tominersen (RG6042) / Ionis, Roche - LARVOL DELTA

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

Huntington Study Group and Roche Collaborate on Generation HD2 Study (Huntington Study Group) - "The Huntington Study Group together with its wholly-owned clinical research organization, HSG Clinical Research, Inc. (HSGCR), is pleased to announce a collaboration with Roche-Genentech to optimize our collective experiences in Huntington’s disease (HD) clinical research. Together we are working to understand the recruitment and enrollment needs of Roche’s GENERATION HD2 study....Together with Roche, HSG will work to offer further opportunities to explore and incorporate strategies to successfully identify potential participants for the GENERATION HD2 study focused on the US sites."

Licensing / partnership • Huntington's Disease

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

Journal • Huntington's Disease • Movement Disorders

Huntington's Disease Drug Development: A Phase 3 Pipeline Analysis. (PubMed, Pharmaceuticals (Basel)) - "Of the nine clinical trials that met these criteria, eight involved the following drugs: metformin, dextromethorphan/quinidine, deutetrabenazine, valbenazine, Cellavita HD, pridopidine, SAGE-718, and RO7234292 (RG6042). Of these drug treatments, four are already FDA approved. This systematic review provides a resource that summarizes the present therapies for treating this devastating condition that are currently in phase III clinical trials in the United States."

Journal • P3 data • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Huntington's Disease • Movement Disorders • Psychiatry

Emerging treatments targeting DNA and RNA in Huntington’s disease: a review of future perspectives and current challenges (MDS Congress 2023) - "Tominersen was able to reduce mHTT levels significantly but patients had poorer clinical performance than controls and one of the possible causes is the concomitant lowering of wild type HTT (wtHTT)... One of the most important issues now is to lower mHTT levels while maintaining wtHTT. Significant advances were made with different techniques and we are closer to develop a commercially available medication. Efforts are also being made to improve the administration techniques."

Review • CNS Disorders

Huntington's Disease Clinical Trials Corner: July 2023. (PubMed, J Huntingtons Dis) - "In this edition of the Huntington's Disease Clinical Trials Corner, we expand on the GENERATION HD2 (tominersen) and on the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001. We also comment on the recent findings from the PROOF-HD trial, and list all currently registered and ongoing clinical trials in Huntington's disease."

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

Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The developed population PK model was able to describe tominersen PK in plasma and CSF after intrathecal administration across a range of dose levels, and relevant covariate relationships were identified. This model has been applied to guide dose selection for future clinical trials of tominersen in patients with Huntington's disease."

Journal • PK/PD data • Huntington's Disease • Movement Disorders

Therapeutic targeting of Huntington's disease: Molecular and clinical approaches. (PubMed, Biochem Biophys Res Commun) - "The road to success has not been without bumps since a big phase III trial of tominersen was unexpectedly discontinued due to exceeding risks than drug's benefit to the patients...We have reviewed the present disease-modifying therapies in clinical development for HD and examined the current landscape of developing clinical therapies. We further investigated the pharmaceutical development of Huntington's medicine in the pharma industries and addressed the existing challenges in their therapeutic success."

Journal • Huntington's Disease • Movement Disorders • Proteinopathy

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials. (PubMed, Neural Regen Res) - "Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of..."

Clinical • Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • APP

Clinical and biomarker characteristics of Huntington’s Disease patients recently proposed for huntingtin-lowering clinical trial inclusion (MDS Congress 2022) - "However, while the drug candidate tominersen was not deemed clinically effective overall, it was suggested that it might be more useful for a subset of trial participants ≤48 years of age with a CAG repeat-Age Product (CAP) score <500... Our data suggests significant differences between participants ≤48 years of age with CAP scores below and above 500. While we have previously proposed that a plasma NfL cut-off value of <45.0 pg/ml may be useful in excluding participants who are too far from manifest onset to progress during the time frame of a clinical trial, thereby providing a lower limit for exclusion, these new findings provide an upper limit, by potentially excluding participants who may have progressed too far to benefit from therapeutic treatment."

Biomarker • Clinical • CNS Disorders • Plasma NfL

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=360 | Recruiting | Sponsor: Hoffmann-La Roche

Biomarker • New P2 trial • Genetic Disorders • Huntington's Disease • Movement Disorders • NEFL

An Open-Label Extension Study to Evaluate Long-Term Safety and Tolerability of RO7234292 (RG6042) in Huntington's Disease Participants Who Participated in Prior Roche and Genentech Sponsored Studies (clinicaltrials.gov) - P3 | N=236 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Trial completion date: Mar 2023 ➔ Mar 2022

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