Phase 1b/2a study of WVE-120101 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-120101 Administered Intrathecally in Patients with Huntington’s Disease
IRAS ID
235436
Contact name
Timothy Harrower
Contact email
Sponsor organisation
WAVE Life Sciences Ltd
Eudract number
2016-005095-10
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-120101 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-120101.The purpose of this double-blind study is to test the safety and tolerability of single and multiple doses of WVE-120101 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-120101 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 Results:
Patients received 3 or 4 monthly doses of WVE 120101 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 mHTT, total huntingtin protein, wild-type huntingtin protein, or analysis of MRI parameters.Clinical Effects:
Following 3 or 4 monthly doses of WVE 120101, there were no apparent trends in measurements of clinical effects, including the UHDRS and PBA-s.PK Results:
Peak plasma concentrations and exposure as measured by maximum plasma concentration and area under the plasma concentration-time curve from time zero to the last quantifiable concentration both increased with increasing dose. Terminal half-life and clearance were comparable between dose groups. At 4 weeks postdose for the second, third, and fourth doses, there was a measurable amount of WVE-120101 in CSF in all but the 2 mg dose group. This had been cleared in all but the 32 mg dose group by 12 weeks post last dose. There was little to no apparent accumulation.Safety Results:
The incidence of TEAEs was similar between the pooled active dose groups and the pooled placebo group. The most frequently reported TEAEs across all groups (placebo and active) were generally those associated with route of administration (IT), such as back pain, headache, procedural pain, dizziness, and fall.Administration of WVE-120101 at the highest dose level (32 mg) was associated with more treatment-related TEAEs and more severe TEAEs compared with lower doses and placebo. Despite 3 patients in the 32 mg cohort meeting stopping criteria in the single-dose, dose escalation phase, the benefit-risk profile remained favourable.
WVE-120101 was not associated with any significant dose-related changes in clinical chemistry, hematology, coagulation, or urinalysis parameters. WVE-120101 was also not associated with any significant changes in CSF safety laboratory assessments. In addition, no dose-related trends were observed in vital signs, ECGs, or C SSRS.
Conclusion:
Based on the efficacy findings in this study at the time of the interim analysis, in combination with the safety findings observed at higher doses, 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/1891
Date of REC Opinion
16 Feb 2018
REC opinion
Further Information Favourable Opinion