The failure of Roche’s Ionis-partnered tominersen in Huntington’s disease may indicate that Wave Life Sciences’ allele-specific antisense oligonucleotide candidate WVE-003 is on the right track, according to analysts at Rodman & Renshaw.
The end of Roche’s antisense oligonucleotide tominersen in Huntington’s disease may bode well for Wave Life Sciences’ WVE-003, also an antisense drug but with an allele-selective mechanism, analysts say.
Last week, Roche announced its decision to end development of tominersen after it failed a Phase 2 trial, performing no better than placebo in terms of efficacy. This is despite lowering levels of the mutant huntingtin protein and neurofilament light chain, two key biomarkers of the brutal neurodegenerative disease.
Investment banking firm Rodman & Renshaw attributed the failure to tominersen’s mechanism of action, lowering both mutant and wild-type huntingtin (HTT) protein. “We believe this non-selective knockdown, sustained over 16 months, is the most likely driver of the lack of clinical benefit despite clear target engagement,” the analysts wrote in a letter to investors on Friday.
Wave’s WVE-003—currently on the cusp of a Phase 2/3 registrational trial—is more specific, targeting SNP3, a polymorphism unique to the mutant huntingtin allele, the firm explained, “enabling selective degradation of mHTT mRNA while preserving wtHTT protein and its neuroprotective function, which tominersen’s approach necessarily depletes.”
The analysts concluded, “Roche’s exit tightens the case for WVE-003 as the leading allele-selective, wtHTT-sparing candidate remaining in HD.”
From failure to fruition?
There are currently no disease-modifying treatments available for Huntington’s—but that could soon change, with uniQure on the cusp of a regulatory filing for investigational gene therapy AMT-130. If the treatment makes it to market, it will not have been an easy journey.
In September 2025, patients and providers were gearing up for a potential FDA filing after AMT-130 slowed disease progression by 75% after three years. Five weeks later, however, the FDA reversed its initial position that data from the company’s Phase 1/2 trial would be sufficient to support a biologics license application (BLA) and requested that uniQure run a sham-surgery–controlled Phase 3 trial. Then last month, under the leadership of acting Commissioner Kyle Diamantas, the FDA again reversed course, deeming that the same three-year data could support an accelerated BLA. UniQure plans to file for approval of AMT-130 this quarter.
Roche and Ionis were also aiming to bring a disease-modifying Huntington’s treatment to patients with tominersen but the partners had already faced their fair share of challenges even before the final termination of the asset’s development. The Phase 3 GENERATION HD1 trial was discontinued after a pre-planned review of the drug’s benefit/risk profile in patients with later-stage Huntington’s showed the drug actually worsened outcomes when given more frequently.
Roche went ahead with the Phase 2 GENERATION HD2 study in patients with prodromal and early manifest disease when “a post hoc analysis of the data suggested that low-exposure tominersen may benefit younger adult patients with lower disease burden,” Peter McColgan, lead clinical director for the Huntington’s Disease program at Roche, told PharmaVoice in 2022. But the failure of that trial turned out to be the final death knell for the ASO.
Meanwhile, Wave has been toiling away on its own ASO. Just over two years ago, the biotech reported that WVE-003 significantly and selectively reduced levels of the mHTT protein in the Phase 1b/2a SELECT-HD trial. After 24 weeks, treatment led to a 46% drop in mHTT levels in patients’ cerebrospinal fluid versus placebo.
Wave has reached alignment with the FDA on a path to accelerated approval of WVE-003, with slowing of caudate atrophy acting as a clinical surrogate endpoint, CEO Paul Bolno told BioSpace last fall. At CHDI’s 20th annual HD Therapeutics Conference, Wave highlighted results from SELECT-HD showing “a statistically significant correlation between mHTT reduction and slowing of caudate atrophy.”
Rodman & Renshaw hedged their optimism over WVE-003 by saying that the SELECT-HD trial “was not powered to demonstrate clinical benefit, and this remains unproven in a larger, longer study.”
The biotech has prepared an investigational new drug (IND) application for a potentially registrational Phase 2/3 trial but is seeking a “prospective strategic partner” before submitting, according to a business update in January at the J.P. Morgan Healthcare Conference. Takeda walked away from a partnership to co-develop the asset in October 2024. No reason was given at the time for terminating the agreement.
Rodman & Renshaw declared the submission of this planned IND “the key near term value driver” for WVE-003.
Like Roche and uniQure, Wave is no stranger to setbacks in the Huntington’s space. The company shelved two earlier antisense candidates, WVE-120101 and WVE-120102, in March 2021 following disappointing data from a pair of Phase 1b/2a trials. Both assets also selectively targeted mHTT. Michael Panzara, former chief medical officer at the biotech, suggested in May 2021 that not enough drug had reached the target to elicit a therapeutic effect.
WVE-003 incorporates the company’s novel PN backbone chemistry modifications, which have been shown in preclinical and clinical studies to enhance the potency and durability of its molecules, Bolno told BioSpace in 2022.
Only time—and a potential partnership—will tell if Rodman & Renshaw’s theory bears out, and WVE-003 follows AMT-130 to the FDA.
