tominersen (RG6042) / Ionis, Roche - LARVOL DELTA

Development of Antisense Gapmers for the Treatment of Huntington's Disease. (PubMed, Methods Mol Biol) - "Antisense-mediated knockdown of mutated huntingtin is a promising therapeutic approach for Huntington's disease (HD), a devastating disorder affecting motor and cognitive abilities. This chapter focuses on the modified gapmer AOs for the treatment of HD."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders

A Cost-Effectiveness Analysis for Treatments of Patients with Early Stage Huntington's Disease in the USA. (PubMed, Pharmacoecon Open) - "From a modified US societal perspective, this analysis suggests that AMT-130 may be cost-effective relative to SoC, whereas Tominersen exceeds the WTP threshold of $500,000 per QALY gained. Further evidence on long-term effectiveness and durability is needed to inform policy and reimbursement decisions."

HEOR • Journal • CNS Disorders • Huntington's Disease • Movement Disorders • Rare Diseases

GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease (clinicaltrials.gov) - P2 | N=301 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Apr 2027 ➔ Oct 2026

Biomarker • Trial completion date • CNS Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders

Next Steps (Roche Press Release) - "Communications to Study Participants: Our immediate focus is supporting participants and sites regarding these announcements. Earlier this week, sites were notified so they could contact participants and discuss transition plans and support...Sharing Data & Learnings: Data will continue to be analysed and presented at future medical meetings. We are committed to sharing learnings with the research and family communities to advance the understanding of drug development for HD; Further Research: Roche’s Phase I/II study of investigational gene therapy RG6662 (formerly from Spark Therapeutics; study SPK-101, NCT06826612) is ongoing as planned. Additionally our interest in exploring multiple HD therapeutic approaches remains, and we will continue to follow promising science."

P1 data • P2 data • Trial status • CNS Disorders • Huntington's Disease

Half-Life as a Therapeutic Design Axis: Targeting Short-Lived lncRNAs With Antisense Oligonucleotides. (PubMed, IUBMB Life) - "Two back-to-back 2012 surveys-BRIC-seq in human HeLa and actinomycin-D microarray in mouse Neuro-2a-yielded similar median lncRNA half-lives of 3.4 and 3.5 h, with a short-lived fraction we term short-lived noncoding transcripts (SLiTs; t1/2 < 4 h). We (i) develop a kinetic framework for how target half-life shapes ASO pharmacodynamic onset, (ii) survey the cross-species half-life landscape, (iii) propose a decay-pathway-aware ASO design framework aligning modality choice with endogenous decay machinery, (iv) re-read representative clinical ASO cases (nusinersen, tofersen, tominersen, MALAT1 ASOs) through the half-life lens, and (v) outline a half-life-aware preclinical roadmap. Treating half-life symmetrically-engineered up in vaccine RNAs, exploited downward in endogenous targets-highlights a largely unoccupied design space for next-generation oligonucleotide therapeutics."

Journal • Review • CDKN2B • GAS5 • HOTAIR • MALAT1 • NEAT1

Update on Two Clinical Studies: GENERATION HD2 (tominersen) and POINT-HD (RG6496) (Roche Press Release) - "Consequently, we have made the difficult decision to discontinue both clinical development programmes based on: Phase II GENERATION HD2 top-line results...While the study met its safety and biomarker objectives, it did not meet its efficacy objective; Phase I POINT-HD (evaluating investigational drug RG6496) study discontinuation based on new data from a separate non-clinical (animal) study....Initial results of the primary analysis show...Biomarkers: Tominersen significantly lowered mutant huntingtin protein and Neurofilament Light Chain (NfL) (a protein linked to neuronal damage that is elevated in people with HD)...Efficacy: There was no meaningful impact on clinical efficacy for the study participants receiving tominersen, compared to those on placebo...While there is no safety concern for people to receive one dose, we have chosen to stop the POINT-HD study early, because we can no longer offer participants the possibility of long-term treatment."

Discontinued • P1 data • P2 data • Preclinical • Trial termination • CNS Disorders • Huntington's Disease

NanoSentinel: A Nanoparticle Carrier to Enhance Blood–Brain Barrier Delivery of Huntingtin-Lowering Therapy in Huntington’s Disease – A Conceptual Feasibility Study (AAN 2026) - "Antisense oligonucleotide (ASO) therapy (tominersen) demonstrated robust mHTT lowering in cerebrospinal fluid but failed to show clinical benefit, in part due to poor penetration into striatal medium spiny neurons...By combining targeted delivery with real-time monitoring, this platform could revive ASO-based approaches in HD by addressing limitations observed in prior clinical trials. Preclinical BBB organoid and HD mouse model studies are warranted to validate these predictions."

CNS Disorders • Huntington's Disease • Inflammation • Movement Disorders

Huntington's disease clinical trials update: October 2025. (PubMed, J Huntingtons Dis) - "In this edition of the Huntington's Disease Clinical Trials Update, we expand on the launch of the phase II/III clinical trial of SKY-0515 from Skyhawk Therapeutics and the phase I/II clinical trial of SPK-10001 from Spark Therapeutics. Further updates include recent developments in Roche's tominersen programme within GENERATION HD2, progress with votoplam (PTC518) in PIVOT-HD by PTC Therapeutics and developments in the collaborative PTC Therapeutics/Novartis programme. We also report positive topline data from uniQure's phase I/II clinical trial of AMT-130 after 36 months of follow-up. We additionally discuss regulatory developments regarding pridopidine following the negative PROOF-HD study. Finally, we provide an updated listing of all registered and ongoing clinical trials in Huntington's disease."

Journal • Huntington's Disease • Movement Disorders

Quantitative relationship between tominersen concentrations in cerebrospinal fluid and biomarker changes in Huntington's disease patients. (PubMed, Br J Clin Pharmacol) - "The PKPD model quantitatively confirms the relationship between tominersen exposure and CSF mHTT lowering. The ER analysis suggests that lower tominersen exposure levels may offer a better benefit-risk profile."

Biomarker • Journal • Huntington's Disease • Inflammation • Movement Disorders

Molecular and imaging biomarker responses to brain mutant HTT lowering in a mouse model of Huntington disease. (PubMed, Mol Ther Nucleic Acids) - "HTT ASO also partially reversed striatal transcriptome dysregulation and restored oligodendrocyte-specific gene expression. Plasma NEFL, but not brain imaging, emerges as a sensitive and dynamic response biomarker for mHTT-lowering therapies."

Journal • Preclinical • Genetic Disorders • Huntington's Disease • Movement Disorders • Solid Tumor • GFAP • NEFL • Plasma NfL

GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease (clinicaltrials.gov) - P2 | N=301 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Feb 2026 ➔ May 2026

Biomarker • Trial primary completion date • Genetic Disorders • Huntington's Disease • Movement Disorders

Roche provides an update on tominersen: What’s next for this huntingtin-lowering drug? (HDBuzz) - "This week, we heard an update from Roche about their huntingtin-lowering therapy, tominersen, currently being tested in the GENERATION HD2 trial. An independent data monitoring committee (iDMC) that regularly reviews all of the data from the trial recently held their scheduled meeting and made a recommendation to modify the trial design. To cut to the chase and set everyone’s mind at ease - the trial is continuing and there are no major safety concerns."

Trial status • Huntington's Disease

A digital motor score for sensitive detection of progression in Huntington's disease. (PubMed, Brain) - P1, P2, P3 | "It was developed and subsequently validated using data from four separate studies (HD Natural History Study [NCT03664804], open-label extension [OLE] of the tominersen Phase I/IIa study [NCT03342053], GENERATION HD1 [NCT03761849], and Digital-HD)...In a post-hoc analysis of GENERATION HD1, the STC of HDDMS at Week 20 was comparable to that of the cUHDRS at Week 68. The HDDMS promises substantial reduction in sample size in clinical trials."

Journal • Huntington's Disease • Movement Disorders

GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease. (clinicaltrials.gov) - P2 | N=301 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Huntington's Disease • Movement Disorders

A narrative review of phase III and IV clinical trials for the pharmacological treatment of Huntington's disease in adults. (PubMed, Medicine (Baltimore)) - "The medications used in phase III and IV trials are minocycline, valbenazine, deutetrabenazine, tominersen, pridopidine (phase III), and memantine (phase IV)...Current medications aim to manage HD symptoms, potentially improving outcomes and reducing disease progression risks. The growing emphasis on specific approaches reflects a better understanding of HD's diverse symptoms, presenting opportunities for more effective and personalized treatment strategies."

Journal • P3 data • Review • CNS Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders • Psychiatry

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington's disease mice. (PubMed, Transl Neurodegener) - "Our data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD."

Journal • Preclinical • CNS Disorders • Huntington's Disease • Movement Disorders • Solid Tumor • CSF NfL • NEFL • Plasma NfL

Mapping the Efficacy Landscape: A Network Meta-Analysis of Pharmacological Interventions in Huntington's Disease (MDS Congress 2024) - "UHDRS TMS scores for Laquinimod 1.5mg OD showed a significant mean difference of 9.7 (95% CI: 2.55 to 16.85). RO7234292 ODC 120 mg once every 4 weeks showed a mean difference of 4.55 (95% CI: 1.59 to 7.5)... Rivastigmine incremental dose (1.5-3 mg BID) , Creatinine (40mg), HUFAs mixture (400mg), and Riluzole (200mg) show significant improvements with regards to UHDRS TMS score, in order of decreasing efficacy. Further research is required to validate these results. Fig."

Retrospective data • CNS Disorders

Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT. (PubMed, Mol Ther Nucleic Acids) - P1/2 | "Through comparisons with a surrogate for the nonselective investigational compound tominersen, we also demonstrate that allele-selective molecules display equivalent potency toward mHTT with improved durability while sparing wtHTT. Our preclinical findings support the advancement of WVE-003, an investigational allele-selective compound currently in clinical testing (NCT05032196) for the treatment of patients with HD."

Journal • Preclinical • Huntington's Disease • Movement Disorders

Huntington's Disease: Latest Frontiers in Therapeutics. (PubMed, Curr Neurol Neurosci Rep) - "After initial negative results with ASO molecules Tominersen and WVE-120101/ WVE-120102, the therapeutic landscape continues to expand, with various trials currently under development to document proof-of-concept and safety/tolerability. The possibility of quantifying mHTT in CSF, along with the development of an integrated biological staging system in HD are important innovations applicable to clinical trial design that enhance the drug development process. Although a future in HD with DMTs remains a hope for those living with HD, care partners and care providers, the therapeutic landscape is promising, with various drug development programs underway following a targeted approach supported by disease-specific biomarkers and staging frameworks."

Journal • Review • CNS Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease

Exploring molecular mechanisms, therapeutic strategies, and clinical manifestations of Huntington's disease. (PubMed, Arch Pharm Res) - "Antisense oligonucleotides, such as Tominersen, play a leading role in targeting and modulating the expression of mutant huntingtin...Collaborative interdisciplinary endeavors and a more insightful understanding of HD pathogenesis are on the verge of reshaping the therapeutic landscape. As we navigate the intricate landscape of HD, this review serves as a guide for unraveling the intricacies of this disease and progressing toward transformative treatments."

Journal • Review • CNS Disorders • Huntington's Disease • Metabolic Disorders • Movement Disorders

Understanding Pharmacy Costs and the Changing Treatment Landscape in Huntington's Disease (HD) in the US: A Systematic Literature Review (SLR) and Database Review for Disease-Modifying Therapies (DMT) in Development (ISPOR 2024) - "Motor symptoms incur the greatest annual drug cost, with high median costs per patient (2019) for tetrabenazine ($24,996), deutetrabenazine ($69,972), and valbenazine ($76,908). Ten clinical trials are investigating potential future DMTs: two-antisense oligonucleotides (n=5; Tominersen [RO7234292, ISIS 443139], WVE-003), two-RNA-targeting small molecules (n=2; PTC518, Branaplam), monoclonal antibodies (n=2; ANX005, VX15/2503), and gene therapy (n=1; rAAV5-miHTT). Pharmacy costs for symptomatic treatment are substantial in HD, with these costs increasing as HD progresses and symptom severity increases. This significant burden illustrates the importance of developing new DMTs that can prevent or slow disease progression for patients with HD."

Review • CNS Disorders • Depression • Gene Therapies • Huntington's Disease • Mood Disorders • Movement Disorders • Psychiatry

Concern about Tominersen in Patients with Huntington's Disease. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Huntington's Disease • Movement Disorders

Concern about Tominersen in Patients with Huntington's Disease. (PubMed, N Engl J Med) - No abstract available

Journal • Huntington's Disease • Movement Disorders

Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease. (PubMed, J Control Release) - "Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD."

Journal • CNS Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders • APOA1

GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease. (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Jan 2025 ➔ Feb 2026

Biomarker • Trial primary completion date • Genetic Disorders • Huntington's Disease • Movement Disorders