Abbott Announces Interim Safety Data on Levodopa-Carbidopa Intestinal Gel (LCIG) as Treatment for Advanced Parkinson's Disease in the United States
On June 7, 2011, at the 15th International Congress of Parkinson's Disease and Movement Disorders (MDS) in Toronto, Canada, Abbott Laboratories revealed interim data from a long-term, open-label study treating advanced PD patients with levodopa-carbidopa intestinal gel (LCIG).
The Michael J. Fox Foundation spoke with Dr. Irene Richard, Associate Professor in the Department of Neurology at the University of Rochester, as well as Cleveland Clinic physician Dr. Hubert Fernandez, to discuss what it might mean for PD patients living in the United States should LCIG become a viable treatment here (The treatment is already available in Europe, under the brand name Duodopa).
Fernandez is one of the Abbott study investigators, and a first author on one of the LCIG posters that will be presented at MDS.
MJFF: First off, can you explain how levodopa and carbidopa alleviate Parkinson's symptoms?
IR: Normally, when a Parkinson's patient takes a levodopa pill, it gets absorbed into the bloodstream, and subsequently taken into the brain. The remaining nerve cells in the brain then convert this levodopa into dopamine.
The role of carbidopa is to ensure that the levodopa is not converted into dopamine in the bloodstream before it reaches the brain. Dopamine cannot pass the blood-brain barrier, and so if it were converted in the blood, it would be useless in treating PD. Dopamine in the bloodstream can also lead to bad side effects.
MJFF: If we already have a successful pill formulation of levodopa-carbidopa, why do we need to develop a different delivery system?
IR: To date, the only practical way levodopa could be administered was orally, and in this form it is somewhat erratically absorbed. Early on in PD, there are still enough dopamine nerve cells in the brain to provide fairly continuous conversion of levodopa into dopamine, and so the introduction of the drug simply mimics what the brain would normally do. But several years into the disease, people's nerve cells have continued to degenerate, which leads to a less continuous conversion of the drug into dopamine -- they get a more "peak and valley" conversion. This, along with other brain changes, can leading to what are referred to as motor fluctuations, sometimes referred to as the "on-off" phenomenon. "Wearing off" is when the effects of the medication wears off before people are ready for their next dose. This can leave patients in an "off" state characterized by poor mobility and a return of their symptoms. When the medication is working well (usually when levels of levodopa are optimal) patients have good symptom control and are said to be in an "on" state. However patients can develop excessive involuntary movements known as dyskinesias. This usually happens when the levels of levodopa are at their highest) Patients are only too familiar with wearing-off and dyskinesias that are very disabling. For example, patients may have to plan daily activities of living around the timing of their medications, which seriously detracts from quality of life.
We've known for years that if you could administer levodopa continually and more evenly, without the peaks and valleys, you can minimize motor fluctuations. But this has not yet been very practical: You can't stay hooked up to an IV all day, for example. However, another way to do this is to insert a tube directly into the intestinal tract. LCIG is a method of delivering a gel form of levodopa-carbidopa through the intestine so that there's a more even absorption of the levodopa into the bloodstream, and therefore, into the brain as well. The gel is continuously infused with a portable pump and a tube that is permanently inserted into the small intestine to provide an ongoing delivery of treatment. This methodology is proving more feasible.
MJFF: Tell us about the LCIG data Abbott is releasing today.
HF: To me, the major highlight of the interim results that we presented today is that LCIG reduced wearing off by an average of 3.9 hours per day. And it improved on time without troublesome dyskinesias by 4.6 hours per day. This is four times the magnitude of improvement from what we see in oral agents. The only other therapy we know of that has achieved these numbers is Deep Brain Stimulation (DBS), a surgical therapy for Parkinson's.
Moreover, we asked doctors to respond to how well they felt their patients were doing now compared to before the study, using a seven-point scale called the Clinical Global Impression Scale (from -3 "very much worse" to +3 "very much improved"). The mean CGI rating for our study was +2. You don't really see that very much in studies.
IR: It's important to note that what we're seeing today is still open-label safety data, and that we do need to wait for the results of the blinded study to fully confirm the robustness of these results. That said, it does appear that this sort of treatment shows promise for improving quality of life, without serious events. One question is how feasible this will be from an economic standpoint and whether or not insurance companies will cover the costs. LCIG is significantly more expensive than an oral medication. Moreover, since the apparatus requires care, nursing costs needs to be addressed.
MJFF: Speaking of the apparatus, tell us about the practicality of LCIG. What is it like to go through day-to-day life with this treatment?
HF: There are certainly pros and cons to the LCIG pump, and we came across some of these throughout the course of our research with Abbott. The cons mostly have to do with the device. It is external and requires maintenance -- it is taken off every night before bed and reattached every morning, and there is a relatively long travel distance throughout the body, which can sometimes kink, twist or form a knot. This distance is necessary for the tube to end in the small intestine and not in the stomach, in order to avoid interfering with the natural motions of the stomach.
But on balance, we believe that for patients with advanced PD, LCIG greatly improves quality of life. The pump allows for a constant delivery of the medication for 16 hours per day, which is enough to make a major difference in limiting side effects for patients taking levodopa. Moreover, we have worked to make the pump itself more user-friendly. We understand that PD patients are going to want to do things like shower and swim, and that they will be unable to do so with an external pump attached to their body. So we've developed a mechanism that can provide an extra booster dosage for when you do remove the pump.
MJFF: Why is the drug itself administered in gel form?
IR: Levodopa is not very water-soluble. If you were to administer it in a liquid form, you'd need huge, impractical volumes. The gel allows for delivery of the medication in a reasonable volume.
MJFF: Can you expand on some of the side effects/risks of LCIG?
IR: In order to get this type of gel into the intestine, you have to either insert a tube going through the nose into the intestine or you use something called a PEG tube which is inserted through a hole in the abdominal wall directly into the gastrointestinal tract. This can lead to complications like infection, and the tube itself can get blocked off or dislodged. Certainly, there are also cosmetic issues that come along with having an external device attached to the body.
But especially for those patients with advanced PD who for a variety of reasons can't or choose not to undergo the neurosurgery necessary for Deep Brain Stimulation (DBS), the PEG tube may in fact be the best option.
MJFF: You mentioned Deep Brain Stimulation (DBS) earlier. How does this compare to LCIG?
IR: In DBS, we insert an electrical stimulator that will modify the brain's activity in order to mimic dopaminergic stimulation. I actually think DBS is the intervention most relevant to use for comparison to LCIG. DBS may be an excellent option for many patients but not for those who have cognitive impairment, significant psychiatric problems, or who for any reason cannot undergo an invasive neurosurgery.
LCIG is an alternative to DBS for advanced PD patients. Someone who is not able to undergo DBS may still be able to handle the insertion of the PEG tube. This is the same procedure for patients needing a feeding tube when they are unable to eat later in life, so it's done all the time. For these patients, LCIG would likely be the better option.
MJFF: When could a U.S. PD patient realistically expect to see this treatment approved by the FDA and brought to market?
HF: The Swedes started with this treatment in the 1980s, but the technology was not yet sufficient nor user-friendly. The pump was huge and noisy, the tube wasn't very strong and it kinked and broke often.
Since then, our European colleagues have done a great deal of work in developing the technology. Two decades forward, we have a more nimble, silent, lighter, smaller pump, a stronger PEG tube and a more stable delivery system. The treatment is already approved in Europe.
LCIG is not yet commercially available in the United States as it has yet to satisfy FDA require
NOTE: This information should not be taken as medical advice. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.