Patients

Table 1. Table 1. Characteristics of the Patients at Baseline.

From August 2015 through April 2017, a total of 52 patients were screened for eligibility, and 46 patients underwent randomization according to the protocol. All the patients received all scheduled doses of the assigned trial agent (HTT Rx or placebo), and all the patients who had undergone randomization completed the trial according to the protocol. (A diagram of the flow of patients through the trial is provided in Fig. S3 in the Supplementary Appendix.) The characteristics of the patients at baseline were representative of early-stage Huntington’s disease and were similar across the trial groups (Table 1).

Primary End Point of Safety

Table 2. Table 2. Adverse Events Reported in at Least Three Patients Receiving HTT Rx , According to Grade.

The incidence of adverse events was similar among patients receiving HTT Rx and those receiving placebo (Table 2). Adverse events were reported in 98% of the patients; all events were mild (83%) or moderate (17%) in severity. The most commonly reported adverse events in patients who received HTT Rx were procedural pain and post–dural-puncture headache, which occurred after approximately 10% of lumbar punctures and had no apparent relationship to trial duration or dose. There was no evidence of an increased risk of post–dural-puncture headache with successive lumbar punctures. All post–dural-puncture headaches resolved (median duration, 2 days), and no blood patches were used. Very few adverse events (6%) were considered by the investigators (who were unaware of the trial-group assignment) to be related to HTT Rx or placebo, and most of the related events (83%) were also considered to be related to a trial procedure. There were no deaths, dose-limiting adverse events, discontinuations of regimens, or delays in trial-agent administration during the trial.

The only serious adverse event was an inpatient admission of a patient in the placebo group for observation of a mild post–dural-puncture headache. Neither suicidal behavior nor serious suicidal ideation emerged in any patient during the trial. One case of a mildly increased CSF leukocyte count (20 to 23 cells per cubic millimeter, measured in triplicate) without associated symptoms was observed 8 weeks after the last 60-mg dose of HTT Rx was administered; the clinical safety MRI and electroencephalographic results were normal. The asymptomatic elevation persisted throughout the post-treatment period and resolved before the patient’s initiation of treatment in the extension study, 64 weeks after the last dose in this trial.

Secondary End Point

Figure 2. Figure 2. HTT Rx Exposure. Panel A shows the maximum predose (i.e., 28-day trough) concentration of the antisense oligonucleotide drug HTT Rx in CSF according to dose group (placebo or the various HTT Rx dose groups). Panel B shows the mean concentration of HTT Rx in plasma, according to dose group, over the 24-hour periods after the administration of the first dose (left side; day 1) and fourth dose (right side; day 85). Error bars indicate the standard error. Further discussion of the observed concentrations of HTT Rx is provided in the Supplementary Appendix.

HTT Rx was measurable in the CSF of most patients who received doses of 30 mg or more. Trough concentrations increased with increasing dose, from below the limit of quantification at the 10-mg dose through the 60-mg dose, with a plateau in the concentration in CSF beyond the 60-mg dose (Figure 2A). No accumulation of HTT Rx in CSF was observed over time.

Exploratory End Points

Plasma Concentrations of HTT Rx

The median peak plasma concentrations of HTT Rx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. The concentration of HTT Rx in plasma increased approximately proportionally to the dose over the explored dose range (Figure 2B). There was no evidence of accumulation of concentration in plasma 24 hours after dose administration over the course of the trial, and there was a minor increase (<20%) in the peak concentration at the 120-mg dose level.

Concentrations of Mutant HTT in CSF

Figure 3. Figure 3. Effect of HTT Rx on CSF Concentrations of Mutant Huntingtin Protein (HTT). Panel A shows the concentrations of mutant HTT in CSF over time for individual patients in each dose group; absolute values, measured in femtomoles per liter, are shown in the top graphs, and the percentage changes from baseline (dotted line) are shown in the bottom graphs. Arrowheads indicate the 4 days on which HTT Rx or placebo was administered. A discussion of the individual patient data that were observed in the 120-mg dose group is provided in the Supplementary Appendix. Panel B shows the percentage change in the concentration of mutant HTT in CSF from baseline (dotted line) to the last available time point 28 days after the previous dose (i.e., either day 113 for the patients who underwent CSF sampling at day 113 or day 85 for the other patients). Circles indicate individual patients, and horizontal lines indicate group means; 95% confidence intervals are also shown for the active-agent dose groups. Panel C shows the mean concentration of mutant HTT in CSF (left) and the mean percentage change from baseline (right) over time according to dose group. Error bars indicate the standard deviation. Samples from days 113 and 141 were each obtained in a randomized subgroup of patients (dotted lines).

In patients who received HTT Rx , there were dose-dependent decreases in the concentration of mutant HTT in CSF at the last available 28-day post-dose sampling point (mean percentage change from baseline of −20%, −25%, −28%, −42%, and −38% in the HTT Rx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively), with a maximum reduction of 63% in an individual patient (in the 120-mg cohort). In patients who received placebo, the mean percentage change from baseline was an increase of 10% in the concentration of mutant HTT in CSF (Figure 3A and 3B, and Table S1 in the Supplementary Appendix). Steady-state maximal reduction of the concentration of mutant HTT in CSF did not appear to have been reached during the 3-month trial period (Figure 3A and 3C).

Additional Exploratory Outcomes

Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received HTT Rx , regardless of the dose level (Table S2 in the Supplementary Appendix). The ventricular volume showed dose-dependent and time-dependent increases at day 113 and at day 197, without adverse consequences, in the 90-mg and 120-mg dose groups that were greater than those in the placebo group (boundary shift integrals at days 113 and 197 were 2.6 ml and 5.0 ml, respectively, in the 90-mg group and 2.3 ml and 5.3 ml, respectively, in the 120-mg group).

Elevations of the concentration of neurofilament light protein in CSF occurred in some patients in the 90-mg and 120-mg cohorts at day 113 or day 141 (i.e., 1 or 2 months after cessation of the regimen, respectively), but there were no associated adverse events or safety changes on MRI (Fig. S4 in the Supplementary Appendix). By the start of the extension study (7 to 27 months after the final doses were administered in this trial), the concentrations of neurofilament light protein in the CSF had generally returned to pretrial concentrations. During the extension study, the concentrations rose with a time course and magnitude that were similar to those observed in this trial and then decreased at later time points despite continued treatment (unpublished data).

Post Hoc Analyses

In parallel with this trial, the composite Unified Huntington Disease Rating Scale (cUHDRS) was developed to serve as a measure of clinical progression in early Huntington’s disease.14 We examined the relationships between the degree of lowering of the CSF concentration of mutant HTT and changes in the cUHDRS score and its four components and observed correlations between reduction in the CSF concentration of mutant HTT and improvements in the cUHDRS score and two of its components (Fig. S5 in the Supplementary Appendix). These correlations should be interpreted with caution, because the tests were not prespecified and the coefficients of correlation were not adjusted for multiple testing.