Adjunctive Use of Tavapadon in Parkinson’s Disease: Interpreting the TEMPO-3 Evidence in Patients With Motor Fluctuations

Review this video on tavapadon as adjunctive therapy for Parkinson’s disease in patients experiencing motor fluctuations. 

Hello, and welcome to this overview of tavapadon as adjunctive therapy for Parkinson’s disease, or PD, in patients experiencing motor fluctuations. 

I’m Dr Stuart Isaacson, Director of the Parkinson’s Disease & Movement Disorders Center in Boca Raton, Florida.

In this video, we will review how findings from the TEMPO-3 trial may help inform treatment decisions for patients experiencing motor fluctuations.

In the current treatment landscape for PD, oral levodopa remains a foundational treatment for motor symptoms. However, long-term use with increasing dose is associated with motor fluctuations, which can negatively impact functioning and quality of life in patients with PD.  

Adjunctive therapy becomes especially important as PD progresses and patients receiving oral levodopa begin to experience less predictable motor control.

Motor fluctuations are common in patients with PD receiving oral levodopa treatment and can negatively affect activities of daily living and quality of life. Up to 75% of patients develop motor or nonmotor fluctuations after 4 to 6 years of levodopa therapy.

As motor fluctuations emerge, clinicians often evaluate whether additional therapy can extend the periods of good “ON” time when patients function well during the day.  

Good “ON” time refers to time with good mobility, smoother movement, and fewer motor and nonmotor symptoms without troublesome dyskinesia. Good “ON” time in PD is a key patient-relevant endpoint.  

Levodopa-treated motor fluctuations progress as the therapeutic window narrows. During “ON” periods, patients may have medication benefit but also develop involuntary movements; when these movements are bothersome or functionally disruptive, this is considered “ON” time with troublesome dyskinesia.

On the other hand, motor fluctuations and “OFF” time refers to the return or worsening of motor and nonmotor symptoms between medication doses.

Taken together, good “ON” time and “OFF” time help clinicians understand both sides of the patient’s day: the time when treatment supports functional mobility and the time when symptoms return or worsen. This patient-centered view of daily motor states provides the clinical context in which TEMPO-3 was designed.

The TEMPO-3 trial evaluated once-daily, flexible-dose tavapadon as adjunctive therapy to oral levodopa in adults with PD experiencing motor fluctuations.  

TEMPO-3 was a phase 3, double-blind, placebo-controlled, 27-week randomized clinical trial.  

The trial included adults aged 40 to 80 years with PD and motor fluctuations who were receiving stable oral levodopa, with a minimum stable dose of 400 mg per day. Participants also had at least 2.5 hours of daily “OFF” time on 2 consecutive screening days.

Patients were randomized 1:1 to tavapadon flexible dosing (5 mg to 15 mg once daily) or placebo, each adjunctive to levodopa. The levodopa dose was fixed throughout the trial. Tavapadon was titrated and dose-adjusted to the maximum tolerated dose, followed by maintenance dosing.  

This design reflects a practical clinical question: in patients already receiving levodopa but still experiencing motor fluctuations, can adjunctive tavapadon improve the amount and quality of functional motor time?

The primary endpoint directly addressed that question. TEMPO-3 evaluated the change from baseline to week 26 in total daily “ON” time without troublesome dyskinesia.

At week 26, daily good “ON” time was increased from baseline by 1.70 hours with tavapadon compared with 0.60 hours with placebo, for a treatment difference of 1.10 hours.

The timing of response is also clinically informative. Separation from placebo was observed as early as week 8, at which point the clinical difference was statistically significant, and was sustained through week 26 and the end of treatment.

For clinical interpretation, this means tavapadon was associated with an increase in daily “ON” time when patients had functional mobility without troublesome dyskinesia. In practice, that type of endpoint can be meaningful because it connects treatment effect to daily function, not only to motor examination findings.

The key secondary endpoint of TEMPO-3 focused on the change from baseline to week 26 in daily “OFF” time.

At week 26, daily “OFF” time was reduced from baseline by 1.88 hours with tavapadon compared with 0.93 hours with placebo, for a treatment difference of -0.94 hours.

Reductions in “OFF” time were observed starting at week 8, which was statistically significant, and continued through the end of treatment.

These findings demonstrated that adjunctive tavapadon increased good “ON” time and reduced “OFF” time in patients with PD experiencing motor fluctuations.

Beyond diary-based outcomes, TEMPO-3 also evaluated additional motor measures, such as the Movement Disorder Society–Unified Parkinson Disease Rating Scale, or MDS-UPDRS, Parts II and III, which were secondary endpoints.

MDS-UPDRS Part II assesses motor experiences of daily living, such as speech, swallowing, dressing, hygiene, handwriting, walking, tremor, and getting out of bed or a chair. MDS-UPDRS Part III is the clinician-rated motor examination, assessing signs such as tremor, rigidity, bradykinesia, gait, posture, and postural stability.

At week 26, tavapadon showed nominal improvements versus placebo on MDS-UPDRS Part II and Part III. The exploratory analysis of combined MDS-UPDRS Parts II and III scores also showed nominal improvement with tavapadon.

Now, let’s review the safety and tolerability data from TEMPO-3 to consider alongside the efficacy data.

Adverse events occurred in 71.1% of participants treated with tavapadon compared with 55.1% of those treated with placebo. Most adverse events were nonserious and mild to moderate in severity, and serious adverse events were similar between groups. The majority of adverse events occurred during the dose titration and adjustment phases and then decreased in the maintenance phase. Adverse events led to discontinuation in 17.1% of participants treated with tavapadon versus 9.1% of participants treated with placebo.  

The most common adverse events with tavapadon were nausea, reported in 14.3%; dyskinesia, 10.0%; dizziness, 7.6%; headache, 6.8%; fall, 6.4%; orthostatic hypotension, 6.0%; visual hallucination, 5.6%; and somnolence, 5.2%.  

Somnolence rates were similar between treatment groups, reported in 5.2% of participants treated with tavapadon and 4.3% of participants treated with placebo.

Impulse control disorder-related adverse events were reported at a similar rate between the tavapadon and placebo groups: 2.4% of tavapadon-treated participants versus 1.2% of placebo-treated participants. These events were nonserious and mild to moderate in severity.  

TEMPO-3 provided 27-week evidence in a levodopa-treated population with motor fluctuations, a clinically relevant setting for evaluating tavapadon as adjunctive therapy for patients with PD.  

The key takeaways from TEMPO-3 are clinically meaningful.

First, in patients with PD experiencing motor fluctuations while receiving oral levodopa, adjunctive tavapadon improved daily good “ON” time and reduced daily “OFF” time.

Second, the timing of separation from placebo, beginning at week 8 and continuing through the end of treatment, provides context for how clinicians may interpret treatment response over time.  

Third, the safety profile was monitored over 27 weeks in a levodopa-treated population. Most adverse events were nonserious and mild to moderate in severity. Serious adverse events were similar between treatment groups, and somnolence and impulse control disorder rates were similar between the tavapadon and placebo groups.  

Overall, TEMPO-3 provides clinically relevant evidence for evaluating tavapadon as an adjunctive option for patients whose oral levodopa therapy no longer provides consistent motor control throughout the day.

Thank you for joining this discussion of TEMPO-3 and the clinical evidence supporting tavapadon as adjunctive therapy for patients with Parkinson’s disease experiencing motor fluctuations on oral levodopa.

In Parkinson’s disease management, tavapadon’s selective D1/D5 agonism and clinical evidence in adjunctive settings helps inform its role as a treatment option that may support individualized care and address the patient burden of motor fluctuations.

INDICATION

Tavapadon is indicated for the treatment of Parkinson’s disease in adults.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hypotension/Orthostatic Hypotension: Patients with Parkinson’s disease (PD) may have an impaired capacity to respond to an orthostatic challenge. In clinical studies and clinical experience, dopaminergic medications appear to impair the systemic regulation of blood pressure, resulting in hypotension and/or orthostatic hypotension, especially during dose escalation. Patients with PD being treated with tavapadon should be monitored for signs and symptoms of hypotension/orthostatic hypotension, especially during dose escalation, and should be informed of this risk.

Impulse Control/Compulsive Behaviors: Patients may experience intense urges while on tavapadon. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while on tavapadon. Consider reducing the dose or discontinuing tavapadon if a patient develops such urges.

Hallucinations and Psychotic-like Behavior: Medications for the treatment of PD, including tavapadon, can have effects on thinking and behavior. Age appears to increase the risk of hallucinations in patients taking tavapadon. The risk of hallucination may be increased when tavapadon is co-administered with strong CYP3A inhibitors during the maintenance phase. Consider the risks and benefits prior to initiating treatment with tavapadon in patients with a major psychotic disorder because of the risk of exacerbating psychosis. Consider stopping tavapadon if hallucinations or psychotic-like behaviors occur.

Dyskinesia: Tavapadon may cause or exacerbate pre-existing dyskinesia. Consider decreasing the dosage of tavapadon or other dopaminergic medications if dyskinesia occurs.

Adverse Reactions 

The most common adverse reactions (≥5%) for tavapadon without concomitant levodopa were nausea, headache, dizziness, fatigue, dysgeusia, vomiting, dry mouth, and anxiety.

The most common adverse reactions (≥5%) for tavapadon with concomitant levodopa were nausea, dyskinesia, dizziness, headache, hallucinations, and orthostatic hypotension.

Drug Interactions 

Strong CYP3A inducers: Avoid use with tavapadon. Strong and moderate CYP3A inhibitors: avoid use with tavapadon during titration; tavapadon dosage modification is recommended during maintenance.

Moderate CYP3A inducers: Tavapadon dosage modification is recommended during titration and maintenance. Consult the full Prescribing Information for tavapadon for more information on drug interactions and recommended dosage modifications.

Dosage Forms and Strengths 

Tavapadon is available as 5 mg, 10 mg, and 15 mg tablets, as well as 0.25 mg and 1 mg tablets contained in a Titration Pack.

Please see full Prescribing Information or visit https://www.rxabbvie.com/pdf/juvmo_pi.pdf.

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