BACE1

Data underscore the unique potential of Vivoryon's N3pE-focused strategy in mono- and combination therapy settings in AD Combination treatment of aducanumab and varoglutamstat achieves additive effect on Abeta pathology, indicating feasibility of dose reduction to improve safety of Abeta antibody-based AD treatments Further evidence demonstrating potential benefit of a combination therapy designed to simultaneously make use of two different and independent molecular N3pE-related MoAs: small molecule based QPCT/L inhibition and anti-N3pE-immunotherapy Additional data from murine analog of PBD-C06 highlight differentiated safety pro other anti-Abeta antibodies at N3pE amyloid-lowering concentrations Breakfast and networking event with webcast scheduled for August 2, 2022, at 7:15 am PDT (4:15 pm CEST) HALLE (SAALE) / MUNICH, GERMANY / ACCESSWIRE / July 31, 2022 / Vivoryon Therapeutics N.V. (Euronext Amsterdam:VVY; NL00150002Q7) (Vivoryon), a clinical stage company focused on the discovery and development of small molecule medicines to modulate the activity and stability of pathologically altered proteins, today announced the presentation of preclinical data on the Company's N3pE amyloid-targeting molecules at the prestigious Alzheimer's Association International Conference (AAIC) in San Diego. The results underscore the unique potential of Vivoryon's N3pE amyloid-targeting therapeutic strategy in both mono- and combination therapy settings in Alzheimer's disease (AD). Background: Vivoryon pursues two different approaches to target N3pE amyloid. Firstly, the Company is developing varoglutamstat, an oral small molecule inhibitor of glutaminyl cyclase (QPCT) and its isoenzyme QPCTL, currently in Phase 2 clinical studies in Europe (NCT04498650) and the U.S. (NCT03919162). Safety data from different Phase 1 and 2 clinical studies of varoglutamstat, including the ongoing Phase 2b study VIVIAD (poster P1-403, abstract 69290; PR on key results here ), show no on-target toxicity and no clinical signs of ARIA (amyloid-related imaging abnormalities), the major severe side effects of antibody-based AD therapies. Secondly, in an effort to overcome the limitations of existing anti-Abeta antibody-based approaches, Vivoryon is developing the monoclonal antibody PBD-C06. PBD-C06 is specifically designed to bind to and remove neurotoxic N3pE amyloid from the brain. The antibody is optimized with respect to low immunogenicity and low ARIA-inducing potential. N3pE amyloid (pGlu3-Abeta) is a toxic form of Abeta that leads to faster aggregation and seeding of plaques. This pivotal role in the development and progression of AD makes it an important therapeutic target. Formation of N3pE amyloid is catalyzed by the enzyme QPCT, which is expressed predominantly in the brain's learning and memory centers. Toxic N3pE amyloid correlates with cognitive (MMSE) status in patients suffering from AD and is not found in healthy individuals. Preclinical Data on Vivoryon's Molecules Presented at AAIC 2022 Poster P1-457 / Abstract 69050: "Exploring Combination Therapies in AD: Additive Effects of the QPCT Inhibitor Varoglutamstat and Aducanumab on Abeta Pathology and Biomarkers In Vivo" Vivoryon recently published data demonstrating that a combination of the QPCT/L inhibitor varoglutamstat and the N3pE amyloid-specific antibody PBD-C06 had an additive effect on lowering of N3pE amyloid in vivo (Hoffmann et al., ). Building on these results, the Company analyzed whether a similar additive effect could be achieved when combining varoglutamstat with the Abeta-plaque-specific antibody aducanumab in a double transgenic mouse model overexpressing a variant of the human amyloid precursor protein (APP) and human QPCT (APPSLxhQC). The animals were treated with either varoglutamstat, chimeric aducanumab (chAdu) or a combination of both for 16 weeks. Brains were analyzed for accumulation of total Abeta, N3pE amyloid and the AD-related biomarkers neurogranin, BACE-1 and YKL-40. Single agent treatment with either varoglutamstat or chAdu significantly reduced the accumulation of N3pE and total Abeta in brain of APPSLxhQC mice. As anticipated, the effect for chAdu appeared to be more pronounced on total Abeta, while varoglutamstat mediated a stronger decrease in N3pE amyloid. The combination of both agents led to a stronger decrease of both N3pE amyloid and total Abeta, with a Bliss combination index (CI) near 1 suggesting an additive effect of both treatments in this setup. Importantly, and in line with its secondary mode of action, modulating the CCL2 axis, varoglutamstat significantly reduced brain levels of YKL40, an inflammatory marker (-27%), which corroborates results from Vivoryon's completed Phase 2a study SAPHIR (NCT02389413). Taken together, the results presented at AAIC support the hypothesis of a potential benefit of a combination therapy designed to simultaneously target two different and independent molecular pathways, namely reducing N3pE amyloid production by QPCT/L inhibition and clearing existing Abeta deposits through anti-N3pE-immunotherapy. For example, therapeutic regimens aiming at an initial antibody-mediated Abeta clearance followed by long-term suppression of N3pE amyloid formation and inflammation by varoglutamstat ("treat and maintain") could be envisioned. "Alzheimer's disease is a very complex disease state which may require us to work together as a field to combine different therapeutic interventions for the highest benefit of patients as is the standard of care in many other complex diseases. The additive effect of varoglutamstat and Abeta-targeting antibodies we have described to date for our own PBD-C06 and aducanumab underscores this concept and highlights the unique positioning of varoglutamstat as a drug candidate that offers strong potential both as a monotherapy and in combination," commented Dr. Michael Schaeffer, Vivoryon's CBO. "While our focus will very much remain on developing varoglutamstat as a monotherapy, we are excited that the further preclinical characterization of our lead candidate continues to expand its therapeutic depth and the potential for its application in a variety of therapeutic settings." Poster P1-04 / Abstract 67892: "Therapeutic Efficacy of the Murine Precursor to PBD-C06: a Novel CDC-Mutant Anti-pGlu3Abeta mAb" A study led by Cynthia Lemere, Ph.D., Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, analyzed the therapeutic efficacy of 07/2a-k, a novel murine precursor to PBD-C06, Vivoryon's N3pE amyloid-targeting monoclonal antibody, in comparison to 3D6-L, a murine analog of the classical anti-Abeta antibody bapineuzumab in two AD mouse models (aged APP/PS1 mice and aged APP/PS1;hApoE4 mice). The group had previously demonstrated reductions in plaques and cognitive deficits using the PBD-C06 precursor 07/2a. The novel version, 07/2a-k, is a CDC-mutant version to avoid complement system activation to reduce vascular-related inflammation associated with anti-amyloid antibodies. The data presented at AAIC include a dosing and a therapeutics study. In the dosing study (APP/PS1 mice treated weekly from 12-13.5 months of age), treatment with the PBD-C06 precursor 07/2a-k had no effect on biochemical levels of Abeta and did not change overall Abeta levels, but significantly reduced N3pE amyloid plaque load in the hippocampus, a region essential for learning and memory at two different doses (300 μg, p<0.0005; 600 μg, p<0.005). In the therapeutics study (APP/PS1;E4 mice treated weekly from 16 to almost 20 months of age), 07/2a-k had no effect on biochemical or pathological measures of Abeta, but modestly improved memory in the Novel Object Recognition (NOR) task, while having no effect in the Barnes maze task. Importantly, 07/2a-k did not induce any micro- or macrohemorrhages. The bapineuzumab analog 3D6-L lowered Abeta levels (biochemically and N3pE amyloid plaque load), increased movement of the mice in the NOR, but had no benefit on cognition in either the NOR or Barnes maze test. In contrast to 07/2a-k, 3D6-L induced a high number of micro- and macrohemorrhages. "Safety is a main concern in antibody-based AD therapies, as anti-amyloid antibodies, e.g. bapineuzumab, are associated with ARIA involving vasogenic edema and microhemorrhages in AD patients, especially in ApoE4 carriers," commented Cynthia Lemere, Brigham and Women's Hospital and Harvard Medical School. "Both Vivoryon's PBD-C06 and the murine precursor 07/2a-k we tested in this study have been designed with a site-specific CDC mutation to prevent complement system activation and, thus, could potentially reduce inflammation and ARIA. Our data presented at AAIC confirm that 07/2a-k treatment lowered N3pE amyloid levels in the hippocampus, a region essential for learning and memory in APP/PS1 mice and also had a modest cognitive benefit without eliciting microhemorrhages in aged APP/PS1;APOE4 mice. Based on these encouraging results, we look forward to further investigating the potential of 07/2a-k in earlier disease stages." Vivoryon is conducting a number of preclinical studies to further characterize PBD-C06 and evaluate its differentiation from other Abeta antibodies. PBD-C06 is partnered with Simcere Pharmaceuticals, Ltd., for development in Greater China. ### Webcast Information: Breakfast and Networking Event at AAIC Vivoryon will host a webcasted breakfast and networking event on August 2, 2022 at 7:15 am PDT (4:15 pm CEST), available at . For in-person attendance, please RSVP at Eva.Hoffmann@vivoryon.com. About Varoglutamstat Varoglutamstat (PQ912) is a differentiated oral small-molecule targeting the toxic Abeta species N3pE which is being developed as disease-modifying therapy and is designed to target AD pathology upstream of Abeta-antibody focused approaches. Varoglutamstat blocks the enzyme glutaminyl cyclase (QPCT) and its isoenzyme QPCTL. QPCT catalyzes the formation of N3pE amyloid, a particularly neurotoxic variant of Abeta peptides, which is only found in AD patients and not present in the brains of healthy individuals. N3pE amyloid in the brain acts as a seeding element for Abeta aggregation, thus providing a starting point for plaque formation. It has been described to correlate with the cognitive ability of AD patients. Beyond Abeta pathology, varoglutamstat has also been shown to impact synaptic impairment. Through a second mode of action, the inhibition of full CCL2 maturation via QPCTL, varoglutamstat modulates pro-inflammatory signaling and tau pathology, thereby simultaneously addressing multiple hallmarks of AD. Data from the completed Phase 2a SAPHIR study of varoglutamstat (NCT02389413) provided important safety information and also showed first evidence of the disease-modifying capabilities of varoglutamstat, most importantly with statistically significant changes from baseline in working memory as an important cognitive ability after only 12 weeks of treatment. Vivoryon has received Fast Track designation for varoglutamstat in early AD by the U.S. Food and Drug Administration (FDA) and is currently in clinical Phase 2 development with studies ongoing in Europe (VIVIAD, NCT04498650) and the U.S. (VIVA-MIND, NCT03919162). Varoglutamstat has not yet been approved by any regulatory authority and the safety and efficacy have not yet been established. About PBD-C06 PBD-C06 is Vivoryon's preclinical stage N3pE amyloid-targeting monoclonal antibody. Seeking to overcome the limitations of existing anti-Abeta antibody-based approaches, PBD-C06 is specifically designed to bind to and remove neurotoxic N3pE amyloid from the brain. The antibody is optimized with respect to low immunogenicity and low potential to induce amyloid-related imaging abnormalities (ARIA). In particular, PBD-C06 is a CDC-mutant antibody, avoiding complement system activation to potentially reduce vascular-related inflammation associated with anti-amyloid antibodies. In preclinical studies, PBD-C06 has not only shown the ability to reduce N3pE amyloid, but also to significantly improve cognitive deficits in aged Alzheimer's mice. Moreover, no evidence was found of increased microhemorrhages under treatment with PBD-C06. About Vivoryon Therapeutics N.V. Vivoryon is a clinical stage biotechnology company focused on developing innovative small molecule-based medicines. Driven by our passion for ground-breaking science and innovation, we strive to change the lives of patients in need suffering from severe diseases. We leverage our in-depth expertise in understanding post-translational modifications to develop medicines that modulate the activity and stability of proteins which are altered in disease settings. Beyond our lead program, varoglutamstat, which is in Phase 2 clinical development to treat Alzheimer's disease, we have established a solid pipeline of orally available small molecule inhibitors for various indications including cancer, inflammatory diseases and fibrosis. Vivoryon Forward Looking Statements This press release includes forward-looking statements, including, without limitation, those regarding the business strategy, management plans and objectives for future operations of the Vivoryon Therapeutics N.V. (the "Company"), estimates and projections with respect to the market for the Company's products and forecasts and statements as to when the Company's products may be available. Words such as "anticipate," "believe," "estimate," "expect," "forecast," "intend," "may," "plan," "project," "predict," "should" and "will" and similar expressions as they relate to the Company are intended to identify such forward-looking statements. These forward-looking statements are not guarantees of future performance; rather they are based on the Management's current expectations and assumptions about future events and trends, the economy and other future conditions. The forward-looking statements involve a number of known and unknown risks and uncertainties. These risks and uncertainties and other factors could materially adversely affect the outcome and financial effects of the plans and events described herein. Actual results, performance or events may differ materially from those expressed or implied in such forward-looking statements and from expectations. As a result, no undue reliance should be placed on such forward-looking statements. This press release does not contain risk factors. Certain risk factors that may affect the Company's future financial results are discussed in the published annual financial statements of the Company. This press release, including any forward-looking statements, speaks only as of the date of this press release. The Company does not assume any obligation to update any information or forward-looking statements contained herein, save for any information required to be disclosed by law. For more information, please contact: Investor Contact Vivoryon Therapeutics N.V. Dr. Manuela Bader, Director IR & Communication Tel: +49 (0)345 555 99 30 Email: IR@vivoryon.com Media Contact Trophic Communications Stephanie May Tel: +49 171 185 5682 Email: vivoryon@trophic.eu SOURCE: Vivoryon Therapeutics N.V. View source version on accesswire.com:

FORT WASHINGTON, Pa. & INGELHEIM, Germany--(BUSINESS WIRE)--Boehringer Ingelheim and Vitae Pharmaceuticals, Inc., announced today that they have entered into a significant worldwide collaboration to research and develop beta-secretase (BACE) inhibitors for the treatment of Alzheimer’s disease. Current therapies for Alzheimer’s disease can improve symptoms, but do not affect the progression of the disease. The inhibition of BACE - an enzyme involved in the formation of amyloid-beta plaques which accumulate in the brains of patients with Alzheimer’s disease - offers the potential to slow or even halt disease progression. Under the terms of the collaboration agreement, Vitae will receive $42 million in upfront and near-term payments from Boehringer Ingelheim, consisting of upfront cash, an equity investment in Vitae, and research funding to support further discovery efforts. In addition, Vitae will be eligible to receive $200 million in pre-commercial milestone payments based on the achievement of clinical and regulatory goals, as well as further milestone payments based on potential additional compounds and / or other approved indications. Vitae will receive commercial performance payments and royalties from Boehringer Ingelheim on all potential future product sales. Further financial details were not disclosed. The companies will work jointly to identify and advance candidates for clinical development. Thereafter, Boehringer Ingelheim will lead development and commercialization of all products for Alzheimer’s disease to capitalize on its global marketing and sales expertise. Vitae will have the right to develop products independently for certain other indications. “I am very pleased to be working with Boehringer Ingelheim’s exceptional neuroscience group on this program,” said Jeffrey Hatfield, CEO of Vitae. “This collaboration accomplishes three important objectives for our company. It adds substantial neuroscience expertise and specialized resources to the BACE program, which has advanced remarkably during its 16-month life. It also extends what is already a very successful partnership model with Boehringer Ingelheim, stemming from our existing diabetes and metabolic syndrome collaboration. Boehringer Ingelheim’s team-oriented culture presents an ideal environment for partnership success. And finally, it continues Vitae’s business model of financing the company’s growth through rapid value creation and partnering versus relying on the capital markets – which is favorable for our shareholders.” Dr Manfred Haehl, Corporate Senior Vice President R&D and Medicine of Boehringer Ingelheim worldwide, added that “Based on our research experience in Alzheimer's disease and our excellent experience in collaborating with Vitae for the diabetes program, we will be using our overall expertise in CNS disease research, drug development and commercialization to strengthen our current neuroscience portfolio. Ultimately, we all aim to create new treatments for patients suffering from this serious debilitating disease. We therefore will see the companies' joint efforts expanding to create medicines that are urgently needed in two widespread disease areas, namely diabetes and Alzheimer’s disease. It is part of our core development strategy to establish long-term alliances with innovative companies that broaden the scope of our own exciting pipeline successes." About BACE Inhibition Alzheimer’s disease is a chronic neurodegenerative disorder characterized by progressive memory loss associated with the deposition of neuritic plaques in the brains of patients. The amyloid-beta peptide is the major component of such plaques and is considered to be the major culprit in the pathogenesis of Alzheimer’s disease. Amyloid-beta is generated from amyloid precursor protein (APP) by proteolytic processing by beta and gamma secretases. Since beta-secretase (beta-site APP cleaving enzyme 1, or BACE1) cleavage is rate limiting for the production of amyloid-beta, inhibition of this enzyme represents an attractive strategy to ameliorate amyloid-beta plaque deposition in Alzheimer’s disease. Supporting this notion are studies demonstrating that deletion of the BACE1 gene in mice prevents the formation of amyloid-beta in cultured neurons and the brain. In addition, it has been shown that amyloid-beta-associated memory deficits, which occur in mutant mice overexpressing APP, are prevented when the BACE1 gene is deleted. Thus in patients, it is anticipated that inhibitors blocking BACE1 could prevent the build up of amyloid-beta plaques and help slow or stop the progression of disease. About Alzheimer’s Disease Alzheimer's disease (AD) is the most common form of dementia in adults. It is estimated to affect 4.5 million American‘s and over 30 million people worldwide with an average course of 8 -12 years. It is projected that the prevalence of AD will double over the next 20 years. Marketed treatments address some symptoms, however there are no treatments available that delay or halt the progression of the disease. Global sales of Alzheimer’s drugs were approximately $5 billion in 2008 and are expected to exceed $14 billion by 2015. Vitae Pharmaceuticals Vitae Pharmaceuticals is an emerging pharmaceutical company building a clinical stage pipeline of novel drug candidates in important therapeutic categories, such as cardiovascular disease, diabetes and Alzheimer’s disease. Vitae discovers and develops solutions to biologically validated but hard-to-drug targets by fully integrating its proprietary structure-based drug design platform - delivering unprecedented accuracy, speed and novelty – with the targeted efforts of highly experienced and successful discovery scientists. Vitae Pharmaceuticals is financed by leading corporate and venture capital investors, completing its last venture round in 2004. Vitae’s forty scientists are located in Fort Washington, Pennsylvania. For additional information, please visit the company’s website, Boehringer Ingelheim The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 138 affiliates in 47 countries and 41,300 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine. In 2008, Boehringer Ingelheim posted net sales of 11.6 billion euros while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development. For more information please visit Contact: KMorrisPR Kathryn Morris, +1 845-635-9828 or Boehringer Ingelheim GmbH Julia Meyer-Kleinmann, +49 6132 77 8271