ATXN1

First clinical data of VO659 demonstrated 28% mean reduction in CSF mutant HTT at day 85 in HD patients in 40 mg dose cohort with an effect after the first dose No sustained increase in CSF neurofilament light chain (Nf-L) protein observed through day 85 VO659 is generally safe and well tolerated with an anticipated dosing regimen of 1-2 times per year in future studies Data highlighted in oral presentation at EHDN & Enroll-HD 2024 LEIDEN, Netherlands, Sept. 13, 2024 /PRNewswire/ -- Vico Therapeutics B.V., a clinical-stage genetic medicines company developing therapies for severe neurological diseases, today announced new positive interim data in Huntington's disease (HD) from the ongoing Phase 1/2a clinical trial of VO659, an investigational allele-preferential antisense oligonucleotide (ASO) therapy. Results will be highlighted in an oral presentation at the European Huntington's Disease Network's EHDN & Enroll-HD 2024 meeting on Friday, September 13, 2024 at 9:45 a.m. CET. This is the first clinical data reported of VO659, which is designed to target the CAG repeat expansion that causes all nine known polyglutamine diseases, including HD as well as spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3). VO659 has a unique allele-preferential mechanism of action that targets expanded CAG repeats in the mutant mRNA transcript and inhibits mRNA translation leading to a reduction of mutant protein, with the potential to halt or slow disease progression. VO659 is the only clinical-stage program that directly targets the underlying CAG repeat expansion that causes HD. The Phase 1/2a clinical trial is a multi-center, open-label, multiple ascending dose study designed to assess the safety and tolerability of four doses of VO659 administered intrathecally every four weeks in participants with early manifest HD, or mild to moderate SCA1 or SCA3. Exploratory endpoints include the assessment of pharmacodynamic (PD) biomarkers (mHTT, mATXN3, and Nf-L protein) in cerebrospinal fluid (CSF), pharmacokinetics in CSF and plasma, and clinical outcome measures. The interim analysis provides a look at available safety, tolerability and PD data for HD participants in the 40 mg cohort through at least day 85 of the study. The Phase 1/2a trial interim data presented at the EHDN meeting demonstrated: A mean reduction of 28% in CSF mutant huntingtin protein (mHTT) in treated HD participants at day 85 compared to baseline with an immediate effect observed after the first dose at day 29 No sustained increase or decrease in Nf-L protein in CSF across treated participants at day 85 compared to baseline VO659 appears generally safe and well tolerated at the 40 mg dose level in treated HD patients through the available clinical follow-up period VO659 has a long half-life, indicating the potential for infrequent dosing estimated at 1-2 times per year "We are very pleased to announce these first data from our Phase 1/2a clinical trial of VO659 in participants living with HD," said Micah Mackison, chief executive officer at Vico. "It is highly encouraging that we saw immediate reductions in CSF mHTT and no changes in Nf-L protein, two key biomarkers in HD, in treated patients over the available follow-up period. Given VO659's long anticipated half-life, there is clear potential for this therapy to have an infrequent dosing schedule, and we look forward to exploring this further in clinical trials. These data are a significant milestone for our team and for the HD community that so desperately needs treatment options, and we look forward to continuing assessments from the trial and advancing VO659 as quickly as possible for patients and their families." These interim data build on preclinical data of VO659 demonstrating potent target engagement across multiple disease models. Preclinical research showed significant and dose-dependent reductions of mHTT and improvement in motor function in vivo in disease mouse models of HD and allele-preferential reductions of mHTT in vitro in HD patient cell models. "VO659's allele-preferential action and direct targeting of the CAG repeat expansion that causes HD is a unique approach to treating this disease with a promising future for the HD community," said Scott Schobel, M.D., chief medical officer at Vico. "The Phase 1/2a interim clinical data reinforce the potent, targeted nature of VO659 and add to a growing body of evidence supporting VO659's advancement in the clinic for HD as well as its broad potential applications for all CAG repeat expansion diseases." The Phase 1/2a trial remains ongoing and Vico plans to meet with regulators later this year to discuss the optimal path forward for the VO659 program. The company plans to provide an update from the SCA1 and SCA3 patient cohorts at a future scientific meeting. About Huntington's Disease and VO659 Huntington's disease (HD) is a rare genetic, progressive neurodegenerative disorder characterized by movement disorders, cognitive impairment, and psychiatric manifestations including depression and psychosis. The disease varies in terms of age of onset, typically starting in mid-adulthood, and it is ultimately fatal. The disease is caused by a CAG trinucleotide repeat expansion in the coding region of exon 1 of the huntingtin (HTT) gene, which results in production of mutant HTT protein (mHTT) with an elongated polyglutamine (polyQ) stretch at its N-terminus. This expanded polyQ stretch confers a toxic gain-of-function to mutant protein forms, ultimately resulting in widespread neuronal death. Currently available therapies for HD focus on alleviating some of the movement and psychiatric symptoms, with a significant unmet need for disease-modifying therapies. VO659 is designed to suppress mHTT in an allele-preferential manner and slow or halt disease progression. VO659 was granted both FDA and EMA Orphan Drug designation for the treatment of HD. About Vico Therapeutics B.V. Vico Therapeutics is a clinical-stage genetic medicines company developing antisense oligonucleotide (ASO) RNA modulating therapies for patients with severe neurological diseases. Our lead product candidate, VO659, is currently in Phase 1/2a clinical development for the treatment of spinocerebellar ataxia types 1 and 3 and Huntington's disease and is the only ASO in the clinic that targets the underlying CAG repeat expansions that cause all nine known polyglutamine diseases. Vico's research platform designs fit-for-purpose ASOs by applying precision chemistry with mechanisms of action ideally suited to target genetic neurological diseases. For more information, visit . Media Contact Jenna Urban Berry & Company Public Relations [email protected] 212-253-8881 SOURCE Vico Therapeutics B.V. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Pictured: A doctor holds an MRI of the brain/iStock, Chinnapong Several late-stage clinical trials are expected to produce data in the final months of 2023 that could spell new approaches to treating Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis. Mizuho Securities recently published a report highlighting some of the trials to watch as the year comes to a close, and BioSpace spoke with Graig Suvannavejh, managing director of equity research in biopharmaceuticals and biotechnology at the firm, to find out more. Alzheimer’s Disease Eisai and Biogen’s subcutaneous Leqembi In July, the FDA fully approved Leqembi (Lecanemab), a monoclonal antibody developed by Eisai and Biogen that binds to soluble and insoluble amyloid-beta peptides to treat Alzheimer’s. Leqembi is currently administered only through intravenous injection, which limits the locations where patients can obtain treatment. To enhance its accessibility, the partners launched an open-label, randomized Phase I clinical trial in September 2022 to evaluate the bioequivalence of a single subcutaneous dose (720 milligrams) of Leqembi compared to an equivalent dose delivered through intravenous injection. Data from the subcutaneous study are anticipated in October 2023, and regulatory submissions for the maintenance dosing regimen and subcutaneous formulation are expected in the first quarter of 2024. Currently, to receive treatment, “You have to drive to an infusion center and sit in a chair for a few hours,” Suvannavejh told BioSpace. He emphasized the strategic value of a treatment that could be administered under the skin at home by a caregiver and said this readout is important for Leqembi’s commercial success. Huntington’s Disease Wave Life Sciences’ WVE-003 WVE-003, developed by Wave Life Sciences, is an allele-selective oligonucleotide that attacks mutant proteins that produce the symptoms of Huntington’s disease (HD). It is designed to target the huntingtin (HTT) mRNA that carries a single nucleotide polymorphism that appears on the mutant HTT (mHTT) allele. By lowering the quantity of the mutant form of this protein, WVE-003 allows the wildtype (wtHTT) allele to function, preserving its beneficial effects in the central nervous system. “HD is a tragic and unrelenting disease that passes through generations of families and has been compared to having ALS, Parkinson’s and Alzheimer’s all at once,” Paul Bolno, Wave’s president and CEO, told BioSpace by email. “Currently, there are no disease-modifying treatments for HD, so our primary goal is to develop a treatment that slows or stops progression of the disease.” The Phase Ib/IIa SELECT-HD trial is evaluating WVE-003’s ability to reduce mutant HTT in the cerebrospinal fluid compared to a placebo. The study aims to optimize the dose level—30 mg, 60 mg or 90 mg—and frequency of WVE-003 administration to reach the desired early indicators. "If WVE-003 is successful in the clinic, it has potential to be truly transformational,” Bolno said. Beyond treating symptomatic disease, he said Wave’s mHTT-lowering approach, which spares wtHTT, may also be beneficial in treating patients earlier, perhaps before symptoms of the disease present. “We are resolutely focused on what clinical success would mean to these families—and to future generations.” Wave expects to deliver additional single-dose and available multi-dose biomarker and safety clinical data in the second half of 2023. Amyotrophic Lateral Sclerosis Seelos Therapeutics Inc.’s SLS-005 Developed by Seelos Therapeutics, SLS-005 (Trehalose) is being evaluated in the HEALEY ALS Platform Trial, a novel approach by which companies can conduct ALS clinical trials more efficiently. “Currently, there are no treatments available that address the entire broad spectrum [of] patients with ALS,” Seelos Founder and CEO Raj Mehra told BioSpace in an email. “SLS-005, if successful in the HEALEY trial, would become the first drug to treat the broad ALS population based on a well-established and specific mechanism of action," he said. The registrational Phase II/III trial is examining the effectiveness of SLS-005 at stabilizing proteins and promoting autophagy in the brain to clear toxic protein aggregations characteristic of ALS. The results compare disease severity following a 90.5 mg/mL infusion of SLS-005 or a placebo for 24 weeks. Seelos plans to release top-line data from the trial before the end of 2023. The company initiated an Expanded Access Program in April 2023 for ALS patients who are ineligible for the clinical trial. “SLS-005 is not just one drug for one disease but one drug for multiple diseases,” Mehra said. The company is also evaluating SLS-005 in a late-phase registration-directed trial for SCA3 (or Machado-Joseph disease), an autosomal dominant cerebellar ataxia that occurs due to CAG repeat expansions in the ataxin protein. SLS-005 received the FDA’s Orphan Drug designation in 2020. Multiple Sclerosis Atara Biotherapeutics’ ATA188 Developed by Atara Biotherapeutics, ATA188 is a T-cell immunotherapy that targets Epstein-Barr virus (EBV)-infected B cells to treat nonactive secondary progressive multiple sclerosis (MS) and nonactive primary progressive MS. Most treatment options for relapsing-remitting MS reduce flares but do not inhibit the worsening of disability in progressive forms of the disease. Current research supports the role that EBV plays in the development of MS. ATA188 is composed of T-cells obtained from healthy donors previously infected with EBV. The cells are primed to recognize and attack EBV proteins to potentially slow or halt disease progression. Atara initiated the Phase I/II EMBOLD clinical trial in 2017 to determine the safety, tolerability and optimal dose of ATA188 and to evaluate its effect on clinical disability using the Expanded Disability Status Scale. The second half of the study evaluated the drug in participants with progressive forms of MS. Data from this phase, which will detail the drug’s ability to ease disease-related disability, is anticipated in November 2023. Stacy Kish is a freelance science writer based in Pittsburgh, PA. Reach her at earthspin.blog.

LEIDEN, Netherlands, April 3, 2023. Vico Therapeutics B.V., a clinical-stage genetic medicines company developing therapies for severe neurological diseases, today announced that the first patient has been dosed in a Phase 1/2a clinical study evaluating VO659 for the treatment of Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3). VO659 is an antisense oligonucleotide (ASO) investigational therapy designed to target the CAG repeat expansion that causes all nine known polyglutamine diseases including HD, SCA1 and SCA3. "We are encouraged by the continued progress of our development program and very pleased to announce the first patient dosed in this Phase 1/2a study of VO659 in HD, SCA1 and SCA3," said Scott Schobel, MD, chief medical officer at Vico. "VO659 is the first allele-preferential ASO in clinical development with broad application to all CAG repeat expansion diseases. The robust preclinical data package for VO659 demonstrates favorable brain uptake, potency and durability of effect, and we look forward to assessing the translation of these characteristics in this clinical trial." VO659's unique target and dual mechanism of action enable potent target engagement across multiple disease models. In preclinical studies, significant and dose-dependent reductions of mutant huntingtin protein (mHTT) and improvement in motor function were observed in vivo in disease mouse models of HD. Allele-preferential reductions of mHTT were observed in vitro in HD patient cell models. Preclinical data also showed VO659 induced a significant reduction of mutant ATXN1 (mATXN1) and mutant ATXN3 (mATXN3) protein levels in vivo and in vitro in disease mouse models and patient cell models of SCA1 and SCA3, respectively. The Phase 1/2a clinical trial is a multi-center, open-label basket study designed to assess the safety and tolerability of multiple ascending doses of VO659 administered intrathecally in participants with early manifest HD or mild to moderate SCA1 or SCA3. Exploratory endpoints include the assessment of pharmacodynamic biomarkers (mHTT, total HTT, mATXN3, total ATXN3 and neurofilament light chain) in cerebrospinal fluid, plasma pharmacokinetics, and clinical outcome measures. The study is expected to enroll approximately 71 participants. "It is our mission to bring safe, effective therapies to patients and families affected by devastating neurological diseases, and today marks an important milestone in our journey to realize this mission. We are grateful to the trial investigators and patients participating in our Phase 1/2a study as we assess the potential of VO659 in HD, SCA1 and SCA3. We also look forward to sharing more details about the study at CHDI's Annual Huntington's Disease Therapeutics Conference later this month," said Micah Mackison, chief executive officer at Vico. About Vico Therapeutics B.V. Vico Therapeutics is a clinical-stage genetic medicines company developing antisense oligonucleotide (ASO) RNA modulating therapies for patients with severe neurological diseases. Vico's platform designs ASOs to modulate RNA through multiple approaches including inhibition of translation, modulation of splicing, editing, degradation, and activation. We apply precision chemistry to identify an RNA modulator that achieves the desired target engagement and safety profile for different diseases. Our lead product candidate, VO659, is currently in Phase 1/2a clinical development for the treatment of Huntington's disease and spinocerebellar ataxia types 1 and 3. For more information, visit www.vicotx.com. SOURCE Vico Therapeutics B.V. Posted: April 2023