Product information and disease description Place of product in therapy Approaches to treatment

Expected outcomes of therapy

14 evidence topics · 10 sources

Summary

Available treatments, tavapadon included, are symptomatic. Clinically meaningful thresholds used in this indication are about 1 hour per day for change in off-time or on-time without troublesome dyskinesia (MDS review threshold 1 hour; pramipexole extended-release trials 1.0 to 1.3 hours), 4 points for MDS-UPDRS Part III in the MDS review (anchor-based estimates of -3.25 points for improvement and 4.63 points for worsening), and 4.9 points for combined MDS-UPDRS Parts II and III as cited by TEMPO-1. In early disease, tavapadon reduced the combined Parts II and III score from baseline by 9.7 points (5 mg) and 10.2 points (15 mg) at week 26 in TEMPO-1, which the investigators described as approximately twice the minimal clinically important difference, and a meta-analysis of 2 monotherapy trials estimated a placebo-adjusted improvement of 10.55 points. As an adjunct, TEMPO-3 reported a least-squares mean reduction in off-time of 1.88 hours from baseline and a placebo-adjusted increase in good on-time of 1.1 hours; the pooled estimate from 2 adjunctive trials was 1.09 hours. No randomized trial of tavapadon identified by that meta-analysis lasted longer than 27 weeks.

Summary of efficacy and tolerability outcomes across the phase 3 trials

“Both studies met their primary efficacy endpoint of change from baseline of MDS-UPDRS part II + III scores with a statistically significant difference in favour of tavapadon vs placebo: − 11.5 points for 5 mg, − 12.1 points for 15 mg, and − 9.1 points in the flexible-dose study” (opens the source at this quote in a new tab)
“This study also met its primary endpoint with a significantly greater increase in ‘good ON-time’ versus placebo (+ 1.1 h)” (opens the source at this quote in a new tab)
“Discontinuation rates ranged from 24.3% in the 5 mg tavapadon treatment arm of the TEMPO-1 trial to 36.9% in the flexible-dose tavapadon treatment arm of the TEMPO-3 trial compared to 15.4% and 19.2% in the placebo arms” (opens the source at this quote in a new tab)
“Incidence rates for ICDs with tavapadon treatment were 0.8% and 2.4% in the RCTs and 1.4% in a preliminary interim analysis of a 58-week, open-label study (TEMPO-4, NCT04760769)” (opens the source at this quote in a new tab)

Minimal clinically important differences used to judge efficacy

“For changes in duration of ON‐time, OFF‐time, and time without dyskinesia, MCID was 1 h per day.” (opens the source at this quote in a new tab)
“For the UPDRS‐Part III and the MDS‐UPDRS‐Part III, MCID was 4 points.” (opens the source at this quote in a new tab)
“For the UPDRS and MDS‐UPDRS‐Part II, MCID was 3 points,” (opens the source at this quote in a new tab)
“and for the PDQ‐39, MCID was 5 points.” (opens the source at this quote in a new tab)

Minimal clinically important difference for off-time and UPDRS

“MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were -1.8 and -2.0, for UPDRS III -6.2 and -6.1, and for UPDRS II + III -8.0 and -8.1.” (opens the source at this quote in a new tab)
“MCID for "OFF" time (pramipexole ER, pramipexole IR) was -1.0 and -1.3 hours.” (opens the source at this quote in a new tab)

Minimal clinically important difference for MDS-UPDRS Part III

“Therefore, 728 paired follow-up visits of 260 patients were utilized for the analyses.” (opens the source at this quote in a new tab)
“The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening.” (opens the source at this quote in a new tab)
“Based on the ROC analysis, the best cut-off values discriminating no change from minimal clinical improvement and no change from minimal clinical worsening were −3.5 and +4.5, respectively (Table 3).” (opens the source at this quote in a new tab)
“Based on our data, all three measurements gave similar MCID threshold values: Any improvement larger than 3.25 points or any worsening larger than 4.63 points on MDS-UPDRS ME represent minimal, but clinically meaningful change.” (opens the source at this quote in a new tab)
“Based on these data, we can conclude that our MCID estimates for MDS-UPDRS are mostly in the range of previously published estimates for UPDRS and MDS-UPDRS.” (opens the source at this quote in a new tab)

Minimal clinically important differences for MDS-UPDRS Parts I and II

“In reference to Part II, the smallest changes considered clinically relevant were 3.05 and 2.51 points for improvement and deterioration, respectively.” (opens the source at this quote in a new tab)
“Investigations utilizing Parts I and II as outcome measure should apply the threshold of –2.64 and –3.05 points for revealing improvement or the threshold of 2.45 and 2.51 points for observing deterioration.” (opens the source at this quote in a new tab)
“Similarly, any improvement larger than –5.73 points or worsening more than 4.7 points on MDS-UPDRS I+II composite score represents meaningful perceived changes.” (opens the source at this quote in a new tab)
“Though Hauser and colleagues established markedly smaller MCID values for UPDRS-II (0.7 points for improvement and 0.5 points for worsening) examining patients treated with rasagiline” (opens the source at this quote in a new tab)
“they calculated similar estimates for improvement in early (– 1.8 and –2.0) and advanced PD patients receiving pramipexole (–1.8 and –2.3 points).” (opens the source at this quote in a new tab)

Minimal clinically important differences for the MDS-UPDRS composite scores

“Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change.” (opens the source at this quote in a new tab)
“should apply the threshold of –4.9 and +4.2 points for revealing improvement or deterioration.” (opens the source at this quote in a new tab)
“Based on our calculations, the MCID thresholds for the MDS-UPDRS I+II+III are –6.7 and +5.2 points for identifying clinically relevant improvement and worsening.” (opens the source at this quote in a new tab)
“Hauser and colleagues estimated the MCID thresholds for UPDRS 2 + 3 as being – 8.0 and –8.1 points in early PD and –7.1 and -8.8 points for advanced PD.” (opens the source at this quote in a new tab)
“Of note, our thresholds are considerably smaller, which may be partly explained by the different structures of these scales.” (opens the source at this quote in a new tab)

Minimal clinically important change in off time

“MCIC for reduction in ‘‘off’’ hours using this methodology is 1.0 hours (1.9–0.9 hours).” (opens the source at this quote in a new tab)
“Similarly, we found that a reduction in ‘‘off’’ time of 1.2 hours best distinguished active treatment subjects rated minimally improved from those rated unchanged.” (opens the source at this quote in a new tab)
“By definition, MCICs derived from ROC cutoffs are smaller than those derived using mean scores. Whether one approach is superior to the other to MCIC is unknown.” (opens the source at this quote in a new tab)

Expected magnitude of benefit with tavapadon monotherapy

“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.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“Further studies are needed to support the long-term safety and efficacy of tavapadon in this population.” (opens the source at this quote in a new tab)

Expected magnitude of benefit with adjunctive tavapadon

“The LSM decrease in off-time from baseline to week 26 observed in the tavapadon group (−1.88 hours) is comparable with improvements in off-time seen with other adjunctive PD therapies, including D2/D3 agonists, and surpasses the previously reported minimum clinically important difference for a reduction in off-time of approximately 1.0 hour.” (opens the source at this quote in a new tab)
“No significant differences between groups were observed in the PDQ-39, EQ-5D-5L index, and VAS scores.” (opens the source at this quote in a new tab)
“The 27-week treatment duration was comparable with other phase 3 trials investigating therapies for PD with motor fluctuations” (opens the source at this quote in a new tab)
“research is needed to support the long-term safety and efficacy of tavapadon.” (opens the source at this quote in a new tab)

Pooled efficacy estimates relative to minimal clinically important differences

“The effect substantially exceeded the minimal clinically important difference for the combined score, variously estimated at approximately 5 to 7 points” (opens the source at this quote in a new tab)
“the pooled estimate exceeds the commonly cited minimal clinically important difference of approximately 0.5 to 1.0 h for this endpoint, ascertained with the validated patient home diary” (opens the source at this quote in a new tab)

Pooled MDS-UPDRS Part II mean differences that differ between the secondary outcome text and figure 4 of a meta-analysis

“Tavapadon significantly improved patient-reported motor experiences of daily living, with a pooled LS mean difference of − 2.00 points (95% CI − 3.11 to − 0.90; p = 0.010) across all four poolable studies (Fig. 4).” (opens the source at this quote in a new tab)
“difference was − 1.65 points (95% CI − 3.01 to − 0.30; p = 0.030). Heterogeneity was moderate (I² = 58.4%, τ² = 0.39, Q(3) = 7.47, p = 0.058)” (opens the source at this quote in a new tab)
“Random effects model (HK) 100.0% -1.65 [-3.01; -0.30]” (opens the source at this quote in a new tab)

MDS-UPDRS Part II trial intervals stated to lie entirely below zero, one of which includes zero

“With the TEMPO-1 dose arms combined, four trials contributed: TEMPO-1 (− 2.55; 95% CI − 3.28 to − 1.81), TEMPO-2 (− 1.50; −2.40 to − 0.60), Fernandez et al. [12] (− 1.20; −2.20 to − 0.20) and B7601003 (− 0.08; −2.68 to 2.52).” (opens the source at this quote in a new tab)
“All individual studies favoured tavapadon with CIs entirely below zero.” (opens the source at this quote in a new tab)

Pooled adverse event profile of the D1/D5 partial agonist class

“Adverse events (RR 1.36, 1.09 to 1.71), nausea (6.38, 3.23 to 12.59), dizziness (3.03, 2.15 to 4.27) and discontinuation due to adverse events (2.72, 1.07 to 6.96) were more frequent with tavapadon.” (opens the source at this quote in a new tab)
“Serious adverse events were not increased (Peto OR 1.13, 0.69 to 1.85).” (opens the source at this quote in a new tab)
“Selective D1/D5 partial agonism improves motor function in early-stage and levodopa-treated Parkinson’s disease, at moderate certainty.” (opens the source at this quote in a new tab)