Enalapril Maleate

If subsequently approved, Entresto will be the first and only approved therapy for the treatment of symptomatic chronic heart failure patients aged 1 to <18 years in the European Union Pediatric heart failure is an important cause of childhood morbidity and mortality – up to a third of all pediatric cardiac admissions are due to heart failure; these hospitalizations are associated with a 20-fold increase in the risk of death1,2 The positive opinion is based on final data from the 52-week Phase III PANORAMA-HF trial, the largest pediatric heart failure study ever conducted, and extrapolation of adult heart failure data from the Phase III PARADIGM-HF trial to pediatric patients3,4 In this new indication the CHMP concluded that Entresto brings an important contribution to patient care and therefore fulfills the criteria of significant clinical benefit; if approved, this would support extension of the regulatory data protection to November 2026 Basel, 31 March, 2023 — Novartis announced today that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending approval of Entresto (sacubitril/valsartan) for a new indication to treat symptomatic chronic heart failure with left ventricular systolic dysfunction in pediatric patients aged from 1 to <18 years. “Many children diagnosed with heart failure will need a heart transplant before they turn five or in the worst cases almost a third will die within a year. However, the disease is largely managed with treatments approved for adults, based on data from adult studies,” said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. “This positive opinion paves the way towards Novartis being able to provide children diagnosed with heart failure due to left ventricular systolic dysfunction in the EU and their families with an effective therapy in an age-appropriate formulation, helping to address what is a major unmet need.” The positive opinion is based on final data from the 52-week Phase III PANORAMA-HF trial – the largest pediatric heart failure study ever conducted – and extrapolation of adult heart failure data from the Phase III PARADIGM-HF trial to pediatric patients3,4. The data showed Entresto provided similar clinically meaningful reductions from baseline in the cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) – a biomarker commonly used to assess the severity and prognosis of heart failure – in adult heart failure patients and pediatric patients aged 1 to <18 years with heart failure due to left ventricular systolic dysfunction, allowing extrapolation of the demonstrated efficacy in adults to pediatric patients3,4. Compared to enalapril, the current standard of care in pediatric heart failure (but not specifically approved for pediatric heart failure), Entresto provided comparable to numerically better improvements from baseline on a number of clinically relevant endpoints3,4. Safety and tolerability of Entresto in pediatric patients were consistent with that observed in adult patients3,4. Pediatric heart failure represents an important cause of morbidity and mortality in childhood. Up to 33% of all pediatric cardiac admissions are related to heart failure, and children whose hospitalization is complicated by heart failure can have more than a 20-fold increase in the risk of death1,2. In this new indication the CHMP concluded that Entresto brings an important contribution to patient care and therefore fulfills the criteria of significant clinical benefit. If approved, Entresto will become available to children with a new age-appropriate formulation to enable accurate and convenient administration for these patients and their caregivers. This would support extension of the regulatory data protection to November 2026. Entresto has been approved in the EU since 2015 in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF)4. In the US, Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure, and has been approved since October 2019 to treat childhood heart failure due to left ventricular systolic dysfunction5. About PANORAMA-HF PANORAMA-HF was a two-part study3. Part 1 was an open-label dose determination study3. Part 2 was a randomized, double-blind, 52-week study comparing Entresto to the active comparator enalapril in patients aged 1 month to <18 years old with heart failure (HF) (NYHA/Ross Class II-IV) due to systemic left ventricular systolic dysfunction (LVEF <45% or fractional shortening ≤22.5%)3. It is the largest prospective pediatric HF trial conducted to date and employs the use of a global rank primary endpoint, based on clinical events encompassing death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores) and patient-reported HF symptoms3. Additionally, NT-proBNP was used in the trial as a bridging biomarker for extrapolation from adults to the pediatric population3. The trial was conducted in 30 countries and 105 clinical sites across North America, Europe, Asia and Latin America3. About our longstanding commitment to heart failure Our goal is to reimagine medicine for HF patients. Novartis established the largest global clinical program in the HF disease area across the pharma industry to date. Known as FortiHFy, it is comprised of more than 40 clinical studies designed to generate an array of additional data on efficacy, quality of life, patient-reported outcomes and real-world evidence with Entresto, as well as to extend understanding of HF. FortiHFy includes trials across the spectrum of HF, such as PARADIGM-HF, PIONEER-HF, PANORAMA-HF, TRANSITION, PROVE-HF, PARAGON-HF and PARAMOUNT. Worldwide, it is estimated that more than 30,000 patients have participated in the Entresto clinical trials program, and it is estimated that around 10 million patients are on treatment with Entresto today. About Entresto In Europe, Entresto is indicated in adult patients for the treatment of symptomatic chronic HFrEF4. In the United States, Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for HF in adult patients with chronic HF5. Benefits are most clearly evident in patients with LVEF below normal5. LVEF is a variable measure, so use clinical judgment in deciding whom to treat5. In the US, Entresto is also indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older5. Entresto reduces NT-proBNP and is expected to improve cardiovascular outcomes5. Approved indications may vary depending upon the individual country. Entresto is a twice-a-day medicine that reduces the strain on the failing heart4,5. It does this by enhancing protective neurohormonal systems (i.e., natriuretic peptide system) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS)4,5. Other common HF medicines, called angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), only block the harmful effects of the overactive RAAS. Entresto contains the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan4,5. Entresto was included in the 2021 European Society of Cardiology HF Guidelines as a cornerstone, first-line treatment to reduce the risk of death and HF hospitalization in patients with HFrEF6. This includes patients who have not previously been treated with ACEis or angiotensin-receptor blockers (ARB) and to replace ACEis or ARBs in symptomatic HFrEF patients6. These Guidelines are in line with the ACC Expert Consensus Decision Pathway (ECDP) also published in 2021, which recognize the value of Entresto by elevating it to a foundational first-line treatment7. The ACC ECDP states that Entresto is preferred over ACEi and ARB in all appropriate patients with HFrEF7. DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About NovartisNovartis is reimagining medicine to improve and extend people’s lives. We deliver high-value medicines that alleviate society’s greatest disease burdens through technology leadership in R&D and novel access approaches. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. About 106,000 people of more than 140 nationalities work together to bring Novartis products to nearly 800 million people around the world. Find out more at https://www.novartis.com Novartis is on Twitter. Sign up to follow @Novartis at https://twitter.com/novartisnewsFor Novartis multimedia content, please visit https://www.novartis.com/news/media-libraryFor questions about the site or required registration, please contact media.relations@novartis.com References Das, BB. Current State of Pediatric Heart Failure. Children. 2018 Jul; 5(7): 88.Castro Díez C, Khalil F, Schwender H, et al. Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey. BMJ Paediatrics Open. 2019;3:e000365. Novartis Data on FileEuropean Medicines Agency. Entresto (sacubitril/valsartan). Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004062/WC500197536.pdf. Accessed March 2023ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; October 2019.McDonagh T, Metra M, Adamo M, et. Al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;00:1-128. doi:10.1093/eurheartj/ehab368.Maddox TM, Januzzi JL Jr, Allen LA, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution. 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Atrasentan was well-tolerated with no treatment-related serious adverse events (SAEs) Atrasentan demonstrated mean proteinuria reductions of 38.1% proteinuria at six weeks of treatment, 48.3% at 12 weeks of treatment and 54.7% at 24 weeks of treatment There were no meaningful changes in blood pressure or acute eGFR, suggesting proteinuria reductions were not primarily due to hemodynamic effects of atrasentan, and there were no increases in brain natriuretic peptide (BNP) or mean bodyweight, suggesting minimal fluid retention Preclinical data was presented on single-cell RNA-seq of a mouse model of IgAN, revealing a prominent expansion of failed repair proximal tubular epithelial cells, which was reversed by atrasentan but not ACE inhibition Three informational trial-in-progress posters were presented on the ongoing phase 3 ALIGN, phase 2 AFFINITY and phase 1/2 BION-1301 clinical trials Chinook to host live investor conference call, webcast and in-person event on Friday, November 4th at 6:30 pm EDT with Dr. Sreedhar A. Mandayam, Professor of Nephrology at the University of Texas MD Anderson Cancer Center and Baylor College of Medicine, and Laura Kooienga, MD, practicing nephrologist and director of research at Colorado Kidney Care SEATTLE, Nov. 03, 2022 (GLOBE NEWSWIRE) -- Chinook Therapeutics, Inc., (Nasdaq: KDNY), a biopharmaceutical company focused on the discovery, development and commercialization of precision medicines for kidney diseases, today announced two posters and three informational posters being presented today at ASN Kidney Week 2022 being held virtually and live in Orlando, Florida. “The updated interim data from the IgAN patient cohort of the atrasentan phase 2 AFFINITY basket trial continue to demonstrate highly consistent and clinically meaningful proteinuria reductions in patients with IgAN already on a maximally tolerated and stable dose of a RAS inhibitor,” said Eric Dobmeier, president and chief executive officer of Chinook Therapeutics. “We are encouraged by these results, and look forward to reporting topline proteinuria data from our ongoing phase 3 ALIGN trial in 2023.” TH-PO497 – Atrasentan for the Treatment of IgA Nephropathy: Interim Results from the AFFINITY Study Atrasentan is a potent and selective endothelin A (ETA) receptor antagonist that has the potential to provide benefit in multiple chronic kidney diseases by reducing proteinuria and having direct anti-inflammatory and anti-fibrotic effects to preserve kidney function. Chinook selected IgAN as the lead indication for atrasentan due to the role of ETA activation in driving proteinuria, mesangial cell activation, kidney inflammation and fibrosis, the hallmarks of IgAN disease progression. The AFFINITY Study (see , identifier NCT04573920) is an ongoing global phase 2, open-label, basket study to evaluate the safety and efficacy of atrasentan in patients with proteinuric glomerular disease who are at risk of progressive loss of kidney function. The four AFFINITY cohorts consist of patients with: biopsy-proven IgAN with urine protein to creatinine ratio (UPCR) of 0.5 to 1.0 g/g, focal segmental glomerulosclerosis (FSGS), Alport syndrome and diabetic kidney disease (DKD) in combination with an SGLT2 inhibitor. The 20 patients enrolled in each cohort receive 0.75 mg oral atrasentan daily for 52 weeks while continuing to receive a maximally tolerated and stable dose of a RAS inhibitor as standard of care. The study is also evaluating the safety and efficacy of a higher 1.5 mg oral daily dose of atrasentan in patients with FSGS for whom the 0.75 mg dose is well tolerated. Key highlights from the presentation include the following: In the IgAN cohort, median baseline 24-hour urine protein excretion was 1.2 g/day. Overall, 14 of 20 patients enrolled had baseline total proteinuria over one gram per day despite optimized RAS inhibitor treatment, representing an IgAN patient population at high risk for progression. As of the October 19, 2022 data cutoff, atrasentan was well-tolerated in patients with IgAN, with no treatment-related SAEs. Of the 20 patients enrolled, ten patients remained on study, nine patients completed 52 weeks of treatment and one patient discontinued after 13 weeks of treatment due to a headache. Mean time on treatment for all patients was 45 weeks. One patient had an unrelated serious adverse event of a traffic accident, but remained on study. Five patients had a treatment-related adverse event, all of which were considered mild or moderate. Two patients experienced peripheral edema - one mild and one moderate - which resolved in less than seven days with temporary use of low-dose diuretics. All other treatment-emergent adverse events have resolved. There were no meaningful changes in blood pressure or acute eGFR effects, suggesting proteinuria reductions were not primarily due to hemodynamic effects of atrasentan. There were no increases in BNP or mean bodyweight, suggesting minimal fluid retention. Atrasentan demonstrated mean reductions in 24-hour urine protein creatinine ratio (UPCR) of 38.1% at six weeks of treatment, 48.3% at 12 weeks of treatment and 54.7% at 24 weeks of treatment (see figure below). After 24 weeks of treatment, 15 of the 19 patients (79%) who had completed this visit had greater than a 40% reduction in UPCR. TH-PO419 – Single Nuclei RNA-seq Reveals Cell-type Specific Responses to Disease and Enalapril in the gddY Mouse Model of IgAN The gddY mouse model, a spontaneous model of early-onset IgAN, is characterized by IgA immune complex deposition in the mesangium of the kidney, leading to significant proteinuria, glomerular hypercellularity, mesangioproliferative glomerular lesions, glomerulosclerosis and reduced kidney function, all hallmarks of human IgAN. The gddY mouse was utilized as a model to create a high-resolution single-cell dataset to characterize the kidney cell-type specific transcriptional networks that drive IgAN, and to assess the impact of pharmacological intervention with ACE inhibition or atrasentan on these disease-driving transcriptional pathways. Failed repair proximal tubular epithelial cells (FR PTEC) were identified as the most expanded kidney cell type in the gddY mouse model of IgAN, and may play a major role in tubulointerstitial inflammation and fibrosis leading to progressive kidney function loss. Atrasentan significantly reversed the pathogenic gene expression changes in FR PTECs that were induced in the IgAN model. However, ACEi had minimal impact on IgAN-induced gene expression changes in FR PTECs and rather primarily induced new gene expression changes, unrelated to disease pathogenesis, most prominently in vascular smooth muscle cells. The atrasentan transcriptional response signature identified in this study is currently being evaluated in IgAN patient kidney biopsies, and matched urine and serum samples are being screened for non-invasive surrogate biomarkers. INFO27 – A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Atrasentan in Patients with IgA Nephropathy – The ALIGN Study A trial-in-progress overview for the global, phase 3, randomized, double-blind, placebo-controlled ALIGN study of atrasentan was presented as an informational poster. INFO31 – Atrasentan in Patients with Proteinuric Glomerular Diseases – The AFFINITY Study A trial-in-progress overview for the ongoing, global, phase 2, open-label AFFINITY basket study of atrasentan was presented as an informational poster. INFO28 – A Phase 1/2 Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BION-1301 in Healthy Volunteers and Adults with IgA Nephropathy A trial-in-progress overview for the ongoing phase 1/2 study of BION-1301 was presented as an informational poster. All five presentations can be found in the Scientific Publications section of Chinook’s website. Live Conference Call and Webcast Chinook will host a live conference call, webcast and in-person event on Friday, November 4th at 6:30 pm EDT to discuss the presentations at ASN Kidney Week 2022 and provide program updates. Members of the Chinook executive team will be joined by Dr. Sreedhar A. Mandayam, Professor of Nephrology at the University of Texas MD Anderson Cancer Center and Baylor College of Medicine, and Laura Kooienga, MD, practicing nephrologist and director of research at Colorado Kidney Care. Conference Call and Webcast Details To access the call, please dial (800) 715-9871 (domestic) or (646) 307-1963 (international) and provide the Conference ID 7505851 to the operator. To access the live webcast and subsequent archived recording of this and other company presentations, please visit the Investors section of Chinook’s website. The archived webcast will remain available for replay on Chinook’s website for 90 days. About Chinook Therapeutics, Inc. Chinook Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing precision medicines for kidney diseases. Chinook’s product candidates are being investigated in rare, severe chronic kidney disorders with opportunities for well-defined clinical pathways. Chinook’s lead program is atrasentan, a phase 3 endothelin receptor antagonist for the treatment of IgA nephropathy and other proteinuric glomerular diseases. BION-1301, an anti-APRIL monoclonal antibody, is being evaluated in a phase 1/2 trial for IgA nephropathy. CHK-336, an oral small molecule LDHA inhibitor for the treatment of hyperoxalurias, is being evaluated in a phase 1 healthy volunteer trial. In addition, Chinook is advancing research programs for other rare, severe chronic kidney diseases. Chinook is building its pipeline by leveraging insights in kidney single cell RNA sequencing, human-derived organoids and new translational models, to discover and develop therapeutics with differentiating mechanisms of action against key kidney disease pathways. To learn more, visit . Cautionary Note on Forward-Looking Statements Certain of the statements made in this press release are forward looking, including those relating to Chinook’s business, future operations, advancement of its product candidates and product pipeline, clinical development of its product candidates, including expectations regarding cash forecasts and timing of initiation and results of clinical trials, and regulatory submissions, including the timing of the results of our phase 3 ALIGN trial and phase 2 AFFINITY trial of atrasentan and submission for potential accelerated approval. In some cases, you can identify these statements by forward-looking words such as “may,” “will,” “continue,” “anticipate,” “intend,” “could,” “project,” “expect” or the negative or plural of these words or similar expressions. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, our ability to develop and commercialize our product candidates, including initiation of clinical trials of our existing product candidates or those developed as part of the Evotec collaboration, whether results of early clinical trials or preclinical studies will be indicative of the results of future trials, our ability to obtain and maintain regulatory approval of our product candidates, our ability to operate in a competitive industry and compete successfully against competitors that may be more advanced or have greater resources than we do, our ability to obtain and adequately protect intellectual property rights for our product candidates and the effects of COVID-19 on our clinical programs and business operations. Many of these risks are described in greater detail in our filings with the SEC. Any forward-looking statements in this press release speak only as of the date of this press release. Chinook assumes no obligation to update forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. A photo accompanying this announcement is available at Contact: Noopur Liffick Vice President, Investor Relations & Corporate Communications investors@chinooktx.com media@chinooktx.com Atrasentan Treatment Results in Clinically Meaningful Proteinuria Reductions in Patients with IgAN Treatment with atrasentan results in durable and clinically meaningful proteinuria reductions in patients with IgAN receiving optimized standard of care