The SNP-targeting agents showed no evidence of dose response in PRECISION-HD2 and similar results in PRECISION-HD1, though development of SNP3-targeted agent WVE-003 in HD will continue.
Wave Life Sciences has announced that the results of its phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials (NCT03225846 and NCT03225833, respectively) do not suggest the clinical development of WVE-120102 and WVE-120101 for the treatment of Huntington disease (HD) should continue. The agents targeted the single nucleotide polymorphisms (SNPs) SNP1 and SNP2.1
The results from all participants (n = 88) in the PRECISION-HD2 core trial showed no evidence of a dose-response across the dose levels tested. As well, there was no statistically significant change in mutant huntingtin protein (mHTT) compared to placebo after single or multiple doses of WVE-120102, up to and including 32 mg monthly. The 16-mg dose of WVE-120101 being evaluated in PRECISION-HD1 (n = 51) yielded similar results, and thus Wave elected to halt clinical development.
Additionally, the PRECISION-HD2 open-label extension showed inconsistent results, and that in addition to the core trial results, there were no changes in cerebrospinal fluid (CSF) neurofilament light (NfL) over time, nor worsening of disease progression. Adverse events were mostly mild to moderate across trials (FIGURE).
Wave did announce that it anticipates that it will complete the analysis of the 32-mg cohort in the PRECISION-HD1 study in the second quarter of this year.
“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, Therapeutics Discovery and Development, Wave Life Sciences.
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In PRECISION-HD2, those who received 3-4 doses of 32-mg WVE-120102 had a non-statistically significant median reduction of 9.9% in mHTT in CSF compared to a pooled placebo group with a median decrease of 0.8% (P = .74). Likewise, in PRECISION-HD1, those who received 3-4 doses of 16-mg WVE-120101 had a non-statistically significant median reduction of in mHTT of 11.6% compared to the placebo group of 10.0% (P = .56).
“For PRECISON-HD, I think the easiest way to interpret this is that this drug didn’t reduce mHTT enough. I believe there are other SNP targets that the company is exploring, but this is why you do phase 1 studies—[to find out] are they safe, and to they hit the target?” Daniel Claassen, MD, MS, associate professor of neurology, Vanderbilt University Medical Center, told NeurologyLive.
Panzara added in his statement that the company did gain an understanding from the data and “are encouraged by data that suggest our SNP targeting approach may achieve allele-selectivity.” He alluded to the ongoing collaboration with research partners on its next-generation HD candidate, WVE-003, which uses its “next-generation PN backbone chemistry.”
Paul Bolno, MD, MBA, president and chief executive officer of Wave Life Sciences, noted that Wave’s pipeline also includes WVE-004 for amyotrophic lateral sclerosis and frontotemporal dementia and WVE-N531 for Duchenne muscular dystrophy, all of which utilize this novel PN backbone chemistry.
“[It] 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,” Bolno said in a statement.
WVE-003 is designed to selectively lower mHTT by targeting SNP3, an SNP found in an estimated 40% of adults with HD on the expanded CAG allele. This allele-selective approach was developed due to the nature of those with HD having a smaller collective of wild-type HTT protein, and the literature suggesting that favorable outcomes can be achieved by preserving the wild-type protein.
The company noted that it plans to initiate dosing in a phase 1b/2a clinical trial for WVE-003 this year. Those who participated in the PRECISION-HD trials will be offered the chance to screen for enrollment in the trial.
This news comes on the heels of Roche’s discontinuation of dosing in its phase 3 GENERATION HD1 study of tominersen in manifest HD, based on a decision from the unblinded Independent Data Monitoring Committee’s pre-planned review. It made the recommendation based on the investigational therapy’s potential benefit/risk profile for study participants. Additionally, Roche paused dosing in its open-label extension study (GEN-EXTEND) of tominersen while the data are analyzed.2
“For GENERATION-HD, this has been a terribly discomforting time for all of us in HD. To stop dosing suggests that tominersen is not providing any clinical benefit, and this was certainly touted as a way forward for HD treatments,” Claassen told NeurologyLive. He added, however, that the optimism of those working to treat and develop treatments for HD is unchanged, with a number of other targets being assessed to reduce mHTT. “Right now, we are trying to help our patients, who like us are frustrated, but living in hope,” he said.