Brain Death

Treatment with GT-02287 also restored glucocerebrosidase (GCase) enzymatic function, reduced aggregated α-synuclein, neuroinflammation and neuronal death, increased dopamine levels and improved motor function Data presented at the International Congress of Parkinson's Disease and Movement Disorders® Gain remains on track to begin a Phase 1 clinical study of GT-02287 later this year Gain Therapeutics, Inc. (Nasdaq: GANX) (“Gain”, or the “Company”), a biotechnology company leading the discovery and development of the next generation of allosteric small molecule therapies, today announced preclinical data demonstrating the Company’s lead drug candidate GT-02287 significantly decreased Parkinson’s disease (PD)-associated pathology and improved motor dysfunction in two different preclinical models of Parkinson’s disease. Of note, GT-02287 significantly reduced plasma Neurofilament Light Chain (NfL) levels, an emerging biomarker for neurodegeneration, in a mouse model of GBA1-PD. The findings are being presented in two posters, including one that was accepted as a late breaking abstract, at the International Congress of Parkinson's Disease and Movement Disorders® being held in Copenhagen, Denmark from August 27-31, 2023. "The compelling data from two preclinical Parkinson’s disease models with our lead drug candidate GT-02287 show that this orally administered allosteric regulator of GCase restored enzymatic function and significantly reduced the pathological hallmarks and motor dysfunction associated with Parkinson’s disease,” said Joanne Taylor, Ph.D., Senior Vice President of Research at Gain. “GT-02287 also markedly decreased plasma NfL, an emerging and important neurodegeneration biomarker that can be measured in blood, which is very exciting as we consider its application in clinical trials.” The first poster titled “Neuroprotective effect of GT-02287, a brain-penetrant structurally targeted allosteric regulator of glucocerebrosidase, leads to a significant reduction of plasma NfL levels and improvement in behavioural deficits in a mouse model of GBA1 Parkinson’s disease” (Late-breaker Abstract #LBA-13) will be presented by Dr. Taylor on each poster presentation date between 13:00 and 15:00 in the exhibition hall. Researchers used a mouse model of GBA1-PD, created using conduritol beta epoxide (CBE) to induce GCase deficit comparable to GBA1-PD. Oral administration of GT-02287 over 14 days significantly reduced aggregated α-synuclein, neuroinflammation and neuronal death in the brain. Treatment with GT-02287 also increased tyrosine hydroxylase (TH) immunostaining, a marker of dopaminergic neurons, as well as dopamine levels, and improved motor strength and motor coordination. Prominently, GT-02287 significantly reduced plasma NfL levels in this GBA1-PD model. The emerging neurodegeneration biomarker was previously accepted by the U.S. Food and Drug Administration (“FDA”) for the accelerated approval of tofersen for the treatment of amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS) and was recommended by the FDA as an exploratory endpoint for neuronopathic mucopolysaccharidosis II (MPS II) clinical trials. Dr. Taylor will also present a second poster on August 30th between 13:00 and 15:00 titled “GT-02287, a brain-penetrant structurally targeted allosteric regulator for glucocerebrosidase shows evidence of pharmacological efficacy in an animal model of Parkinson’s disease” (Abstract #1376). Data from the poster describes the effect of GT-02287 on rotenone-induced neurotoxic effects in a PD animal model. GT-02287 restored GCase levels in the brain and reduced the accumulation of toxic GCase substrates in the cerebrospinal fluid. Additionally, GT-02287 reduced aggregated α-synuclein and TNF-α levels, improved lysosomal health, as well as increased TH expression levels in the substantia nigra. “Together, the data from both posters demonstrate that our lead drug candidate GT-02287 can restore GCase protein function, protect against the neuropathological features of Parkinson’s disease, and reduce neurodegeneration measured by the emerging biomarker NfL,” said Matthias Alder, Chief Executive Officer of Gain Therapeutics. “Buoyed by these encouraging data, we look forward to initiating the Phase 1 clinical study with GT-02287 and advancing the development of this potentially best-in-class treatment for GBA1 Parkinson’s disease.” About Gain Therapeutics, Inc. Gain Therapeutics, Inc. is a biotechnology company leading the discovery and development of next generation allosteric therapies. Gain’s lead drug candidate GT-02287, in development for the treatment of GBA1 Parkinson’s disease, has completed IND-enabling GLP toxicology studies. Clinical evaluation of GT-02287 is expected to begin this year. Leveraging AI-supported structural biology, proprietary algorithms and supercomputer-powered physics-based models, the company’s SEE-Tx® discovery platform can identify novel allosteric binding sites on disease-implicated proteins, pinpointing pockets that cannot be found or drugged with current technologies. Gain’s unique approach enables the discovery of novel, allosteric small molecule modulators that can restore or disrupt protein function. Deploying its highly advanced platform, Gain is accelerating drug discovery and unlocking novel disease-modifying treatments for untreatable or difficult-to-treat disorders including neurodegenerative diseases, rare genetic disorders and oncology. For more information, please visit GainTherapeutics.com and follow us on LinkedIn. 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Adults with type 2 diabetes treated with Tresiba® (insulin degludec injection) had a significant reduction in HbA1c and a 30% lower rate of hypoglycaemic episodes after starting basal insulin Orlando, US, 23 June 2018 ­- Findings from CONFIRM - a large real-world evidence (RWE) study comparing the effectiveness of Tresiba® (insulin degludec injection) versus insulin glargine U300 - will be presented on Monday, 25 June 2018 at the American Diabetes Association's 78th Scientific Sessions (ADA) in Orlando, US. The retrospective, non-interventional comparative effectiveness study, which included more than 4,000 adults with type 2 diabetes who were starting basal insulin for the first time, showed that after six months those treated with Tresiba® had significantly lower HbA1c compared to those treated with insulin glargine U300 (-1.5% vs. -1.2% respectively; p=0.029).1 As a secondary endpoint, there was a 30% lower rate of hypoglycaemic episodes with Tresiba® compared to insulin glargine U300 (p=0.045).1 In this study, hypoglycaemic events, ranging from mild to severe, were registered using the International Classification of Diseases (ICD) codes 9/10 following diagnosis from a physician.2 This real-world study also showed in another secondary endpoint that people treated with Tresiba® were more likely to stay on their treatment. Those treated with insulin glargine U300 had a 37% higher rate of discontinuing treatment after two years (p<0.001).1 "Real-world studies are important to understanding how clinical trials may translate into real value for patients in everyday clinical practice," said Todd Hobbs, vice president and US chief medical officer of Novo Nordisk. "The CONFIRM results add to the body of evidence on Tresiba® for adults with type 2 diabetes."   About the CONFIRM study The CONFIRM study is a retrospective, non-interventional comparative effectiveness study that investigated Tresiba® and insulin glargine U300 (Toujeo®) in 4,056 insulin-naïve (defined as no evidence of basal insulin use at least 365 days prior to index date) adults with type 2 diabetes in the US. Study groups were equal in size (n=2,028) and patients in each group were comparable after matching for baseline characteristics. Patients were uncontrolled on one or more oral antidiabetic drugs or a GLP-1 (glucagon-like peptide-1) receptor agonist and prescribed Tresiba® or insulin glargine U300 according to local practice. Electronic health records were sourced from multiple health systems in the US. The primary endpoint was change in HbA1c (blood sugar control) from baseline to six months follow-up. Secondary endpoints included rate of hypoglycaemia, proportion of patients with at least one hypoglycaemic episode and the rate of treatment discontinuation. As with all real-world studies, CONFIRM was not randomised and it carries the limitations of real-world evidence. This includes potential under-reporting of hypoglycaemia (however, this is the case in both treatment arms in CONFIRM meaning that the rate ratio as well as the odds ratio are expected to be preserved), and the short follow-up period of 3-6 months (though this corresponds to when the largest changes in HbA1c tend to occur and is commonly used in many trials). Additionally, in CONFIRM there is only evidence of prescribed basal insulin and not actual use (whether the medication was picked up at the pharmacy).   About hypoglycaemia Hypoglycaemia occurs when blood sugar levels are too low and cannot provide the body's organs with the energy they need. Hypoglycaemia can cause a range of symptoms including confusion, trembling, sweating, increased heart rate, difficulty with concentration and speech, and in severe cases can lead to a seizure or coma.3-6   About Tresiba®Tresiba® (insulin degludec) is a once-daily basal insulin that provides a duration of action beyond 42 hours with a flat and stable glucose-lowering effect.7,8 It has been shown to provide a lower risk of overall, nocturnal and severe hypoglycaemia, and low variability in blood sugar levels versus insulin glargine U100.8,9 Tresiba® received its first regulatory approval in September 2012 and has since been approved in more than 80 countries globally. It is now commercially available in more than 61 countries. Further information Media:     Katrine Sperling +45 4442 6718 krsp@novonordisk.com Åsa Josefsson +45 3079 7708 aajf@novonordisk.com Michael Bachner (US) +1 609 664 7308   mzyb@novonordisk.com   Investors:     Peter Hugreffe Ankersen +45 3075 9085 phak@novonordisk.com Anders Mikkelsen +45 3079 4461 armk@novonordisk.com Christina Kjær +45 3079 3009 cnje@novonordisk.com References 1.         Tibaldi J, Haldrup S, Sandberg V, et al. Clinical Outcome Assessment of the Effectiveness of Insulin Degludec (Degludec) in Real-life Medical Practice (CONFIRM): A Comparative Effectiveness Study of Degludec and Insulin Glargine 300U/mL (Glargine U300) in 4,056 Insulin-Naïve Patients with Type 2 Diabetes (T2D) Oral/poster presentation. 78th Annual Scientific Sessions of the American Diabetes Asosciation (ADA), Orlando, Florida, US; 22-26 June 2018. 2.         Ginde AA, Blanc PG, Lieberman RM, et al. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008; 8:43.         Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013; 36:1384-1395. 4.         International Hypoglycaemia Study Group. Diagnosis of hypoglycaemia. Available online at http://ihsgonline.com/understanding-hypoglycaemia/diagnosis. Last accessed: June 2018. 5.         Cryer PE. Hypoglycemia, functional brain failure, and brain death. J Clin Invest. 2007; 117:868-870. 6.         Ahrén B. Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. Vasc Health Risk Manag. 2013; 9:155-163. 7.         Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014; 53:787-800. 8.         EMA. Tresiba® Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002498/WC500138940.pdf. Last accessed: June 2018. 9.         Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017; 377:723-732.