MR

October 1, 2024 – Santhera Pharmaceuticals (SIX: SANN) announces the positive outcome of the LIONHEART study, confirming vamorolone’s distinctive action also as a mineralocorticoid receptor antagonist, setting it apart from other corticosteroids. The LIONHEART study, an open-label randomized, placebo- and eplerenone-controlled study involving 30 healthy adult male subjects, met its primary endpoint. It demonstrated a statistically significant increase in the urinary sodium/potassium ratio in the vamorolone arm compared to placebo (p<0.0001) following a fludrocortisone challenge. This increased ratio in urine provides clinical evidence for vamorolone’s unique mode of action also as a mineralocorticoid receptor antagonist (MRA) in humans. Combined with its known properties as a dissociative glucocorticoid receptor agonist, these findings further differentiate vamorolone’s pharmacological profile, distinguishing it from other corticosteroids. Cardiac complications such as cardiomyopathy are a leading cause of morbidity and mortality in boys with Duchenne muscular dystrophy (DMD). While treatment with corticosteroids (and ACE inhibitors) has demonstrated a delay in the onset of cardiomyopathy, the addition of MRAs including eplerenone to standard of care has also shown an improvement in left ventricular systolic dysfunction, the benefit of which increases with earlier initiation [1-3]. “Mineralocorticoid receptor antagonists are strongly recommended but late when cardiac function is already reduced and tend to be used in the presence of myocardial fibrosis as detected in magnetic resonance imaging,” explained Prof Karim Wahbi, PhD, MD, Cardiologist at the APHP Hospital Cochin, Paris, France. “What is intriguing about this mechanistic study is whether there is a synergistic benefit of the anti-inflammatory and MRA effects of vamorolone on the evolution of cardiac disease in children who started treatment early or if vamorolone could be of benefit to those who are already experiencing cardiac symptoms and wish to remain on a corticosteroid” “The LIONHEART study is an important milestone to establish the proof of concept for a cardioprotective potential of vamorolone,” stated Shabir Hasham, MD, Chief Medical Officer of Santhera. “We continue to collect data from patients who have been on vamorolone for up to seven years allowing us to better characterize long-term outcomes including any beneficial impact on cardiac complications in DMD.” AGAMREE is a novel drug with a mode of action based on binding to the same receptor as glucocorticoids but modifying its downstream activity. Moreover, it is not a substrate for the 11-β-hydroxysteroid dehydrogenase (11β-HSD) enzymes that may be responsible for local drug amplification and corticosteroid-associated toxicity in local tissues [4-7]. This mechanism has shown the potential to ‘dissociate’ efficacy from steroid safety concerns and therefore AGAMREE is positioned as a dissociative anti-inflammatory drug and an alternative to existing corticosteroids, the current standard of care in children and adolescent patients with DMD [4-7]. In the pivotal VISION-DMD study, AGAMREE met the primary endpoint Time to Stand (TTSTAND) velocity versus placebo (p=0.002) at 24 weeks of treatment and showed a good safety and tolerability profile [4]. The most commonly reported side effects were cushingoid features, vomiting, weight increase and irritability. Side effects were generally of mild to moderate severity. Currently available data show that AGAMREE, unlike corticosteroids, has been shown to be a dual mineralocorticoid antagonist and a dissociative glucocorticoid agonist based on animal experiments [7]. It has no restriction of growth [8] and no negative effects on bone metabolism as demonstrated by normal bone formation and bone resorption serum markers [9]. AGAMREE (vamorolone), an orphan medicinal product, is approved for use in the United States (Prescribing Information), the European Union (Summary of Product Characteristics) and the United Kingdom for the treatment of DMD. The LIONHEART study (SNT-I-VAM-026) is an open label randomized, 3-arm, parallel-group, placebo and eplerenone controlled study to evaluate the mineralocorticoid receptor antagonism (MRA) effect of vamorolone in 30 healthy adult male subjects after challenge with fludrocortisone, a known mineralocorticoid receptor agonist. The primary endpoint was defined as the ratio of sodium to potassium (Na/K) and the corresponding logarithm of the ratio (log10(10*Na/K) in urine at different time-points. Further analysis of the data is ongoing and will be presented at medical conferences. References: [1] Birnkrant et al. (2018) Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5. [2] Raman et a. (2015) Lancet Neurol 14: 153–161 doi:10.1016/s1474-4422(14)70318-7 [3] Raman et al. (2017) Orphanet J Rare Dis 12: 39. doi:10.1186/s13023-017-0590-8 [4] Dang UJ et al. (2024) Neurology 2024;102:e208112. doi.org/10.1212/WNL.0000000000208112. Link. [5] Guglieri M et al (2022). JAMA Neurol. 2022;79(10):1005-1014. doi:10.1001/jamaneurol.2022.2480. Link. [6] Liu X et al (2020). Proc Natl Acad Sci USA 117:24285-24293 [7] Heier CR et al (2019). Life Science Alliance DOI: 10.26508 [8] Ward et al., WMS 2022, FP.27 - Poster 71. Link. [9] Hasham et al., MDA 2022 Poster presentation. Link. Duchenne muscular dystrophy (DMD) is a rare inherited X-chromosome-linked disease, which almost exclusively affects males. DMD is characterized by inflammation which is present at birth or shortly thereafter. Inflammation leads to fibrosis of muscle and is clinically manifested by progressive muscle degeneration and weakness. Major milestones in the disease are the loss of ambulation, the loss of self-feeding, the start of assisted ventilation, and the development of cardiomyopathy. DMD reduces life expectancy to before the fourth decade due to respiratory and/or cardiac failure. Corticosteroids are the current standard of care for the treatment of DMD. Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular diseases with high unmet medical need. The Company has an exclusive license from ReveraGen for all indications worldwide to AGAMREE® (vamorolone), a dissociative steroid with novel mode of action, which was investigated in a pivotal study in patients with Duchenne muscular dystrophy (DMD) as an alternative to standard corticosteroids. AGAMREE for the treatment of DMD is approved in the U.S. by the Food and Drug Administration (FDA), in the EU by the European Medicines Agency (EMA), and in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA). Santhera has out-licensed rights to AGAMREE for North America to Catalyst Pharmaceuticals and for China to Sperogenix Therapeutics. For further information, please visit www.santhera.com. The content above comes from the network. if any infringement, please contact us to modify.

Finerenone is the first mineralocorticoid receptor (MR) antagonist to demonstrate definitive cardiovascular benefits in a Phase III study in patients with heart failure (HF) with a left ventricular ejection fraction (LVEF) of ≥40%, i.e. mildly reduced or preserved LVEF Finerenone showed a 16% relative risk reduction of the composite primary endpoint of cardiovascular death and total (first and recurrent) heart failure events compared to placebo The primary endpoint results were consistent across all prespecified subgroups including those based on comorbidities, hospitalization status, ejection fraction or baseline use of SGLT2-inhibitors Results from FINEARTS-HF were simultaneously published in the New England Journal of Medicine Unmet medical need is high for patients with heart failure (HF) and a LVEF of ≥40%: Hospitalization and mortality rates are comparable to those in patients with HF with reduced ejection fraction (LVEF≤40%), however, only limited approved and guideline-directed treatment options are currently available BERLIN, Germany I September 1, 2024 I Detailed results from the Phase III study FINEARTS-HF demonstrate that compared to placebo, finerenone (Kerendia™/ Firialta™) showed a statistically significant improvement in cardiovascular outcomes in patients with heart failure (HF) and a left ventricular ejection fraction (LVEF) of greater than or equal to 40%. Finerenone significantly reduced the risk of the composite primary endpoint of cardiovascular death and total (first and recurrent) HF events, defined as hospitalizations for HF or urgent HF visits, by 16 % (relative risk reduction, rate ratio (RR) 0.84 [95% CI, 0.74-0.95; p=0,0072]) over a median duration of 32 months. Based on the results of FINEARTS-HF, finerenone is the first MR antagonist to demonstrate definitive cardiovascular benefits in a Phase III study in patients with this common form of heart failure. The FINEARTS-HF findings were presented today during a Hot Line session at ESC Congress 2024 and simultaneously published in the New England Journal of Medicine . “Treating heart failure patients with LVEF ≥ 40% has provided a significant challenge for many physicians, and there is a high unmet medical need as these patients have a substantial risk for serious cardiovascular events. Unlike heart failure with reduced ejection fraction, where many treatments are now available, for heart failure with LVEF ≥ 40%, we currently have limited treatment options with proven efficacy,” said Scott D. Solomon, MD, The Edward D. Frohlich Distinguished Chair, Professor of Medicine at Harvard Medical School, Director of Non-invasive Cardiology and Senior Physician at Brigham and Women’s Hospital and Chair of the study’s Executive Committee. “With FINEARTS-HF as the first large-scale study of a non-steroidal, selective mineralocorticoid receptor antagonist in these underserved heart failure patients, finerenone, if approved, has the potential to help these vulnerable patients.” The benefits shown in the primary endpoint were consistent across all prespecified subgroups, regardless of background therapy, comorbidities, or hospitalization status, including those based on disease state (ejection fraction) or baseline use of SGLT2-inhibitors. Finerenone also significantly reduced the secondary endpoints of total HF events (RR 0.82 [95% CI, 0.71-0.94; p=0.0062]) and improved patient-reported health status as measured by the change from baseline in Total Symptom Score of Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), (between-group difference 1.6 points [95% CI, 0.8-2.3; p<0.0001]). Heart failure (HF) affects over 60 million people worldwide; approximately half of these patients suffer from HF with a LVEF of ≥40%.HF with a LVEF ≥40% is associated with multimorbidity, making the condition complex to manage. Time trends suggest this growing population will soon account for the majority of patients hospitalized with HF. Patients with HF LVEF ≥40% have similar hospitalization and mortality rates as those with HF LVEF ≤40% (HF with reduced ejection fraction, HFrEF). More than half of patients with HF LVEF ≥40% will die within 5 years. The high residual risk of CV events and mortality remains high despite available treatments in patients with HF LVEF ≥40%. “Bayer has a strong heritage in cardiology, and heart failure is a key focus area for us, with these promising results underpinning our ongoing commitment to patients with this devastating condition. In FINEARTS-HF, finerenone reduced cardiovascular outcomes in a complex to treat patient population. This confirms the potential of finerenone, if approved, as a valuable treatment option in heart failure with mildly reduced or preserved ejection fraction irrespective of background therapy and disease state,” said Dr. Christian Rommel, Head of Research and Development at Bayer’s Pharmaceuticals Division. “FINEARTS-HF included a high percentage of hospitalized or recently hospitalized patients, which means the results are highly relevant for improving cardiovascular outcomes for patients who do not have enough options.” Finerenone is a non-steroidal, selective mineralocorticoid receptor (MR) antagonist. By targeting MR and renin-angiotensin-aldosterone system (RAAS) overactivation, finerenone addresses hallmarks of HF with a LVEF ≥40%, such as fibrotic drivers. Finerenone was well-tolerated in the FINEARTS-HF study, which is consistent with the well-established safety profile of finerenone. The overall incidence of treatment-emergent serious adverse events was comparable between finerenone and placebo groups. Hyperkalemia-related adverse events occurred more frequently with finerenone than placebo (9.7 % and 4.2%, respectively). There were no fatal adverse events of hyperkalemia in either treatment group, and hospitalization or discontinuation due to hyperkalemia was rare. The occurrence of increased potassium and creatinine levels was also more frequent in the finerenone group, but the incidence of potassium above 6.0 mmol/L was generally low. Bayer plans to submit applications for marketing authorization for finerenone for an indication in heart failure with a LVEF of ≥40% to health authorities in due course. About FINEARTS-HF FINEARTS-HF is a randomized, double-blind, placebo-controlled, multicenter, event-driven Phase III study investigating the efficacy and safety of finerenone (Kerendia™) for the prevention of cardiovascular death and heart failure (HF) events in patients with a diagnosis of symptomatic heart failure (New York Heart Association class II-IV) with a left ventricular ejection fraction (LVEF) of ≥40%, measured by any modality within the last 12 months as well as receiving diuretic treatment for at least 30 days prior to randomization. The primary endpoint of FINEARTS-HF was the composite of cardiovascular death and total (first and recurrent) HF events, defined as hospitalizations for HF or urgent HF visits. Around 6,000 patients were randomized from more than 630 sites across 37 countries worldwide to receive either finerenone or placebo once daily. In addition, patients in the study received usual therapy to treat symptoms and comorbidities. Finerenone once daily significantly reduced the combined risk of cardiovascular death and total (first and recurrent) HF events, defined as hospitalizations for HF or urgent HF visits, by 16 % (relative risk reduction, rate ratio (RR) 0.84 [95% CI, 0.74-0.95; p=0,0072]) over a median duration of 32 months. The results for the individual components of the primary endpoint are: cardiovascular death: hazard ratio (HR) 0.93 [95% CI, 0.78-1.11]; total (first and recurrent) HF events, defined as hospitalizations for HF or urgent HF visits: RR 0.82 [95% CI, 0.71-0.94; p=0.0062]). Finerenone also significantly reduced the secondary endpoint of improved patient-reported health status as measured by the change from baseline in Total Symptom Score of Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS) (between-group difference 1.6 points [95% CI, 0.8-2.3; p<0.0001]). There was no difference in the finerenone and placebo groups for NYHA class (odds ratio (OR) 1.01 [95% CI, 0.88-1.15]; the composite kidney outcome (HR 1.33; [95% CI, 0.94–1.89]), or all-cause mortality (HR 0.93; [95% CI, 0.83–1.06]). With overall more than 15,000 patients, the ongoing MOONRAKER clinical trial program with finerenone, including FINEARTS-HF, is one of the largest HF study programs to date, and aims to establish a comprehensive understanding of finerenone in HF across a broad spectrum of patients and clinical settings. About Kerendia ™ / Firialta ™ (finerenone) Kerendia™ and Firialta™ are globally protected trademarks for finerenone. Finerenone is a non-steroidal, selective mineralocorticoid receptor (MR) antagonist that has been shown to block harmful effects of MR overactivation. MR overactivation contributes to chronic kidney disease (CKD) progression and cardiovascular damage which can be driven by metabolic, hemodynamic, or inflammatory and fibrotic factors. Finerenone is marketed as Kerendia™ or, in some countries, as Firialta™, and approved for the treatment of adult patients with CKD associated with type 2 diabetes (T2D) in more than 90 countries worldwide, including in China, Europe, Japan, and the U.S. The study program with finerenone, FINEOVATE, currently comprises ten Phase III studies with dedicated programs in HF and CKD respectively. The MOONRAKER program includes FINEARTS-HF, as well as the ongoing collaborative, investigator-sponsored studies REDEFINE-HF, CONFIRMATION-HF, and FINALITY-HF. The THUNDERBALL CKD program consists of the completed studies FIDELIO-DKD and FIGARO-DKD, as well as the ongoing studies FIND-CKD, FIONA, FIONA-OLE, FINE-ONE, and the Phase II study CONFIDENCE. About Heart Failure Heart failure is a complex clinical syndrome, characterized by a progressive decline in the heart’s ability to fill with and pump enough blood to meet the body’s needs for blood and oxygen. HF affects more than 60 million people worldwide and is the leading cause of hospitalization in people over 65. Prevalence of HF is projected to increase drastically over the next decade, partly as a consequence of the ageing population. Patients with HF face a poor prognosis, with mortality rates similar to or worse than the most common cancers. HF can be complicated by several comorbidities, with more than half of patients living with conditions such as obesity, chronic kidney disease, diabetes mellitus, hypertension, and/or atrial fibrillation. Symptoms of HF may include dizziness, shortness of breath, fatigue, sleep disturbance, chest discomfort, edema (swelling of feet and legs), and chronic coughing or wheezing. Risk factors include hypertension, diabetes mellitus, smoking, a past myocardial infarction, and coronary artery disease. Despite advances in treatment, around 30% of people diagnosed with HF die within one year, increasing to around 40% after five years. When categorized by left ventricular ejection fraction (LVEF), which is a measure of cardiac function indicating how much blood the left ventricle pumps out with each contraction, HF is divided into three different categories: ·       Heart failure with reduced ejection fraction (HFrEF) is characterized by the compromised ability of the heart to eject oxygen-rich blood sufficiently during its contraction phase, where LVEF is ≤40% ·       Heart failure with mildly reduced ejection fraction (HFmrEF) is a category for patients whose LVEF is between 41 to 49% and who have some impairment in the heart’s ability to pump ·       Heart failure with preserved ejection fraction (HFpEF) is a condition characterized by stiffness of the heart, leading to filling abnormalities as the left ventricle is unable to relax sufficiently to fill with blood, where LVEF is ≥50% While LVEF ≤40% and LVEF ≥40% each account for approximately half of all HF cases, the burden of CV and non-CV comorbidities is higher in patients with LVEF ≥40%. Time trends also suggest that LVEF ≥40% will soon account for the majority of patients hospitalized with HF. While advances in therapy have been achieved in HF with LVEF ≤40%, there are limited treatment options for HF with LVEF ≥40%. About Bayer’s Commitment in Cardiovascular and Kidney Diseases Bayer is an innovation leader in the area of cardiovascular diseases, with a long-standing commitment to delivering science for a better life by advancing a portfolio of innovative treatments. The heart and the kidneys are closely linked in health and disease, and Bayer is working in a wide range of therapeutic areas on new treatment approaches for cardiovascular and kidney diseases with high unmet medical needs. The cardiology franchise at Bayer already includes a number of products and several other compounds in various stages of preclinical and clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cardiovascular diseases are treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to www.bayer.com . Find more information at https://pharma.bayer.com Follow us on Facebook: http://www.facebook.com/bayer Follow us on Twitter: @BayerPharma SOURCE: Bayer

Novo Nordisk acquired ocedurenone in a $1.3bn deal in 2023. Image credit: oleschwander / Shutterstock. Novo Nordisk has said it will take a DKr5.7bn ($816m) hit after its acquired drug ocedurenone flopped in the Phase III trial. The Phase III CLARION-CKD trial (NCT04968184) failed to meet its primary endpoint in patients with uncontrolled hypertension and moderate or severe (stage 3b/4) chronic kidney disease (CKD) . The drug was acquired by the Danish pharma giant from KBP Biosciences last year in a $1.3bn deal . At the time of the acquisition, KBP Biosciences was already conducting the Phase III study. The company said that following the trial data, it recognises an impairment loss of $816m related to ocedurenone in Q2 2024. The trial design included a prespecified interim analysis by an independent data monitoring committee after 12 weeks of treatment. The analysis showed that the trial had not met its primary endpoint of change in systolic blood pressure (SBP), leading Novo to terminate the study. See Also: AstraZeneca’s Tagrisso receives approval in Japan for lung cancer AstraZeneca’s Truqap and Faslodex combo receives approval in EU The trial was estimated to enrol approximately 600 patients from 150 sites in the US, Europe, and Asia, with the first patient dosed at the end of 2021. Novo had also announced plans to investigate the candidate in other cardiovascular and kidney disease indications in the coming years. Novo has announced it is now evaluating the further development of ocedurenone. Kajal Jaddoo, senior pharma analyst at GlobalData, said: “ CKD clinical trials have very broad and complex primary endpoints that need to be met. Several promising CKD drug candidates failed to meet their endpoints in late-stage trials in recent years, which is a huge economic burden to pharmaceutical companies pursuing kidney disease drug discovery and a huge disappointment to patients. “Trial issues may cause pharmaceutical companies to switch their investments to more profitable disease areas, which will have a negative impact on the production of new CKD medications on the global market.” Ocedurenone is a non-steroidal, mineralocorticoid receptor antagonist that blocks the binding of aldosterone. Aldosterone binds to mineralocorticoid receptors in both epithelial and non-epithelial tissues, as well as increases blood pressure and kidney disease through induction of sodium reabsorption and possibly other mechanisms. The Phase IIb trial (NCT03574363) of the candidate, also run by KBP Biosciences ahead of the acquisition, met its primary endpoint with ocedurenone demonstrating a clinically meaningful and statistically significant improvement in SBP in the same patient population. Novo Nordisk has a market cap of $499bn, according to GlobalData’s Pharmaceutical Intelligence Center. GlobalData is the parent company of the Clinical Trials Arena.