Huntington Disease
Conditions
Keywords
Neurodegenerative disorder, Rare disease
Brief summary
The primary goal of this study is to evaluate the safety and pharmacodynamic effects of PTC518 compared with placebo in participants with HD.
Detailed description
Participants will first be randomized to Part A or Part B or Parts D or E in a 1:1 randomization ratio, depending on their Huntington's disease Integrated Staging System (HD-ISS) staging criteria and then to active treatment (PTC518 5 mg in Parts A and D and 10 mg in Parts B and E) or matching placebo within each part in a 2:1 ratio of active treatment to placebo. A Drug Safety Monitoring Board (DSMB) Charter will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide a recommendation on when Parts C and F (with a 20 mg active treatment arm) can be initiated. At that time, participants will be randomized to any study Part that is currently open for enrollment, and then to either active treatment or placebo (in a 2:1 ratio) within that Part. Participants who complete this study and agree to participate in a long-term extension (LTE) study, will be enrolled in a separate LTE study PTC518-CNS-004-HD (NCT06254482).
Interventions
DRUGPTC518
PTC518 will be administered per dose and schedule specified in the arm.
DRUGPlacebo
Placebo matching to PTC518 will be administered per schedule specified in the arm.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 40 to 50, inclusive Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C): * A Unified Huntington's Disease Rating Scale (UHDRS)-Independence Scale (IS) score of 100 * A UHDRS Total Functional Capacity (TFC) score of 13 * A score between 0.18 and 4.93 inclusive on the normed version of the HD prognostic index (PINHD) Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, and F): * A UHDRS Total Functional Capacity (TFC) score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of \<100 Key
Exclusion criteria
* Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, ribonucleic acid (RNA)- or deoxyribonucleic acid (DNA)-targeted HD-specific investigational agents such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery * Any history of gene therapy exposure for the treatment of HD * Participation in an investigational study or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation, etc) within 90 days prior to Screening or anytime over the duration of this study * Any medical history of brain or spinal disease that would interfere with the lumbar puncture process safety assessments * Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (for example, implanted shunt, conditions precluding magnetic resonance imaging \[MRI\] scans) * Pregnancy, planning on becoming pregnant during the course of the study or within 6 months of end of treatment, or currently breastfeeding Note: Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline up to Month 18 | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as an AE that had an onset date or date of worsening on or after the first dose of study drug. A summary of other non-serious AEs and all serious adverse events (SAEs), regardless of causality is located in the 'Reported AE section'. |
| Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3 | Baseline, Month 3 | Least square (LS) mean and 95% confidence interval (CI) were calculated using mixed-model repeated measures (MMRM). The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12 | Baseline, Month 12 | LS mean and standard error (SE) were calculated using MMRM. |
| Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12 | Baseline, Month 12 | cUHDRS includes the Total Functional Capacity (range, 0-13; higher score means better functioning), Total Motor Score (range, 0-124; higher score means worse motor severity), Symbol Digit Modality Test (range, 0-110, correctly paired numbers-symbols in 90 seconds; higher score means better cognitive performance), and Stroop Word Reading (range, 0-no max value, correctly read colour words in 45 seconds; higher score means better cognitive performance) scores. The total score for the cUHDRS ranges from approximately 3 to 18, where higher scores indicated better functioning. LS mean and SE were calculated using analysis of covariance (ANCOVA) model. |
| Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12 | Baseline, Month 12 | LS mean and 95% CI were calculated using MMRM. The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes. |
| Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12 | Baseline, Month 12 | LS mean and 95% CI were calculated using MMRM. The CSF mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes. |
| Percent Change From Baseline in Blood mHTT Protein at Month 12 | Baseline, Month 12 | LS mean and 95% CI were calculated using MMRM. The blood mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes. |
Countries
Australia, Austria, Canada, France, Germany, Italy, Netherlands, New Zealand, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were randomized to receive placebo, PTC518 5 milligrams (mg), or PTC518 10 mg. While the Independent Data Monitoring Committee authorized opening of the 20 mg dosing arm, the sponsor elected not to open PTC518 20 mg dosing arm for enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to PTC518 tablets once daily (QD) orally for 12 months. | 53 |
| PTC518 5 mg Participants received 5 mg tablet of PTC518 QD orally for 12 months. | 52 |
| PTC518 10 mg Participants received 10 mg tablet of PTC518 QD orally for 12 months. | 54 |
| Total | 159 |
Baseline characteristics
| Characteristic | Placebo | PTC518 5 mg | PTC518 10 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 9.59 | 49.2 years STANDARD_DEVIATION 9.04 | 47.8 years STANDARD_DEVIATION 9.1 | 48.5 years STANDARD_DEVIATION 9.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 49 Participants | 53 Participants | 153 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) White | 52 Participants | 47 Participants | 52 Participants | 151 Participants |
| Sex: Female, Male Female | 33 Participants | 26 Participants | 29 Participants | 88 Participants |
| Sex: Female, Male Male | 20 Participants | 26 Participants | 25 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 53 | 1 / 52 | 0 / 54 |
| other Total, other adverse events | 32 / 53 | 34 / 52 | 41 / 54 |
| serious Total, serious adverse events | 4 / 53 | 1 / 52 | 2 / 54 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as an AE that had an onset date or date of worsening on or after the first dose of study drug. A summary of other non-serious AEs and all serious adverse events (SAEs), regardless of causality is located in the 'Reported AE section'.
Time frame: Baseline up to Month 18
Population: Safety Population included all randomized participants who received at least 1 dose of the study drug, with participants grouped according to the treatment they received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 46 Participants |
| PTC518 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 43 Participants |
| PTC518 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 49 Participants |
Primary
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3
Least square (LS) mean and 95% confidence interval (CI) were calculated using mixed-model repeated measures (MMRM). The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 3
Population: ITT Population included all randomized participants who took at least 1 dose of the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3 | -1.40 percent change | 95% Confidence Interval -7.25 |
| PTC518 5 mg | Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3 | -17.36 percent change | 95% Confidence Interval -22.36 |
| PTC518 10 mg | Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3 | -28.67 percent change | 95% Confidence Interval -32.74 |
p-value: <0.000195% CI: [-23.59, -8.34]Mixed Models Analysis
p-value: <0.000195% CI: [-34.45, -20.1]Mixed Models Analysis
Secondary
Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12
cUHDRS includes the Total Functional Capacity (range, 0-13; higher score means better functioning), Total Motor Score (range, 0-124; higher score means worse motor severity), Symbol Digit Modality Test (range, 0-110, correctly paired numbers-symbols in 90 seconds; higher score means better cognitive performance), and Stroop Word Reading (range, 0-no max value, correctly read colour words in 45 seconds; higher score means better cognitive performance) scores. The total score for the cUHDRS ranges from approximately 3 to 18, where higher scores indicated better functioning. LS mean and SE were calculated using analysis of covariance (ANCOVA) model.
Time frame: Baseline, Month 12
Population: ITT Population included all randomized participants who took at least 1 dose of the study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12 | -0.64 units on a scale | Standard Error 0.168 |
| PTC518 5 mg | Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12 | -0.61 units on a scale | Standard Error 0.176 |
| PTC518 10 mg | Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12 | -0.92 units on a scale | Standard Error 0.164 |
Secondary
Percent Change From Baseline in Blood mHTT Protein at Month 12
LS mean and 95% CI were calculated using MMRM. The blood mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 12
Population: ITT Population included all randomized participants who took at least 1 dose of the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Blood mHTT Protein at Month 12 | 13.89 percent change | 95% Confidence Interval 6.33 |
| PTC518 5 mg | Percent Change From Baseline in Blood mHTT Protein at Month 12 | -14.11 percent change | 95% Confidence Interval -19.99 |
| PTC518 10 mg | Percent Change From Baseline in Blood mHTT Protein at Month 12 | -28.20 percent change | 95% Confidence Interval -32.89 |
Secondary
Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12
LS mean and standard error (SE) were calculated using MMRM.
Time frame: Baseline, Month 12
Population: ITT Population included all randomized participants who took at least 1 dose of the study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12 | 4.42 percent change | Standard Error 0.413 |
| PTC518 5 mg | Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12 | 4.99 percent change | Standard Error 0.413 |
| PTC518 10 mg | Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12 | 5.74 percent change | Standard Error 0.391 |
Secondary
Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12
LS mean and 95% CI were calculated using MMRM. The CSF mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 12
Population: ITT Population included all randomized participants who took at least 1 dose of the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12 | -15.64 percent change | 95% Confidence Interval -26.71 |
| PTC518 5 mg | Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12 | -23.68 percent change | 95% Confidence Interval -33.97 |
| PTC518 10 mg | Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12 | -23.28 percent change | 95% Confidence Interval -32.84 |
Secondary
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12
LS mean and 95% CI were calculated using MMRM. The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 12
Population: ITT Population included all randomized participants who took at least 1 dose of the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12 | 8.19 percent change | 95% Confidence Interval 1.99 |
| PTC518 5 mg | Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12 | -14.18 percent change | 95% Confidence Interval -19.25 |
| PTC518 10 mg | Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12 | -28.44 percent change | 95% Confidence Interval -32.45 |