HER4

Researchers have found a gene associated with longevity in golden retrievers, one of the most popular breeds of dogs. Golden retrievers are one of the most popular breeds of dogs. But research shows they have up to a 65% chance of dying from cancer. In a new study, University of California, Davis, researchers set out to find if certain genetic factors could help their survival rate. But instead of searching for genes associated with a cancer diagnosis in the breed, they instead chose to look for genes associated with longer life. The gene they found is in a family of proteins long known to be important in human cancers. Specific versions or variants of the gene were associated with an increased lifespan of nearly two years. The study was published in the journal GeroScience. "We assume that the majority of golden retrievers have a genetic predisposition to cancer, but if some of them are living to be 14, 15 or 16, we thought there could be another genetic factor that is helping to mitigate the bad genes, and the gene that popped out for us is HER4," said co-corresponding author Robert Rebhun, Maxine Adler Endowed Chair in oncology at the UC Davis School of Veterinary Medicine. HER4, also known as ERBB4, is a member of the family of human epidermal growth factor receptors. It is the same family of genes in humans as HER2, a gene well-known for making cancer cells grow quickly. Rebhun said dogs get many of the same kinds of cancers as humans, which could make this discovery important for humans, as well. "If we find that this variant in HER4 is important either in the formation or progression of cancer in golden retrievers, or if it can actually modify a cancer risk in this cancer predisposed population, that may be something that can be used in future cancer studies in humans," he said. Hope for golden retrievers More than 300 golden retrievers were part of the study. Researchers compared the DNA from blood samples of golden retrievers that were alive at 14 years of age to those that died before age 12. They found that dogs with certain variants of the gene survived longer, on average 13.5 years compared to 11.6 years. "Almost two years is a significant difference in a dog's life," said co-corresponding author Danika Bannasch, Maxine Adler Endowed Chair in genetics with the UC Davis School of Veterinary Medicine. "Wouldn't we all want our beloved pets to live another two years? Two years in goldens is about a 15-20% increase in lifespan, the equivalent of 12-14 years in humans." Bannasch said the finding is still one small piece to the complex puzzle of what could cause a golden retriever to get cancer. "There are going to be many genes involved, but the fact that the gene associated with longevity is also a gene involved in cancer was really interesting to us." The study also found the gene variant seemed to be most important to the longevity of female dogs compared to male dogs. HER4 has been shown to interact with hormones such as estrogen and may also play a role in processing environmental toxins. Rebhun said the next step is to enroll a larger population of golden retrievers in a study to see if they can reproduce these results and discover how this genetic variant may impact expression or function of the gene. Co-authors include Daniel York, Michael Kent, Madison Luker, Flora MD De Graaf, Kevin Batcher, Stephanie Ryan, Paula Yoon, and Jamie Peyton of UC Davis, and Joshua A. Stern of North Carolina State University. The study was funded in part by the UC Davis Center for Companion Animal Health, Maxine Adler Endowed Chair Funds, and private donor funds specifically designated for longevity studies in golden retrievers.

≥31% Average Improvement in Ejection Fraction (EF) Observed at the Mid and High Dose Levels Full Study Results Show JK07 to be Well Tolerated with No Dose-Limiting Toxicities Observed Company on Track to Initiate Phase 2 Repeat-Dose Study of JK07 in Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved Ejection Fraction (HFpEF) in H1 2024 GAITHERSBURG, Md.--(BUSINESS WIRE)-- Salubris Biotherapeutics, Inc. (SalubrisBio), a clinical-stage biotechnology company dedicated to discovering and developing novel complex biologic therapeutics, today announced positive updated results from the completed Phase 1b study of JK07 in patients with HFrEF. The data were presented in a late breaking oral session during the Heart Failure Society of America Annual Scientific Meeting 2023. JK07 is the first investigational antibody fusion protein and first selective ErbB4 agonist to enter clinical development for heart failure. Heart failure is a leading cause of morbidity and mortality globally, with estimates of more than 6 million patients affected by HFrEF and HFpEF in the US. “We are highly encouraged by the meaningful improvements in ejection fraction JK07 has demonstrated through 6 months following a single dose,” said Sam Murphy, Chief Executive Officer of SalubrisBio. “The durable and sustained responses observed to date suggest that JK07 has the potential to improve functional capacity, quality of life, and long-term outcomes for these patients, who currently have limited treatment options. We are pleased to be advancing JK07 into a multiple-dose Phase 2 study in both HFrEF and HFpEF to further evaluate its clinical potential in these prevalent heart failure populations.” In the completed Phase 1b study, fourteen patients were randomized 3 to 1 active treatment to placebo (11 JK07 : 3 placebo), with five patients in each of the first two cohorts (0.03mg/kg and 0.09 mg/kg, respectively), and four in the third cohort (0.27 mg/kg). Single doses were administered intravenously and changes from baseline values of left ventricular EF were measured for each patient. Key findings include: Robust dose-dependent changes in a biomarker of target engagement Meaningful changes in LVEF observed across all dose groups in comparison with placebo: Placebo 0.03 mg/kg 0.09 mg/kg 0.27 mg/kg Mean Baseline LVEF (absolute) 31% 34% 28% 25% Relative mean change from baseline at Day 30 +4% +20% +19% +22% Relative mean change from baseline at Day 60 -6% +14% +28% +50% Relative mean change from baseline at Day 90 -19% +9% +27% +14% Relative mean change from baseline at Day 135 -33% +5% +23% +43% Relative mean change from baseline at Day 180 +10% +7% +49% +31% JK07 has been generally well-tolerated with most adverse events mild to moderate. Only one serious adverse event occurred (Grade 3), at the top dose level. A double-blind, randomized, multiple-dose Phase 2 trial of JK07 in patients with HFrEF and HFpEF is expected to begin in 1H 2024. About Heart Failure Heart failure affects an estimated 6.2 million Americans1 and more than 64 million people worldwide2. Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) each affect over 3 million patients in the US alone. Heart failure is a chronic condition in which patients experience progressively worsening symptoms and quality of life, hospitalizations and death. In HFrEF, the left ventricle loses its ability to contract normally, and the heart cannot pump with sufficient force to push enough blood into circulation. In HFpEF the heart becomes stiff and loses its ability to function properly. JK07 is in development for the treatment of both HFrEF and HFpEF. About JK07 JK07 is a recombinant fusion protein consisting of a fully human immunoglobulin IgG1 monoclonal antibody and an active polypeptide fragment of the human growth factor neuregulin [NRG-1]. NRG-1 is a clinically validated growth factor that has shown promising activity in heart failure, but also undesirable side effects. Research has shown that NRG-1 induces signaling through interaction with two different receptors – ErbB3 and ErbB4. The ErbB4 pathway appears to be responsible for the regenerative effects in the heart, while the ErbB3 pathway appears primarily responsible for safety and tolerability limitations of recombinant NRG-1. By blocking ErbB3 signaling with an antibody fusion design, JK07 selectively stimulates the ErbB4 pathway with a favorable pharmacokinetic profile, which has the potential to significantly widen the therapeutic window of NRG-1 and yield better clinical effects. About SalubrisBio SalubrisBio is a clinical-stage biotechnology company dedicated to discovering and developing complex biologics for cardiovascular, oncology, and neurodegenerative diseases. SalubrisBio was founded in August 2016 as a wholly-owned subsidiary of the China-based pharmaceutical company Shenzhen Salubris Pharmaceuticals Co. Ltd. Headquartered in the US, SalubrisBio reflects Shenzhen Salubris Pharmaceuticals’ commitment to innovation and expansion into the global market and retains the core philosophy of developing therapeutics for large patient populations with significant unmet needs. 1 Centers for Disease Control and Prevention, Heart Failure, , (accessed May 8, 2023). 2 Groenewegen, A., Rutter, F., Mosterd, A., & Hoes, A. (2020). Epidemiology of heart failure. European Journal of Heart Failure, 22(8), 1342-1356.

GAITHERSBURG, Md.--( BUSINESS WIRE )--Salubris Biotherapeutics, Inc. (SalubrisBio), a clinical-stage biotechnology company dedicated to discovering and developing novel complex biologic therapeutics, today announced positive updated results from the ongoing Phase 1b study of JK07 in heart failure with reduced ejection fraction (HFrEF). The data were presented in a late breaking oral session during the annual congress of the European Society of Cardiology’s Heart Failure Association. JK07 is the first investigational antibody fusion protein and first selective ErbB4 agonist to enter clinical development for heart failure. Heart failure is a serious health condition that contributes to one in eight deaths in the U.S. and impacts nearly 6.5 million Americans 1 . Fourteen patients were randomized 3 to 1 (11 JK07 : 3 placebo), with five patients in each of the first two cohorts (0.03mg/kg and 0.09 mg/kg, respectively), and four in the third cohort (0.27 mg/kg). Single doses were administered intravenously and changes from baseline values of left ventricular EF were measured for each patient. Results from the study were presented by principal investigator Dr. W. H. Wilson Tang, Research Director and staff cardiologist in the Section of Heart Failure and Cardiac Transplantation Medicine at the Cleveland Clinic. Key findings include: Robust dose-dependent biomarker changes demonstrated target engagement at all dose levels. Meaningful changes in LVEF were observed across all dose groups in comparison with placebo: Placebo 0.03 mg/kg 0.09 mg/kg 0.27 mg/kg Mean Baseline LVEF (absolute) 31% 34% 28% 25% Relative mean change from baseline at Day 30 +4% +20% +19% +22% Relative mean change from baseline at Day 60 -6% +14% +28% +50% Relative mean change from baseline at Day 90 -19% +9% +27% +14% JK07 has been generally well-tolerated with most adverse events mild to moderate. Only one serious adverse event occurred (Grade 3), at the top dose level. “Heart failure is a leading cause of morbidity and mortality in the US and globally. These new interim results demonstrate that JK07 achieved robust target engagement and encouraging signs of potential clinical benefit with a single administration,” said Sam Murphy, Chief Executive Officer of SalubrisBio. “The durable and sustained responses observed, coupled with a favorable safety profile, support further investigation of JK07 and we look forward to building upon these findings with the initiation of a Phase 2 trial later this year." A double-blind, randomized, repeat-dose Phase 2 trial of JK07 in patients with HF is expected to initiate in the second half of 2023. About Heart Failure Heart failure affects an estimated 6.2 million Americans 2 and more than 64 million people worldwide 3 . Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) each affect over 3 million patients in the US alone. Heart failure is a chronic condition in which patients experience progressively worsening symptoms and quality of life, hospitalizations and death. In HFrEF, the left ventricle loses its ability to contract normally, and the heart cannot pump with sufficient force to push enough blood into circulation. In HFpEF the heart becomes stiff and loses its ability to function properly. JK07 is in development for the treatment of both HFrEF and HFpEF. About JK07 JK07 is a recombinant fusion protein consisting of a fully human immunoglobulin IgG1 monoclonal antibody and an active polypeptide fragment of the human growth factor neuregulin [NRG-1]. NRG-1 is a clinically validated growth factor that has shown promising activity in heart failure, but also undesirable side effects. Research has shown that NRG-1 induces signaling through interaction with two different receptors – ErbB3 and ErbB4. The ErbB4 pathway appears to be responsible for the regenerative effects in the heart, while the ErbB3 pathway appears primarily responsible for safety and tolerability limitations of recombinant NRG-1. By blocking ErbB3 signaling with an antibody fusion design, JK07 selectively stimulates the ErbB4 pathway with a favorable pharmacokinetic profile, which has the potential to significantly widen the therapeutic window of NRG-1 and yield better clinical effects. About SalubrisBio SalubrisBio is a clinical-stage biotechnology company dedicated to discovering and developing complex biologics for cardiovascular, oncology, and neurodegenerative diseases. SalubrisBio was founded in August 2016 as a wholly-owned subsidiary of the China-based pharmaceutical company Shenzhen Salubris Pharmaceuticals Co. Ltd. Headquartered in the US, SalubrisBio reflects Shenzhen Salubris Pharmaceuticals’ commitment to innovation and expansion into the global market and retains the core philosophy of developing therapeutics for large patient populations with significant unmet needs. ___________________________________ 1 https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure . 2 Centers for Disease Control and Prevention, Heart Failure, https://www-cdc-gov.libproxy1.nus.edu.sg/heartdisease/heart_failure.htm , (accessed May 8, 2023). 3 Groenewegen, A., Rutter, F., Mosterd, A., & Hoes, A. (2020). Epidemiology of heart failure. European Journal of Heart Failure, 22(8), 1342-1356. https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/ejhf.1858