Setting the TEMPO: What have we learned about D1/D5 dopamine stimulation in Parkinson’s disease?

Our focus is the TEMPO program, and in particular, the recently published TEMPO-2 trial that evaluated flexible-dose tavapadon as monotherapy in people with early Parkinson's disease. And I'm delighted to have with me today someone who is particularly well-placed to discuss these data, Professor Hubert Fernandez from the Cleveland Clinic, Cleveland, Ohio, who is the lead author of the TEMPO-2 publication.

Professor Fernandez, welcome to the [00:01:00] "MDS Podcast." It's a pleasure to have you.

Dr. Hubert Fernandez: Thank you for having me.

Dr. Divyani Garg: Perhaps the best place to start is not with the numbers, but let's get into the biology and the clinical rationale behind the program. We have spent decades using dopamine receptor agonists that predominantly stimulate the D2, D3 receptors. So what was the rationale for selectively targeting the D1 receptors, and what did you hope to achieve that the conventional agonists could not?

And was the primary attraction predominantly related to avoiding some of the adverse events, or was there some broader physiological rationale related to the basal ganglia pathways?

Dr. Hubert Fernandez: Yeah, I think this is a great question and thanks again for having me. The rationale for developing a D1 family dopamine agonist receptor, which stimulates the D1 and the D5 receptors in particular, stems from the success we had efficacy-wise on the D2, [00:02:00] D3, D4 receptor agonism.

So, these are the D2 family receptor agonism. This is, in different parts of the world, pramipexole or ropinirole or piribedil, maybe. And there is no question that clinicians and patients appreciated the significant efficacy in improving Parkinson's symptoms in these older-generation dopamine agonists.

And I have practiced long enough to remember the days where nearly every newly diagnosed Parkinson patient would be placed on a dopamine agonist. And if patients on levodopa developed motor fluctuations, nearly everyone would at least be tried on an older-generation dopamine agonist.

But of course, the world fell apart when we started noticing idiosyncratic side effects of these dopamine agonists. Impulse control behavior [00:03:00] disorders, sudden onsets of sleep, which we term sleep attacks. I think our sleep colleagues don't like that term very much. But then other things like weight gain, leg swelling, and things like that.

These side effects, idiosyncratic side effects, are purported to be due to the distribution of these D2 family receptors. They're not only spread into the striatonigral pathway, but also in the mesolimbic and cortical pathways and other pathways. And therefore, if you stimulate these D2 family receptors, you get not only the good things, but possibly the side effects as well.

Now, truth be told, these dopaminergic side effects can be seen in any dopaminergic medication, dopamine-enhancing medication, but they were really in higher percentages compared to, say, [00:04:00] levodopa or MAO-B inhibitors, COMT inhibitors. Even the generic, what we call generic side effects such as hallucinations, orthostatic hypotension, excessive daytime sleepiness occurred in a higher percentage in these older-generation dopamine agonists.

With a more selective D1/D5 receptor agonism, the hope was that it would be as good as these older-generation dopamine agonists in improving motor symptoms of Parkinson's, but with much less frequency of developing these idiosyncratic dopamine agonist side effects, and maybe even lesser frequency of developing generic dopaminergic medication side effects.

So that was the promise, or that was the hope that propelled this development of a D1 [00:05:00] family selective dopamine agonist. Now, there have been, truth be told, previous D1 agonist compounds that have been studied in the past, and indeed they improved motor symptoms, but perhaps they improved it too much, and they had a propensity to develop dyskinesias. And so they weren't marketed further in development. What's different with tavapadon is not only is it a selective D1/D5 receptor agonist, but it is also what we call a partial agonist.

Meaning the agonism isn't full, so as to cause a lot of dyskinesias, but it is selective enough to minimize this idiosyncratic side effect. Best case scenario we were hoping for is that it would be as equally efficacious as its old-generation dopamine [00:06:00] agonist available, the D2 receptor agonists.

But just as good and just as good as the older non-developed D1 agonists, but less likely to cause idiosyncratic side effects and less likely to cause dyskinesias as well. That is our kind of our best case scenario.

Dr. Divyani Garg: That's really helpful. So that brings us to the first major question about the clinical program. So TEMPO-1 and TEMPO-2 both studied early Parkinson's disease, but with differing dosing strategies. So TEMPO-1 had fixed dose strategy and TEMPO-2 had a flexible dosing strategy. So what did TEMPO-2 add beyond simply replicating the efficacy signal seen in TEMPO-1?

And when we talk about flexible dosing in the trial, does that largely mean that patients were given the opportunity to reach the higher dose if they could tolerate it?

Dr. Hubert Fernandez: Yeah. So truth be told, TEMPO-1, which is the fixed dose, we studied 5 [00:07:00] milligrams and 15 milligrams because the earlier phase 2 trials showed that perhaps the optimal dose is perhaps between 5 and 15. Anything more than 15 caused more side effects, and anything less than 5 was not as efficacious as if you reach 5.

So our best guess is between those two doses. But we weren't sure, so one had to be a flexible dosing. But it's likely between these two, and so concurrently, we did the TEMPO-2 and the TEMPO-1 study all together. So if you were a site, you were assigned either the TEMPO-1 or the TEMPO-2, but they were occurring together.

And the difference in the design, why do you need a flexible dosing and why do you need a fixed dosing? So there are advantages and disadvantages of either one. The flexible dosing, obviously the [00:08:00] advantage is, what if the ideal dose is 10 milligrams or 9 milligrams, then you wouldn't have known that if fixed dosing was your only pivotal trial, correct?

And if you made it fixed 5, 10, and 15, then you would need a much larger study trying to get the right number for each randomization, and it will be an uneven randomization of one is to one, because including the last one is the placebo. So you'll have a three is to one treatment randomization, which is a little bit uneven.

So, that's the benefit of what flexible dosing would... It could give you closer to the truth in the optimal dosing, efficacy-wise and safety-wise. Now, why not just a flexible dosing then, if that tells you everything you need? There is a negative in the flexible dosing, in that if you don't force someone to go a certain distance, [00:09:00] they might be content with a lower dose, and then you have a medication that works, but not as optimal as you'd like it to be.

Maybe there'll only be a 3-point improvement in the Parkinson motor score as opposed to 6 points if you force them, and they were able to tolerate it anyways, so you get the best of both worlds. So, we felt that we needed a little bit of both. We needed some, as close to a real-world experience in a flexible dosing on where they would land if they were given the option to stop at any time.

But we also needed to know how much improvement we can get if we force them to a lower dose and if we force them to a higher dose, and how many drop-offs do we get? How many people would not tolerate 15 if that was the only other choice that they [00:10:00] had? Both gave us important lessons, and I think that hindsight is always 20/20, and we're happy that we did TEMPO-1 and TEMPO-2.

Dr. Divyani Garg: That's really interesting actually, and thanks for explaining why both were important in their own ways. Let's move to the discussion of the outcome, because I think that is where there is an important methodological discussion. So why select a combined MDS-UPDRS Part II and III as the primary outcome?

For our listeners, Part II captures the motor aspects of experiences of daily living, whereas Part III is the clinician-rated motor outcome. So why combine these two?

Dr. Hubert Fernandez: Yeah so that's, it's a great question, why do you have an activities of daily living and a clinician-rated motor score together as your primary endpoint? This is probably in large part driven by the regulatory agencies. And so the US Food and Drug Administration, for [00:11:00] example, has a new emphasis to say that primary outcomes need to be relatable to patients and need to be appreciated by patients, right?

So the closest one we have there is their day-to-day functioning, their activities of daily living, so that is captured clearly in the Part II of the UPDRS. On the other hand, sometimes if it's only a patient-driven outcome, there is some subjectivity to it. They don't know. They have expectations on blindness and of study drug and hopes of getting the real drug and things like that.

And so if it is only on a subjective basis, it is relatable, but it is also subjective, right? And so you need an objective measure. The objective measure is the clinician-rated Parkinson motor score, the Part III of the MDS-UPDRS, which for decades has been time-tested. And so we [00:12:00] hope to get, again, the best of both worlds, very similar to a D1 selective but partial agonist getting the best of both worlds mechanism-wise, but here in primary outcome measure. If you combine a patient-relatable subjective outcome with a more stable, objective clinician-administered outcome, then you get the best of both worlds.

Thus, the birth of Part II plus Part III MDS- UPDRS combined.

Dr. Divyani Garg: Yeah, that is really interesting actually, and that may also shed some light on why this combined score showed a good large treatment effect, but Part II alone showed a more modest effect, and the PDQ-39 summary index, in fact, did not show significant improvement. That may be one way to reconcile these kind of observations that were seen in the trial.

Do you think that makes sense?

Dr. Hubert Fernandez: Yes. Yes, but there is some nuance to this, right? So, you [00:13:00] have what you call the MCID, the minimum clinically important difference, for the Part II, the activities of daily living. Believe it or not, it's just 1 point. If you have more than 1.5 point before versus after or after versus before, then you have a clinically significant difference.

The studies have shown for the Part III, the motor portion, you need 3 points. So if your score then was 15 and your score after the study drug exposure as a patient is now 12, that's a 3-point improvement for the better. That is clinically significant. Whereas if you improved from 15 to 13 or 15 to 14, that is a numerical improvement, but that is probably not clinically significant, at least in our studies, right?

And so the modest difference that you noted on the Part II [00:14:00] is certainly, it is modest numerically, but it has more than doubled the threshold of 1, which is all we need. So in the TEMPO studies, for example, in the flexible dosing, the TEMPO-2 trial, the combined difference compared to placebo of II plus III of the UPDRS was 9 points.

And so if you calculate the minimum clinically important difference of 2 plus 3, it'll be 1 plus 3, it'll be 4. So 4 is your threshold for the combined one, and we got 9, so it's more than doubled what we appreciated. Now, this is where I will go back to what I was saying, if you force people to go up higher for as long as they tolerate it, and tell them, "Don't stop, you just go to 15. That's your target is 15." So in the 15 milligrams treatment arm for the flexible [00:15:00] dosing study, the combined difference of II plus III MDS-UPDRS compared to baseline is 12 points, so it has tripled the minimum clinically important difference just by forcing people.

So the, the lesson here is if your patient is able to tolerate 15, there will likely be an even bigger treatment effect. In the 5 milligrams, there was 11-point difference. Of course, these are not the same participants, not the same sites, 'cause you have to choose between whether you're on the TEMPO-1 or the TEMPO-2.

So there are a few variabilities, but the bottom line is, yeah, although it seems modest for the Part II, the minimum clinically important difference is also more modest in the Part II compared to Part III.

With regards to your question on the PDQ-39, that's not surprising to us.

Our clinical trial experiences have shown that [00:16:00] the quality of life is the last to move the needle. They're usually seen in long-term studies. You need 6 months, preferably 1 year, of exposure to make a change in the quality of life. Which makes sense, right? So, in activities of daily living, what are you probing?

Whether you can dress easily, you could change clothes easily, your handwriting, your speech, and things like that. Which is the first relatable level of improvement. In quality of life, we're probing communication with others, social isolation, things like that.

So that is a higher order of improvement that you're probing. So obviously, if you have improvement in your function day to day, at some point it's going to translate into better social interaction, better communication, and things like that. But it's not immediate. It's very difficult [00:17:00] to appreciate that within 3 months of exposure.

Usually, you'll see that in 6 months and for sure in a year. Our studies lasted 26 weeks. And so it is for the most part, a short-term clinical trial. And so it's not surprising that the PDQ-39 wouldn't move a whole lot.

Dr. Divyani Garg: Yeah. So the efficacy signal, as you've explained, is impressive. But one striking finding was the 38% discontinuation rate tavapadon compared with the 15% with placebo and with adverse events being there in 24% versus 4%. And we can talk about that for a bit, but how should we interpret that when thinking about the real-world tolerability of tavapadon?

And does this have to do with the molecule or with how it was titrated? Because here we again talk about the going higher.

Dr. Hubert Fernandez: I think you hit the nail on the head that I think it's both. It is about the molecule in the [00:18:00] sense that it is still a dopamine agonist, and levodopa will cause nausea and vomiting and lightheadedness and sleepiness. Rasagiline will do the same thing, entacapone will do the same thing.

And so this drug is not exempt from that. But I think we need to interpret this with caution as well. We should know from this clinical trial that we have to be vigilant about this. But the other half of the story I truly believe is also the titration. In clinical trials, you have to go a little bit slower so that patients can tolerate the study and they can be in the study.

But you also have to be quicker because if it's too slow, you will lose patients. You might not see them back in follow-up. The study will be longer. It'll be more expensive. Every week extension of the study is more millions of dollars spent. In TEMPO-2, for example, we have over 500 patients [00:19:00] in 100 clinical trial sites.

So imagine one more, two more weeks of a study delay because of a very slow titration would cost a lot more money and resources. So it is always a science and an art in designing a study that is feasible but also will have the highest chance of showing what you have.

And so this is our best guess in finding the happy medium. But personally, the clinical trials are showing that your best guess could be even slower, I think. So the good news about this is in the real world, we can be as slow as we want to be. And as clinicians, we cut levodopa in half, in quarters, in however way we want it.

We tell our patients, for those who are very sensitive to the side effects, just take a half a tablet three times a day for three weeks. We go with what our [00:20:00] patients tell us, and there's nothing preventing us from being a bit more creative and slower in titration. So my prediction is, in the real world, we will likely have a slower titration than what we have done in clinical trials for some patients, not for all patients.

But it will still happen. These side effects will still occur despite our best intentions. And then for some patients, it may not be the drug, but I think for most other patients, if we do it in a slower titration, we counsel our patients enough before they start on it, they would appreciate the benefit very much.

Yeah.

Dr. Divyani Garg: I think what I find particularly interesting is that the same drug has been investigated both early in the disease and as an adjunct to levodopa later on. What does TEMPO-3, just touching on TEMPO-3 for a bit, what do you think that tells us about where this D1/D5 stimulation may fit across the trajectory of [00:21:00] Parkinson's disease?

And also understanding that these trials have looked at early Parkinson's disease and advanced possibly more advanced patients who are already on levodopa as an adjunct. But there's a large group of patients who are in between these two. Most of our patients may probably fall in that.

Where do you think the D1/D5 stimulation fits?

Dr. Hubert Fernandez: Yeah. I think this is-- it's a great question. But I think this is where our continued vigilance and monitoring on how best used this medication is will help us, right? Because we only have three clinical trials, pivotal clinical trials, in the extremes of the population.

It's not very extreme because the extreme end on the advanced are more for clinical trials on device-aided therapies and things like that. So it's a little bit, it's moderate, moderately advanced is one study, and then you have very early on the two other studies. And you have a lot of people [00:22:00] who are, doing okay on levodopa three times a day.

They technically aren't wearing-off, but they can also benefit from improvement, right? You have a whole lot of them. And do we have to wait for a wearing-off before we try someone on tavapadon, for example, is probably your question. We don't, but I think when ... as we are learning how to use the medication, I would encourage clinicians to use it in the official indication first.

Meaning you have newly diagnosed Parkinson patients. They're symptomatic now. They're ready for treatment. This would be a legitimate consideration. You have levodopa, you could try the tavapadon, the new drug, once it becomes available, or you can try other, rasagiline, for example, or other MAO-B inhibitors.

Those are all options, right? And then when they're on levodopa and they're experiencing motor [00:23:00] fluctuations, they're experiencing OFF time after each dose, then that would also be a good niche for tavapadon. The one in the middle would likely lag behind a little bit and would require your general sense of comfort as to what this medication is doing and as to how to use it how quick or slow the titration should be, and which patient you should be looking for.

And this is where the art of medicine comes into play. Truth be told, we have attempted, a few times, the middle population that you so want and we all clamor for. What about the middle? And the middle, unfortunately, in clinical trials is very tricky. We have medications that work in the beginning and in the moderately advanced.

You put it in the middle, no difference than placebo. There is something about this that maybe our endpoints are a little bit off, maybe we have [00:24:00] to define the population a little bit more, but those that are, "Eh, I'm okay. I could be better, but I'm not bad," and you test them, usually it's a very high risk for the industry to invest in that because they don't show a difference, and then they have a negative trial, and then you spent all that money for nothing.

Now, the world has changed. As you notice, we are now including the Part II as part of the primary endpoint. We didn't do that then because we were always Part III, and maybe with the patient's appreciation taken into consideration, the middle group could now have an indication for themselves. So it's still evolving and yeah, certainly this podcast gave me that idea that maybe we should retry this but have a combined Part II and III.

Yeah.

Dr. Divyani Garg: That's really wonderful. Now, this is my last question to you. So if you had to give one practical message about tavapadon to a movement disorders clinician [00:25:00] listening to this podcast, what would it be?

Dr. Hubert Fernandez: I think the biggest lesson that I could probably impart is that use the information in the clinical trials as a starting point when you want to consider using tavapadon. There is still a lot of things that we need to know, and certainly each patient is different, right?

Feel free to titrate slower than need be for patients that are very sensitive or quicker than need be for patients who are impatient and need symptomatic control very quickly, very readily. So the clinical trial is just your starting guide. But the road, the journey, really is mapped by you and your patient together.

And then the one other lesson is that do not be too puristic about this selective D1 agonism. Any dopaminergic medication can cause any side effects. The percentages [00:26:00] should be lower with the right mechanism of action, but it's not absent. Do not be discouraged by a few side effects here and there.

It is not the perfect molecule. It is certainly, in our opinion, a much improved molecule, but it is not the perfect molecule.

Dr. Divyani Garg: Those are great messages to end the podcast with. Thank you so much, Professor Fernandez, for joining me today.

Dr. Hubert Fernandez: My pleasure