Phase 1b/2a study of WVE-120102 in patients with Huntington's Disease
Research type
Research Study
Full title
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120102 Administered Intrathecally in Patients with Huntington’s Disease
IRAS ID
235437
Contact name
Timothy Harrower
Contact email
Sponsor organisation
WAVE Life Sciences Ltd
Eudract number
2016-005142-39
Duration of Study in the UK
1 years, 1 months, 5 days
Research summary
Research Summary
There is no cure for HD and it is invariably fatal. Some symptoms can be managed with existing medications, but none of these medicines can slow or reverse the disease. HD is caused by known mutations on a single gene, called the Huntingtin gene. All people carry the Huntingtin gene, which makes Huntingtin protein that is important for normal brain development.
The mutation on the HTT gene in people with HD leads to production of another type of protein known as the mutant Huntingtin (mHTT) protein. Study drug WVE-120102 is designed to selectively reduce mHTT protein while leaving normal Huntington protein intact.
Research suggests that selectively lowering mHTT protein has the potential to slow the progression of HD. This is the first clinical study conducted with WVE-120102.The purpose of this double-blind study is to test the safety and tolerability of single and multiple doses of WVE-120102 in patients with early HD.
Forty-eight eligible patients will be enrolled into 1 of 4 dose cohorts (2, 4, 8 and 16 mg). In each cohort, 12 patients (9 active and 3 placebo) will receive a single dose of WVE-120102 or placebo and be followed for at least 8 weeks before any additional dosing may occur.
Following safety review of each single dose cohort, patients may receive 3 additional doses of study drug or placebo at the same dose they received before. These 3 doses will be administered once every 4 weeks, and patients will be followed for 14 weeks after the last dose. Study procedures will include analysis of blood, urine, and spinal fluid, vital signs, ECGs, physical exams, MRI, and HD clinical assessments.Summary of Results
Pharmacodynamic (PD) Results and MRI:
Patients received 3 or 4 monthly doses of WVE-120102 or placebo in this study. Following multiple-dose treatment, there were no apparent trends in terms of target engagement, as measured by changes in PD biomarkers of mutant huntingtin protein (mHTT), total huntingtin protein (tHTT), wild type huntingtin protein (wtHTT), or neurofilament light (NfL) or analysis of MRI parameters.Clinical Effects:
Following 3 or 4 monthly doses of WVE-120102, there were no apparent trends in measurements of clinical effects, including the Unified Huntingtons Disease Rating Scale (UHDRS) and Short Problem Behaviors Assessment (PBA-s)PK Results:
WVE-120102 was measurable in the plasma and cerebrospinal fluid (CSF) at all evaluated dose levels after intrathecal (IT) administration. WVE-120102 plasma exposure (as measured by area under the plasma concentration-time curve from time zero to the last quantifiable concentration [AUClast] and maximum plasma concentration [Cmax]) increased with increasing dose level. Similarly, concentrations of WVE-120102 in the CSF increased with increasing dose level. WVE-120102 had been cleared in all but the 32 mg dose group by 12 weeks after the last dose. There was little to no apparent accumulation in plasma and CSF after 3 or 4 monthly IT doses of WVE-120102.Safety Results:
Of the 88 patients enrolled in this study, 66 received 1 to 4 doses of 2, 4, 8, 12, 16, or 32 mg WVE-120102. Twenty-two patients received placebo. The incidence of treatment-emergent adverse event (TEAEs) was similar between the pooled active (WVE-120102) dose groups and the pooled placebo group. The most frequently reported TEAEs across all groups (placebo and active) were generally common side effects that occur following lumbar puncture, such as headache, procedural pain, or back pain. No TEAEs associated with the High Level Group Term (HLGT) Spinal cord and nerve root disorders were reported in the course of the study.At higher dose levels (≥16 mg), administration of WVE-120102 was associated with more treatment-related TEAEs and more severe TEAEs compared to lower doses and placebo. In addition, administration of WVE-120102 at the 32 mg dose level was associated with an increased incidence in SAEs, primarily in the system organ classes (SOCs) of nervous system disorders and psychiatric disorders. Eight of these patients experienced at least 1 SAE assessed as related to study drug and 6 patients discontinued due to an SAE.WVE-120102 was not associated with any dose-related changes in clinical chemistry, hematology, coagulation, or urinalysis parameters. WVE-120102 was also not associated with any changes in CSF safety laboratory assessments. In addition, no dose-related trends were observed in vital signs, electrocardiograms (ECGs), or Columbia-Suicide Severity Rating Scale (C-SSRS).
Conclusion:
Based on the efficacy findings in this study at the time of the interim analysis, the Sponsor decided to terminate the study as the benefit-risk analysis did not warrant continued dose escalation.REC name
London - West London & GTAC Research Ethics Committee
REC reference
17/LO/1892
Date of REC Opinion
16 Feb 2018
REC opinion
Further Information Favourable Opinion