Not Your Mother’s Dopamine Agonist: Tavapadon

This transcript has been edited for clarity.Kathrin LaFaver, MD: Hi, and welcome on behalf of Medscape. My name is Dr Kathrin LaFaver. I'm a neurologist and Parkinson's specialist in Saratoga Springs, New York. I have the great pleasure today of talking with Dr Zoltan Mari, who is the Ruvo Family Chair for Parkinson's Disease and Movement Disorders Research at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. Welcome.Zoltan Mari, MD: Thank you for having me.Tavapadon vs Other Dopamine AgonistsLaFaver: We will be talking about tavapadon today. Now, tavapadon, as many know, was recently approved in the US by the FDA on September 28, and there has been a large amount of excitement around this approval. Zoltan, you were involved with many of the TEMPO studies leading up to the approval of this medication. To get us started, why don't we talk a little bit about how this medication is different from other medications already on the market, specifically other dopamine agonists.Mari: Dr Hubert Fernandez was working with Cerevel at the time and brought me in early at the clinical trial design phase, well before AbbVie acquired the company and the intellectual property to develop this.The idea was that dopamine agonists are sort of a yin and yang. On the one hand, they were hoped to relieve the burden of putting patients on large doses of levodopa early on in the disease. The promise was that it would mitigate or delay late motor complications of levodopa therapy. At the same time, their use was limited because of side-effect concerns, such as impulse-control disorders (ICDs), hallucinations, somnolence, and many other problems. That’s why they really never fulfilled the promise that they originally had. That put the emphasis on something new.Many people were skeptical about the whole dopamine agonist and direct receptor stimulation approach. But some people believed in it and kept at it. We are seeing the fruits of that work with tavapadon being approved.The idea was that the limiting side effects and problems with the classic dopamine agonists largely come from the D2, D3 receptor subfamily and engagement of those receptor types. A big part comes from the mesocortical and mesolimbic dopaminergic systems and the D2, D3 receptor family in those systems. While there are many benefits of direct receptor engagement other than levodopa and the buffer capacity of the nigrostriatal dopaminergic system, going directly to the receptor had great promise, but it was thwarted by the D2, D3 receptor adverse side.To solve that, the idea was to act selectivity on the D1, D5 receptor subfamily, which is different from other dopamine agonists. I consider tavapadon to be first in class because it is a dopamine partial agonist, if you will. It's selective to the D1, D5 receptor system.It has major advantages over levodopa in terms of continuous stimulation rather than pulsatile stimulation of the dopamine receptors, which has clear downstream benefits and allows for once-a-day dosing. None of the levodopa products are once-a-day dosing. It has that advantage, but without the bad part. Many describe dopamine agonists with "warts and all," but this one comes without the warts. That's why it represents something truly novel, which should carve out its own niche alongside many of the other treatment options we have in Parkinson's.Dual Approval as Monotherapy and Add-On TherapyLaFaver: That's certainly very important to understand the subtype receptor selective mechanism. A very unique feature is that tavapadon was approved for both monotherapy and add-on therapy for Parkinson's disease right from the get-go. Of course, that goes back to the trial design of the TEMPO studies. Could you just elaborate on what led to this dual approval?Mari: That was a bit of a surprise to many of us, and I think to AbbVie as well. The FDA decision took much longer than anyone anticipated, but when it did come on September 28, it came in flying colors better than anyone anticipated. It was worth the wait because the result was very much welcomed.It ties back to the planning phase of the trials, where the idea was that there could be a monotherapy and an add-on therapy purpose for the drug, and that is why there were three trials to begin with: TEMPO-1, TEMPO-2, and TEMPO-3. Then, all of them were rolled into the open-label extension called TEMPO-4.The TEMPO-1 and -2 trials were as monotherapy in treatment-naive patients. TEMPO-1 used a fixed dose; TEMPO-2 had a flexible dose. No site was supposed to get activated for both TEMPO-1 and TEMPO-2 because the study population was the same, so you could choose, as a site, which trial to participate in.Interestingly, my site was unique because we had patients in both trials. That was because there was a TEMPO-2 site in Las Vegas that had to shut down, and so all those patients were transferred to me. We were the highest enroller of TEMPO-1 and then also had TEMPO-2 patients, but it wasn't really a problem because patients did very well in both. This was, again, monotherapy in medication-naive, de novo diagnosed patients. With TEMPO-3, the primary goal was to enroll patients who already fluctuated and to see if tavapadon add-on therapy could reduce the OFF time. There are many extenders and other medications to do that, so the bar is lower to get that approval. From the initial communications with the FDA, it appeared that the approval would be as an add-on and just a general approval, but mostly it would be for patients who were already on levodopa, who had some OFF time.Then the FDA message came that it was approved for both indications, which is amazing. On the one hand, it was interesting that for the TEMPO-1 effort, the original clinical trial design included a combination of Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts 2 and 3 — so patients’ self-reports as well as the objective exam. The combined endpoint was significant as was part 2 alone, but not part 3 alone For some reason, the FDA said, "Just use part 2 of the UPDRS in our approval language." At this point, it doesn't matter as long as it's approved. That's how this evolved, and I think we all benefit from that because we can now gather real-world experience for both uses.Tavapadon Titration ChallengesLaFaver: Now that the medication is available, could you talk a little bit more toward the practical aspects of the prescribing, so the titration that is needed, and then also the side effects to watch out for? You mentioned there might be fewer side effects, such as somnolence, compared to the traditional dopamine agonists. There were also some discontinuations during the TEMPO trial. Why don't we talk some about these aspects?Mari: First of all, when it comes to titration, many of us who were involved with the tavapadon testing phase had some concerns about the rather long titration scheme. The company has developed a kit, which makes it easier and less burdensome for the patients, but it still takes a relatively long time. A silver lining, or bright spot, that I'd like to emphasize is that, based on the FDA's comments, it appears that the 5-mg dose is about as effective as the 15-mg dose. We have a very good therapeutic window. It also cuts down the titration time if you just have to get to 5 mg. The titration phase is not as daunting, but it's still relatively long. Now, I believe that when you have patients who are medication-naive who are starting one treatment or another, that investment of extra time with a patient-friendly and easy-to-follow titration scheme is not going to be as great of a concern, and it gives us the opportunity to intervene or slow the titration if they have any sort of tolerance or side-effect concerns.Tavapadon has an amazing tolerability and side-effect profile compared to traditional dopamine agonists. The most dreaded side effects, such as ICDs and hallucinations, were well in the single digits (< 5%).That's amazing.When it comes to somnolence, it is interesting that D1, D5 receptors probably wake you up a little bit. There was a little less somnolence in the actively treated group vs the placebo group, but the difference was not statistically significant. That’s big, because as much as everybody is aware of people gambling away their retirement funds and shopping and other types of ICDs, or hallucinations, the main reason patients can't take therapeutic levels of the traditional dopamine agonists is somnolence, sudden falling asleep, and narcolepsy type of problems. That’s at least as great of a fear as the ICDs. As it turns out, in the tavapadon group, there was no somnolence reported. There were discontinuations. We had patients who reported brain fog and other vaguely defined issues that need to be further investigated, because obviously the trial was set up for the traditional effects or fears associated with dopamine agonists. At least in terms of those side effects, we can check the box and say that it really outperformed and did exceptionally well. But we need to do more work to understand the other contributors to the relatively high discontinuation rate.Cost and Access IssuesLaFaver: As with all new medications on the market, cost and access to the medication, of course, is always a consideration. The Institute for Clinical and Economic Review actually had a public meeting about tavapadon on October 1 and had a somewhat cautious perspective, especially in regard to cost considerations. With that in mind, in your opinion, who would be the ideal patients to consider for tavapadon treatment, especially as it's just coming on the market now?Mari: The ideal patient is the one who can afford it. Seriously, I don't have my mind made up completely as to whether I would go for the fluctuating patient with the OFF time as an add-on or the de novo patient. I feel like the fluctuating patients probably have many more options available already in terms of extenders, infusion pumps, and long-acting forms of carbidopa/levodopa that work quite well. I would certainly have an open mind about using this in the that type of patient. I am a little bit more inclined toward the de novo patients because a drug-naive patient who is going on a monotherapy currently has fewer options available outside of levodopa.There is a study planned, INITIATE-PD by Amneal, which will evaluate whether late motor complications will be less severe, or delayed, if you start on a levodopa that is balanced and longer acting, closer to the physiologic state. It's still using levodopa. There's no question in my mind that if you eliminate any pulsatile stimulation, you will have a much better chance of helping these patients, especially younger patients who are more prone to developing early and more severe motor complications. That would be my ideal tavapadon patient, based on what I know today.But if their insurance company says, “Well, why don't you just use Sinemet [carbidopa/levodopa]? That's dirt cheap,” then we have a hard time because we don't have rock-solid evidence to support my belief that it would be good for them to have no compromise in their motor symptomatic treatment without being exposed to levodopa.LaFaver: I think that's a really important perspective. Of course, things will evolve over time. I think this was a really comprehensive overview of some of the nuts and bolts of this new medication, which we're all excited to see used more. Thank you so much, Dr Mari. Have a good day, everyone.Mari: Thank you so much for the opportunity.