mHTT results from PRECISION-HD trials do not support further development of WVE-120102 and WVE-120101
No observed change in wtHTT and NfL during trials
Advancing Phase 1b/2a trial for WVE-003 (SNP3) program in HD; WVE-003 uses new PN backbone chemistry modifications, which demonstrate improved preclinical pharmacology
Wave to host investor conference call and webcast today at 4:30 p.m. ET
CAMBRIDGE, Mass., March 29, 2021 (GLOBE NEWSWIRE) — Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced data from the Phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluating investigational treatments WVE-120102 and WVE-120101, respectively, in Huntington’s disease (HD).
In the PRECISION-HD2 core trial, results from all participants (n=88) showed no statistically significant change in mutant huntingtin protein (mHTT) versus placebo after single or multiple doses of WVE-120102 up to and including 32 mg monthly. There was no evidence of a dose response across the dose levels tested.
In the PRECISION-HD2 open label extension (OLE) trial, results from all participants (n=28) showed modest reductions in mHTT after a mean of 8.1 monthly doses (range: 1-17), but effects were inconsistent over the course of the trial. While there was a correlation between WVE-120102 cerebrospinal fluid (CSF) concentrations and mHTT lowering, pharmacokinetic (PK) modeling suggests that additional dose escalation is unlikely to achieve drug concentrations needed for robust mHTT knockdown. Given the lack of consistent and significant reductions in mHTT and the PK modeling projections, Wave will stop clinical development of WVE-120102. Trial participants will have a final follow-up visit but receive no further doses.
Results in all participants through 16 mg (n=51) from the PRECISION-HD1 core trial are similar to those in PRECISION-HD2 at those dose levels. Given these and results from Wave’s previous clinical trials, as well as current understanding of the limitations of the company’s first-generation candidates, Wave will also stop clinical development of WVE-120101. Dosing in the 32 mg cohort of the PRECISION-HD1 core trial is complete, and core and OLE trial participants will have a final follow-up visit but receive no further doses. Wave expects to complete analysis of the 32 mg cohort in the second quarter of 2021.
“We are disappointed not to have better news to share with the HD community and would like to extend our gratitude to the trial participants and their families for their commitment to these programs,” said Michael Panzara, MD, MPH, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. “However, we have learned an enormous amount from these trials and are encouraged by data that suggest our SNP targeting approach may achieve allele-selectivity. We look forward to continuing our collaboration with our research partners to advance our first HD clinical candidate that incorporates our next-generation PN backbone chemistry, WVE-003, and remain committed to the science of HD and, in particular, selective mutant huntingtin lowering.”
WVE-003 is an investigational drug designed to selectively lower mHTT by targeting a specific single nucleotide polymorphism (SNP3) that is commonly found on the expanded CAG allele. This allele-selective approach is guided by the recognition that, in addition to a gain of function of mHTT, people with HD have lost one copy of the wild-type HTT allele, leaving them with a smaller protective reservoir of healthy, wild-type HTT protein (wtHTT) than unaffected individuals. A growing body of scientific evidence suggests that preserving as much of this essential protein as possible is important for favorable health outcomes.
Wave expects to initiate dosing in a Phase 1b/2a clinical trial for WVE-003 in 2021. As people with HD can carry multiple SNPs, participants from the PRECISON-HD trials will be offered the opportunity to undergo screening for potential enrollment in the WVE-003 trial. It is estimated that approximately 40% of adults with HD carry SNP3 in association with the HD mutation.
“Everyone at Wave wishes our PRECISION-HD programs had yielded different results, but we believe our WVE-003 program will enable us to address deficiencies with our first-generation candidates while maintaining our commitment to developing wild-type sparing therapies for HD,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “Our next generation of investigational clinical candidates, which also includes WVE-004 for amyotrophic lateral sclerosis and frontotemporal dementia and WVE-N531 for Duchenne, as well as our current preclinical and discovery programs, all use novel PN chemistry, which has been shown to increase potency, exposure, and durability across our silencing, splicing, and editing modalities in preclinical studies. Our clinical candidates have also been optimized with pharmacodynamic and pharmacokinetic insights from in vivo models, which were not available for our first-generation compounds. For example, we selected WVE-003 as our next HD candidate after years of optimization and demonstrated target engagement in vivo. Moreover, we are implementing innovative, adaptive designs across our new clinical programs to speed development and help us make data-driven decisions more quickly. These collective advances and learnings will improve our ability to deliver transformative genetic medicines.”
Additional Results from the PRECISION-HD Trials
- PRECISION-HD2 core trial participants who received three or four 32 mg doses of WVE-120102 had a non-statistically significant median reduction of 9.9% in mHTT in the CSF (p=0.74) as compared to a pooled placebo group who had a median decrease in mHTT of 0.8%.
- PRECISION-HD1 core trial participants who received three or four 16 mg doses of WVE-120101 had a non-statistically significant median reduction of 11.6% in mHTT in the CSF (p=0.56) as compared to a pooled placebo group who had a median decrease in mHTT of 10.0%.
wtHTT and Neurofilament Light Chain (NfL) Assessments
- Observations from PRECISION-HD2 OLE participants with >20% reduction in mHTT were used to determine whether wtHTT was similarly affected by treatment. There was no correlation between mHTT reduction and wtHTT change, suggesting allele-selectivity.
- This analysis was not performed for the PRECISION-HD2 or the PRECISION-HD1 core trials given insufficient mHTT reduction.
- In the PRECISION-HD trials (core and OLE), there were no changes in CSF NfL over time. NfL is a protein component of the neuronal cytoskeleton, which has been shown to increase in the CSF with disease severity in HD.
- In the PRECISION-HD trials (core and OLE), there was no worsening of disease progression in treated participants versus progression expected based upon natural history studies.
Safety and Tolerability
Overall, adverse events (AEs) were balanced across treatment groups in the PRECISION-HD2 core trial (83% of WVE-120102-treated participants versus 90% on placebo) and most events were mild to moderate in intensity. The most common AEs (those occurring in at least 10% of participants receiving WVE-120102) were headache, procedural pain, back pain, falls, viral upper respiratory tract infection, dizziness, and post-lumbar puncture syndrome. There was an increase in serious adverse events (SAEs) in the 32 mg group as compared to lower doses. Seven of 13 participants in the 32 mg group were reported with an SAE related to treatment and six participants discontinued treatment due to an AE. SAEs were transient and included disorientation, delirium, ataxia, slurred speech, amnesia, meningitis, fever, and vertigo.
Adverse events were similar in the PRECISION-HD2 OLE to those that occurred in the core trial. Thirty-six participants reported with an event over 327 person/months of exposure. The incidence of SAEs related to treatment with 32 mg WVE-120102 was lower than in the core trial. Three participants discontinued treatment due to AEs (two receiving 16 mg, one receiving 32 mg).
In the PRECISION-HD1 core trial, 91% of participants who received up to 16 mg of WVE-120101 were reported with an AE compared with 75% who received placebo, most of which were mild to moderate in intensity. The most common AEs were headache, procedural pain, dizziness, back pain, falls and viral upper respiratory infection. There were no participants with SAEs related to WVE-120101 up through 16 mg. Two participants discontinued treatment due to AEs, one participant each in the 2 mg and 4 mg groups.
Adverse events were similar in the PRECISION-HD1 OLE as in the core trial, with 25 participants experiencing an event over 95 person/months of exposure. There were no discontinuations due to AEs. One participant experienced a related SAE of gait disturbance.
Across both PRECISION-HD programs (core and OLE), there were no clinically meaningful trends in clinical laboratory values including no CSF white blood cell and protein elevations.
WVE-003 Targeting SNP3 in HD To Begin Dosing in 2021
Site activation and enrollment in the Phase 1b/2a clinical trial of WVE-003 for adults with HD that carry SNP3 are currently underway and Wave expects to begin dosing in 2021. Preclinical models that have established pharmacologic activity have informed the starting dose for this trial. Additionally, Wave will incorporate an adaptive design, intended to support data-driven decisions regarding dosing and to potentially accelerate time to proof-of-concept.
In preclinical studies, WVE-003 showed dose-dependent and selective reduction of mHTT mRNA in vitro, and potent and durable knockdown of mHTT mRNA and protein in vivo. Based on the modeling of the pharmacokinetic-pharmacodynamic (PK-PD) relationship for WVE-003, the model predicts that WVE-003 will attain sufficient concentrations to engage mHTT transcript in both the cortex and striatum and decrease expression of mHTT protein.
Additional Clinical Trials Initiating in 2021
Wave also expects to initiate dosing in two other clinical trials this year, which will assess target engagement, impact on key disease biomarkers, and initial safety of WVE-004 (targeting C9orf72) for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and WVE-N531 (targeting exon 53) for Duchenne muscular dystrophy (DMD). Wave submitted a clinical trial application (CTA) for WVE-N531 in March 2021. These clinical candidates also utilize PN backbone chemistry modifications and have been optimized based on the evolution of Wave’s PRISM™ discovery and drug development platform.
Wave expects that its existing cash and cash equivalents, together with expected and committed cash from its existing collaboration, will enable the company to fund its operating and capital expenditure requirements into the second quarter of 2023.
Source: Wave Life Sciences