Cardiac magnetic resonance imaging (MRI) measures of myocardial interstitial fibrosis (MIF) are elevated in heart failure with preserved ejection fraction (HFpEF) patients and associated with poor prognosis. Extracellular volume (ECV) is the most reproducible and best validated cardiac MRI measure of MIF. Sacubitril/valsartan reduces histological MIF in mice and levels of some extracellular matrix regulatory proteins in humans with HFpEF. However, the effect of sacubitril/valsartan on robust measures of MIF in humans is unknown. Demonstrating reductions in ECV with sacubitril/valsartan would clarify the mechanism of this approved medication. Given the borderline reduction in heart failure hospitalizations with sacubitril/valsartan and the heterogeneity of HFpEF pathophysiology, this result would suggest that neprilysin inhibition may particularly benefit HFpEF patients with greater MIF. The investigators propose a proof-of-concept clinical trial to evaluate the effect of neprilysin inhibition (sacubitril/valsartan vs valsartan alone) on cardiac MRI measures of fibrosis (principally ECV) and circulating protein levels.

Start Date01 Dec 2024

Sponsor / Collaborator

The Brigham & Women's Hospital, Inc.

NCT06643819 / Not yet recruitingPhase 3

A Randomized, Double-blind, Active-controlled, Multi-center, Therapeutic Confirmatory, Phase 3 Trial to Evaluate the Efficacy and Safety of CKD-202A

Phase 3 Trial to Evaluate the Efficacy and Safety of CKD-202A(Sacubitril∙Valsartan)

Start Date14 Oct 2024

Sponsor / Collaborator

Chong Kun Dang Pharmaceutical Corp.

CTRI/2024/09/074343 / Not yet recruitingPhase 3IIT

Sacubitril Valsartan versus Telmisartan in remodeling of left ventricleafter acute anterior wall myocardial infarction - NIL

Start Date11 Oct 2024

Sponsor / Collaborator

Government Medical College

100 Clinical Results associated with Sacubitril/Valsartan

100 Translational Medicine associated with Sacubitril/Valsartan

100 Patents (Medical) associated with Sacubitril/Valsartan

466

Literatures (Medical) associated with Sacubitril/Valsartan

01 Jan 2025·JOURNAL OF ETHNOPHARMACOLOGY

Qianyang Yuyin granules alleviate hypertension-induced vascular remodeling by inhibiting the phenotypic switch of vascular smooth muscle cells

Article

Author: Zheng, Yawei ; Fan, Yadong ; Liu, Ming ; Zhang, Siqi ; Zhang, Haitao ; Sun, Zeqi ; Zheng, Ziwen ; Jialiken, Dinala ; Fang, Zhuyuan ; Yan, Xiwu ; Zhang, Weiting

ETHNOPHARMACOLOGICAL RELEVANCE:

Qianyang Yuyin granules (QYYY) have been used clinically to treat hypertension for over two decades. Previous clinical trials have shown that QYYY can improve vascular elastic function in hypertensive patients. However, the underlying pharmacological mechanism is unclear.

AIM OF THE STUDY:

To elucidate the effects and mechanisms of QYYY on vascular remodeling using a multidisciplinary approach that includes network pharmacology, proteomics, and both in vitro and in vivo experiments.

MATERIALS AND METHODS:

The main components of QYYY were identified using ultra-high-performance liquid chromatography and high-resolution mass spectrometry. Network pharmacology and molecular docking were employed to predict QYYY's primary active ingredients, potential therapeutic targets and intervention pathways in hypertensive vascular remodeling. We induced hypertension in male C57BL/6 mice by infusing angiotensin II (Ang II) via osmotic minipumps, and performed pre-treatment with QYYY or Sacubitril/valsartan (Entresto). Blood pressure was monitored in vivo, followed by the extraction of aortas to examine pathological structural changes and alterations in protein expression patterns. The expression and location of proteins involved in the HIF-1α/TWIST1/P-p65 signaling pathway were investigated, as well as markers of vascular smooth muscle cells (VSMCs) phenotypic switch. In vitro, we studied the effects of QYYY water extract on Ang II-stimulated human aortic VSMCs. We investigated whether QYYY could affect the HIF-1α/TWIST1/P-p65 signaling pathway, thereby ameliorating apoptosis, autophagy, and phenotype switch in VSMCs.

RESULTS:

We identified 62 main compounds in QYYY, combined with network pharmacology, speculated 827 potentially active substances, and explored 1021 therapeutic targets. The KEGG pathway analysis revealed that the mechanisms of action associated with QYYY therapy potentially encompass various biological processes, including metabolic pathways, TNF signaling pathways, apoptosis, Ras signaling pathways, HIF-1 signaling pathways, autophagy-animal pathways. In hypertensive mice, QYYY restored abnormally elevated blood pressure, vascular remodeling, and inflammation with a dose-response relationship while altering abnormal protein patterns. In vitro, QYYY could inhibit abnormal proliferation, migration, intracellular Ca²⁺ accumulation and cytoskeletal changes of VSMCs. It improved mitochondrial function, reduced ROS levels, stabilized membrane potential, prevented cell death, and reduced overproduction of TGF-β1, TNF-a, and IL-1β.

CONCLUSION:

QYYY may be able to inhibit the overactivation of the HIF-1α/TWIST1/P-p65 signaling pathway, improve the phenotypic switch, and balance apoptosis and autophagy in VSMCs, thereby effectively improving vascular remodeling caused by hypertension.

01 Dec 2024·Current pharmaceutical biotechnology

The Role of NAD⁺ in Myocardial Ischemia-induced Heart Failure in Sprague-dawley Rats and Beagles

Article

Author: Pei, Zuowei ; Dong, Min ; Wang, Fang ; Guo, Ying ; Yang, Chenguang

Introduction::

Nicotinamide adenine dinucleotide (NAD+) participates in various processes that are dysregulated in cardiovascular diseases. Supplementation with NAD+ may be cardioprotective. However, whether the protective effect exerted by NAD+ in heart failure (HF) is more effective before acute myocardial infarction (MI) or after remains unclear. The left anterior descending arteries of male Sprague Dawley rats and beagles that developed HF following MI were ligated for 1 week, following which the animals were treated for 4 weeks with low, medium, and high doses of NAD+ and LCZ696.

Methods::

Cardiac function, hemodynamics, and biomarkers were evaluated during the treatment period. Heart weight, myocardial fibrosis, and MI rate were measured eventually.

Results::

Compared with the HF groups, groups treated with LCZ696 and different doses of NAD+ showed increased ejection fractions, fractional shortening, cardiac output, and stroke volume and decreased end-systolic volume, end-systolic dimension, creatine kinase, and lactic dehydrogenase. LV blood pressure was lower in the HF group than in the control group, but this decrease was significantly greater in the medium and high NAD+ dose groups.

Conclusion::

The ratios of heart weight indexes, fibrotic areas, and MI rates in the CZ696 and medium and high NAD+ dose groups were lower than those in the HF group. Medium and high-dose NAD+ showed superior positive effects on myocardial hypertrophy, cardiac function, and myocardial fibrosis and reduced the MI rate.

01 Dec 2024·Contemporary Clinical Trials Communications

A clinical randomized trial: Effects of early application of sacubitril/valsartan on ventricular remodeling and prognosis in acute myocardial infarction patients

Article

Author: Yao, Qiong ; Cui, Kun ; Zhang, Yuanzheng ; Liu, Zhengfeng ; Jin, Wenqing ; Wang, Guangdong

Objectives:

To explore the effects of early application of sacubitril/valsartan on ventricular remodeling and prognosis in patients with acute myocardial infarction (AMI).

Methods:

Total of 295 patients with AMI admitted to the hospital were enrolled between August 2019 and August 2021. According to different treatment methods, they were divided into observation group (sacubitril/valsartan sodium tables combined with standard treatment, 132 patients) and control group (benazepril hydrochloride tablets combined with standard treatment, 163 patients). The levels of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine (Cr) and serum K⁺ before and at 6 months after treatment, standard deviation of all normal-to-normal intervals (SDNN), standard deviation of the average all normal-to-normal intervals (SDANN), root mean square of differences between adjacent normal-to-normal intervals/root mean square differences of successive R-R (RMSSD), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume (LVESV) in the two groups were compared. The adverse reactions during treatment and major adverse cardiac events (MACE) during 6 months of follow-up in both groups were statistically analyzed.

Results:

The levels of NT-proBNP, Cr and K⁺, LVEDV and LVESV in observation group were significantly lower than those in control group (P < 0.05), while LVEF, SDNN, SDANN and RMSSD were significantly higher than those in control group (P < 0.05). The incidence of MACE in observation group was lower than that in control group during 6 months of follow-up (7.58 % vs 27.61 %, P < 0.05), but there was no significant difference in the incidence of adverse reactions (9.85 % vs 12.88 %, P > 0.05).

Conclusion:

Early application of sacubitril/valsartan sodium can effectively delay ventricular remodeling, improve cardiac function and heart rate variability indexes, reduce NT-proBNP level and improve prognosis in AMI patients.

136

News (Medical) associated with Sacubitril/Valsartan

29 Oct 2024

·endpts.com

Novartis takes $800M MorphoSys writedown mere months after closing acquisition

Just five months after closing its $2.9 billion deal for MorphoSys, Novartis has recorded an $800 million impairment on the acquisition after a review of “certain clinical trial data,” the company said in its third-quarter earnings report . A company spokesperson confirmed that the review was triggered by pelabresib, an oncology candidate at the center of the MorphoSys buyout. Novartis shared Tuesday that it’s expecting a delayed regulatory submission for pelabresib, as it needs to follow patients longer to assess concerns about emergent malignancies. The company had initially hoped to file for approval in myelofibrosis this year. Emergent malignancies in patients treated with pelabresib were first reported by STAT earlier this year. Novartis will “look at the data over the course of next year,” and assess the potential need for additional studies, CEO Vas Narasimhan said during its Q3 earnings call with the media. Novartis also disclosed three Phase 2 pipeline cuts Tuesday: a BCMA cell therapy called durcabtagene autoleucel or PHE885 in multiple myeloma; XXB750 in hypertension and heart failure; and an IL-17 inhibitor subbed CMK389 in pulmonary sarcoidosis. Overall, Barclays analysts said Novartis had a “strong” quarter. The company raised its end-of-year guidance, with Narasimhan saying its “pure-play” strategy is starting to pay off. While executives previously expected net sales growth in the high single digits to low double digits, Novartis now says the low end of that range will be in the double digits. “The changes we’ve made to become a focused, pure-play company focused on key therapeutic areas, focused on key geographies, is really working,” Narasimhan told reporters. Elsewhere, Narasimhan also fielded a variety of questions about Novartis’ new structure, legal strategy and manufacturing capacity: On the company’s reorganization: It’s been roughly two years since Novartis announced a global restructuring that impacted thousands of positions and involved the spinout of generics unit Sandoz. The company said it completed its transformation in November 2023, though “additional streamlining” this year brought some cuts on the development side. Narasimhan said Novartis is “always going to be fine-tuning at a low level, but we don’t foresee any other large changes at this time.” On radioligand supply: Novartis applied for a label expansion last quarter to bring Pluvicto into the pre-taxane setting for patients with metastatic castration-resistant prostate cancer. But despite recent shortage concerns across the radiopharma space, Narasimhan said Novartis’ manufacturing plans will enable not only the supply of Pluvicto, but also “a very large pipeline of radioligand therapies moving forward.” He added that Novartis’ supply has been “unconstrained for most of this year,” with the ability to produce volumes that support $7 billion to $8 billion-plus in sales. The company has plans to expand its Indianapolis site, and is putting up new sites in California, China and Japan. On the Inflation Reduction Act and a recent court loss: A New Jersey federal court recently rejected Novartis’ legal challenge to the IRA. The company has appealed, though Narasimhan said it’s “difficult to say” whether Novartis’ case or cases brought by other drugmakers will conclude before negotiated prices take effect in 2026. For now, the CEO said Novartis is pushing for legislative changes, including around a provision that calls for negotiations to occur sooner for small molecule drugs than for biologics. “We are operating under the assumption that we need to work under the rules of the law and rather focus on trying to educate policymakers,” he said. On generic entry: Novartis said it expects generic rivals to Tasigna, Promacta and Entresto to hit the US market in mid-2025. “That will certainly be a headwind we’ll face in the second half of 2025,” Narasimhan said. “We still expect good growth next year, both on the top and bottom line.” Editor’s note: This story has been updated to include comment from Novartis on the MorphoSys impairment.

Phase 2Cell TherapyAcquisition

29 Oct 2024

·www.globenewswire.com

Novartis continues strong momentum in Q3 with 10% sales growth, 20% core operating income growth, and important innovation milestones; raises FY 2024 guidance

Ad hoc announcement pursuant to Art. 53 LR Q3 net sales grew +10% (cc1, +9% USD) with core operating income up +20% (cc, +17% USD) Sales growth driven by continued strong performance from Entresto (+26% cc), Cosentyx (+28% cc), Kisqali (+43% cc), Kesimpta (+28% cc), Pluvicto (+50% cc) and Leqvio (+119% cc)Core operating income margin 40.1%, +340 basis points (cc), mainly driven by higher net sales Q3 operating income grew +123% (cc, +106% USD); net income up +121% (cc, +111% USD)Q3 core EPS grew +20% (cc, +18% USD) to USD 2.06Q3 free cash flow1 of USD 6.0 billion (+18% USD) driven by higher net cash flows from operating activitiesStrong nine months performance with sales up +11% (cc, +9% USD) and core operating income up +20% (cc, +17% USD)Q3 selected innovation milestones: Kisqali FDA approval and positive CHMP opinion for HR+/HER2- stage II and III eBC Fabhalta FDA accelerated approval for IgANPluvicto FDA filing for pre-taxane mCRPC Full-year 2024 guidance raised2 Net sales expected to grow low double-digit (from high single to low double-digit)Core operating income expected to grow high teens (from mid to high teens) Basel, October 29, 2024 – commenting on Q3 2024 results, Vas Narasimhan, CEO of Novartis, said: “Novartis delivered another quarter of strong operational performance in Q3, with sales up 10% and core operating income up 20%. All key growth drivers contributed to the momentum. We achieved important indications expansions for Kisqali in early breast cancer and Fabhalta in IgA nephropathy, and we completed our PSMAfore filing for Pluvicto in the US. With the momentum in our business and pipeline, we were able to once again upgrade our full-year guidance and remain highly confident in our mid-term outlook.” Key figuresContinuing operations3 Q3 2024Q3 2023% change9M 20249M 2023% change USD m USD mUSDcc USD m USD mUSDccNet sales12 82311 782910 37 16434 017911Operating income3 6271 762106123 11 0147 1875361Net income3 1851 513111121 9 1195 9345462EPS (USD)1.580.73116127 4.502.845867Free cash flow5 9655 04318 12 61811 01915 Core operating income5 1454 4051720 14 63512 5511720Core net income4 1333 5851517 11 82210 3201518Core EPS (USD)2.061.741820 5.834.951821 1. Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 46 of the Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year. 2. Please see detailed guidance assumptions on page 7. 3. As defined on page 35 of the Interim Financial Report, Continuing operations include the retained business activities of Novartis, comprising the innovative medicines business and the continuing corporate activities and Discontinued operations include operational results from the Sandoz business.StrategyOur focus In 2023, Novartis completed its transformation into a “pure-play” innovative medicines business. We have a clear focus on four core therapeutic areas (cardiovascular-renal-metabolic, immunology, neuroscience and oncology), with multiple significant in-market and pipeline assets in each of these areas, that address high disease burden and have substantial growth potential. In addition to two established technology platforms (chemistry and biotherapeutics), three emerging platforms (gene & cell therapy, radioligand therapy and xRNA) are being prioritized for continued investment into new R&D capabilities and manufacturing scale. Geographically, we are focused on growing in our priority geographies – the US, China, Germany and Japan. Our priorities Accelerate growth: Renewed attention to deliver high-value medicines (NMEs) and focus on launch excellence, with a rich pipeline across our core therapeutic areas.Deliver returns: Continuing to embed operational excellence and deliver improved financials. Novartis remains disciplined and shareholder-focused in our approach to capital allocation, with substantial cash generation and a strong capital structure supporting continued flexibility. Strengthening foundations: Unleashing the power of our people, scaling data science and technology and continuing to build trust with society. Financials Following the September 15, 2023, shareholder approval of the spin-off of Sandoz, Novartis reported its consolidated financial statements as “continuing operations” and “discontinued operations.” Continuing operations include the retained business activities of Novartis, comprising the innovative medicines business and the continuing corporate activities. Discontinued operations include the Sandoz Division and selected portions of corporate activities attributable to Sandoz’s business, as well as certain expenses related to the spin-off. While the commentary below focuses on continuing operations, we also provide information on discontinued operations. Continuing operations Third quarter Net sales were USD 12.8 billion (+9%, +10% cc), with volume contributing 12 percentage points to growth. Generic competition had a negative impact of 2 percentage points and pricing was flat. Operating income was USD 3.6 billion (+106%, +123% cc), mainly driven by lower impairments and higher net sales, partly offset by higher R&D investments. Net income was USD 3.2 billion (+111%, +121% cc), mainly driven by higher operating income. EPS was USD 1.58 (+116%, +127% cc), benefiting from the lower weighted average number of shares outstanding. Core operating income was USD 5.1 billion (+17%, +20% cc), mainly driven by higher net sales, partly offset by higher R&D investments. Core operating income margin was 40.1% of net sales, increasing 2.7 percentage points (+3.4 percentage points cc). Core net income was USD 4.1 billion (+15%, +17% cc), mainly due to higher core operating income. Core EPS was USD 2.06 (+18%, +20% cc), benefiting from the lower weighted average number of shares outstanding. Free cash flow from continuing operations amounted to USD 6.0 billion (+18% USD), compared with USD 5.0 billion in the prior-year quarter, driven by higher net cash flows from operating activities from continuing operations. Nine months Net sales were USD 37.2 billion (+9%, +11% cc) with volume contributing 14 percentage points to growth. Generic competition had a negative impact of 2 percentage points and pricing had a negative impact of 1 percentage point. Operating income was USD 11.0 billion (+53%, +61% cc), mainly driven by higher net sales, lower impairments and restructuring charges, partly offset by prior-year one-time income from legal matters and higher R&D investments. Net income was USD 9.1 billion (+54%, +62% cc), mainly driven by higher operating income. EPS was USD 4.50 (+58%, +67% cc), benefiting from the lower weighted average number of shares outstanding. Core operating income was USD 14.6 billion (+17%, +20% cc), mainly driven by higher net sales, partly offset by higher R&D investments. Core operating income margin was 39.4% of net sales, increasing 2.5 percentage points (+3.2 percentage points cc). Core net income was USD 11.8 billion (+15%, +18% cc), mainly due to higher core operating income. Core EPS was USD 5.83 (+18%, +21% cc), benefiting from the lower weighted average number of shares outstanding. Free cash flow from continuing operations amounted to USD 12.6 billion (+15% USD), compared with USD 11.0 billion in the prior-year period, driven by higher net cash flows from operating activities from continuing operations. Discontinued operations Discontinued operations include the Sandoz generic pharmaceuticals and biosimilars division, certain corporate activities attributable to Sandoz and certain other expenses related to the spin-off of the Sandoz business. Third quarter As the Sandoz spin-off was completed on October 3, 2023, there were no operating results in the third quarter of 2024 related to discontinued operations. In the third quarter of 2023, discontinued operations net sales were USD 2.5 billion, operating loss amounted to USD 86 million and net income from discontinued operations was USD 250 million. For further details see Note 3 “Significant acquisition of businesses and spin-off of Sandoz business” and Note 11 “Discontinued operations” to the condensed interim consolidated financial statements. Nine months As the Sandoz spin-off was completed on October 3, 2023, there were no operating results in the first nine months of 2024 related to discontinued operations. In the first nine months of 2023, discontinued operations net sales were USD 7.4 billion, operating income amounted to USD 265 million and net income from discontinued operations was USD 440 million. For further details see Note 3 “Significant acquisition of businesses and spin-off of Sandoz business” and Note 11 “Discontinued operations” to the condensed interim consolidated financial statements. Total Company Third quarter Total Company net income was USD 3.2 billion in 2024, compared to USD 1.8 billion in 2023 and basic EPS was USD 1.58 compared to USD 0.85 in prior year quarter. Net cash flows from operating activities for total Company amounted to USD 6.3 billion and free cash flow amounted to USD 6.0 billion. Nine months Total Company net income was USD 9.1 billion in 2024, compared to USD 6.4 billion in 2023 and basic EPS was USD 4.50 compared to USD 3.05 in prior year. Net cash flows from operating activities for total Company amounted to USD 13.4 billion and free cash flow amounted to USD 12.6 billion. Q3 key growth drivers Underpinning our financial results in the quarter is a continued focus on key growth drivers (ranked in order of contribution to Q3 growth) including: Entresto(USD 1 865 million, +26% cc) sustained robust, demand-led growth, with increased penetration in the US and Europe following guideline-directed medical therapy in heart failure, as well as in China with increased penetration in hypertensionCosentyx(USD 1 693 million, +28% cc) sales grew mainly in the US, Europe and emerging growth markets, driven by recent launches (including the HS indication and the IV formulation in the US) and volume growth in core indicationsKisqali(USD 787 million, +43% cc) sales grew strongly across all regions, based on increasing recognition of its overall survival benefit in HR+/HER2- advanced breast cancer and Category 1 NCCN guidelines recommendationKesimpta(USD 838 million, +28% cc) sales grew reflecting increased demand for a high efficacy product with convenient self-administered dosing; the prior-year period benefited from a one-time revenue deduction adjustment in EuropePluvicto(USD 386 million, +50% cc) sales grew in the US and Europe. Q3 sales benefited from a one-time revenue deduction adjustment in Europe. With supply now unconstrained, the focus is on increasing share in established RLT sites, while opening new sites and referral pathways, and initiating new patientsLeqvio(USD 198 million, +119% cc) continued to show steady growth, with a focus on increasing account and patient adoption, and continuing medical educationJakavi(USD 500 million, +18% cc) sales grew across all regions driven by strong demand across indicationsScemblix(USD 182 million, +72% cc) sales grew across all regions demonstrating the continued high unmet need in CMLTafinlar + Mekinist(USD 534 million, +12% cc) sales grew mainly in the US and emerging growth markets, driven by increased demandXolair(USD 418 million, +15% cc) grew mainly in emerging growth markets and EuropeFabhalta(USD 44 million) launch continues in PNH with an approval in IgAN in Q3Ilaris(USD 372 million, +12% cc) sales grew across all regions, led by the US and EuropeLutathera(USD 190 million, +19% cc) sales grew across all regions due to increased demand and earlier line adoption (within indication) in the US and Japan Emerging Growth Markets*Grew +12% (cc) overall. China grew +18% (cc) to USD 1.0 billion, mainly driven by Entresto, Cosentyx and Leqvio *All markets except the US, Canada, Western Europe, Japan, Australia, and New Zealand Net sales of the top 20 brands in the third quarter and nine months Q3 2024 % change9M 2024 % change USD mUSDccUSD mUSD ccEntresto1 86526265 6422830Cosentyx1 69327284 5452425Kesimpta- excl. PY revenue deduction adjust. 838 285528562 27449614962Kisqali 78740432 1314548Promacta/Revolade 569-101 633-4-3Tafinlar + Mekinist 53411121 53179Jakavi 50017181 4491416Tasigna 419-10-91 260-10-9Xolair 41813151 2441517Ilaris 37211121 0961216Pluvicto- excl. revenue deduction adjust. 38651375036 1 04147424742Sandostatin Group 305-10-8 973-3-1Zolgensma 30801 95234Lucentis 245-33-32 834-29-28Exforge Group 174-7-4 544-21Lutathera 1901919 5341717Leqvio 198120119 531129130Scemblix 1827272 4826769Galvus Group 159-12-6 458-15-8Diovan Group 150-22 450-31Top 20 brands total10 292171829 6041719 R&D update - key developments from the third quarter New approvals Kisqali(ribociclib)FDA approved Kisqali with a broad indication for HR+/HER2- stage II and III early breast cancer (eBC) at high risk of recurrence, approximately doubling the population eligible for CDK4/6 inhibitor adjuvant therapy, with the inclusion of those without nodal involvement. In addition, the CHMP issued a positive opinion for Kisqali in eBC in October. Fabhalta(iptacopan)FDA granted accelerated approval to Fabhalta for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression. Regulatory updates Pluvicto (lutetium Lu177 vipivotide tetraxetan)Completed FDA submission for Pluvicto pre-taxane mCRPC label expansion based on the positive Phase III PSMAfore study.Scemblix(asciminib)FDA granted Priority Review status to Scemblix for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive CML in chronic phase (Ph+ CML-CP). Scemblix is also under regulatory review in this indication in key international markets worldwide, including in China and Japan.Fabhalta(iptacopan)Submissions for the treatment of C3 glomerulopathy (C3G) completed in the EU, China and Japan. Results from ongoing trials and other highlights Kisqali(ribociclib)Results from a four-year post-hoc analysis of the pivotal Phase III NATALEE trial showed the addition of Kisqali to endocrine therapy (ET) in patients with stage II and III HR+/HER2- eBC reduced the risk of recurrence by 28.5% compared to ET alone. This invasive disease-free survival benefit was consistent across all pre-specified patient subgroups, including those with node-negative disease. Results were also consistent across secondary efficacy endpoints, with a trend for improvement in overall survival. Safety and tolerability remained consistent with previously reported results. Data presented at ESMO Congress 2024.Leqvio(inclisiran)In the Phase III V-MONO study, Leqvio demonstrated clinically meaningful and statistically significant low-density lipoprotein cholesterol (LDL-C) lowering versus both placebo and ezetimibe in patients who were at low or moderate risk of developing atherosclerotic cardiovascular disease (ASCVD) and not receiving lipid-lowering therapy. Novartis plans to present results from this trial at an upcoming medical meeting and share with regulatory agencies including FDA.Kesimpta(ofatumumab)Data from the ALITHIOS open-label extension study showed first-line Kesimpta treatment for up to six years led to less disability and disease progression in recently diagnosed (≤3 years) and treatment-naïve people with relapsing multiple sclerosis (RMS), compared to those who switched from teriflunomide.In the separate US-based single-arm OLIKOS Phase IIIb study, all clinically stable RMS patients who switched from intravenous anti-CD20 therapy to Kesimpta showed no new gadolinium-enhancing (Gd+) T1 lesions at 12 months. Data from both studies were presented at the ECTRIMS 2024 Annual Meeting.PelabresibBased on Novartis review of 48-week data from the Phase III MANIFEST-2 study, longer follow-up time is needed to determine, in consultation with Health Authorities, the regulatory path for pelabresib in myelofibrosis. We will continue to follow patients in MANIFEST-2 and evaluate the potential for additional studies to support registration. The 48-week data will be presented at an upcoming medical meeting.XXB750Novartis will not advance further development of XXB750 in resistant hypertension and heart failure, following current scientific assessment and review of available data from early investigational studies.BD&LNovartis, in collaboration with Versant Ventures, established Borealis Biosciences, an independent, discovery-stage biotechnology company focused on developing next-generation RNA-based medicines for kidney diseases. Under the agreement, Novartis has the option to acquire two future development-ready programs to augment its renal portfolio, a strategic area of focus for the company.Novartis entered into a collaboration agreement with Generate: Biomedicines to discover and develop protein therapeutics across multiple disease areas with generative AI. The collaboration will combine Generate’s AI platform with Novartis expertise and capabilities in target biology, biologics development, and clinical development to create novel therapeutics and to accelerate the pace of drug discovery and development. Capital structure and net debt Retaining a good balance between investment in the business, a strong capital structure, and attractive shareholder returns remains a priority. During the first nine months of 2024, Novartis repurchased a total of 52.7 million shares for USD 5.7 billion on the SIX Swiss Exchange second trading line. These purchases included 45.4 million shares (USD 4.8 billion) under the up-to USD 15 billion share buyback announced in July 2023 (with up to USD 7.9 billion still to be executed). In addition, 7.3 million shares (USD 0.9 billion) were repurchased to mitigate dilution related to participation plans of associates, with the remainder of repurchases for this purpose to be executed in Q4 2024. Further, 1.1 million shares (for an equity value of USD 0.1 billion) were repurchased from associates. In the same period, 9.1 million shares (for an equity value of USD 0.8 billion) were delivered as a result of share deliveries related to participation plans of associates. Consequently, the total number of shares outstanding decreased by 44.7 million versus December 31, 2023. These treasury share transactions resulted in an equity decrease of USD 5.0 billion and a net cash outflow of USD 5.5 billion. As of September 30, 2024, net debt increased to USD 16.3 billion compared to USD 10.2 billion net debt at December 31, 2023. The increase was mainly due to the free cash flow of USD 12.6 billion being more than offset by the USD 7.6 billion annual dividend payment, net cash outflow for M&A / intangible assets transactions of USD 5.5 billion, and cash outflow for treasury share transactions of USD 5.5 billion. As of Q3 2024, the long-term credit rating for the company is Aa3 with Moody’s Ratings and AA- with S&P Global Ratings. 2024 outlook Barring unforeseen events; growth vs prior year in ccPrevious guidanceNet salesExpected to grow low double-digit(from high single to low double-digit)Core operating incomeExpected to grow high teens(from mid to high teens) Key assumptions: We assume Tasigna, Promacta and Entresto US generic entry mid-2025 for forecasting purposes Foreign exchange impact If late-October exchange rates prevail for the remainder of 2024, the foreign exchange impact for the year would be negative 1 percentage point on net sales and negative 3 to negative 4 percentage points on core operating income. The estimated impact of exchange rates on our results is provided monthly on our website. Key figures1 Continuing operations2Q3 2024Q3 2023% change 9M 20249M 2023% change USD m USD mUSDcc USD m USD mUSDccNet sales12 82311 782910 37 16434 017911Operating income3 6271 762106123 11 0147 1875361As a % of sales28.315.0 29.621.1 Net income3 1851 513111121 9 1195 9345462EPS (USD)1.580.73116127 4.502.845867Cash flows from operating activities6 2865 30419 13 42611 67315 Non-IFRS measures Free cash flow 5 9655 04318 12 61811 01915 Core operating income5 1454 4051720 14 63512 5511720As a % of sales40.137.4 39.436.9 Core net income4 1333 5851517 11 82210 3201518Core EPS (USD)2.061.741820 5.834.951821 Discontinued operations2Q3 2024Q3 2023% change 9M 20249M 2023% change USD m USD mUSDcc USD m USD mUSDccNet sales 2 476nmnm 7 428nmnmOperating (loss)/income -86nmnm 265nmnmAs a % of sales -3.5 3.6 Net income 250nmnm 440nmnmNon-IFRS measures Core operating income 250nmnm 1 185nmnmAs a % of sales 10.1 16.0 Total CompanyQ3 2024Q3 2023% change 9M 20249M 2023% change USD m USD mUSDcc USD m USD mUSDccNet income3 1851 763nmnm 9 1196 374nmnmEPS (USD)1.580.85nmnm 4.503.05nmnmCash flows from operating activities6 2865 378nmnm 13 42611 911nmnmNon-IFRS measures Free cash flow 5 9655 043nmnm 12 61811 038nmnmCore net income4 1333 784nmnm 11 82211 209nmnmCore EPS (USD)2.061.83nmnm 5.835.37nmnm nm=not meaningful 1. Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 46 of the Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year.2. As defined on page 35 of the Interim Financial Report, Continuing operations include the retained business activities of Novartis, comprising the innovative medicines business and the continuing corporate activities and Discontinued operations include operational results from the Sandoz business. Detailed financial results accompanying this press release are included in the Interim Financial Report at the link below:https://ml-eu.globenewswire.com/resource/download/6504f5e3-a14c-43ba-8b72-44dcc5a45156/ DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995, that can generally be identified by words such as “may,” “can,” “will,” “continue,” “ongoing,” “grow,” “launch,” “expect,” “deliver,” “focus,” “address,” “accelerate,” “deliver,” “remain,” “scaling,” “guidance,” “outlook,” “long-term,” “priority,” “potential,” “momentum,” or similar expressions, or by express or implied discussions regarding potential new products, potential new indications for existing products, potential product launches, or regarding potential future revenues from any such products; or regarding results of ongoing clinical trials; or regarding potential future, pending or announced transactions; regarding potential future sales or earnings; or by discussions of strategy, plans, expectations or intentions, including discussions regarding our continued investment into new R&D capabilities and manufacturing; or regarding our capital structure; or regarding the consequences of the spin-off of Sandoz and our transformation into a “pure-play” innovative medicines company. Such forward-looking statements are based on the current beliefs and expectations of management 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. You should not place undue reliance on these 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. Neither can there be any guarantee expected benefits or synergies from the transactions described in this press release will be achieved in the expected timeframe, or at all. In particular, our expectations could be affected by, among other things: uncertainties regarding the success of key products, commercial priorities and strategy; uncertainties in the research and development of new products, including clinical trial results and additional analysis of existing clinical data; uncertainties regarding the use of new and disruptive technologies, including artificial intelligence; global trends toward healthcare cost containment, including ongoing government, payer and general public pricing and reimbursement pressures and requirements for increased pricing transparency; uncertainties regarding our ability to realize the strategic benefits, operational efficiencies or opportunities expected from our external business opportunities; our ability to realize the intended benefits of our separation of Sandoz into a new publicly traded standalone company; our ability to obtain or maintain proprietary intellectual property protection, including the ultimate extent of the impact on Novartis of the loss of patent protection and exclusivity on key products; uncertainties in the development or adoption of potentially transformational digital technologies and business models; uncertainties surrounding the implementation of our new IT projects and systems; uncertainties regarding potential significant breaches of information security or disruptions of our information technology systems; uncertainties regarding actual or potential legal proceedings, including regulatory actions or delays or government regulation related to the products and pipeline products described in this press release; safety, quality, data integrity, or manufacturing issues; our performance on and ability to comply with environmental, social and governance measures and requirements; major political, macroeconomic and business developments, including impact of the war in certain parts of the world; uncertainties regarding future global exchange rates; uncertainties regarding future demand for our products; and other risks and factors referred to in Novartis AG’s most recently filed Form 20-F and in subsequent reports filed with, or furnished to, 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 as a result of new information, future events or otherwise. All product names appearing in italics are trademarks owned by or licensed to Novartis. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitter and Instagram. Novartis will conduct a conference call with investors to discuss this news release today at 14:00 Central European time and 9:00 Eastern Time. A simultaneous webcast of the call for investors and other interested parties may be accessed by visiting the Novartis website. A replay will be available after the live webcast by visiting https://www.novartis.com/investors/event-calendar. Detailed financial results accompanying this press release are included in the condensed interim financial report at the link below. Additional information is provided on our business and pipeline of selected compounds in late-stage development. A copy of today's earnings call presentation can be found at https://www.novartis.com/investors/event-calendar. Important dates November 20-21, 2024Meet Novartis Management 2024 (London, UK)December 9, 2024Impact & Sustainability annual investor event (virtual)January 31, 2025 Fourth quarter & full year 2024 results Please find full media release in English attached and on the following link:Media Release (PDF) Further language version is available through the following link: German version is available through the following link:Medienmitteilung (PDF)

Clinical ResultPhase 3Drug ApprovalFinancial StatementAccelerated Approval

29 Oct 2024

·www.biospace.com

Novartis Gets Q3 Beat on Strong Cosentyx Sales, But Pluvicto Disappoints

iStock, JHVEPhoto Novartis exceeded analyst expectations in the third quarter, driven primarily by the strong U.S. sales of Cosentyx, as well as the robust performances of Kesimpta and Kisqali. Novartis released its third-quarter financial report Tuesday, touting a 10% year-over-year growth in net sales and again lifting its full-year earnings outlook, buoyed by the strong performance of its prescription medicines. The Swiss multinational brought in more than $12.8 billion in net sales for the quarter, beating consensus forecast by 1%. Core earnings-per-share (EPS) was 2.06, coming in 6% ahead of analyst estimates and representing a 20% jump from the same period last year. Novartis’ third-quarter net income was nearly $3.2 billion, with free cash flow of almost $6 billion. Jefferies analyst Peter Welford in an investor note attributed Novartis’ Q3 performance to the anti-IL-17A antibody Cosentyx (secukinumab), which is indicated for psoriasis, ankylosing spondylitis and psoriatic arthritis. Cosentyx surged 28% in the quarter to earn $1.7 billion, beating the consensus projection by 7%. Novartis also highlighted its heart failure therapy Entresto (sacubitril/valsartan) as a key growth driver in the third quarter, with $1.86 in net sales and a 26% year-over-year growth. Welford, however, called the drug’s performance “a big Entresto miss,” falling short of analyst forecasts by 2%. Other drivers for Novartis include the breast cancer therapy Kisqali (ribociclib) and the multiple sclerosis medication Kesimpta (ofatumumab). Pluvicto (lutetium (177Lu) vipivotide tetraxetan), Novartis’ targeted prostate cancer therapy, grew 50% year-over-year to bring in $386 million in the quarter, though this calculation benefited from a one-time revenue adjustment in Europe. Without this adjustment, Pluvicto would have seen a 36% bump in sales, which according to a trader interviewed by Reuters falls short of expectations. Novartis is down around 3% in Tuesday morning trading, in response to its Q3 results. Still, the pharma appears to be optimistic about its business for the remainder of the year. As in the first two quarters of 2024, Novartis on Tuesday again lifted its forecast for its net sales, which it now expects to grow in the low-double-digit range, whereas previous guidance pegged growth from the high single to low double digits. Novartis now anticipates core operating income growth in the high teens range. As for its pipeline, Novartis announced on Tuesday that it will need a longer follow-up time to determine the appropriate regulatory path forward for its BET inhibitor pelabresib. The drug candidate joined the Novartis fold in February 2024 when the pharma bought MorphoSys for $2.9 billion . Novartis is trialing pelabresib, in combination with Jakafi (ruxolitinib), in the Phase III MANIFEST-2 study for myelofibrosis. In conjunction with this acquisition, Novartis took an $800 million impairment in the third quarter.

AcquisitionPhase 3Financial StatementBiosimilar

100 Deals associated with Sacubitril/Valsartan

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KEGG	Wiki	ATC	Drug Bank
-	-	C09DX04	-

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Essential Hypertension	CN	Novartis Pharma Schweiz AG	24 May 2021
Hypertension	JP	Novartis Pharma KK	29 Jun 2020
Left ventricular systolic dysfunction	US	Novartis Pharmaceuticals Corp.	01 Oct 2019
Heart Failure	CH	Novartis AG	17 Sep 2015
Chronic heart failure	US	Novartis Pharmaceuticals Corp.	07 Jul 2015

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Kidney Diseases	Phase 3	KR	Chong Kun Dang Pharmaceutical Corp.	14 Oct 2024
Postmyocardial infarction syndrome	Phase 3	-	Novartis Pharmaceuticals Corp.	26 May 2021
Hydrops Fetalis	Phase 3	JP	Novartis Pharmaceuticals Corp.	07 May 2019
Erectile Dysfunction	Phase 3	DE	Novartis Pharmaceuticals Corp.	16 Apr 2019
Heart Failure, Systolic	Phase 3	DE	Novartis Pharmaceuticals Corp.	16 Apr 2019
Acute myocardial infarction	Phase 3	US	Novartis Pharmaceuticals Corp.	09 Dec 2016
Acute myocardial infarction	Phase 3	CN	Novartis Pharmaceuticals Corp.	09 Dec 2016
Acute myocardial infarction	Phase 3	AR	Novartis Pharmaceuticals Corp.	09 Dec 2016
Acute myocardial infarction	Phase 3	AU	Novartis Pharmaceuticals Corp.	09 Dec 2016
Acute myocardial infarction	Phase 3	AT	Novartis Pharmaceuticals Corp.	09 Dec 2016

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02678312 (PANORAMA-HF, Pubmed \| Circulation) Manual	Phase 2/3	Heart Failure	375	Sacubitril/Valsartan	gsmxflfxhv(kmhngvbykx): OR = 0.91 (95% CI, 0.72 - 1.14), P-Value = 0.42 View more	Negative	25 Sep 2024
				Enalapril
NCT01920711 (PARAGON-HF, Pubmed \| Eur J Heart Fail)	Phase 3	Heart Failure	4,795	Sacubitril/valsartan	moekwkbnpb(etnzkdtfof) = obxsziunce qtgcitixfs (jbhaxflgrf, 0.0 - 0.2) View more	Positive	01 Sep 2024
				Valsartan	fkvgrjmajg(zjsmqgwmza) = eifgbdpqsk wnllgdxlkb (fswjmlajtf ) View more
NCT02884206 (PERSPECTIVE, CTgov)	Phase 3	Chronic heart failure	592	Placebo of Valsartan+LCZ696 (LCZ696 200 mg Bid)	zfuwpumlnz(jvyxlkzvub) = sebupajgeg yqsldwdlur (inrleofsbt, zhyunjmnxm - sjmekinjnh) View more	-	06 Aug 2024
				Placebo of LCZ696+Valsartan (Valsartan 160 mg Bid)	zfuwpumlnz(jvyxlkzvub) = rznakqnrzp yqsldwdlur (inrleofsbt, xnkydfclkw - ksnxcnszhg) View more
NCT03988634 (PARAGLIDE-HF, CTgov)	Phase 3	Heart failure with normal ejection fraction	467	valsartan matching placebo+sacubitril/valsartan (Sacubitril/Valsartan (LCZ696))	fljverjixs(pplmelpjhc) = jovtqapdgm xmhxsydcuc (dtifzjdeis, mhyjhdswai - pgtmeedckr) View more	-	29 Jul 2024
				sacubitril/valsartan matching placebo+valsartan (Valsartan)	fljverjixs(pplmelpjhc) = izpwvmyher xmhxsydcuc (dtifzjdeis, dmgwzisorv - fyxmijckzq) View more
NCT03785405 (CTgov)	Phase 3	Heart Failure \| Left ventricular systolic dysfunction	216	valsartan+sacubitril (Age Group 1)	rrrblpxxrs(cavwrvxisu) = ukddaqontl ermjbyyiix (wbbyurwhhv, bxxgijcdzt - butukbhilk) View more	-	16 Jul 2024
				valsartan+sacubitril (Age Group 2)	rrrblpxxrs(cavwrvxisu) = wwymqfthut ermjbyyiix (wbbyurwhhv, pwkghlrjpx - oypdmgxaxa) View more
NCT04883528 (PARACOR-19, CTgov)	Phase 1/2	COVID-19	42	Sacubitril / Valsartan Oral Tablet [Entresto] (Sacubitril/Valsartan)	pwxmdhevvx(mznmimxeri) = ntnjmmnxyu rnhwavdfdp (qypmtwiuhp, mkvfkuhqie - lhsaxungfd) View more	-	03 Jul 2024
				Placebo (Placebo)	pwxmdhevvx(mznmimxeri) = cudrywtcad rnhwavdfdp (qypmtwiuhp, goxplukbzg - yoiedycxbq) View more
NCT01920711 (PARAGON-HF, Pubmed)	Phase 3	Heart failure with normal ejection fraction	2,895	Sacubitril/Valsartan	blnasmmukw(pjcebxatxg) = uifftlhazg brmzkybryy (fwhmqwkqyj, 3.0)	Positive	06 Jun 2024
				Valsartan	blnasmmukw(pjcebxatxg) = otgawybagg brmzkybryy (fwhmqwkqyj, 3.0)
NCT01035255 (PARADIGM-HF, FDA_CDER) Manual	Phase 3	Chronic heart failure	8,399	ENTRESTO (chronic heart failure)	heukgnghwq(knsuiozylk) = sxaiogjqzo pfxrawdvkf (vswwjhbsff ) View more	Positive	12 Apr 2024
NCT02678312 (PANORAMA-HF, FDA_CDER) Manual	Phase 2/3	Left ventricular systolic dysfunction	375	ENTRESTO	bqncccakxy(ccjhxyntjh) = iscrvwzghd uhgphqxftm (tmlbmkgnsw )	Positive	12 Apr 2024
				enalapril	bqncccakxy(ccjhxyntjh) = smxmlvgpng uhgphqxftm (tmlbmkgnsw )
NCT01920711 (PARAGON-HF, FDA_CDER) Manual	Phase 3	Left ventricular systolic dysfunction	4,796	ENTRESTO	xudukxhosj(ghjkjgexue) = ajkifutvse cgbylitztx (mmojmcmdix ) View more	Positive	12 Apr 2024

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