Emerging Therapies for the Management of PD OFF Episodes


Robert A. Hauser, MD, MBA; Laxman Bahroo, DO; and Rajesh Pahwa, MD, review emerging therapies in development for the management of OFF episodes in Parkinson Disease.

Stuart Isaacson, MD: And the emerging data or trials that you're excited about?

Robert A. Hauser, MD, MBA: I mentioned briefly IPX-203. This is the extended-release carbidopa levodopa formulation that just finished it's phase 3 trial. Patients with motor fluctuations that came into the trial. They underwent IR [immediate release] optimization and then were flipped over to 203, given no more frequently than every 6 hours. Then they went to a double dummy, double blind period. And then at the end of the day for good on-time, IPX-203 patients had 53 hours of good on-time than IR patients. Even as IPX-203 was administered on average 3 times a day, compared to IR patients receiving it 5 times a day. When you look at that, it looks like when you do the calculations of IPX-203, each dose provided 1.55 hours more good on-time. To me that's a pretty good result and once it's in our hands and available for clinical use, it will be very useful for patients. That is exciting advance.

Stuart Isaacson, MD: Laxman, do you think that this new IPX-203 will be a most optimal levodopa formulation, or do you think it will supplant your current extended release carbidopa levodopa patients or only at a portion?

Laxman Bahroo, DO: It's worth trying it. I'm curious about the data. I'm more curious about the mechanism of it. It's a mucoadhesive capsule. That is interesting mechanism as opposed to the traditional ways we've tried to extend levodopa with wax matrix or trying to do different level of beads coming in at different times. This is interesting because it has an adhesive component to it which plays into the fact that you want that longer duration. You're playing into a little bit of the GI [gastrointestinal] dysmotility that Parkinson's patients have. It's interesting from that point of view. It's certainly worthy trying and getting real world experience. While trials are helpful, we've realized time and time again, many times medications don't perform as trials show us, and many times we have to get our hands dirty with that medication to find out how we optimally use that medication. I always do the classic example over the last 5, 6 years that we've had which is the extended release carbidopa levodopa, most of us were expecting to dose it 3 times a day. All of us here probably dose more 4 times a day than 3 times a day in many ways. That was a little bit of a learning curve. Same thing with IPX-203 when, if approved will give us the same thing. And I probably extend that statement to the infusions. If these subcutaneous infusions come out, they'll have their own learning curve for how we use it in the American market.

Stuart Isaacson, MD: It seems like this theme to try to get a longer duration benefit from medication reflected in levodopa and now these infusions, it's somewhat interesting. Some people are concerned but it's a testament to the staying power of a precursor to a neurotransmitter that we're still talking about levodopa, Raj. Levodopa is our cornerstone therapy; it has been called the gold standard. But obviously it's not pure gold because we still have all these issues surrounding it. We have apomorphine as another molecule, and now there's 3. The sublingual film, we have the subcutaneous injection, and soon hopefully the subcutaneous infusion device, the continuous infusion device. Raj, do you think it would still be a change in focus from levodopa to apomorphine as a molecule that can more directly stimulate the dopaminergic system without having some of the variable absorption in the GI tract, transport across the blood-brain barrier, some of the issues with the levodopa getting into non-dopaminergic neurons perhaps as a false transmitter? Is there a case to be made for apomorphine being a golden standard than perhaps levodopa? You heard a debated recently, what do you think about this?

Rajesh Pahwa, MD: You can make a case for it, but levodopa still has some advantages. We know apomorphine is the most efficacious agonous we have. We know the efficacy of apomorphine is as good as levodopa, but some of the places where levodopa remains the leader or will remain the leader is one, it's a tablet. It's not a sublingual thing, it's not an infusion thing which is very convenient. A very cheap tablet on top of it. Using an apomorphine preparation, whether it's sublingual, whether it's subcutaneous infusion, we are still going a step further. If we look at some of the challenges that are there with these kind of therapies, whether it's skin issues, whether it is the orthostatic hypertension, all those are issues which we often don't have with oral levodopa. And then you have not only subcutaneous infusion of apomorphine, but right behind it are subcutaneous infusion of levodopa therapies. And again, that also gives it a continuous delivery of levodopa. Having said all of that, you can make a case for it but it's still going to be a few challenges to start calling apomorphine the gold ticket for Parkinson's. Levodopa is still going to reign king for a while, or queen for that matter.

Stuart Isaacson, MD: That was a fascinating discussion with everyone.

Transcript Edited for Clarity

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