But if you think about what you’re actually trying to achieve in the long term, it’s also reducing the potential for exposure to new agonists. And so if you think about how you could approach that population, you could actually begin with a lower dose range, gain the benefit of the kappa without having any kind of new antagonism that might induce withdrawal symptoms. And then as the patient progresses, you can actually increase the dose. So you actually bring in the Mu antagonism potential. What that does is, it has the ability to block the opioid activation if there is an exposure to an opioid in the future with that patient. So let’s say they have a relapse, they take an opioid agonist at that point. Having an anti-agonist could benefit that patient population both as a safety measure in terms of blocking activation with an opioid so you can prevent the potential for harm, but you can also, potentially depending on what exposure they get to what opioid, you can actually prevent the rewarding benefit.
And so you can imagine where you would start a patient going through the phase of withdrawal, starting with more of a kappa selectivity dose range. And what you could do is build up that dose range over time so that if there is an exposure, you have the protection of having a Mu antagonism benefit on board in that same patient. So that’s how we’re thinking about it.
Paul Matteis: Thanks a lot.
Ray Sanchez: Thanks, Paul.
Operator: Thank you. One moment for our next question. And our next question comes from Mohit Bansal of Wells Fargo.
Mohit Bansal: Great. Thank you for taking my question and thank you for having an [uneventful] (ph) quarter. I really appreciate it and congrats on the financing. I have two questions. One is on tavapadon. In our checks, doctors are suggesting that the dopamine agonists are a little bit out of fashion, they’re not used as much. So could you talk a little bit about how you’re thinking about the bar for success clinically, not just static benefit, what it should be? And then on second one, can you remind me, darigabat — about darigabat, what was the reason for slow enrollment and how you are mitigating that? Thank you.
Ray Sanchez: So, Mohit, thanks for that question on tavapadon. So if you think about the novel mechanism of tavapadon being a D1/D5 partial agonist that selectively targets those receptors of the direct nigrostriatal pathway, it really gives us the confidence that it’s going to be a transformative therapy in symptomatically treating Parkinson’s disease. Clinically, we’ve designed a program to show the benefits of both the monotherapy and as an adjunctive therapy in the monotherapy, 27-week trials looking at the UPDRS, Parts II which looks at the daily functioning and Part III that looks at the motor symptoms, and that’s the primary endpoint, and change from baseline is the primary endpoint on that. So to show really the benefits on not only motor symptoms but the quality of life as impacted by motor symptoms.
For the adjunctive trial, which is our first trial to read out in the first half of next year, we’re looking at the benefit of tavapadon as the best adjunctive treatment with levodopa to decrease the off time, but importantly increase the on time without troublesome dyskinesis, which is the primary endpoint, and really what’s clinically relevant. So that’s how we are thinking about that program. And really we’re thinking of it as really backbone therapy, meaning that when the patient is first diagnosed as being the best therapy to initiate patients on and then when levodopa needs to be introduced as the best adjunctive treatment. So we’re hoping that if the results read out as we expect that they will next year, that we will then proceed to file an NDA and give patients a transformative therapy for symptomatic treatment of Parkinson’s.
Ron Renaud: [indiscernible]
Ray Sanchez: So can — and, Mohit, can you repeat that question?
Mohit Bansal: Yeah, I mean, so the question was, can you remind me what was the reason for slow enrollment in the beginning and how are you trying to mitigate that? I think it was more to do with the fact that you were taking patients off the background medication, right? I mean, what was the issue there?
Ray Sanchez: No. So, there are a couple of reasons for the enrollment issues with the epilepsy program. Remember, these are patients who are drug resistant. There are at least one and no more than three anti-epileptics. They continue on those therapies at a static dose, so that’s not changed. One of the challenges that that program has had is the fact that the concomitant medications, concomitant anti-epileptics are 3A4 inducers. In fact, they are all 3A4 inducers and we, as you know, cannot allow patients who are on drugs that are 3A4 inducers because it impacts the pharmacokinetic profile of the therapy and it will impact the outcome of the trial. So the challenge there has been to find the right patient profile, but there are non-concomitant medications like carbamazepine, oxcarbazepine, and other therapies that are 3A and 4A inducers.
So we’ve been challenged by that. The good news is that John and his team have conducted a drug-drug interaction trial that will allow us to then overcome that obstacle in Phase III. But we really had to know the actual dose data based on those individuals that are not on those concomitant medications that would impact the pharmacokinetic profile. So what we’ve done is we’ve heightened the number of sites, the number of countries that we know well to increase the enrollment. We’re seeing great momentum. And so the good news is that we are planning to read out in mid-year next year. And if the results are what they are, then we can proceed with a robust Phase III program.
Ron Renaud: The other thing I might add here, I know there’s going to be more questions on tavapadon, Mohit, and as I mentioned in my prepared comments, we’re going to host an investor webcast focused on tavapadon on December 11th at 10 a.m. So tune into that and I think if you have additional questions, that will be a good forum to get some clarity.
Mohit Bansal: Thank you very much. Congrats on the progress.
Operator: Thank you. One moment for our next question. And our next question comes from Joseph Thome of TD Cowen. Joseph Thome, your line is open. Please check your mute. One moment for our next question. And our next question comes from Jeff Hung of Morgan Stanley.
Jeff Hung: Thanks for taking my questions. For CVL-871, can you talk about the challenges clinical sites are facing on patient identification for dementia-related apathy. And then for the darigabat realized study in focal epilepsy, what do you need to see next year to consider the proof-of-concept a success? Is there a particular bar for reduction in seizure frequency? Thanks.
Ray Sanchez: Hi, Jeff. Good morning. So the apathy program, as you know, the 871 program is a Phase 2a trial that’s really experimental in nature. As you know, it’s the leading neuropsychiatric syndrome that you see in patients with dementia, and we’re conducting in all of the dementias experimentally as a first step. It’s also a predictor of disease progression. There’s three components, and it’s really decreased goal-directed behavior, decreased emotional responsiveness, and lack of motivation. The challenge with that is that the landscape is really still trying to understand what that patient profile looks like. Remember, these are patients that are not agitated, they’re not really a problem clinically, but it does impact their quality of life.
