The NeuRX Diaphragm Pacing System. The NeuRX DPS phrenic pacer, developed by Case Western’s; Ray Onders MD, FACP, may condition the diaphragm muscles in people with ALS by stimulating the phrenic nerve that controls these muscles through implanted electrodes.  Recently approved by the FDA, the device is available by prescription to people with ALS that are battling chronic hypoventilation. Image: Synapse Biomedical.

Over 75% of people with ALS ultimately lose the battle with the disease due to respiratory failure.  To combat the decline of the diaphragm muscles, physicians at Case Western Reserve University School of Medicine introduced a phrenic pacer called the NeuRX  DPS in hopes to strengthen these muscles to bolster diaphragm function.  Recently approved by the FDA, this device according to anecdotal evidence may delay the need for mechanical ventilation.

But some ALS experts argue that the NeuRX DPS has not yet been sufficiently demonstrated through clinical studies to slow respiratory decline or even improve the quality of the life of people with ALS.  And with a cost of upwards of $20,000 USD, insurance providers may therefore be reluctant to cover this device for patients.

Now, University of Paris’ Groupe Hospitalier Pitié-Salpêtrière physicians in a preliminary study report that the NeuRX DPS may increase the stamina of the diaphragm muscles, helping people with ALS sleep more soundly.

The team found that patients implanted with the device after four months of diaphragm conditioning experienced a median increase in sleep efficiency of 9%, dropping the time awake after falling asleep by 40%, about one hour.  18 patients participated.

“Even if we would have shown a maintenance in sleep quality would have been a surprise,” says Thomas Similowski, Groupe Hospitalier Pitié-Salpêtrière Chief of Respiratory and Intensive Care Medicine who led the study. “Showing that we actually improve sleep efficiency is very spectacular.”

A larger study is now ongoing.

Keeping Pace

Phrenic pacemakers substitute for brain centers that become decoupled due to injury or disease from the neuronal circuitry controlling respiratory muscles by electrically signaling at regular intervals the diaphragm to contract, allowing patients to breathe without mechanical ventilation.

 

Just breathe. Phrenic nerve (red) impulses trigger the contraction of the muscles (blue) in the diaphragm, enabling us to breathe air in. Here, only slow muscle fibers and their attachments to nerve terminals called neuromuscular junctions (yellow) are shown. Image: Gary Sieck PhD, Mayo Clinic.  Copyrighted and used with permission from the Mayo Foundation for Medical Education and Research. All rights reserved.

Harvard cardiologist Stanley Sarnoff MD first introduced the idea of phrenic pacing in 1944 to support breathing of a 5 year old boy who suffered from paralysis of the diaphragm.  And in 1968, Yale cardiologists William Glenn MD and John Judson MD demonstrated that these devices can help regulate the breathing of a patient suffering from chronic hypoventilation – the inability to bring enough air into the lungs to support respiration.  Introduced into routine clinical practice in the early 1970s, phrenic pacemakers are typically prescribed to support ventilation of people who suffer from spinal cord injuries or experience certain chronic sleep or breathing difficulties.

But physicians remained skeptical about whether or not phrenic pacemakers could benefit people with ALS.  This is because the phrenic nerves in patients are deteriorating making it more difficult for these electrical impulses to reach the diaphragm.  And at the same time, these nerves are inflamed and may be inadequately myelinated in places in people with ALS resulting in the inefficient delivery of these impulses, making it harder to stimulate the contraction of these respiratory muscles.

Physicians at Case Western Reserve University School of Medicine nevertheless suspected that phrenic pacemakers may help people with ALS.  Their idea: these devices could strengthen the muscles in the diaphragm and thereby slow respiratory decline. 

“They are applying stimulation not to produce ventilation,” explains Similowski, “but to train the diaphragm muscles.”

In 2007, a multinational team led by Case Western surgeon Ray Onders MD, FACP, launched a clinical trial in the United States and France to evaluate the potential benefits of the NeuRX DPS phrenic pacemaker in people with ALS with chronic hypoventilation.  86 patients participated.   

The physicians found according to results submitted to the FDA that the device extended the median survival of participants 16 months than those in a comparable study supported by noninvasive ventilation alone.  But the team was unable to definitively demonstrate that this device slowed respiratory decline in people with ALS – at least as determined by monitoring participants’ forced vital capacities.

”It looks like it may be helpful but the scientific evidence is truly lacking,” says Methodist Neurological Institute neurologist Stan Appel MD.  “We just don’t know.”

Goodnight DPS

But breathing is powered by much more than a diaphragm during waking hours.  And forced vital capacity therefore evaluates the health of other respiratory muscles in the chest that are also deteriorating in people with ALS. 

Groupe Hospitalier Pitié-Salpêtrière physicians decided therefore to take a look at people with ALS after bedtime.  This is because the diaphragm alone powers breathing during sleep.  By evaluating sleep quality of patients, the physicians could compare the function of the diaphragm before and after being conditioned. 

“A decrease in breathing during sleep is a very sensitive marker of diaphragm dysfunction in ALS,” says Similowski.  “That’s a very early marker of the disease.”

The team found that people with ALS stayed asleep longer and slept more soundly.  But surprisingly, the team found that key indicators of diaphragm strength continued to decline such as Sniff Nasal Inspiratory Pressure (SNIP) – about 8% on average during the duration of the study.

The team speculates that this is because the device does not make the diaphragm stronger but instead boosts the stamina of these muscles by promoting the conversion of the fibers to so-called slow twitch ones that are designed for endurance.   Typical tests such as those the team used according to Similowski predominately evaluate fast twitch fibers in the diaphragm which are designed for speed.  Studies to test this idea are ongoing.

Before NIV?

Physicians at the University of Paris however suspect that phrenic pacemakers such as the NeuRX DPS can make more of difference for people with ALS.  Anecdotal evidence suggests that the device may prolong the need for a mechanical ventilator up to 24 months.  And suspects Similowski, conditioning the diaphragm just as these respiratory muscles start to deteriorate might even delay the time when noninvasive ventilation is needed.

Starting in 2012, Similowski’s team is launching a clinical trial to test just that.  People with ALS experiencing the first signs of respiratory dysfunction with or without the NeuRX DPS implanted will be monitored for two years and compared.  About 75 patients are expected to be enrolled.  Results are expected in early 2015.

References

Gonzalez-Bermejo, J., et al. (2011) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. doi:10.3109/17482968.2011. 597862  Abstract | Full Text (Subscription Required)

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7): 1433-1440.  Abstract | Full Text (Subscription Required)

Sarnoff, S.J., Hardenbergh, E., and Whittenberger, J.L. (1948) Electrophrenic respiration. Science, 108(2089), 482.  Full Text (Subscription Required)

Judson, J.P. and Glenn, W.W. (1968) Radio-frequency electrophrenic respiration. Long-term application to a patient with primary hypoventilation. Journal of the American Medical Association, 203(12), 1033-1037.  Abstract | Full Text (Subscription Required)

Further Reading

Marion, D.W. (2011) Diaphragm Pacing.  UpToDate.  Excerpt | Full Text  (Subscription Required)  

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), 1-10.  Abstract | 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), 502-507.  Abstract | Full Text (Subscription Required)

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