FormalPara Key Summary Points

Pridopidine is an investigational oral drug in clinical development for the treatment of HD, a fatal neurodegenerative disease for which no effective treatment is available

The PRIDE-HD phase 2 trial evaluated pridopidine in HD patients and included frequent ECG recordings with simultaneous drug plasma concentration measurements

We performed a concentration-QTc (C-QTc) analysis on data from PRIDE-HD to assess its potential to cause QTc prolongation, following the 2015 revisions to the International Conference on Harmonisation (ICH) E14 guidelines

The C-QTc analysis demonstrates that pridopidine causes a dose-dependent prolongation of the QT interval which is below the level of concern and is not clinically relevant at the therapeutic dose of 45 mg bid (ΔΔQTcF < 10 ms)

Analysis of an integrated safety dataset from three placebo-controlled studies of pridopidine in HD patients shows an overall low incidence of potential cardiac adverse events in patients receiving pridopidine, which is generally comparable to that in the placebo group

Introduction

Pridopidine is a highly potent and selective sigma-1 receptor (S1R) agonist [1]. The S1R is an endoplasmic reticulum (ER) protein located mainly at the mitochondria-associated membrane (MAM). The MAM regulates crucial cellular functions including calcium signaling, mitochondrial function, and the ER stress response, known to be impaired in Huntington’s disease (HD) and other neurodegenerative disorders [2,3,4,5,6,7]. Pridopidine activation of the S1R at the MAM exerts neuroprotective effects in various pre-clinical models of HD and other neurodegenerative diseases, including ALS, Parkinson’s disease (PD), and Alzheimer’s disease (AD) [8,9,10,11,12,13,14,15,16,17].

Pridopidine is currently being evaluated in a phase 3, double-blind, placebo-controlled study for the treatment of HD (PROOF-HD, NCT04556656, EudraCT 2020-002822-10).

HD is a rare, fatal, neurodegenerative disorder caused by polyglutamine-encoding cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin (HTT) gene, with an autosomal dominant mode of inheritance [18]. The disease is characterized by progressive motor abnormalities, cognitive decline, and psychiatric and behavioral disturbances. The estimated prevalence of HD in northwestern Europe, North America, and Australia ranges from 5.96 to 13.7 cases per 100,000 people [19,20,21]. In the United States (US), there are approximately 42,000 patients with manifest HD. In addition, ~ 100,000 people are at-risk mutation expansion carriers in whom the disease will appear should they live long enough [22,23,24].

The Unified Huntington Disease Rating Scale—Total Functional Capacity (UHDRS-TFC) is the standard, validated, and well-accepted clinical scale for tracking the clinical progression of HD [25,26,27,28,29]. No therapy has yet proven able to modify the inevitable and progressive functional decline due to the disease [30,31,32], representing a significant unmet medical need. PRIDE-HD was a global phase 2, double-blind, placebo-controlled study that evaluated the efficacy and safety of pridopidine in HD patients. Pridopidine 45 mg bid demonstrated a statistically significant effect in maintaining total functional capacity (TFC) compared to placebo at week 52 (pre-specified exploratory endpoint, mean change vs. placebo 0.87, nominal p = 0.0032) in all patients, irrespective of stage of disease. The effect of pridopidine 45 mg bid on TFC was mostly contributed by patients with mild to moderate HD (baseline TFC 7–13), as they represent ~ 70% of the patient population (post-hoc analysis, mean change vs. placebo 1.16, nominal p = 0.0003) [33].

Pridopidine’s safety and efficacy were also assessed in two prior randomized, placebo-controlled studies in HD patients. HART (ACR16C009) was a 12-week, phase 2 trial assessing pridopidine doses of 10, 22.5, and 45 mg bid vs. placebo. MermaiHD (ACR16C008) was a 26-week, phase 3 trial assessing pridopidine doses of 45 mg once daily (qd) and 45 mg bid vs. placebo. Both studies evaluated the safety and efficacy of pridopidine for motor symptoms of HD. In both HART and MermaiHD, pridopidine demonstrated a beneficial effect on motor function. Pridopidine showed a favorable safety and tolerability profile, with no cardiac safety concerns, no clinically significant arrhythmias, and no clinically significant changes in QTc intervals observed in any of the active treatment groups [34,35,36].

Corrected QT (QTc) prolongation is a risk factor for sudden cardiac death [37], as it increases the risk for torsade de pointes (TdP) as an immediate precursor to ventricular fibrillation and cardiac arrest. Thus, an increased QTc interval is a proxy biomarker for drug-induced risk of sudden cardiac death [38].

C-QTc analysis has gained international regulatory acceptance as a method to predict potential QTc effects for drugs not directly studied in a thorough QT (TQT) study. Revisions to the International Conference on Harmonisation (ICH) E14 Questions and Answers (Q&A) document made in 2015, reflect the acceptability and validity, according to regulators in all jurisdictions, of C-QTc analysis as the primary analysis to exclude that a drug has an effect on the QTc interval [39,40,41,42,43]. The revised E14 guideline states that: “Concentration–response analysis, in which all available data across all doses are used to characterize the potential for a drug to influence QTc, can serve as an alternative to the by-time-point analysis or intersection–union test as the primary basis for decisions to classify the risk of a drug.” Importantly, the guideline specifies that “The upper bound of the two-sided 90% confidence interval (CI) of the predicted placebo adjusted ∆QTc should be below 10 ms at the highest clinically relevant plasma concentrations of the drug.”

To investigate the potential of pridopidine to cause QTc prolongation, a C-QTc analysis was performed, following the specific revised ICH E14 guidelines and recommendations detailed by Garnett et al. in 2018 [44, 45]. A comprehensive C-QTc analysis was conducted on data from 402 patients with HD treated with pridopidine or placebo in PRIDE-HD.

The objective of the analysis was to assess the relationship between pridopidine plasma concentration and QT prolongation and to predict the QT effect (placebo-corrected ∆QTc) at the clinically relevant dose of pridopidine 45 mg bid (i.e., the dose currently evaluated in the HD clinical trial). Furthermore, the cardiac safety profile of pridopidine was evaluated in PRIDE-HD alone and in an integrated safety dataset from the three placebo-controlled clinical trials of pridopidine in HD (HART, MermaiHD, and PRIDE-HD).

Methods

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Statistical Analysis

General Methodology

All statistical reporting of the study was performed using the statistical software R for Windows (version 3.2.2 or a later version).

PRIDE-HD

PRIDE-HD was a dose-finding phase 2 trial assessing pridopidine in 408 HD patients at four doses: 45, 67.5, 90, and 112.5 mg bid vs. placebo (1:1:1:1:1 randomization ratio) for 52 weeks. ECGs were collected and centrally read. Simultaneous drug plasma concentration measurements and ECGs were obtained at baseline (pre-dose), before the afternoon dose at three visits, and 1–2 h (estimated time to peak plasma concentration (Tmax) after the afternoon dose at seven visits. Time points for blood draws for the determination of plasma concentrations of pridopidine and ECGs are shown in Table 2.

Analysis Sets (PRIDE-HD)

For each timepoint and each treatment group, summary statistics, including mean, median, and a two-sided 90% CI, were calculated based on all patients with a valid baseline Fridericia-corrected QT interval (QTcF) value (i.e., the average of at least two pre-dose values) who had at least one valid post-baseline QTcF value. Any values obtained more than 1 day after the last dose of pridopidine were excluded.

The pharmacokinetic (PK) analysis set includes all randomized participants who received at least one dose of pridopidine and had at least one plasma concentration result to allow the intended PK analysis. Patients who had drug concentrations above the limit of quantification at the pre-dose visit on the baseline day were excluded from the PK and the ECG analysis set.

PK data from PRIDE-HD were analyzed to see if there were differences in pridopidine plasma concentrations across the different doses and if the differences in mean concentrations between successive increasing doses were statistically significant. Since PK data tend to be skewed, they were log (base 10) transformed. The log-transformed data were analyzed to compute means and CIs. Hypothesis testing was performed using a two-sample t-test. Means and CIs were back transformed and are presented in original units.

ECG Analysis Set

In PRIDE-HD, for all ECG parameters, the baseline value was the average of the three ECGs, each performed in triplicate (nine readings in total), obtained at the baseline visit at the pre-dose timepoint. All ECGs were centrally evaluated at an ECG laboratory using a semi-automated measurement technique. In HART and MermaiHD, the baseline pre-dose values were the averages of triplicate ECGs, with single ECGs performed at all other visits.

QTcF

QT corrected according to Fridericia’s formula is defined as QTcF = QT/RR0.33, where RR is the interval between two consecutive R waves [46].

Exposure Response Analysis

The C-QTc analysis for PRIDE-HD was performed using data from all patients with valid ECGs and PK data. Individual post-baseline values (including the post-drug timepoint at the baseline visit) where the PK blood sample was drawn more than 30 min from the time of the last ECG replicate assessment were excluded.

ECGs were paired with PK samples (n = 3071) and were used for the development of a cardiac C-QTc model. In total, there were 2753 ECGs from pridopidine-treated patients and 763 from placebo-treated patients. The relationship between the change from baseline in the corrected QT interval (ΔQTc) and pridopidine plasma concentrations was investigated by linear mixed-effects modeling. A series of models were fitted. All models used the change-from-baseline Fridericia-corrected QT interval (QTcF) (ΔQTcF) as the dependent variable and the plasma concentration observed at the same timepoint as a covariate. The “base” model included two factors, one for time and one for treatment. The time factor had a level for each visit/timepoint combination at which a pair of QTc and PK values were obtained. Given the irregular sampling pattern, no further substructure was used (i.e., the levels of this factor are baseline post-dose, week 2 post-dose, week 4 pre-dose, week 4 post-dose, etc., see Table 2). The treatment factor has the levels “active” and “placebo,” with it mainly serving as a check for the appropriateness of the model. If the model is appropriate, i.e., the relationship is well estimated by the linear model and there is no delay between PK and QTc, the treatment effect should be small and not significantly different from zero. A second model, “with baseline,” included the observed baseline QTcF as an additional covariate. Finally, a model with only concentration and intercept (“simple”) was added. All models used random effects per subject for the intercept and concentration of pridopidine. Model fit was investigated by quantile–quantile (QQ) probability plots for the random variables and plots of residuals by predicted value and by concentration. Models were evaluated for goodness of fit and according to their Akaike information criterion (AIC) value. A similar series of models using the Emax function of concentration (i.e., the concentration giving the maximal effect of the drug) instead of concentration itself was considered for the case of nonlinearity, but was not pursued since a linear model provided an acceptable fit to the data. Predictions of the effect on QTcF based on all three models were made for each dose group at the geometric mean of the individual maximum plasma concentration (Cmax) values of the patients in the respective group.

For the evaluation of pridopidine’s potential for QTc prolongation, we have followed the E14 Questions & Answers (R3) guideline published in 2015 and calculated the largest time-matched mean difference between the drug and placebo (placebo corrected or ∆∆QTcF) over the collection period.

Integrated Safety Dataset of HART, MermaiHD and PRIDE-HD

The PRIDE-HD, HART, and MermaiHD studies were approved by the institutional review boards (IRBs) and were performed in accordance with the Helsinki Declaration. All patients in the studies provided informed consent to participate in the study.

The study design and the visits at which PK and ECG data were collected in each of the three studies are presented in Tables 1 and 2, respectively.

Table 1 Double-blind, placebo-controlled clinical trials in HD patients that informed pridopidine’s cardiac safety profile
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Table 2 Schedule for ECG and PK assessments used in the PRIDE-HD C-QTc analysis
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The HART and MermaiHD studies included high-quality, centrally read ECG assessments, but did not collect concordant PK samples. Thus, safety and ECG data were analyzed, but no C-QTc analysis was performed. Adverse event analysis datasets from HART, MermaiHD and PRIDE-HD were pooled to create an integrated safety database. Adverse event analysis was performed on the pooled dataset to determine incidence rates of cardiac events.

Results

Participant Disposition, Demographics, and Baseline Characteristics

Demographics and baseline cardiac safety characteristics in PRIDE-HD were generally similar across the treatment groups (Table 3). The mean age was 50.4 years (range 22–81 years). The majority (93%) of patients were white, and the percentages of male and female patients were similar (50% males and 50% females).

Table 3 Demographics and baseline characteristics in PRIDE-HD
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Pharmacokinetics

The time courses of post-dosing plasma concentration by dose group in PRIDE-HD are provided in Fig. 1. Pridopidine shows a dose-dependent increase in plasma concentrations, which reached steady state and did not vary much further beyond the week 6 visit. At the clinically relevant dose of 45 mg bid, mean plasma concentration taken 1–2 h post-dose (approximate Tmax) varied between 637 and 699 ng/mL from week 6 onwards. Mean plasma concentrations varied between 1020 and 1130 ng/mL, between 1364 and 1461 ng/mL, and between 1636 and 1760 ng/mL in the 67.5 mg, 90 mg, and 112.5 mg bid dose groups, respectively. Summary statistics of mean plasma concentrations (ng/mL) by group and visit are presented in Table S3 in the Supplementary Information.

Fig. 1
figure 1

Dose-dependent increase in pridopidine plasma concentration over 20 weeks (PRIDE-HD). Plasma concentrations were measured 1–2 h post-dose. Data are mean ± standard error (SE)

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Effect on Heart Rate (HR)

In PRIDE-HD, pridopidine generally had a small effect, with little variation of the mean change in HR from baseline (ΔHR). For the placebo-treated patients, ΔHR had mean values within ± 2 beats per minute (bpm) at all post-dosing timepoints. At the clinically relevant dose of 45 mg bid, mean ΔHR at all post-dose timepoints varied between 2.5 and 4.3 bpm. In the two treatment groups with the highest doses (90 and 112.5 mg bid), the mean ΔHR varied between 1.7 and 6.1 bpm and between 5.1 and 9.9 bpm, respectively (Fig. 2 and Table S2 in the Supplementary Information). Based on these small changes in heart rate, it was appropriate to use QTcF for the heart rate correction of the QT interval assessment [47].

Fig. 2
figure 2

Effect of pridopidine on the mean change in heart rate from baseline (ΔHR) (PRIDE-HD). Each measurement represents the difference between the HR assessed 1–2 h post-dose at a given visit and the pre-dose HR at the baseline visit. Data are mean ± standard error (SE)

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Pridopidine’s Effect on the QTc Interval

The time courses of the mean ΔQTcF value with pridopidine doses between 45 and 112.5 mg bid compared to the placebo are shown in Fig. 3A. Overall, pridopidine causes a dose-dependent increase in QTcF. In the placebo group, mean change from baseline QTcF was very small across all post-dosing timepoints, with values varying between − 1.4 and 0.7 ms. Pridopidine’s effect on QTcF prolongation corresponded to its plasma concentration, with its effect increasing up to week 6 and plateauing thereafter. At the clinically relevant dose of 45 mg bid, the largest mean placebo-corrected ΔQTcF at any post-dosing timepoint was 8.3 ms (week 20 post-dose). At doses higher than 45 mg bid, the largest mean increase in ΔQTcF was 11.1 ms in the 67.5 mg bid group (week 12, post-dose), 16.0 ms in the 90 mg bid group (week 6, post-dose), and 18.5 ms in the 112.5 mg bid group (week 4, post-dose) (Tables S4 and S5 in the Supplementary Information).

Fig. 3
figure 3

A Effect of pridopidine on mean change in QTcF from baseline (ΔQTcF, ms) (PRIDE-HD). Each measurement represents the difference between the QTcF assessed 1–2 h post-dose at a given study visit and the pre-dose QTcF at the baseline visit. Data are mean ± standard error (SE). B Effect of pridopidine on the placebo-corrected change from baseline QTcF (∆∆QTcF) (PRIDE-HD). Each measurement represents the difference between the placebo-corrected QTcF assessed 1–2 h post-dose at a given visit and the pre-dose QTcF at the baseline visit. Data are mean ± standard error (SE)

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Concentration-QTc Analysis in PRIDE-HD

Data from 402 HD patients were included in the C-QTc analysis. Six patients out of the 408 randomized (1.5%) were excluded from the analysis due to ECG values with a date after the last day of study treatment or a measurable pridopidine plasma level at baseline, prior to the first pridopidine administration.

Using this model, a linear concentration-dependent effect of pridopidine on the QTcF interval was demonstrated, with a slope of the relationship of 0.012 ms per ng/mL (90% CI 0.0109–0.0127). A scatter plot of the observed QTcF/plasma concentration pairs is shown in Fig. 4A. Values are symmetrically distributed around the model-predicted effect, and the plot therefore supports the appropriateness of the selected linear model. The goodness-of-fit plot using the selected linear model with baseline as a covariate is shown in Fig. 4B. The CIs for the predicted QT effect overlap with most within-decile median QTcF values without any clear or consistent violations. Therefore, the linear mixed effects model with a baseline provides a good estimation of the drug effect in this HD population.

Fig. 4
figure 4

Estimation of the effect of pridopidine on QTc prolongation using a linear mixed effects model with a baseline (PRIDE-HD). A Observed QTcF/plasma concentration pairs vs. predicted QTcF effect. Values are symmetrically distributed around the model-predicted effect. B Goodness-of-fit plot for the mixed effects linear model with a baseline. The predicted QT effect with 90% CI overlaps most within-decile median QTcF values; the model is a good estimate of the drug effect in this population

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The predicted placebo-corrected QT effect (ΔΔQTcF, 90% CI) at plasma concentrations resulting from dosing to steady state at the clinically relevant dose of 45 mg bid is 6.6 ms, with an upper bound of 8 ms (Fig. 3B, Table 4). At a higher dose of 67.5 mg bid, the predicted mean effect is 11.2 ms (upper bound of 90% CI: 12.6 ms).

Table 4 Predicted QT effect at the observed geometric Cmax of pridopidine concentration across dose groups (PRIDE-HD)
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Pridopidine plasma exposure at steady state was significantly different between the 45 and 67.5 mg bid dose groups. At 45 mg bid, mean (95% CI lower limit (LL), upper limit (UL)) plasma exposure was 541.6 (433.5, 676.7) ng/mL vs. 950.7 (854.9, 1057.2) ng/mL in the 67.5 mg bid group (p < 0.0001, Fig. 5, Table 5). Higher doses had higher mean (95% CI) plasma exposures of 1293.9 ng/mL (1085.3, 1542.9) and 1597.6 ng/mL (1435.9, 1777.4) in the 90 and 112.5 mg bid groups, respectively.

Fig. 5
figure 5

Mean (95% CI) pridopidine plasma exposure per dose group (PRIDE-HD)

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Table 5 Summary of mean (95% CI) pridopidine plasma exposure per dose group (PRIDE-HD)
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Of note, the study was not powered to detect gender differences regarding potential QTc effects, but an exploratory by-timepoint analysis of data from day 1 and day 20 did not disclose any significant differences between male and female subjects (data not shown).

Categorical QTc Analysis (PRIDE-HD)

Categorical analysis of QTcF from the PRIDE-HD study shows no increased risk for cardiac events at the clinically relevant dose of 45 mg bid. There were no patients with QTcF > 500 ms in any of the dose groups. There were seven patients with QTcF values > 480 ms at any time post-baseline: three in each of the 45 mg bid and 112.5 mg bid groups and one in the 90 mg bid group (Table 6A). There were more patients with QT prolongation > 30 ms in the active groups versus placebo. There were four patients with QT prolongation > 60 ms at any timepoint post-baseline during the study: one patient each in the 45 mg bid and 90 mg bid pridopidine groups and two patients in the 112.5 mg bid group (Table 6B).

Table 6 Number of patients (%) and timepoints with values exceeding categorical thresholds for absolute QTcF (A) and ΔQTcF (B) at any time post-baseline (PRIDE-HD)
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Effect of Pridopidine on QT Prolongation from Prior Trials in HD

Pridopidine was evaluated in two placebo-controlled trials in HD patients with valid central ECG assessments prior to PRIDE-HD (Table 1). HART was a phase 2, double-blind, placebo-controlled study in which 227 HD patients were randomized to either placebo or pridopidine 10, 22.5 or 45 mg bid for 12 weeks. The MermaiHD study was a phase 3, double-blind, placebo-controlled study in which 437 HD patients were randomized to either placebo or pridopidine 45 mg qd or 45 mg bid for 26 weeks. In both HART and MermaiHD, ECGs were recorded in triplicate at baseline (pre-dose) and in single readings (~ 3 h post-dose) at weeks 1, 4, 5, 12 (HART and MermaiHD), and 26 (MermaiHD) of treatment.

In the HART study, small increases in mean change from baseline for ΔQTcF and ΔHR were noted. ΔHR increased by 1.4, 1.7, and 2.1 in the 10, 22.5, and 45 mg bid groups, respectively. Mean ΔΔQTcF exhibited a small increase of 4 to 4.5 ms for pridopidine 22.5 mg bid and 45 mg bid, respectively (Table 7A). Results from MermaiHD were consistent with the findings from HART, showing mean ΔHR changes of − 0.1 and 1.6 and ΔΔQTcF increases of around 3 ms and 4 ms for 45 mg qd and 45 mg bid, respectively (Table 7B). There were no patients with a QTcF value exceeding 500 ms at any time point in either study. One patient demonstrated ΔQTcF > 60 ms (MermaiHD), one patient had a QTcF value > 480 ms (HART), and the proportion of patients with ΔQTcF > 30 ms was either higher in the placebo group (in HART) or comparable across treatment groups (in MermaiHD).

Table 7 ECG parameters from the HART (A) and MermaiHD (B) studies
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Incidence of Relevant Cardiac Clinical Adverse Events

In accordance with the ICH E14 Guideline, Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, the safety database was analyzed for rates of clinical cardiac AEs in the pridopidine- and placebo-treated groups in PRIDE-HD (Table 8).

Table 8 Number of patients (%) with relevant cardiac-related clinical adverse events (PRIDE-HD)
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There were no cases of TdP in any of the placebo or pridopidine groups and no cases of sudden death. Syncope was reported with an overall low incidence, but its incidence in pridopidine-treated patients, 4 out of 327 (1.2%), was higher than in placebo-treated patients (0%). This finding prompted further investigation, which showed that none of the patients with reports of syncope experienced any other AE indicating proarrhythmic potential, and none had an underlying QTcF prolongation to account for their syncopal episode. There was no evidence of dose–response for syncope in the PRIDE-HD study.

The cardiac safety profile of pridopidine was further assessed in an integrated safety dataset from the three placebo-controlled trials of pridopidine in HD: HART, MermaiHD, and PRIDE-HD (Table 9). Analysis was performed according to the following dose groups: placebo (n = 284); pridopidine 45 mg bid (n = 284), and all pridopidine doses (ranging from 10 to 112.5 mg bid, n = 788). The 45 mg bid dose was evaluated in all three trials, and doses higher than 45 mg bid (i.e., 67.5 mg and higher) were investigated only in the PRIDE-HD study.

Overall, the integrated safety data analysis shows similar frequencies of cardiac-related AEs in the pridopidine and placebo groups (Table 9). Ten patients (4%) in the placebo group, 10 (4%) in the 45 mg bid group, and 25 (3%) in the all-pridopidine group had any cardiac AE. There was one serious adverse event (SAE) of myocardial infarction, which was deemed not to be related to the study drug by the investigator, reported in the 67.5 mg bid group.

Table 9 Number of patients (%) with relevant cardiac-related clinical adverse events from a pooled safety dataset from HART, MermaiHD, and PRIDE-HD
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Discussion

A C-QTc analysis of data from the PRIDE-HD study demonstrated a concentration-dependent effect of pridopidine on the QTcF interval, with a slope of the relationship of 0.012 ms per ng/mL (90% CI 0.0109–0.0127). The QT effect (ΔΔQTcF) at concentrations resulting from the clinically relevant dose of 45 mg bid in patients with HD can be predicted as 6.6 ms (with an upper bound of the 90% CI of 8 ms), i.e., a clinically concerning effect (above 10 ms) has thereby been excluded [40].

At pridopidine plasma concentrations up to ~ 900 ng/mL, an effect on ΔΔQTcF of more than 10 ms can be excluded (i.e., the upper bound of the 90% CI of the predicted effect is below 10 ms) and an effect of more than 20 ms can be excluded at plasma concentrations up to ~ 1800 ng/mL.

The PRIDE-HD study was well controlled, with little data excluded due to mismatches in the timing between ECG recordings and blood draws for PK determination, and it included a large number of patients (n = 402) for the purpose of C-QTc evaluation. Baseline QTcF values were accurately established using triplicate ECGs, and repeated measurements over time contributed to a large and robust dataset. Furthermore, central reading by a dedicated ECG laboratory with standardization and validated processes contributed to the enhanced validity of the underlying ECG data. Lastly, strict adherence to the use of only tightly concordant ECG and PK measurements, ensuring optimally paired PK/PD data points, provided additional robustness of the analyses. It therefore appears reasonable to estimate the QT effect of pridopidine using the results from this C-QTc analysis.

A limitation on the applicability of the C-QTc analysis in PRIDE-HD is the assumption of the absence of a meaningful delay between plasma concentrations and the QT effect. However, given the sparse sampling in this study, such a hysteresis test cannot be performed. Another limitation is that intradiurnal variation in plasma concentrations has not been captured, since there was one PK measurement per day. Therefore, all PK measurements were taken around Tmax (1–2 h post-dose).

The HART and MermaiHD studies included high-quality, centrally read ECG assessments, but did not collect concordant PK samples. Thus, safety and ECG data were analyzed, but no C-QTc analysis was performed. In HART and MermaiHD, a small and not clinically meaningful effect of pridopidine 45 mg bid on QT prolongation was noted (mean ΔΔQTcF of 4.0–4.5 ms), consistent with the lack of a predicted clinically meaningful QT prolongation effect in PRIDE-HD.

Prolonged QTc interval at screening was an exclusion criterion in PRIDE-HD (QTcF of > 450 ms for males or females) as well as in HART and MermaiHD (QTcF > 450 ms for males or > 470 ms for females) (see Table S1 in the Supplementary Information). Patients with a clinically significant heart disease were excluded, and the use of a co-medication with a proven risk of prolonging QTc interval was prohibited in all three trials.

The cardiac safety analysis from PRIDE-HD demonstrates a low risk for potential cardiac adverse events, based on the ICH E14 Guideline Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. This is in agreement with the overall favorable safety profile of pridopidine reported in PRIDE-HD, where the most frequent events (> 5%) are presented for all AE categories [48].

Analysis of an integrated safety dataset from the three placebo-controlled trials in HD (HART, MermaiHD, and PRIDE-HD, a total of n = 1072 HD patients) shows an overall low incidence of potential cardiac adverse events in patients receiving pridopidine, which is generally comparable to the placebo group. There were no events of cardiac arrest, sudden death, or ventricular arrhythmias, and no cases of TdP. None of the events were of severe intensity.

In summary, pridopidine is an investigational oral drug in clinical development for the treatment of HD with a favorable overall safety profile. A detailed, well-conducted C-QTc analysis did not indicate a heightened risk for QTc prolongation at the clinically relevant dose of 45 mg bid.

PROOF-HD is an ongoing phase 3, double-blind, placebo-controlled trial assessing the safety and efficacy of pridopidine 45 mg bid in maintaining total functional capacity at 65 weeks. The study enrolled 499 HD patients, with the first patient randomized in October 2020. As of December 2022, the blinded safety analysis is consistent with pridopidine 45 mg bid being safe and tolerable, with a high retention rate in the trial of 93%. Topline results are expected in mid-2023. A detailed cardiac-related AE analysis will be performed on this large dataset to further corroborate pridopidine’s cardiac safety profile at the therapeutic dose of 45 mg bid.

Conclusion

At the therapeutic dose of 45 mg bid, pridopidine’s effect on QT prolongation is not clinically significant, with no evidence of a heightened risk for QT prolongation or pro-arrhythmic events.