A Phase 2a, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of PTC518 in Subjects With Huntington’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

PTC Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

6 Jul 2022 → 29 Jul 2025

Decision date (initial)

2024-05-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

PTC Therapeutics, Inc.

External identifiers

EU CT number

2023-509835-26-00

EudraCT number

2021-003852-18

ClinicalTrials.gov

NCT05358717

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Dose response, Pharmacokinetic, Safety, Efficacy

• Evaluate the safety of PTC518 compared with placebo in subjects with Huntington’s disease (HD)
• Evaluate the pharmacodynamic (PD) effects of PTC518 through the reduction in blood total huntingtin (tHTT) protein levels

Secondary objectives 4

1. Assess the effects of PTC518 on change in caudate volume via volumetric magnetic resonance imaging (vMRI) (key secondary)
2. Assess the effects of PTC518 on change in composite Unified Huntington’s Disease Rating Scale (cUHDRS)
3. Determine the effect of PTC518 on mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF) at Month 12
4. Determine the effect of PTC518 on blood mHTT levels at Month 12

Conditions and MedDRA coding

Huntington’s Disease

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Ambulatory male or female patient aged 25 years and older, inclusive
2. Subject is willing and able to provide informed consent and comply with all protocol requirements.
3. Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 40 to 50, inclusive. CAG repeat length may be determined analytically through amplification.
4. Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C): 4. A UHDRS IS score of 100
5. A UHDRS TFC score of 13
6. A score between 0.18 and 4.93 inclusive on the normed version of the HD prognostic index (PINHD)
7. Women of childbearing potential (WOCBP) must agree to use highly effective methods of contraception during dosing and for 6 months after stopping the study medication. Women of childbearing potential are defined as women who are fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Female partners of enrolled males who are of childbearing potential should consider use of highly effective methods of contraception while the enrolled male is taking study drug and for 6 months after stopping study drug.
8. Sexually active and fertile males must agree to use a condom during intercourse while taking study drug and for 6 months after stopping study drug and should neither father a child nor donate sperm in this period. A condom is required to be used also by vasectomized men in order to prevent potential delivery of the drug via seminal fluid.
9. Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, and F): 9. A UHDRS TFC score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of <100

Exclusion criteria 21

1. Inability or unwillingness to swallow oral tablets
2. Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, including RNA- or DNA-targeted HD-specific investigational agents (such as antisense oligonucleotides), cell transplantation, or any other experimental brain surgery
3. Any history of gene therapy exposure for the treatment of HD
4. 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. Observational studies (such as ENROLL-HD) are not exclusionary.
5. Presence of an implanted deep brain stimulation device
6. [CCI]
7. Brain and spinal pathology that may interfere with CSF homeostasis and circulation, increased intracranial pressure (including presence of a shunt for the drainage of CSF or an implanted central nervous system catheter catheter), malformations, and/or tumors
8. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
9. At significant risk of suicide as measured by the C-SSRS Baseline version with a moderate risk rating or higher score
10. Risk of a major depressive episode, psychosis, confusional state, or violent behavior as assessed by the investigator
11. Any medical history of brain or spinal disease that would interfere with the lumbar puncture processor safety assessments
12. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
13. Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (eg, implanted shunt, conditions precluding MRI scans)
14. Antidepressant, antipsychotic, or benzodiazepine use, unless receiving a stable dose for at least 6 weeks prior to Screening and with a dose regimen that is not anticipated to change during the study. Benzodiazepine use for sedation for study-related procedures during the course of the study is permitted.
15. History of illicit/illegal drug use, or alcohol use in the high risk category of risk drinking levels according to the World Health Organization for a duration of 1 month or longer that in the opinion of the investigator could compromise the interpretability of study results
16. Clinically significant medical condition, which in the opinion of the investigator could adversely affect the safety of the subject or impair the assessment of study results (eg, inability to fast or any known hypersensitivity to PTC518 or its excipients)
17. Current significant renal impairment defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 at Screening
18. Current hepatic impairment resulting in elevated liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP]) at 3 times the upper limit of normal at Screening
19. Pregnancy, planning on becoming pregnant during the course of the study or within 6 months of end of treatment, or currently breastfeeding
20. Use of medications that are moderate or strong inhibitors of cytochrome P450 (CYP) 3A4 within 1 week of Screening or medications that are moderate or strong inducers of CYP3A4 within 2 weeks of Screening or planned use of moderate or strong CYP3A4 inhibitor or inducer medications during the study period
21. A diagnosis of Juvenile-Onset Huntington’s Disease

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety Endpoints: Safety profile as characterized by treatment-emergent adverse events (TEAEs), laboratory abnormalities, [CCI], electrocardiogram (ECG), vital signs, [CCI], [CCI], Columbia Suicide Severity Rating Scale (C SSRS), and physical examination
2. Primary Efficacy Endpoint: Change from Baseline in blood tHTT protein at Month 3

Secondary endpoints 5

1. Change from Baseline in caudate volume as assessed via vMRI at Month 12 (key secondary)
2. Change from Baseline in cUHDRS scores at Month 12
3. Change from Baseline in blood tHTT protein at Month 12
4. Change from Baseline in CSF mHTT protein at Month 12
5. Change from Baseline in blood mHTT protein at Month 12

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

PTC Therapeutics Inc.

Sponsor organisation

PTC Therapeutics Inc.

Address

500 Warren Corporate Center Drive

City

Warren

Postcode

07059

Country

United States

Scientific contact point

Organisation

PTC Therapeutics Inc.

Contact name

Allison Fortenberry

Public contact point

Organisation

PTC Therapeutics Inc.

Contact name

Allison Fortenberry

Third parties 11

Locations

6 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications