Recently, there have been conflicting reports regarding the use, safety and efficacy of the diaphragm pacing system (DPS) developed by Synapse Biomedical in ALS patients. These reports included a peer-reviewed publication of a study called DiPALS conducted in the United Kingdom and a press release stating that results from Synapse’s own clinical trial results will be presented at the annual ALS/MND Research Symposium to be held this year in Orlando, Florida. The DiPALS study found those whom had the DPS implanted were more likely to succumb to ALS than those whom used non-invasive ventilation alone whereas the Synapse press release stated that their results were much more positive. Since only the DiPALS study results have been published, it is a challenge to compare the two studies appropriately at this time.

What is DPS?

While the exact causes of all ALS cases are not known, it is generally accepted that as the disease progresses, the ability of an individual to breathe entirely on their own will be lost. Breathing is controlled in part by the diaphragm; an important muscle connected to the lungs. However, in ALS, a person’s motor neurons disconnect from their muscles, which causes those muscles to waste away. As with other muscles, the diaphragm atrophies as a person’s ALS progresses. Some people with ALS will choose to use non-invasive ventilation (NIV) technologies, such as a Bi-Pap, to assist in their respiration. Later on in the disease, some people diagnosed with ALS will choose to connect to a permanent ventilator.

The NeuRx Diaphragm Pacing System (DPS, pictured) system was developed in 2005 by surgeon Raymond Onders and colleagues at Case Western Reserve University and University Hospitals of Cleveland. The idea for the device was to augment the electrical signaling of the diaphragm necessary for respiration which was lost as ALS progresses and the natural connections between the diaphragm and the nervous system deteriorates. The device consists of five electrodes and an external pulse generator. When activated, the generator sends small electrical signals to the electrodes connected to the diaphragm muscle, causing it to become stimulated. By stimulating the diaphragm, the device is designed to aid in respiration, not a permanent replacement for the diaphragm itself.

In 2011, DPS was provided a Humanitarian Use Exemption by the FDA, which means that its effectiveness has not yet been demonstrated. However, on-going clinical research continues on the device, including the research in the two studies recently reporting out results.

What occurred in the Synapse Biomedical Post Approval Study (PAS)?

Following the Humanitarian Device Exemption from the FDA, Synapse Biomedical launched a post approval study (PAS) as is required by the FDA. That study occurred in 11 different sites in the United States online, and it completed its enrollment of 60 PALS in August 2014.  No data outside of that which was provided in the press release has been made available. However, according to the press release, the results of the PAS were similar to the original study – with the median survival of PALS being 20.9 months post-implant.  The original study included 106 PALS and was conducted in 9 centers and had a median survival in PALS of 19.7 months post-implant. Dr. Onders will provide a talk at the Symposium on the original study, whereas Dr. Robert Miller, principal investigator of the PAS, will provide a presentation on the new data from Synapse.

According to Synapse CEO, they are confident that their device is safe and effective when used in patients that are “carefully selected and screened according to proper criteria.”  While it is not entirely clear if this is a suggestion that others have used the device without properly selecting or screening PALS, we expect that these criteria will be discussed at length during the talks from Drs. Miller and Onders later this year.

What occurred in the DiPALS study?

This was an independent study conducted at 7 sites in the United Kingdom which enrolled 74 PALS between 2011 and 2013. The final data from the study was collected in December of last year; the paper was published this July. The study aimed to determine a number of different things, but most generally whether or not the use of DPS together with NIV impacted the survival of PALS. Those not selected for the implantation group acted as the control group receiving NIV only when determined necessary as part of the standard of care of PALS. In total, 32 people in the study underwent DPS implantation.

All studies in the UK are monitored by independent boards of overseers, which in this case with the Data Monitoring and Ethics Committee. That committee determined that the cohort of PALS who received the implantation were succumbing to ALS quicker than those who were on NIV alone. As result, the committee advised the discontinuation of pacing in all patients and the trial stopped. The investigators in the study state that DPS should not be a routine treatment in PALS with respiratory failure.

In comparing their findings to the original work from Synapse which led to the DPS receiving Humanitarian Use Exemption from the FDA, the DiPALS investigators, led by principal investigator Dr. Chris McDermott (pictured), believe that their study was more representative of the general ALS population than the original work. For example, the DiPALS team suggests that the earlier study enrolled more slow progressing PALS in their study because they followed PALS for a period of 3 months before determining whether or not to enroll them, whereas in the DiPALS study they enrolled all PALS with the intent to treat, and randomized regardless of an individual’s progression rate. The DiPALS team leaves open the possibility that a subgroup of ALS patients may be able to be identified and benefit from DPS, but that a “nothing to lose” approach to treating ALS may be harmful to patients.

Bottom Line

This is a confusing topic for anyone in the ALS community whether they are a patient, family member, care provider, neurologist or allied health professional. The DPS story has been an evolving one for more than a decade and there are great differences of opinion between clinics on its potential efficacy and appropriate use. One of the things to note about these recent reports is that they were done in two different countries where the standard of care and practice in treating ALS patients can differ, so it is not as easy as comparing them directly to each other.

Without all of the data available for scrutiny from the new PAS study from Dr. Miller, it is challenging at this time to compare and contrast beyond the top line statements made. We will look forward to seeing that data in Orlando later this year. Since the DiPALS data has been published, we can comment further. It was a well designed study and seems to have been well-controlled as well. There are some questions left open, however, within any of the studies mentioned in this piece, and we look forward to investigating those as well (i.e. were there enrollment site specific adverse events, was there a relationship to FVC at implantation and median survival, was there a co-morbidity relationship in those whom had the device implanted and later removed, etc). Many of the unanswered questions are whether or not there is a specific “type” of ALS patient or correct “time” in the disease course to implant individual patients.

Through it all, PALS considering DPS should consult closely with their medical team regarding whether or not it may be an appropriate option for them. The device has still been granted a Humanitarian Use Exemption from the FDA and individuals must obtain a prescription from a doctor to get it. There are also strict limits set by the FDA on who can receive the device under the Exemption, most notably perhaps to ALS patients is that a person must have a FVC of greater than 45% at the time of implantation, and even then, if the diaphragm is found to not respond to stimulation during surgery or if there are other barriers found, the device will not be implanted. We encourage PALS and CALS to utilize online patient led websites, such as PatientsLikeMe and our ALS Forum, to interact with PALS whom have been implanted to learn more about those individual’s results.

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DISCLOSURE: The ALS Therapy Development Institute invited Dr. Onders to present his data on the device’s use in 2007 at our annual Leadership Summit. As with all Summit speakers, Dr. Onders’ travel costs were paid for by the Institute. As is allowed, we will report findings from the Synapse poster in Orlando via Twitter (@ALSTDI) as well as in a formal report to be posted to this website. 

Image Sources: Dr. McDermott's photo is from the MNDA Blog Post, the NeuRX image from Synapse's press release and the Nature Article image is of the first page of the PDF of that article.