01709149
NurOwn program one BrainStorm Cell Therapeutics/Tel Aviv University Mesenchymal bone marrow stromal cell therapy NCT01051882 
AEN-100 (zinc acetate) Synthetic Biologics CNS agent -
NP001 Neuraltus Pharmaceuticals Macrophage regulator NCT01281631
HYNR-CS Corestem Stem cell therapy NCT01363401
RPI-MN IV Nutra Pharma Nicotinic acetylcholine antagonist -

To contact the writer of this story email Joanne Fagg in London at [email protected]

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