Categories: Spotlight

Timeline: ALS 2012, A Year In Review

clock January 9, 2013

The year 2012 has now drawn to a close.  ALS Today turns back the clock - highlighting key advances in 2012 and key challenges going forward.

Monocytes, T-cells and oligodendrocytes emerged as potentially key players that could be targeted in ALS. Advances in induced pluripotent stem (iPS) cell technologies opened the door toward the discovery of new medicines for the disease.  Emerging antisense-based treatment strategies surfaced for C9- ALS, the most common form of ALS identified to date. GSK’s potential neuromuscular junction protector Ozanezumab (anti-NOGO A) approached phase II. And, Avanir’s emotionality-regulator Nuedexta, Novartis’ T cell sequesterer fingolimod (Gilenya), and the potential neuronal excitability-reducer mexiletine re-entered the pipeline – phase II clinical trials expected to begin sometime in 2013.

Key challenges, however, remain.  The first clinical reports of C9-ALS reawakened the debate about how to define inherited forms of the disease (fALS) and test for them. Clinical trials launched in 2012 hope to establish evidence-based clinical practice guidelines for the NeuRXNIV and feeding tube to help clinicians best meet their ALS patients’ respiratory and nutritional needs. And, the failure of ceftriaxone and dexpramipexole fueled the debate about which drugs to push forward in the clinic and how best to evaluate them.

Take a look back at 2012 by exploring our interactive timeline. Click on key advances and challenges ahead to learn more.

Images courtesy of Arcadian, Bradford Timeline, East Birmingham Hospital's Graham Beards MD, NIGMS' Judith Stoffer.

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Categories: In The Pipeline

Nuedexta, getting more than emotional?

clock August 10, 2012

Nuedexta dextromethorphan quinidine speech swallowing ALS

 

A dynamic duo? Nuedexta contains dextromethorphan (DM) (above) and a small amount of quinidine to slow DM breakdown.

One of the biggest fears for people with ALS is losing the ability to be speak. For many, this is a challenge that might be faced late into the disease. But for people with the bulbar-onset form of ALS, trouble speaking is amongst the first signs of the disease.

Now, US researchers are gearing up to evaluate a medicine that may help people with ALS retain some of this so-called bulbar control.  The drug, called Nuedexta, is currently used in the US to help people, including those with ALS, to control their emotions.

Nuedexta is one of at least three medicines currently or soon to be evaluated that may improve the quality of life for people with ALS.

“If you can improve the quality of life,” says Center for Neurologic Study (CNS) neurologist Richard Alan Smith MD, leader of the study, “This represents real progress in tackling the disease and providing support for patients.” 

The clinical trial is one of a number of studies within the growing “TREAT ALS” portfolio, an ALS Association initiative that helps push emerging ALS medicines into the clinic.

signma 1 receptor brainstem medulla motor neuron speech swallowing ALS

 

To speak, perchance to dream. Scientists suspect that DM may stimulate receptors that decorate motor neurons in the brainstem to help people speak and swallow. Adapted from Longone, P. et al. (2011).

CNS scientists first suspected in the 1990s that dextromethorphan (DM), a neuroprotective substance, might be helpful to people with ALS by slowing down the progression of the disease.  But when people with ALS starting take the drug in a small phase I safety study, the team noticed something else.  DM helped people with ALS control their emotions.  

Subsequent phase II and phase III clinical trials in the early and mid 2000s found that the number of uncontrollable crying and laughing outbursts dropped about 50%.

The condition, known as pseudobulbar affect (PBA), occurs in about 20% - 50% of people with ALS.  PBA is suspected to occur due to structural damage sustained by certain parts of the brain which control emotions.

The medicine, reformulated and named Nuedexta, was FDA-approved for use to treat PBA in October 2010.

Speak Up

Nuedexta, however, may help people with ALS do more than keep their emotions in check. 

A growing number of people with ALS taking Nuedexta for PBA according to anecdotal observations also appear to show signs of improvements in the rate and quality of their speech and their abilities to swallow.

“Nuedexta can help reduce PBA.  We know that,” says Duke University School of Medicine neuorologist Rick Bedlack MD PhD MS. "But what’s shocking is that the drug can, at least temporarily, improve [bulbar] dysfunction when upper motor neurons go bad.” 

The drug, acting on receptors decorating motor neurons in the brainstem, may also be helping people with ALS maintain bulbar control.

Nuedexta dextromethorphan quinidine speech swallowing ALS

 

Measuring stick The CNS-bulbar function scale, a self-reported measure (above) co-developed by Patientslikeme, will be primarily used to estimate Nuedexta's ability to help people with ALS speak and swallow. Courtesy of Paul Wicks PhD. Reproduced with permission.

Now, the US team is gearing up to put Nuedexta to the test in people with ALS that are having trouble speaking and swallowing.  The placebo-controlled randomized crossover clinical trial is to be conducted at 7 Northeast ALS Consortium (NEALS) sites in the US including Massachusetts General Hospital.  All participants are to be treated with Nuedexta and placebo successively for 30 days separated by a 10-15 day washout period.  Primary outcomes include: self-reported and clinician-assessed improvements in speech quality and swallowing abilities.  Other measures include: ALS-FRS. 60 people with ALS are expected to participate.

The trial is scheduled to begin in the spring of 2013.

This is the first medicine to be tested specifically to help people with ALS speak and swallow.

“We can compensate for [abilities] people are losing but we have been unable to take these problems and make them better,” says Bedlack.  “Now, for the first time, we are starting to see things like that.”

Patient Resources 

Clinical Trial of Nuedexta in Subjects with ALS Contact | ALS TDI Website 

References

Pioro, E.P., et al. (2010) Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.  Annals of Neurology 68(5), 693-702.  Abstract | Full Text 

Brooks, B.R., et al. (2004) Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology, 63(8), 1364-1370.  Abstract | Full Text (Subscription Required)

Al-Saif, A., Al-Mohanna, F. and Bohlega S. (2011) A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Annals of Neurology, 70(6), 913-919.  Abstract | Full Text  (Subscription Required)

Mavlyutov, T.A., Epstein, M.L., Andersen, K.A., Ziskind-Conhaim, L. and Ruoho, A.E. (2010) The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. Neuroscience 167(2), 247-255. Abstract | Full Text  

Further Reading

Rosen, H. (2008) Dextromethorphan/quinidine sulfate for pseudobulbar affect.  Drugs of Today 44(9), 661-668. Abstract | Full Text

 

Update (3/10/13) : Clinical trial launch date rescheduled. Patient resources added.

Update (9/10/12) : Researchers recently revised the CNS-BFS scale.  The figure has been updated accordingly.

 

 

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Categories: Roundtable

The Eligible Patient

clock October 19, 2011

Since the discovery of the first ALS-associated gene, superoxide dismutase 1 (SOD1) in 1993, scientists tested more than 30 experimental ALS drugs in clinical trials.  Only Sanofi’s Rilutek is FDA approved and at best moderately treats the disease.

A big part of the problem say ALS experts is that the disease is extremely variable and the underlying mechanism of the disease is not understood.  But despite these obstacles, University of Torino scientists argue based on findings of a new study that more can be done now to increase the chances for a new drug to be successfully developed simply by selecting patients that participate in clinical trials differently.

”I think what we have shown,” says lead author Adriano Chiò MD, “indicates that we are making mistakes.  It is time to correct the mistakes.”

The study is published this month in the journal Neurology.

The University of Torino team compared the local ALS patient population that participated in clinical trials to those diagnosed with the disease between 2003 and 2008.  The researchers found that those enrolled in clinical trials tended to be younger, male and half as likely to have the bulbar form of the disease.

 

ALS clinical trial participants measure for measure. A comparison between Italian ALS patients in the metropolitan Torino area that participated in clinical trials and those diagnosed with the disease between 2003 and 2008.  Adapted from Chio, A. et al. Sept. 28; Neurology doi: 10.1212/WNL.0b013e318232ab9b

These results suggest that experimental ALS medicines may be more difficult to demonstrate to be effective because the people participating in clinical trials tend to be healthier and have a more slowly progressing form of the disease.

The University of Torino team suggests clinical trial investigators should accommodate a broad range of people with ALS by dropping forced vital capacity minimums to 60%.  And these researchers say that clinical trials should instead include people with possible ALS, people with probable ALS or people who are recently diagnosed with the disease.  The researchers argue that by sticking to these patients, the interventions also have a much better chance to be effective since these people are in the early stages of the disease.

“The inclusion of patients in the earliest phase of the disease, when more motor neurons are still present, increase the probability that a drug may be demonstrated to be effective,” explains Chiò.

Rethink the possible

Many of these recommendations have already been put in place.  Within the last two years, clinical trials started to include broader populations of people with ALS by reducing their forced vital capacities to as low as 50%.  And researchers are opening their doors to people suspected to have the disease.  Ongoing trials such as Biogen Idec’s Empower (dexpramipexole), Cytokinetics’ CK-2017357 and GlaxoSmithKline’s “NOGO” trials include people with only a possible ALS diagnosis.

“There has been significant changes in how the trials are designed,” says Massachusetts General Hospital ALS Clinic Director Merit Cudkowicz MD, MSc.  “We already recognize that inclusion criteria were too strict.”

The reason drug developers feel comfortable with including people with possible ALS says Director of Duke University’s ALS Clinic, Rick Bedlack MD, PhD, MS, is that there is growing evidence that these people are extremely like to get the disease.  “Once you get to the category of possible ALS the chances that you are going to move into one of those other areas is incredibly high,” says Bedlack.

And says Knopp Biosciences’ Valentin Gribkoff, who heads the dexpramipexole team, opening the door to people in earlier stages gives them the best chance of detecting efficacy.

“What we think that did for us is allow for a wider-dynamic range for seeing a drug effect,” explains Gribkoff.

 

Diagnosis 101. ALS is often diagnosed in stages which are defined by the number and location of areas affected and the degree of disease spread. Called El Escorial criteria, a combination of clinical, electrical, and imaging measures are typically used. LMN, lower motor neurons.  UMN, upper motor neurons.  EMG, electomyography.

Reality Check

While more and more clinical trials open their doors to people with the first signs of ALS, some researchers however continue to keep them open to prevalent cases – people up to two years into ALS - even when an intervention is expected to be most effective early in the disease. 

One reason says Cudkowicz is that the diagnosis of definite ALS with today’s tools typically takes 12 to 14 months.  It is just not possible to test interventions in people with definite ALS, at least in the U.S., within the first year of experiencing symptoms of the disease.

But this is not the only reason researchers are hesitant to focus clinical trials on so-called incident cases of the disease.  With only a small percentage of people participating in clinical trials, some ALS experts worry that these restrictions will make it that much harder to develop promising medicines for the disease.

“We are really going to magnify the enrollment problem,” says Bedlack. “It’s probably going to be even slower and more difficult to recruit patients.”

Chiò disagrees.  He says that testing early interventions under these restrictions is doable – particularly in large cities in which 100s of cases of ALS are diagnosed annually– and is necessary to give the drugs their best chance of being demonstrated to be effective

“I hope that trials will be modified and will take into account the problems I have found,” says Chiò.

Trials and Tribulations

With the prospect of a growing number of trials however, being restricted to people who experience their first foot drop within 24 months, people with ALS are understandably frustrated.  But says Cudkowicz this is not going to be the case for each and every drug being developed for the disease.  Such decisions are made case by case based on when the medicines are most likely to work during the course of the disease. As researchers learn more about ALS, new treatment strategies may emerge that target more advanced stages of ALS - treatment strategies that must be evaluated in those populations.   

“I don’t think there is one model fits all clinical trials,” says Cudkowicz.

References

Chiò, A., Canosa, A., Gallo, S., Cammarosano, S., Moglia, C., Fuda, G., Calvo. A, and Gabriele, M.. (2011) ALS clinical trials: Do enrolled patients accurately represent the ALS population? Neurology, 77(15), 1432-1437. Abstract Full Text (Subscription Required)

Further Reading

Beghli, E. et al. (2011). The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotrophic Lateral Sclerosis, 12(1), 1-10Abstract Full Text (Subscription Required)

Bedlack, R.S., Wicks, P., Heywood, J. and Kasarskis E. (2010). Modifiable barriers to enrollment in American ALS research studies. Amyotrophic Lateral Sclerosis, 11(6), 502-507Abstract Full Text (Subscription Required)

 

UPDATED 11/21/11:  Knopp Biosciences' Val Gribkoff joins the conversation.

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