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:

It was a typically busy week for clinical trials, with announcements in a wide variety of indications. Here’s a look. It was a typically busy week for clinical trials, with announcements in a wide variety of indications. Here’s a look. Array BioPharma announced the results from its Phase III BEACON CRC trial. The trial evaluated a triple combination of Braftovi (encorafenib), a BRAF inhibitor, Mektovia (binimetinib), a MEK inhibitor, and Erbitux (cetuximab), an anti-EGFR antibody, in patients with advanced BRAF V600E -mutant metastatic colorectal cancer (mCRC) after one or two lines of therapy. The bottom line is that the triple-combination almost doubled overall survival in the patient subpopulation. The patients who received the therapy, dubbed Braftovi Triplet, showed a statistically significant improvement in overall survival (OS) and objective response rate (ORR) compared to cetuximab plus irinotecan-containing regimens. Median progression-free survival (mPFS) for patients receiving Braftovi Triplet was 4.3 months compared to 1.5 months. A group of researchers at the University of Surrey , UK, conducted a clinical trial of 15 patients with non-muscle invasive bladder cancer. The patients were treated with a virus called CVA21, or ICAM-1-targeted immunotherapeutic-coxsackievirus A21. The CVA21 virus is a common cold virus. The trial was published in the journal Clinical Cancer Research . The approach was dubbed CAVATAK. Patients in the trial received CVA21 directly into their bladders by way of a catheter a week before surgery. After surgery, the researched studied tissue samples and found that the CVA21 virus only infected cancer cells, not healthy tissues. In addition, urine samples showed that the virus continued to grow and attack more cancerous cells. One patient was cancer-free one week after receiving the treatment. Sobi and Sanofi presented data from the A-LONG and ASPIRE and B-LONG and B-YOND clinical trials in hemophilia A and B, respectively. The focus was on the long-term outcomes of patients with hemophilia A and B who had switched from prophylaxis with Electa or Alprolix from on-demand treatment. Of 70 patients with hemophilia A who switched in the A-LONG/ASPIRE trials, 96% continued prophylaxis for more than six months with a median duration of 4.8 years. Of the 52 patients in B-LONG/B-YOND, 96% continued prophylaxis for more than six months with a median duration of prophylactic treatment of 3.6 years. New research from three clinical trials supports that Sarepta Therapeutics ’ Exondys 51 (eteplirsen) slows respiratory decline in Duchenne muscular dystrophy (DMD). Sarepta, along with Harvard Medical School, The Children’s Hospital of Philadelphia, Nationwide Children’s Hospital , the Paul D. Wellstone Muscular Dystrophy Cooperative Research Center and Ohio State University published results from three trials in the Journal of Neuromuscular Diseases . These particular trials focused on respiratory function, comparing the patients receiving Exondys 51 to patients matched by age range, steroid use, and genotype from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) global database. They studied eligible ambulatory DMD patients for at least four years, primary non-ambulatory DMD patients for two years, and an ongoing open-label multicenter trial of ambulatory DMD patients aged seven to 16 years. All three studies found significant slowing of respiratory decline in the patients receiving Exondys 51 and it was consistent across all stages of the disease studied. The U.S. Centers for Disease Control and Prevention (CDC) published research in the journal Lancet Infectious Diseases outlining the results from two experimental Ebola drugs, Gilead Sciences ’ remdesivir and Mapp Biopharmaceutical ’s ZMapp. Both successfully inhibited the growth of the virus in human cells in laboratory studies. “They’re currently being tested in a clinical trial but we need to verify and make sure that they were going to be effective,” said Laura McMullan , a CDC microbiologist who led the research, reported MSN . “Information that we knew about how well they worked was based on a different Ebola virus variant so we needed to make sure that, indeed, these compounds were going to bind and block the virus and measure that, and see if it worked as well in order for the clinical trials to proceed.” GlaxoSmithKline ’s ViiV Healthcare reported that HIV patients who shifted to Dovato (dolutegravir plus lamivudine) maintained viral suppression similar to patients on a tenofovir alafenamide fumarate (TAF-containing regimen of at least three drugs) for at least six months. The Phase III TANGO trial met its primary endpoint of non-inferiority, with no patients meeting virologic withdrawal criteria or developing treatment resistance. Biohaven Pharmaceutical Holding Company , based in New Haven, Connecticut, released positive data from its Phase III pivotal trial of rimegepant to treat migraine. The results were published in the New England Journal of Medicine (NEJM) . The patients in the trial, all adults, had at least a one-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month. Of the 1,186 patients, 594 received the drug and 592 received placebo. Of those, 537 in the rimegepant group and 535 in the placebo group were evaluable for efficacy. The overall mean age of the patients was 40.6 years and 88.7% were women. In the rimegepant cohort, 19.6% were pain-free two hours after receiving the drug, while 12% were pain-free in the placebo group. In the rimegepant group, 37.6% were free from their most bothersome symptoms two hours after dosing and 25.2% were in the placebo group. Novartis , Amgen and the Banner Alzheimer’s Institute announced they were halting two pivotal Phase II/III clinical trials in the Alzheimer’s Prevention Initiative Generation Program. The trials were evaluating the BACE1 inhibitor CNP520 (umibecestat). An analysis of unblinded data during a scheduled review showed that the patients were getting worse in some of the measurements of cognitive function, the opposite of what they were hoping. The sponsors all decided that any patient benefit wasn’t worth the risk.

The companies indicate they hope to continue data analysis to better understand the disease and will present anything relevant at a future scientific meeting. Another one bites the dust as Novartis , Amgen and the Banner Alzheimer’s Institute announced they are halting two pivotal Phase II/III clinical trials in the Alzheimer’s Prevention Initiative Generation Program. The trials were evaluating the BACE1 inhibitor CNP520 (umibecestat). An analysis of unblinded data during a scheduled review showed that the patients were getting worse in some of the measurements of cognitive function, the opposite of what they were hoping. The sponsors all decided that any patient benefit wasn’t worth the risk. “Novartis has a strong research focus and commitment to patients,” stated John Tsai, head of Global Drug Development and chief medical officer of Novartis. “As researchers we have to accept today’s disappointing news as part of the search for innovative new treatments. We remain committed to advancing science in Alzheimer’s disease and continue to seek future solutions for people with neurodegenerative conditions.” The Amgen and Novartis Neuroscience Collaboration launched in August 2015 to develop and market treatments for migraine and Alzheimer’s disease. Amgen and Novartis sponsor the work in collaboration with Banner Alzheimer’s Institute. Novartis is the regulatory sponsor and Amgen and Novartis are co-development partners. The companies indicate they hope to continue data analysis to better understand the disease and will present anything relevant at a future scientific meeting. The failure of BACE inhibitors is just another argument against the amyloid theory of Alzheimer’s disease. Beta-amyloid is a protein that is found accumulating in the brains of Alzheimer’s patients. It has long been thought that the protein was the cause of the memory and cognitive issues in the disease, but dozens of clinical trials that successfully cleared or halted the production of beta-amyloid failed to make a difference in the patients’ clinical conditions. BACE1 inhibitors like umibecestat don’t break up or clear amyloid, but block BACE1, an enzyme that helps form amyloid plaques. But BACE inhibitors have failed to make a difference as well. In 2017, Merck gave up on its BACE inhibitor verubecestat. Eisai and Biogen are continuing to work on their BACE inhibitor elenbecestat, after an independent board recommending that two Phase III trials of it continue. But this year alone has marked to prominent failures in the Alzheimer’s arena. Roche and AC Immune gave on their crenezumab in January after an interim analysis of Phase III data. And in March, Biogen halted its late-stage trials of aducanumab after independent analysis concluded the trials would fail. This appears to be something of a turning point for the industry, as it shifts away from beta-amyloid toward other approaches and theories. Although beta-amyloid is still very much a factor in the disease, many believe that it is an uncontrolled or faulty inflammatory and immune reaction to beta-amyloid that causes the majority of the cognitive damage. As a result, many researchers are shifting to the role of microglial cells, which are specialized immune cells in the central nervous system, and the potential use of anti-inflammatories in prevention and treatment. Many researchers are also returning to an infective-agent theory of the disease, where various viruses or other infectious agents play a role in stimulating beta-amyloid and immune responses. As the Alzheimer’s Association International Conference (AAIC) begins this weekend in Los Angeles, a great deal of attention will be focused on alternate approaches. The Alzheimer’s Associate, regarding Amgen, Novartis and Banner, stated, “The Alzheimer’s field has never faced more challenges, but due to increased research funding it has never been more hopeful. We must push forward. We must advance all potential treatment targets and also explore methods for combining these approaches. We must diversify our treatment and prevention strategies, which has been a focus in the last few years and will lead to new generations of approaches to be pursued. No stone can be left unturned. Even knowing the obstacles, we have never been as optimistic as we are today.”