The SELECT-HD trial (NCT05032196) is expected to enroll approximately 36 patients with a confirmed diagnosis of early-stage Huntington disease and carry the SNP3 allele in association with their CAG expression.
The initiation of dosing in the phase 1b/2a SELECT-HD trial (NCT05032196), which will evaluate Wave Life Sciences’ investigational agent WVE-003 in patients with Huntington disease (HD), has just been announced. The news comes months after the company discontinued trials of its 2 other HD agents, WVE-120102 and WVE-120101, which failed to show efficacy.1
SELECT-HD is a multicenter, randomized, placebo-controlled clinical trial that will assess the safety and tolerability of single and multiple-ascending intrathecal doses of WVE-003 in patients with early-stage HD who carry SNP3 in association with their cytosine-adenine guanine (CAG) expansion. It is expected to enroll approximately 36 patients, and is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.
"WVE-003 reflects the significant evolution of our chemistry and the many learnings gained from our first-generation clinical programs," Michael Panzara, MD, MPH, chief medical officer, Wave Life Sciences, said in a statement.1 "Our enthusiasm for this program is bolstered by a compelling set of preclinical data that demonstrated selectivity, potency, and durability of WVE-003 with effects in relevant brain regions. Further, emerging data continue to indicate that a fundamental requirement for clinical success in HD treatment will be the need to preserve wild-type HTT protein, supporting our allele-selective approach to mutant HTT protein reduction.”
WVE-003, a stereopure antisense oligonucleotide, is designed to target SNP3, a single nucleotide polymorphism (SNP) on the mutant huntingtin (mHTT) allele, selectively lowering mHTT protein and sparing healthy, wild-type huntingtin protein. The agent, which incorporates Wave Life’s novel PN backbone chemistry modifications, has demonstrated dose-dependent and selective reduction of mHTT mRNA in vitro and potent and durable knockdown of mHTT mRNA in vivo, both in the cortex and striatum. The starting dose for the SELECT-HD trial was based off data from several preclinical models that evaluated pharmacokinetic to pharmacodynamic relationships.
Wave Life’s previous attempts to build out the already limited treatment landscape have been met with challenges, and even failures at times. The phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials (NCT03225846 and NCT03225833, respectively), which evaluated WVE-120102 and WVE-120101, showed no evidence of a dose-response across any of the dose levels tested, resulting in the discontinuation of the agents in March.2
The data from the PRECISION-HD studies showed no statistically significant change in mHTT compared to placebo after single or multiple doses of WVE-120102, up to and including 32 mg monthly. 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 neurofilament light over time, nor worsening of disease progression.
Another prominent agent, tominersen (Roche), which was the first to successfully target and reduce levels of mHTT protein in patients with HD, was also discontinued earlier this year.3 The decision stepped from a pre-planned review of the results from the phase 3 GENERATION HD1 study (NCT03761849). Despite no new or emerging safety signals, the recommendation was based on the investigational therapy’s potential benefit/risk profile for study participants.
In NeurologyLive’s June 2021 issue, Daniel O. Claassen, MD, MS, director, Level 1 HDSA Center of Excellence, Vanderbilt University Medical Center, detailed the community’s reaction to this litany of disappointing news, calling the mood among the community at the time "flat."
"Given the potential issues with outcomes, treatment adverse effects, and patient inclusion, it is not fair to say we should abandon mutant Htt protein reductions. There is no reason, at present, to believe that the pathophysiologic progression of HD is not driven by mutant Htt protein expression," Claassen wrote, adding that a dive into those data may yet reveal more insights. Additionally, he noted that a number of other areas of interest are being explored, and companies such as UniQure, Voyager, and Spark are AAV-mediated gene therapy approaches, noting that "the potential benefit of direct-to-striatum delivery appears promising."
You can read Claassen’s entire editorial in the NeurologyLive June 2021 issue.