Key Points
Question
Can treatment with tavapadon, an oral, once-daily, selective D1/D5 agonist, safely improve motor control for people with early Parkinson disease (<3 years’ disease duration)?
Findings
In this phase 3, double-blind, placebo-controlled, 27-week randomized clinical trial of 529 participants with early Parkinson disease, treatment with fixed daily doses of tavapadon (5 or 15 mg) resulted in significant improvements in Movement Disorder Society–Unified Parkinson’s Disease Rating Scale parts II and III combined scores at week 26 relative to placebo. Most adverse events were mild to moderate in severity; the most common adverse events in the tavapadon group were nausea, headache, and dizziness.
Meaning
Tavapadon provided statistically significant and clinically meaningful improvements in motor function with an acceptable safety profile in adults with early Parkinson disease.
Abstract
Importance
Tavapadon is an oral, once-daily, selective D1/D5 agonist that may improve Parkinson disease (PD) motor symptoms while minimizing adverse events (AEs) associated with D2/D3 receptor activation.
Objective
To evaluate the efficacy, safety, and tolerability of tavapadon in adults with early PD.
Design, Setting, and Participants
TEMPO-1 was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted at 102 sites across 12 countries between December 2019 and June 2024. Adults with early PD (<3 years’ disease duration) who were treatment naive or had less than 3 months of prior dopaminergic treatment were eligible for enrollment. Data analysis was completed from July 2024 to May 2025.
Intervention
Participants were randomized 1:1:1 to receive 1 of 2 fixed doses of tavapadon (5 or 15 mg once daily) or placebo for 27 weeks, followed by a 4-week safety follow-up period.
Main Outcomes and Measures
The primary end point was least-squares mean (LSM) change from baseline to week 26 in Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II and III combined score. Key secondary end points were LSM change from baseline to week 26 in MDS-UPDRS part II scores and the proportion of participants with a score of “much improved” or “very much improved” on the Patient Global Impression of Change.
Results
Overall, 751 adults with early PD who were treatment naive or had less than 3 months of prior dopaminergic treatment were screened, and 529 participants were enrolled (187 female participants [35.3%]; mean [SD] age, 63.7 [9.6] years; mean [SD] disease duration, 0.7 [0.8] years) and randomized to receive tavapadon, 5 mg (n = 177), tavapadon, 15 mg (n = 177), or placebo (n = 175). The change from baseline to week 26 in the MDS-UPDRS parts II and III combined score was significantly improved in participants treated with both the 5-mg dose of tavapadon (9.7-point decrease vs 1.8-point increase with placebo; treatment difference, −11.5 points; 95% CI, −13.8 to −9.2; P < .001; d = 1.14) and 15-mg dose of tavapadon (10.2-point decrease vs 1.8-point increase with placebo; treatment difference, −12.1 points; 95% CI, −14.4 to −9.8; P < .001; d = 1.20). Tavapadon had a favorable safety profile; most AEs were nonserious and mild to moderate in severity. Common AEs with tavapadon were nausea (90 of 354 with tavapadon [25.4%]), headache (59 of 354 [16.7%]), and dizziness (45 of 354 [12.7%]).
Conclusions and Relevance
In the TEMPO-1 randomized clinical trial, tavapadon improved motor function in participants with early PD and was well tolerated with a favorable safety profile.
Trial Registration
ClinicalTrials.gov Identifier: NCT04201093
The TEMPO-1 randomized clinical trial evaluates the efficacy, safety, and tolerability of tavapadon in adults with early Parkinson disease.
Introduction
Parkinson disease (PD) is a chronic, progressive, and disabling neurodegenerative disease impacting approximately 6.2 million people worldwide and resulting in substantial burden. Initial PD treatment targets motor symptoms by alleviating the progressive loss of dopamine neurons using dopaminergic therapies (eg, levodopa, dopamine agonists [DAs]). Oral levodopa is the preferred initial treatment for PD, but its long-term use is associated with development of motor complications, including so-called on-off fluctuations and dyskinesias. Compared with oral levodopa, currently approved DAs are associated with reduced dyskinesia risk and may be preferred for specific populations with early PD. However, conventional DAs may provide less motor symptom control than oral levodopa. Furthermore, on-market DAs preferentially or selectively target D2/D3 receptors, which may increase risk of adverse events (AEs) including somnolence, impulse control disorders (ICDs), hallucinations, and edema. Therefore, there is a key unmet need for an early PD therapy that improves motor symptoms while reducing the risk of AEs seen with current dopaminergic therapies.
Tavapadon is an oral, once-daily, selective D1/D5 partial agonist that has shown promise in phase 2 trials. By selectively targeting D1/D5 receptors, tavapadon may improve motor symptoms while reducing the risk of AEs linked to D2/D3 receptor overactivation. In a preclinical study, tavapadon was associated with strong motor control and reduced dyskinesias in nonhuman primates with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)–induced PD that had previously developed dyskinesias after long-term treatment with levodopa. In phase 2 trials, tavapadon improved motor function with an acceptable safety profile in people with early PD and PD with motor fluctuations. More recently, in the phase 3 TEMPO-3 trial (Flexible-Dose, Adjunctive Therapy Trial in Adults With Parkinson's Disease With Motor Fluctuations), tavapadon adjunctive to levodopa significantly increased on time without troublesome dyskinesia vs placebo in people with PD and motor fluctuations. The TEMPO-1 trial (Fixed-Dose Trial in Early Parkinson's Disease, NCT04201093) evaluated the efficacy, safety, and tolerability of fixed doses of tavapadon (5 or 15 mg once daily) for treatment of people with early PD.
Methods
Study Design
TEMPO-1 (NCT04201093) was a prospective, phase 3, multicenter, double-blind, placebo-controlled, parallel-group, 27-week randomized clinical trial conducted at 102 sites across 12 countries (see the trial protocol in Supplement 1 for more details). The trial ran from December 2019 to June 2024, and participation lasted approximately 34 weeks (4-week maximum screening period, 27-week treatment period, 4-week safety follow-up period; eFigure 1 in Supplement 3). Independent ethics committees approved the protocol prior to study initiation; the trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice guidelines, and Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. Written informed consent from participants or their representatives was obtained before screening and enrollment.
Participants
Eligible participants included adults aged 40 to 80 years with a diagnosis of PD consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria; a modified Hoehn and Yahr score of 1, 1.5, or 2; disease duration of 3 years or less; and naive to or previously had less than 3 months of treatment with levodopa or DAs. Prior and concurrent use of monoamine oxidase type B (MAO-B) inhibitors was permitted if initiated less than 90 days before the baseline visit (dosage needed to remain stable for the duration of the trial); all other PD medications were prohibited for the duration of the trial. Exclusion criteria included history of essential tremor, atypical or secondary parkinsonian syndromes, any clinically significant medical or psychiatric condition per investigator discretion, cognitive impairment, or abnormal laboratory values during screening. Demographic information (eg, race, ethnicity) was self-reported by participants.
Randomization and Treatment
Participants were randomized 1:1:1 to receive 1 of 2 doses of tavapadon (5 or 15 mg once daily) or placebo using a computer-generated randomization scheme, stratified by concomitant use of MAO-B inhibitors. Participants received the study drug corresponding to their sequentially assigned randomization number. Tablets and packaging were identical in appearance. For participants treated with tavapadon, the dose was titrated to the target dose using a fixed titration scheme (see eTable 1 in Supplement 3); participants were withdrawn from the study if they could not achieve the target dose. Both tavapadon groups were titrated to the 5-mg dose by approximately week 6; the 15-mg group achieved the target dose by approximately week 10.
Outcomes
The primary end point was the change from baseline to week 26 (primary efficacy time point) in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II (motor aspects of experiences of daily living) and part III (motor evaluation) combined score. Key secondary end points were the change from baseline to week 26 in the MDS-UPDRS part II score and the percentage of participants who had a Patient Global Impression of Change (PGIC) score of “much improved” or “very much improved” at week 26 (PGIC responders). Other secondary efficacy end points, assessed at several predefined time points (see eTable 2 in Supplement 3), included change from baseline in the following elements: MDS-UPDRS parts II and III combined score and MDS-UPDRS part II score (other time points beyond week 26), MDS-UPDRS parts I, II, and III combined and individual scores, and Clinician Global Impression–Severity of Illness (CGI-S), CGI-Improvement (CGI-I), and PGIC scores. Other end points included changes from baseline in scores on the 39-item Parkinson Disease Questionnaire, Schwab and England activities of daily living scale, and EuroQol 5-dimension 5-level index and visual analog scale (VAS).
Safety end points included AEs, clinical laboratory values, vital signs, electrocardiograms, and scores on the Columbia–Suicide Severity Rating Scale, Epworth Sleepiness Scale (ESS), and Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease Rating Scale (QUIP-RS).
Statistical Analysis
A sample size of 174 participants per group was determined to provide at least 90% power to detect a 4-point treatment difference in the primary outcome measure (2-sided significance level of 0.05; assumed SD of 9 points; 27% dropout rate). Participants, investigators, and all blinded sponsor personnel remained so until the final database lock. Further statistical analysis details are provided in the protocol (Supplement 1), and the statistical analysis plan is provided in Supplement 2.
Efficacy analyses were performed using a modified intent-to-treat (mITT) population (ie, randomized participants who received ≥1 dose of study treatment and had baseline and ≥1 postbaseline MDS-UPDRS assessment). Primary and key secondary end points were assessed for each of the 2 tavapadon dose groups vs placebo using a hierarchical testing procedure, with comparisons between the 15-mg tavapadon group vs placebo on the primary end point followed by comparison between the 5-mg tavapadon group vs placebo on the primary end point; analysis of key secondary end points followed the same hierarchical test order for MDS-UPDRS part II scores, followed by the PGIC response rate. A mixed model for repeated measures (MMRM) approach was used for analyses of MDS-UPDRS parts II and III combined scores and MDS-UPDRS part II scores, including fixed effects of treatment, visits, interaction between treatment and visit, and concomitant use of MAO-B inhibitors, with baseline scores included as a covariate and participant as a random effect. The proportion of PGIC responders from each postbaseline visit (repeated measures) was analyzed using a generalized linear mixed model with logit link, with the same model specifications as the MMRM previously described. Primary and key secondary analyses used an unstructured covariance structure. Continuous secondary end points were analyzed in a manner similar to the primary end point. The safety population included all participants who received 1 or more doses of the study drug. Statistical analyses were conducted with SAS software version 9.4 or higher (SAS Institute).
Results
Participants
Of 751 screened individuals, 529 were randomized to 5 mg of tavapadon (n = 177), 15 mg of tavapadon (n = 177), or placebo (n = 175); all 529 participants met criteria for the safety population, and 520 met criteria for the mITT population (Figure 1). Mean (SD) age was 63.7 (9.6) years, and 187 participants (35.3%) were female. In total, 129 participants (24.4%) discontinued the trial: 43 (24.3%), 59 (33.3%), and 27 (15.4%) in the tavapadon, 5 mg, tavapadon, 15 mg, and placebo groups, respectively. The most common reasons for discontinuation were AEs and withdrawal by the participant (Figure 1). Demographics and baseline disease characteristics were similar across groups and expected for a population with early PD (Table 1). The mean (SD) duration since diagnosis was 0.73 (0.80) years, mean (SD) baseline MDS-UPDRS parts II and III combined score was 31.8 (10.8), and 137 participants (25.9%) had concomitant use of MAO-B inhibitors.
Figure 1. Flowchart of Participant Disposition.
aReceived ≥1 dose of placebo or tavapadon as randomized (safety analysis set).
bEfficacy assessed in modified intent-to-treat (mITT) population, which included all randomized participants who received ≥1 dose of the study drug and had both a baseline and ≥1 postbaseline Movement Disorder Society–Unified Parkinson’s Disease Rating Scale assessment.
Table 1. Baseline Demographics and Disease Characteristics (Intent-to-Treat Population).
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Placebo once daily (n = 175) | Tavapadon, 5 mg, once daily (n = 177) | Tavapadon, 15 mg, once daily (n = 177) | Overall (N = 529) | |
| Baseline demographics | ||||
| Age, mean (SD), y | 63.5 (9.6) | 63.7 (9.8) | 63.8 (9.4) | 63.7 (9.6) |
| Age group, y | ||||
| <65 | 86 (49.1) | 85 (48.0) | 83 (46.9) | 254 (48.0) |
| ≥65 | 89 (50.9) | 92 (52.0) | 94 (53.1) | 275 (52.0) |
| ≥75 | 22 (12.6) | 27 (15.3) | 22 (12.4) | 71 (13.4) |
| Sex | ||||
| Female | 63 (36.0) | 66 (37.3) | 58 (32.8) | 187 (35.3) |
| Male | 112 (64.0) | 111 (62.7) | 119 (67.2) | 342 (64.7) |
| Racea | ||||
| American Indian or Alaska Native | 1 (0.6) | 0 | 0 | 1 (0.2) |
| Asian | 1 (0.6) | 0 | 1 (0.6) | 2 (0.4) |
| Black | 3 (1.7) | 0 | 2 (1.1) | 5 (0.9) |
| Native Hawaiian or Other Pacific Islander | 0 | 1 (0.6) | 0 | 1 (0.2) |
| White | 168 (96.0) | 174 (98.3) | 172 (97.2) | 514 (97.2) |
| Otherb | 2 (1.1) | 0 | 2 (1.1) | 4 (0.8) |
| Baseline disease characteristics | ||||
| Years since initial diagnosis, mean (SD) | 0.69 (0.77) | 0.75 (0.84) | 0.76 (0.80) | 0.73 (0.80) |
| Modified H&Y stage | ||||
| 1 | 23 (13.1) | 33 (18.6) | 36 (20.3) | 92 (17.4) |
| 1.5 | 23 (13.1) | 29 (16.4) | 14 (7.9) | 66 (12.5) |
| 2 | 129 (73.7) | 115 (65.0) | 127 (71.8) | 371 (70.1) |
| MDS-UPDRS scores, mean (SD) | ||||
| Part I | 5.2 (3.3) | 5.1 (3.8) | 4.8 (3.8) | 5.0 (3.7) |
| Part II | 7.4 (3.8) | 7.1 (4.0) | 7.7 (4.2) | 7.4 (4.0) |
| Part III | 24.7 (8.1) | 24.1 (8.6) | 24.3 (9.1) | 24.4 (8.6) |
| Parts II + III | 32.0 (10.0) | 31.3 (10.9) | 32.1 (11.6) | 31.8 (10.8) |
| CGI-S score, mean (SD) | 3.0 (0.7) | 3.0 (0.6) | 3.1 (0.7) | 3.0 (0.7) |
| Use of MOA-B inhibitor | ||||
| Yes | 42 (24.0) | 47 (26.6) | 48 (27.1) | 137 (25.9) |
| No | 133 (76.0) | 130 (73.4) | 129 (72.9) | 392 (74.1) |
Abbreviations: CGI-S, Clinical Global Impression of Change–Severity; H&Y, Hoehn and Yahr; MDS-UPDRS, Movement Disorder Society–Unified Parkinson’s Disease Rating Scale; MOA-B, monoamine oxidase type B.
Self-reported by participants.
Comprised participants who self-identified as Hispanic or Latino (n = 1), Angloindian (n = 1), North Africa (n = 1), and Caucasic (n = 1).
Efficacy
The change from baseline to week 26 in the MDS-UPDRS parts II and III combined score was significantly improved in both the 5-mg tavapadon group (least-squares mean [LSM] decrease of 9.7 points vs increase of 1.8 points with placebo; LSM treatment difference, −11.5; 95% CI, −13.8 to −9.2; P < .001; d = 1.14) and 15-mg tavapadon group (LSM decrease of 10.2 points vs increase of 1.8 points with placebo; LSM treatment difference, −12.1; 95% CI, −14.4 to −9.8; P < .001; d = 1.20). Improvements in MDS-UPDRS parts II and III combined scores in tavapadon-treated vs placebo-treated participants were observed as early as week 5 and continued through the end of treatment (Figure 2A). Subgroup analyses demonstrated improvements in MDS-UPDRS parts II and III combined scores with tavapadon across various populations (see eFigure 2 in Supplement 3).
Figure 2. Line Graphs Depicting Least-Squares Mean (LSM) Change From Baseline in Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts II and III Combined Scores (A) and Part II Scores (B).
aNominal P < .001.
bNominal P < .01.
cModified intent-to-treat population (all randomized participants who received ≥1 dose of the study drug and had both a baseline and ≥1 postbaseline MDS-UPDRS assessment).
Treatment with tavapadon significantly improved MDS-UPDRS part II scores from baseline to week 26 compared with placebo (LSM decrease of 1.6 points with 5-mg tavapadon vs increase of 0.9 points with placebo; LSM treatment difference, −2.5; 95% CI, −3.3 to −1.7; P < .001; d = 0.68; LSM decrease of 1.7 points with 15-mg tavapadon vs increase of 0.9 points with placebo; LSM treatment difference, −2.6; 95% CI, −3.4 to −1.7; P < .001; d = 0.70). Improvements in the 15-mg tavapadon group started at week 5 and continued to the end of treatment (Figure 2B). Compared with placebo, the proportion of PGIC responders at week 26 was higher with 5-mg tavapadon (45.5% vs 12.2%; odds ratio, 6.15; 95% CI, 3.34-11.32; P < .001) and 15-mg tavapadon (44.4% vs 12.2%; odds ratio, 5.97; 95% CI, 3.22-11.06; P < .001). The difference in the 15-mg tavapadon vs placebo groups started at week 5 and continued through the end of treatment (see eFigure 3 in Supplement 3). Any improvement on the PGIC at week 26 was observed in 73.5%, 72.6%, and 31.3% of the 5-mg tavapadon, 15-mg tavapadon, and placebo groups, respectively. Additional secondary end points are summarized in Table 2.
Table 2. Summary of Secondary Efficacy Outcomes at Week 26 (Modified Intent-to-Treat Population).
| Outcome | Placebo once daily (n = 174), week 26 | Tavapadon, 5 mg, once daily (n = 174) | Tavapadon, 15 mg, once daily (n = 172) | ||||
|---|---|---|---|---|---|---|---|
| Week 26 | Treatment difference | P value | Week 26 | Treatment difference | P value | ||
| MDS-UPDRS, change from baseline, LSM (95% CI)a | |||||||
| Part I | 0.5 (0.0 to 1.0) | 0.2 (−0.3 to 0.8) | −0.3 (−1.0 to 0.5) | .48 | 0.4 (−0.2 to 1.0) | −0.1 (−0.9 to 0.6) | .77 |
| Part III | 0.9 (−0.4 to 2.1) | −8.1 (−9.4 to −6.9) | −9.0 (−10.8 to −7.3) | <.001 | −8.5 (−9.9 to −7.2) | −9.4 (−11.2 to −7.6) | <.001 |
| Parts I + II + III | 2.3 (0.5 to 4.2) | −9.4 (−11.4 to −7.4) | −11.7 (−14.4 to −9.1) | <.001 | −9.7 (−11.7 to −7.7) | −12.0 (−14.7 to −9.3) | <.001 |
| CGI-Ia | |||||||
| Change from baseline, LSM (95% CI) | 0.2 (0.1 to 0.3) | −0.3 (−0.4 to −0.2) | −0.5 (−0.6 to −0.3) | <.001 | −0.2 (−0.3 to −0.1) | −0.4 (−0.5 to −0.2) | <.001 |
| Mean score, LSM (95% CI) | 3.9 (3.8 to 4.1) | 2.8 (2.7 to 3.0) | −1.1 (−1.4 to −0.9) | <.001 | 3.0 (2.8 to 3.1) | −1.0 (−1.2 to −0.7) | <.001 |
| Minimally improved or better, % | 31.76 | 74.24 | NA | NA | 68.38 | NA | NA |
| PGICa | |||||||
| Mean score, LSM (95% CI) | 4.0 (3.8 to 4.2) | 2.8 (2.6 to 3.0) | −1.2 (−1.4 to −0.9) | <.001 | 2.8 (2.6 to 3.0) | −1.2 (−1.5 to −0.9) | <.001 |
| Minimally improved or better, % | 31.3 | 73.5 | NA | NA | 72.6 | NA | NA |
| PDQ-39a | |||||||
| Change from baseline, LSM (95% CI) | 0.09 (−1.18 to 1.36) | −0.92 (−2.25 to −0.42) | −1.00 (−2.78 to 0.77) | .27 | 0.22 (−1.18 to 1.62) | 0.13 (−1.70 to 1.96) | .89 |
| Schwab and England ADL b | |||||||
| Change from baseline, LSM (95% CI) | −0.8 (−1.9 to 0.4) | 1.6 (0.4 to 2.7) | 2.3 (0.7 to 3.9) | .004 | 1.5 (0.3 to 2.7) | 2.2 (0.6 to 3.8) | .006 |
| EQ-5D-5L, change from baseline, LSM (95% CI)b | |||||||
| Index | −0.0223 (−0.0379 to −0.0068) | 0.0157 (−0.0007 to −0.0320) | 0.038 (0.0162 to 0.0598) | .001 | 0.0058 (−0.0113 to 0.0228) | 0.0281 (0.0057 to 0.0506) | .01 |
| VAS | −2.5 (−4.6 to −0.5) | −0.6 (−2.8 to 1.5) | 1.9 (−1.0 to 4.8) | .20 | −1.7 (−4.0 to 0.5) | 0.8 (−2.2 to 3.8) | .60 |
Abbreviations: ADL, activities of daily living; CGI-I, Clinical Global Impression–Improvement; EQ-5D-5L, EuroQol 5-dimension 5-level; LSM, least-squares mean; MDS-UPDRS, Movement Disorder Society–Unified Parkinson’s Disease Rating Scale; NA, not applicable; PDQ-39, 39-item Parkinson Disease Questionnaire; PGIC, Patient Global Impression of Change; VAS, visual analog scale.
Lower scores represent better outcomes.
Higher scores represent better outcomes.
Safety
In the safety population, 100 participants (57.1%) in the placebo group and 281 participants (79.4%) in the tavapadon groups experienced 1 or more AEs (Table 3); rates of AEs were similar in the 5-mg and 15-mg tavapadon groups. AEs led to treatment discontinuation in 7 participants (4.0%) in the placebo group and 64 participants (18.1%) in the tavapadon groups; the risk of discontinuation decreased after the titration phase. Most AEs were nonserious and mild to moderate in severity. Rates of serious AEs were low overall, with lower rates in the tavapadon groups compared to the placebo group. Two deaths occurred in the placebo group due to COVID-19 infection, and 1 death occurred in the 5-mg tavapadon group due to an unknown cause; no deaths were considered by the investigator to be related to the study drug.
Table 3. Summary of Adverse Events (Safety Analysis Set)a.
| Safety outcome | No. (%) | |||
|---|---|---|---|---|
| Placebo once daily (n = 175) | Tavapadon, 5 mg, once daily (n = 177) | Tavapadon, 15 mg, once daily (n = 177) | All tavapadon (n = 354) | |
| AEsb | 100 (57.1) | 142 (80.2) | 139 (78.5) | 281 (79.4) |
| Mild | 55 (31.4) | 73 (41.2) | 54 (30.5) | 127 (35.9) |
| Moderate | 34 (19.4) | 62 (35.0) | 68 (38.4) | 130 (36.7) |
| Severe | 11 (6.3) | 7 (4.0) | 17 (9.6) | 24 (6.8) |
| AE related to study drugc | 34 (19.4) | 90 (50.8) | 99 (55.9) | 189 (53.4) |
| Serious AEs | 11 (6.3) | 4 (2.3) | 10 (5.6) | 14 (4.0) |
| Serious AEs occurring in ≥2 participants in any treatment group | ||||
| COVID-19 | 3 (1.7) | 0 | 0 | 0 |
| COVID-19 pneumonia | 2 (1.1) | 0 | 0 | 0 |
| Pneumonia | 1 (0.6) | 0 | 2 (1.1) | 2 (0.6) |
| AE leading to discontinuation | 7 (4.0) | 29 (16.4) | 35 (19.8) | 64 (18.1) |
| AEs leading to discontinuation and occurring with ≥2% incidence in overall tavapadon group | ||||
| Nausea | 0 | 11 (6.2) | 9 (5.1) | 20 (5.6) |
| Dizziness | 1 (0.6) | 6 (3.4) | 3 (1.7) | 9 (2.5) |
| Headache | 0 | 2 (1.1) | 6 (3.4) | 8 (2.3) |
| Death | 2 (1.1)d | 1 (0.6)e | 0 | 1 (0.3) |
| Most common AEs (occurring with ≥5% incidence in overall tavapadon group and incidence greater than placebo group)f | ||||
| Nausea | 3 (1.7) | 42 (23.7) | 48 (27.1) | 90 (25.4) |
| Headache | 9 (5.1) | 22 (12.4) | 37 (20.9) | 59 (16.7) |
| Dizziness | 8 (4.6) | 24 (13.6) | 21 (11.9) | 45 (12.7) |
| Dysgeusia | 0 | 14 (7.9) | 14 (7.9) | 28 (7.9) |
| Fatigue | 6 (3.4) | 10 (5.6) | 16 (9.0) | 26 (7.3) |
| Vomiting | 1 (0.6) | 12 (6.8) | 9 (5.1) | 21 (5.9) |
| Dry mouth | 0 | 11 (6.2) | 9 (5.1) | 20 (5.6) |
| Anxiety | 5 (2.9) | 10 (5.6) | 9 (5.1) | 19 (5.4) |
| Safety topics of interestg | ||||
| Orthostatic hypotension | 2 (1.1) | 15 (8.5) | 8 (4.5) | 23 (6.5) |
| Hypotension | 4 (2.3) | 7 (4.0) | 9 (5.1) | 16 (4.5) |
| Hallucination | 0 | 0 | 11 (6.2) | 11 (3.1) |
| Somnolence | 6 (3.4) | 6 (3.4) | 5 (2.8) | 11 (3.1) |
| Impulse control disorders | 0 | 2 (1.1) | 1 (0.6) | 3 (0.8) |
Abbreviation: AE, adverse event.
Summary of most common AEs and select safety topics of interest by study phase (ie, titration and maintenance phases) are reported in eTable 3 in Supplement 3.
Any event occurring after initiation of the study drug.
Assessed by investigator as being related to the study drug.
Both due to COVID-19 infection; not considered by investigator to be related to study drug.
Cause of death unknown; not considered by investigator to be related to study drug.
Based on Medical Dictionary for Regulatory Activities (MedDRA) preferred term.
Safety topics of interest based on predefined custom MedDRA queries of several related terms. For example, the safety topic of interest orthostatic hypotension may also include AEs of postural dizziness, syncope, or presyncope.
The most common AEs observed more frequently in the tavapadon vs placebo groups were nausea, headache, and dizziness (Table 3). Common AEs (>5% incidence) occurred less frequently during the maintenance phase relative to titration, except for dysgeusia in the 15-mg tavapadon group, which was higher during the maintenance phase (see eTable 3 in Supplement 3, which reports select AEs by study phase).
Incidence of somnolence was similar across tavapadon and placebo groups (Table 3). Mean changes from baseline to week 27 in ESS scores were comparable between placebo and tavapadon groups (LSM change from baseline: placebo, −0.4; 5-mg tavapadon, −0.7; LSM treatment difference, −0.2; 95% CI, −0.9 to 0.4; P = .44; 15-mg tavapadon, −0.4; LSM treatment difference, 0.0; 95% CI, −0.6 to 0.7; P = .91).
Overall, 3 tavapadon-treated participants experienced AEs suggestive of ICDs (Table 3). All events occurred during the maintenance phase and were nonserious and mild or moderate in severity; 1 event led to treatment discontinuation and 1 event was unresolved at the end of the study. At baseline, mean (SD) total QUIP-RS scores were 5.4 (9.17) and 4.9 (9.34) for placebo and overall tavapadon groups, respectively. Changes from baseline to week 26 in total QUIP-RS scores were comparable between groups (LSM: placebo, −2.1; 5-mg tavapadon, −2.2; 15-mg tavapadon, −2.4; LSM treatment difference for 5-mg tavapadon, −0.1; 95% CI, −1.4 to 1.1; P = .85; treatment difference for 15-mg tavapadon, −0.3; 95% CI, −1.6 to 1.0; P = .64), resulting in mean (SD) total QUIP-RS scores of 2.9 (7.23) in the placebo group and 2.7 (6.82) in the overall tavapadon group.
Hallucination AEs were reported in 11 participants in the 15-mg tavapadon group. All events were mild or moderate in severity and nonserious, except for 1 serious event that led to treatment discontinuation.
Peripheral edema was uncommon in the tavapadon groups (overall, 5 participants [1.4%]; 5-mg tavapadon, 4 [2.3%]; 15-mg tavapadon, 1 [0.6%]) and incident at similar rates during the titration (0.8%) and maintenance (0.7%) phases. Peripheral edema was not reported in the placebo group.
Mean systolic and diastolic blood pressure (BP) decreased during titration in tavapadon-treated participants, with a mean (SD) decrease of −6.7 (7.31) mm Hg in supine diastolic BP in the overall tavapadon group vs a mean (SD) increase of 0.1 (7.45) mm Hg in the placebo group at week 27. The mean (SD) decrease in supine systolic BP at week 27 was −12.0 (13.17) mm Hg in the overall tavapadon group and −1.7 (12.25) mm Hg in the placebo group. These changes were comparable between the 5-mg and 15-mg tavapadon groups and decreased gradually during treatment with tavapadon; no such changes were observed in the placebo group. There was no apparent difference between groups in orthostatic BP assessments (≥20 mm Hg or ≥10 mm Hg decrease upon standing in systolic and diastolic BP, respectively), and reported AEs of hypotension and orthostatic hypotension were low (Table 3). No clinically significant safety trends were observed based on clinical laboratory findings, vital signs, and cardiovascular assessments.
Discussion
In this multinational, phase 3 randomized clinical trial, tavapadon demonstrated significant and clinically meaningful improvements in PD symptoms in participants with early PD. Once-daily dosing with tavapadon, 5 mg or 15 mg, led to reductions from baseline of MDS-UPDRS parts II and III combined scores at week 26 (−9.7 and −10.2 points with 5-mg and 15-mg doses of tavapadon, respectively) that were approximately twice as large as the minimum clinically important difference (>4.9-point improvement) in MDS-UPDRS parts II and III combined scores seen in other studies. Tavapadon also significantly improved MDS-UPDRS part II scores vs placebo. Finally, the proportion of PGIC responders was significantly higher in the tavapadon groups compared with the placebo group at week 26, suggesting that treatment benefits were meaningful to patients.
Nominal improvements in MDS-UPDRS parts II and III combined scores and MDS-UPDRS part II individual scores were observed as early as week 5, before the end of the titration period (tavapadon dose, 3 mg), with continued separation from the placebo group through approximately week 11. Improvements vs placebo were sustained through the end of study. Similarly, a significantly greater proportion of PGIC responders in the tavapadon groups relative to placebo was first observed at week 5; the proportion of responders in the tavapadon groups reached a plateau at week 14 in the 5-mg group and week 18 in the 15-mg group. These findings suggest tavapadon treatment can produce improvements in PD symptoms, even with lower doses.
The safety profile of tavapadon was favorable and consistent with earlier-phase trials; most AEs were mild to moderate in severity and allowed participants to continue tavapadon treatment. The incidence of AEs leading to discontinuation decreased substantially after the titration phase. This may be due in part to the fixed titration schedule and protocol requirement that participants who could not tolerate a titration step were to be withdrawn from the trial, which may have confounded discontinuation rates during titration. Currently available DAs preferentially target D2/D3 receptors, which may increase risk of specific nonmotor AEs (eg, ICDs, hallucinations, somnolence). Few participants treated with tavapadon experienced ICDs, similar to a prior study in participants with early PD treated with the D2/D3 DA pramipexole. Change from baseline to week 26 in QUIP-RS scores was not significantly different in participants treated with tavapadon vs placebo. Mean QUIP-RS scores after 26 weeks of treatment (2.7 in the overall tavapadon group) were well below the threshold when impulsive or compulsive behaviors become concerning (≥10 points), although longer-term evaluation is needed to confirm these findings. Rates of somnolence (3.1%) and hallucinations (3.1%) were also low in this study. Similar rates of hallucinations were reported in previous studies of DAs in participants with early PD treated with pergolide (3.4%), pramipexole (5%), and ropinirole (6% [defined as confusion, hallucinations, or delusions]). Prior studies of D2 or D2/D3 DAs reported higher rates of somnolence in participants with early PD treated with ropinirole (range across studied doses, 8%-15%) and rotigotine (range across studied doses, 18%-24%) compared with this study. Although the trial design precludes head-to-head comparisons, the low rate of these AEs in this study potentially supports the approach of selective D1/D5 agonism relative to on-market dopamine agonists, which primarily target D2/D3 receptors.
This study was designed to compare outcomes following treatment with tavapadon vs placebo, not to compare 5-mg vs 15-mg doses of tavapadon. While comparisons between tavapadon dose groups should be made with caution, similar improvements in the MDS-UPDRS scores were seen across dose groups in this study and are consistent with other studies demonstrating comparable efficacy across varying doses of DAs; for example, a dose-response study of prolonged-release ropinirole found similar efficacy in participants treated with 8 mg vs 12 mg daily, with no incremental improvements at the highest dose (24 mg). In addition to the consistent efficacy outcomes in the overall tavapadon group, subgroup analyses of participants treated with both 5-mg and 15-mg doses of tavapadon demonstrated motor improvement across predefined subgroups, although greatest consistency in improvements was seen in the 15-mg group, which suggests a higher dose of tavapadon may be necessary for specific populations. Further study may be needed to confirm these findings. Finally, efficacy across dose groups should be considered in the context of safety outcomes. For example, rates of certain AEs (eg, headache, hallucinations) were lower in the 5-mg group vs the 15-mg group. However, this should be interpreted with caution, as some AEs observed more frequently with participants randomized to 15-mg tavapadon occurred prior to reaching the target dose, and the overall AE incidence was comparable between the tavapadon groups.
Strengths and Limitations
The strength of this study was its rigorous, multicenter, double-blind, randomized, adequately powered design. Limitations include the fixed-dose design and rigid titration schedule, which precludes determination of optimal dosing, and the relatively short 6-month follow-up duration. Most participants (514 of 529 [97.2%]) were White, which may impact generalizability.
Conclusions
Tavapadon is an investigational, once-daily, selective D1/D5 agonist for the treatment of PD. In this phase 3 randomized clinical trial (TEMPO-1), a fixed daily dose of tavapadon (5 mg or 15 mg) significantly improved motor function in participants with early PD and was well tolerated with a favorable safety profile. Further studies are needed to support the long-term safety and efficacy of tavapadon in this population. An ongoing open-label extension trial, TEMPO-4 (NCT04760769), is enrolling rollover participants from phase 3 tavapadon studies (including TEMPO-1) and de novo participants receiving stable levodopa treatment and will help further characterize the clinical profile of tavapadon.
Trial Protocol
Statistical Analysis Plan
eTable 1. Tavapadon and Placebo Dosing Schedule
eTable 2. Assessment Schedule
eTable 3. Summary of Selected Adverse Events by Study Phase (Safety Analysis Set)
eFigure 1. Trial Design
eFigure 2. Subgroup Analysis of MDS-UPDRS Part II and III Combined Scores in Participants Treated With (A) 5 mg or (B) 5 mg of Tavapadon QD
eFigure 3. (A) Proportions of Participants With a PGIC Response of “Much Improved” or “Very Much Improved” Over Time and (B) PGIC Responses at Week 26
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
eTable 1. Tavapadon and Placebo Dosing Schedule
eTable 2. Assessment Schedule
eTable 3. Summary of Selected Adverse Events by Study Phase (Safety Analysis Set)
eFigure 1. Trial Design
eFigure 2. Subgroup Analysis of MDS-UPDRS Part II and III Combined Scores in Participants Treated With (A) 5 mg or (B) 5 mg of Tavapadon QD
eFigure 3. (A) Proportions of Participants With a PGIC Response of “Much Improved” or “Very Much Improved” Over Time and (B) PGIC Responses at Week 26
Data Sharing Statement
