SYF2

AcuraStem Leverages iNeuroRx® Platform to Drive Innovative SYF2 and UNC13A Treatments Forward Toward Clinical Trials PASADENA, Calif., Jan. 30, 2024 /PRNewswire/ -- AcuraStem, a patient-based biotechnology company advancing treatments for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases, announced today that it has successfully raised nearly $7 million in grant funding for ALS / FTD research from the National Institutes of Health (NIH) and the Department of Defense (DOD). This latest achievement—building upon the recent licensing agreement with Takeda worth $580 million to develop and commercialize AcuraStem's PIKFYVE targeted therapeutics including AS-202—enables the company to advance multiple programs towards clinical trials. "We are thrilled to receive continued support from NIH and the DOD," said Sam Alworth, MS, MBA, AcuraStem co-founder and CEO. "Leaders from the scientific community selected AcuraStem for these awards through a rigorous peer-review process, which demonstrates the excellence of our research." AcuraStem has made a significant advancement in understanding the pathophysiology of ALS, focusing on the crucial role of UNC13A. An overwhelming majority of ALS cases, and roughly half of FTD cases, are characterized by TDP-43 pathology. TDP-43, a RNA-binding protein typically found in the nucleus, is mislocalized to the cytoplasm in affected neurons, leading to RNA processing errors. These errors result in the incorporation of a cryptic exon into the UNC13A messenger RNA, causing a loss of UNC13A protein. This loss is further exacerbated by a risk variant in the UNC13A gene, closely linked to the TDP-43 binding site and associated with reduced survival in ALS and FTD patients. AcuraStem's iNeuroRx® platform has successfully replicated UNC13A pathology in patient neurons, enabling the rapid development and testing of antisense oligonucleotides (ASOs). These ASOs effectively suppress the cryptic exon and restore normal UNC13A function, offering a promising therapeutic approach for TDP-43 proteinopathies and a deeper understanding of UNC13A's role in disease progression. Additionally, AcuraStem has made a pivotal discovery with its focus on SYF2, a novel target in TDP-43 pathology. In collaboration with co-founder Dr. Justin Ichida's lab at USC, AcuraStem's extensive research on patient neurons via the iNeuroRx® platform, coupled with a comprehensive bioinformatic analysis, identified SYF2 as a key therapeutic target. SYF2, a pre-mRNA splicing factor, plays a crucial role in the regulation of splicing affected by the depletion of nuclear TDP-43, a common feature in most ALS cases (Linares GR et al Cell Stem Cell 2023). AcuraStem's findings highlight that SYF2 can address both the toxic aggregation of TDP-43 in cytoplasm and also counter the widespread gene dysregulation, including critical genes like UNC13A and STMN2, caused by TDP-43's absence from the nucleus. Targeting SYF2 could offer a more direct and potentially effective therapeutic strategy compared to addressing each dysregulated gene individually. Funding from NIH and the DOD was awarded through rigorous peer-reviewed processes, suggesting the award matches the health-related missions established by each agency. For additional information, please visit AcuraStem at acurastem.com and follow on LinkedIn, Facebook and X. Disclaimer This project will be supported by an NIH grant (R44AG085411). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, or the U.S. Army Medical Research Acquisition Activity at the U.S. Army Medical Research and Development Command, in the amount of $839,898.40 through the ALSRP under Award No. HT9425-23-1-0469. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. About AcuraStem AcuraStem is a patient-based biotechnology company pioneering treatments for neurodegenerative diseases including sporadic ALS and FTD. AcuraStem's best-in-class disease modeling platform, iNeuroRx®, enables the discovery of innovative, effective, and broadly acting treatments. The team's strong expertise in ASO technology provides for the rapid advancement of treatments to the clinic. AcuraStem's research is funded in part by support from the Alzheimer's Drug Discovery Foundation, Harrington Discovery Institute, Alzheimer's Association, Rainwater Charitable Foundation, Muscular Dystrophy Association, Department of Defense and the National Institute of Neurological Disorders and Stroke. Contact: Kissy Black [email protected] 615.310.1894 SOURCE AcuraStem - Patient-Based Therapeutics

Agreement enables the development of therapeutics, including AcuraStem's AS-202 Candidate, an antisense oligonucleotide that suppresses levels of the PIKFYVE kinase MONROVIA, Calif., Sept. 25, 2023 /PRNewswire/ -- AcuraStem, a patient-based biotechnology company pioneering how treatments are developed for neurodegenerative diseases, announced today that it has entered into a license agreement with Takeda to develop and commercialize AcuraStem's PIKFYVE targeted therapeutics including AS-202, an innovative antisense oligonucleotide (ASO) for the treatment of Amyotrophic Lateral Sclerosis (ALS). Continue Reading PIKFYVE is a novel therapeutic target for ALS and may also be relevant for treating additional TDP-43 proteinopathies such as Frontotemporal Dementia (FTD). AcuraStem's therapeutic strategy for PIKFYVE focuses on addressing neurodegeneration by expelling toxic protein aggregates and protecting healthy neuronal function. "We are delighted to have secured a partner in Takeda...to deliver on our mission," Sam Alworth, AcuraStem CEO. Tweet this This novel therapeutic mechanism was initially discovered at the lab of AcuraStem's co-founder, Justin Ichida, PhD, using patient-derived disease models, is exclusively licensed to AcuraStem by the USC Stevens Center for Innovation, and was further developed on AcuraStem's iNeuroRx® disease modeling platform (Shi Y et al Nat Med 2018, Hung S-T et al Cell 2023). The AcuraStem researchers further demonstrated that ASO-mediated suppression of PIKFYVE can restore motor function, reduce neurodegeneration, and improve survival in multiple in vivo models of both ALS and FTD. Under the terms of the agreement, Takeda will receive an exclusive, worldwide license to AcuraStem's PIKFYVE program. AcuraStem will receive an upfront and milestone payments totaling up to approximately $580 million if all future clinical, regulatory, and commercial milestones are achieved during the term of the agreement plus tiered royalties on potential net sales of any commercial products resulting from this license. "Our mission at AcuraStem is to get our promising therapeutics to the patients who need them as quickly as possible," said Sam Alworth, MS, MBA, CEO of AcuraStem. "We are delighted to have secured a partner in Takeda who has the world class clinical development and commercial capabilities to deliver on our mission." AcuraStem will be responsible for certain activities to help advance AS-202 IND enabling studies and characterizing potential backup ASOs. Takeda will be responsible for all other development activities including clinical development, regulatory affairs, and global commercialization. "We aim to develop transformative treatments for some of society's most debilitating neurological diseases including ALS. Whilst recent treatment advances have brought new hope to some patients, there remains a significant unmet need," said Sarah Sheikh, BM BCh, MSc, MRCP, Head, Neuroscience Therapeutic Area Unit at Takeda. "We believe AS-202 has the potential to address this unmet need through its unique dual mechanism of action, which addresses TDP-43 aggregation and improves TDP-43 function, the pathological hallmark of ALS and other TDP-43 proteinopathies including certain forms of dementia. We look forward to building on AcuraStem's work to progress this exciting science into development and to patients." AcuraStem, co-founded by Alworth, Ichida, Paul August, PhD, and Qing Liu, PhD, in 2016, remains committed to continually improving its patient-based iNeuroRx® technology platform, discovering ever more effective therapeutic approaches across neurodegenerative indications, and rapidly advancing its therapeutic programs to patients including its existing SYF2 and UNC13A programs for ALS and FTD. "I'm very pleased that AcuraStem is partnering with Takeda around their PIKFYVE program," said Justin Ichida, PhD. "We originally identified PIKFYVE as a novel therapeutic target for ALS using nerve cells derived from patient stem cells, and this illustrates the power of using this modern approach. I am grateful for the funding and help we received from philanthropic and government agencies that enabled us to better understand the therapeutic potential of targeting PIKFYVE. AcuraStem has done an outstanding job of generating best-in-class molecules to target PIKFYVE in humans, and I am excited to see this move forward." Destum Partners acted as transaction advisor to AcuraStem, and Foley Hoag acted as legal counsel to AcuraStem. For more information about AcuraStem and their iNeuroRx® platform go to acurastem.com. About AcuraStem AcuraStem is a patient-based biotechnology company pioneering treatments for neurodegenerative diseases including sporadic ALS and FTD. AcuraStem's best-in-class disease modeling platform, iNeuroRx®, enables the discovery of innovative, effective, and broadly acting treatments. The team's strong expertise in ASO technology provides for the rapid advancement of treatments to the clinic. AcuraStem's research is funded in part by support from the Alzheimer's Drug Discovery Foundation, Harrington Discovery Institute, Alzheimer's Association, Rainwater Charitable Foundation, Department of Defense and the National Institute of Neurological Disorders and Stroke. About AS-202 AcuraStem identified clinical candidate AS-202 through screening on its iNeuroRx® patient-based technology platform. AS-202 is an intrathecally delivered ASO that potently suppresses PIKFYVE in the central nervous system and addresses neurodegeneration by expelling toxic protein aggregates and restoring healthy neuronal function in in vivo preclinical models. Contact: Kissy Black Director of Communications, AcuraStem [email protected] 615.310.1894 SOURCE AcuraStem - Patient-Based Therapeutics

Courtesy of Getty Images ALS is the 5,000-piece jigsaw puzzle of the therapeutic world. As the regulatory edges come together, new research pieces are also connecting. In 2022, the association between gene-encoding protein UNC13A and the TDP-43 protein – long implicated in ALS pathology – was discovered by University College London and the NIH. More recently, attention has fallen to two potential therapeutic targets: PIKFYVE and SYF2. A complex neurodegenerative disease with both sporadic and genetic manifestations, ALS is uniformly fatal, claiming the lives of its victims typically within 2-5 years of diagnosis. Two studies published in February, one in Cell, and the other in Cell Stem Cell, highlight the potential of PIKFYVE inhibition and SYF2 suppression in diverse disease models. Justin Ichida, Ph.D., a stem cell scientist at USC, led both studies. Justin Ichida, Ph.D. PIKFYVE: An Underappreciated Mechanism The role of PIKFYVE in ALS was first discovered in 2016 and published in a 2018 paper in Nature Medicine. Ichida told BioSpace that the recently published study outlines how PIKFYVE works and shows that the mechanism applies to almost all the forms of ALS in the models examined. In ALS, TDP-43 is lost from the nucleus, causing toxic aggregates to form. In the Cell paper published on Feb. 7, Ichida et al. reported, "Inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins.” Two companies are making headway toward an even greater understanding of their role in the clinic. One of these is California-based AcuraStem. Co-founded by Ichida, Dr. Paul August and CEO Sam Alworth, AcuraStem launched in 2016 with a lead asset targeting PIKFYVE. “We think we’ve found an underappreciated way of regulating proteostasis in neurons that is helping them cleanse themselves of these toxic protein aggregates,” Alworth told BioSpace. While AcuraStem’s initial focus was on developing a small molecule targeting PIKFYVE, the company decided to prioritize the development of an antisense oligonucleotide (ASO) instead. Sam Alworth “When we did head-to-head testing in vivo, we saw that the ASO is much more effective,” Alworth said. While a small molecule “very transiently inhibits PIKFIVE,” an ASO will suppress it for a month. Restoring Endolysosomal Function Bay Area-based Verge Genomics also has a clinical-stage program targeting PIKFYVE. Verge CEO and co-founder Alice Zhang contributed to the 2018 Nature Medicine paper. Verge’s machine learning-based ConVERGE platform was instrumental in discovering PIKFYVE as a therapeutic target for ALS. The company’s CSO, Robert Scannevin, Ph.D., spoke to BioSpace about the discovery and resulting program. “We were able to connect multiple different ALS driver genes within a…network [that] represents the dysregulated biology that occurs and can be causative in ALS,” he said. PIKFYVE emerged as the top-ranked target. “We’ve learned…that many different genetic drivers of ALS converge on a critical cellular pathway of intracellular trafficking…within the endolysosomal system, causing dysfunction,” Scannevin said. When this intracellular trafficking is negatively affected, several downstream events result in nerve degeneration. “PIKFYVE works to restore proper endolysosomal function,” Scannevin said. Verge is developing a small molecule inhibitor of PIKFYVE called VRG50635. The first participant was dosed in a Phase I trial of healthy volunteers in November 2022. Robert Scannevin, Ph.D. The compound has been “safe and well-tolerated” in five single ascending dose cohorts, Scannevin said. Verge is also seeing good pharmacokinetics. The company expects to complete the trial's first phase by mid-2023 and anticipates beginning studies in ALS patients by the end of this year. With the AcuraStem and Verge trials underway, Ichida said the team would know soon if it worked in patients. The Discovery of SYF2 Ichida, Alworth and their collaborators made a case for SYF2 in a paper published on Feb. 2 in Cell Stem Cell. The researchers reprogrammed skin or blood samples from patients with both sporadic and familial ALS into motor neurons. They used these to screen about 2,000 FDA-approved compounds in search of ones that might be broadly effective against the disease. Out of approximately 40 compounds that worked potently on C9ORF72 ALS lines, Ichida said 11 were androgenic compounds. But, side effects can occur with these compounds, so the team set out to find another target downstream of that androgen signaling with the same therapeutic mechanism of action. Using a public bioinformatics database called the Connectivity Map, developed by the Broad Institute of Harvard and MIT; they identified SYF2. The team found that suppressing the activity of the spliceosome-associated factor protein encoded by the SYF2 gene worked to rescue motor neuron degeneration and relieve motor deficits in mouse models. Alworth called it “the dark horse, fantastic approach.” SYF2 is involved in the same pathway as TDP43, and Alworth said it addresses both gain and loss of function. “It’s one target that seems to affect all these TDP 43 targets that are dysregulated, like UNC13A and stathmin-2,” he said. AcuraStem is testing an asset targeting SYF2 in preclinical studies. The company is also betting on UNC13A, which Alworth said is central to disease progression. “[UNC13A] is highly, highly genetically validated…So, the question is, if we just reverse that…” He left the question hanging, but one thing is clear: the puzzle is coming together for one of the world’s most intractable diseases.