NeuroVoices: Raymond Sanchez, MD, on Tavapadon in Parkinson Disease

Raymond Sanchez, MD

Cerevel Therapeutics recently announced that the first patients in the 3 TEMPO clinical trials have been officially dosed with tavapadon, its investigational Parkinson disease (PD) treatment. All 3 of the trials are of a phase 3 setting, with TEMPO-1 (NCT04201093) and TEMPO-2 (NCT04223193) assessing tavapadon in patients with early-stage PD and TEMPO-3 (NCT04542499) examining those with late-stage disease.¹

The drug’s mechanism contrasts the current landscape of PD treatments, which work at the D2 and D3 dopamine receptors. Tavapadon, a D1 and D5 dopamine receptor partial agonist, has been shown in phase 2 trials to improve motor symptoms of PD as measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 scores.

Its unique formula activates the direct motor pathway, potentially driving motor benefit while minimizing adverse effects typical of drugs that non-selectively stimulate dopamine, such as daytime sedation, or somnolence. In the latest edition of NeuroVoices, Raymond Sanchez, MD, chief medical officer, Cerevel Therapeutics, stopped by to discuss the TEMPO clinical trial development program, and the potential outlook for tavapadon as a new PD treatment.

NeurologyLive: Can you detail the TEMPO clinical development program? How will each study differ?

Raymond Sanchez, MD: There are 10 million individuals worldwide that suffer from Parkinson disease, including about a million in the US. There haven’t been any novel therapies approved in the last 20 years or so. We’ve seen mostly just reformulations and so forth. Tavapadon is a novel D1/D5 partial agonist that selectively targets the nigrostriatal pathway. The hope is that this therapy can enhance efficacy but also have a side effect profile that is much tolerable compared to the standard of care. To that effect, we have 3 clinical trials that are currently enrolling, as well as 1 that will start enrolling probably in the end of the first quarter of 2020.

We’ve got 2 clinical trials in early-stage Parkinson disease, both of which are 27 weeks long. These are patients who have been diagnosed within the past 2 to 3 years. They are not on levodopa but can be on an MAO-B inhibitor such as rasagiline and still qualify for the trial. What we’re trying to understand between both the fixed dose trial and the flexible trial is the impact on the change from baseline on 2 parameters in the MDS Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 2, which is activities on daily living, and part 3, which entails the motor score. We need to get a better understanding of what impact does this treatment have in terms of benefits on the motor score. How does that improve or impact the activities of daily living? Both trials will support our approach to getting this medication approved in early-stage Parkinson disease.

We also have the late-stage Parkinson disease trial in hopes that it can serve as another treatment for this patient population once levodopa is introduced and their disease continues to progress. That 27-week trial is also ongoing as well, but the primary end point is a bit different. We are trying to understand the impact that levodopa has on these patients. There are OFF periods where patients experience Parkinsonian symptoms, and then ON periods when patients are having the symptoms mitigated by the treatment. But you can have periods with dyskinesia and without dyskinesia, which is all secondary to the burden that comes with levodopa exacerbation on the dopamine receptor. The primary end point is ON time without troublesome dyskinesia, which is both the clinically and regulatory viable end point. We expect the early trials to readout in the second half of 2023. The third trial that includes late-stage PD will read out in the first half of 2023. All 3 trials are supported by a 58-week open-label trial that will continue to gather information on safety so that we can submit the dossier of trials to the FDA with all the needed safety information for approval for a broad label for the treatment of Parkinson disease.

What was previously observed in your phase 2 study?

The phase 2 trial was conducted in patients with early-stage PD. Throughout the 15-week study period, we saw separation from placebo as early as week 3, and that was sustained out to week 15, with a placebo adjusted difference of 4.8 points and a P value of .041. Importantly, we also saw a separation on the part 2 of the activities of daily living with a 1-point adjusted difference, which was also clinically meaningful. However, we noted that when we remove the 8 patients who had a 0 or 1 baseline score on part 2, we get closer to point placebo adjusted difference, which shows an even more clinically meaningful effect. Our hope is that in the phase 3 program, we can enrich the population by having that threshold of 2 points or greater. We don’t see that floor effect in the phase 2 setting, but the data gave us great confidence that we could achieve even greater efficacy, as well as the placebo response peaks at week 18. Subsequent to that, the 9 additional weeks of the trial will give us a chance to show a greater placebo adjusted difference because of the nature of the attenuation of placebo response. Again, from an efficacy perspective, there is hope that we can be at least as efficacious as the currently available standard of care than other D2 or D3 agonists, or even hopefully better.²

Of note, D2 and D3 agonists often have tolerability issues that are quite concerning and can actually be more debilitating than the actual symptoms of Parkinson disease themselves, especially in the early to mid-stages where a lot these patients are in their disease progression. From a tolerability perspective, we saw very exciting safety and tolerability data generated from our phase 1 program, as well as our phase 2 trial and from the advanced Parkinson disease phase 2 trial.

What advantages would tavapadon bring to the PD landscape?

It really speaks to the gap that exists in the treatment paradigm. If you look at the MAO-B inhibitors again, efficacy is compromised. They’re minimally efficacious and the D2 and D3 agonists have side effects that are prohibitive, such as somnolence, impulsivity, hallucinations, and hypertension. Within 2 years of having these medications prescribed, they’re either discontinued or something else is added to them, most of the time levodopa. The challenge is the earlier you introduce levodopa, the sooner you start exacerbating the dopamine receptor. As you go up on the dose, that exacerbation of the dopamine receptor causes the desensitization that you see which causes the dyskinesias that patient’s experience. Our hope is that by having a therapy that can actually have good efficacy with a tolerable safety profile, that it can be prescribed at the inception of diagnosis and be continued throughout the progression of the disease. Even when it’s introduced as an adjunct treatment to levodopa, given its long half-life and partial agonist mechanism of action, that it can sustain motor control, allow practitioners to reduce the levodopa dose, reduce the dyskinesia burden, and still have the needed motor control. In fact, our non-human primate trial showed just that.

What is the importance of studying both early-stage and late-stage PD?

It really is about treating the patient holistically and treating the patient’s journey throughout the disease progression. Trying to get those patients from the moment they’re diagnosed to the continuum to later stages of the disease and leverage the benefits of tavapadon at all stages. This would fill the gaps that currently exist in the treatment paradigm while also having a broad label for the treatment of PD, which is very important as well. It’s really to give the patients the treatment option of tapping on and the benefits of tavapadon through all stages of the disease, not just the early or late, but both of them instead.

If successful, would an FDA submission be on the horizon?

The submission to the agency would be a new drug application that would comprise of all 4 studies, both the 2 studies in early PD, 1 study in advanced PD, and the 58-week open-label safety data as well. The readouts for these trials will be collectively by the end of 2023, so our hope is to submit to the agency sometime shortly after that. The rate limiting step throughout the process is the enrollment of these trials. We have calculated these enrollments based on dialogue from the trial sites along with Syneos Health, who were working with to execute these trials. It’s really trying to achieve that enrollment and get the right patients in these trials.

Transcript edited for clarity.

REFERENCES

1. First participant treated in phase 3 trial of tavapadon for motor symptoms of Parkinson disease. News release. Cerevel Therapeutics. October 30, 2020. Accessed January 5, 2021.

2. Cerevel Therapeutics Announces Positive Results from a Phase 2 Study of Tavapadon in Patients with Early-stage Parkinson’s Disease. News release. Cerevel Therapeutics; September 23, 2019. Accessed January 5, 2021. businesswire.com/news/home/20190923005097/en/Cerevel-Therapeutics-Announces-Positive-Results-Phase-2.