ATXN1

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

VO659 is the only clinical-stage candidate targeting the CAG repeat expansion that causes these diseases VO659 was designed to preferentially reduce mutant HTT and spare wild-type HTT Phase 1/2a basket trial design and preclinical VO659 data to be presented at CHDI Foundation's 18th Annual Huntington's Disease Therapeutics Conference LEIDEN, Netherlands, April 3, 2023 /PRNewswire/ -- 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. The company also announced that researchers will be highlighting preclinical data of VO659 in an oral presentation along with poster presentations of the Phase 1/2a trial design and additional preclinical data of VO659 at the CHDI Foundation's 18th Annual Huntington's Disease Therapeutics Conference being held in Dubrovnik, Croatia from April 24-27, 2023. Details of Vico's presentations at CHDI's Annual Conference are as follows: Oral Presentation Title: VO659, an allele-preferential CAG repeat-targeting ASO with therapeutic potential for patients with Huntington's disease and spinocerebellar ataxia types 1 and 3 Presenter: Nicole Datson, PhD, Chief Scientific Officer, Vico Session: Session III - Novel mechanisms, modalities, and candidates for HD therapeutics Date and Time: Wednesday, April 26 at 9:00 am CET Poster Presentations Title: VO659, a CAG repeat-targeting ASO, blocks translation of polyQ proteins in a CAG repeat length dependent and allele preferential manner Presenter: Ruurd Verheul, Scientist, Vico Date and Time: Monday, April 24 – Thursday, April 27 Title: Design of a first-in-human, phase 1/2a trial of VO659, a CAG repeat-targeting ASO in patients with Huntington's disease and spinocerebellar ataxia types 1 and 3 Presenter: Katja Obieglo, PhD, Clinical Scientist, Vico Date and Time: Monday, April 24 – Thursday, April 27 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 . Media Contact Jenna Urban Berry & Company Public Relations [email protected] 212-253-8881 SOURCE Vico Therapeutics B.V.