Given that CD/LD therapy for PD is highly individualized, what are possible advantages of longer-acting formulations of CD/LD and/or the availability of a scored, fractionable formulation of CD/LD highly amenable to titration by the patient or the physician?
the unfortunate reality is that the vast majority, almost all Parkinson patients will eventually experience motor fluctuations. Their initial honeymoon response to levodopa, where their symptoms are rather covered is not going to last forever. At some point in time, at some point in the duration of their disease. The effect of levodopa simply won't last long enough until the next dose. And so the most common motor fluctuation is wearing off initially. They can be predictable or they are predictable and later on. They may not be predictable. And then we have other labels or terms for motor fluctuation, dose failure, for example, is a condition where they take their medication and they don't even feel it working at all. And a delayed on is another one when they take their medication and it takes more than half an hour or 45 minutes for them to feel the on state or the medication working unpredictable off is when the off state occurs at any time and not towards the end of the next of the previous dose and things like that. But the universal, the common currency is that it's an off state and there is a resurgence of their stiffness, slowness, their tremor, and sometimes there is the occurrence of non motor symptoms such as slow thinking, urinary hesitancy, panic attacks, anxiety, depression in these off state. Those are what we call non motor off symptoms and when the medication works, they're no longer depressed, they're no longer anxious. They can pee again, they can think again and certainly they can move better. So the most most FDA approved drugs in Parkinson's disease have been in the area of motor fluctuations and wearing off and there's a big reason for this, the reason for this, the reasons are several fold one, it is so prevalent and therefore there is an unmet need to most. Almost all patients are really bothered by wearing off. If you survey Parkinson patients, what would be the most bothersome aspect of Parkinson's is when you survey patients, six years onwards in their disorder, number one would be motor fluctuations. And then the third reason is because we're rather successful in trying to alleviate it at least to some extent. And so there are many, many classes of drugs that can alleviate or try to alleviate motor fluctuations in patients on Levodopa with Parkinson's disease. Now, the other thing you'll notice is that there are lots of Levodopa formulations and there's a good reason for this as well because levodopa works and it is the most effective and it is the simplest way and the most rational way of addressing motor fluctuations. So you have your standard levodopa carbon dopa, Levodopa, regular or immediate release and that's our best, our favorite drug, most Parkinson's specialists, that's their favorite, that's my favorite. And the reason is because you give the medication and you can predict and what it does and you know which drug or which dose to blame if it's not enough. Right? So let's say you have a patient you give levodopa at 8:00. And the next doses not until 12 but it doesn't last until 12. They start having wearing off symptoms at 11 am. Therefore, you know it's the eight o'clock dose. That's a problem. Right? So you may want to increase your eight o'clock dose now when they take the 12 o'clock, the next doses not until four o'clock, but that works, it connects and therefore you know that the 12 o'clock dose is not a problem. And then they take their four pm dose. Their next doses not until eight p.m. And that falls short again. And so you know that the four p.m. Is a problem. So in this case my strategy would be to increase the dose at eight a.m. And the four p.m. Time slot and keep the dose at the 12 noon and eight p.m. Dozing schedule. So that's one option. So there are many ways of addressing this through levodopa alone. You can stay with regular levodopa and increase or decrease the dose ng as needed. You can add a long acting are controlled release levodopa. The problem with that is that it may not be reliable in its jump start or kick in effect but it may last longer. You have in generic form extended release levodopa in brand name, it's right terry which is a combination of short acting and long acting. So you get the kick effect benefit of the short acting and the long term benefit of the, of the extended release form of it. The conversion though of regular leva dopa to that of right terry or the extended release combination. Maybe a little bit tricky. And so that's something you need to be familiar with before you start converting patients from the combo of levodopa to, to the combo of levodopa from regular levodopa. Now recently there is the fractionated and scored levodopa. What is this? This is the same regular levodopa dozing tablet that we love, this is our favorite but it scored three ways and therefore you can, a patient can cut it conveniently in 25 mg increments. And so you could, the patient can give himself or herself 25 mg. 50 75 100 or 125 151 175 200 etcetera etcetera. Whereas a non scored or fractionated levodopa, you have the benefits of the regular one, the predictability of it. But since it's not scored, the most practical way of fraction ng it would just be in 50s, not in 25 and 75 or so. There is a limitation to that which the fractionated levodopa tablet may alleviate at some point, a subset of Parkinson patients will will have either brittle motor fluctuations where really half 50 mg adjustments may not actually be enough and they require a little less than that. Um because 50 mg jumps may cause these abnormal involuntary movements called Dyskinesia. Whereas If you get rid of the 50 then they'll have wearing off. So what they need is actually something in the middle, which is 25. And so the fractionated levodopa dose, maybe a very practical solution for this because it uses the drug that you are very familiar with, but it customizes it for you and for your patient so that you give the exact dose that they need for that Exact period of time in 25 mg increments.
