BRAF mutation positive Melanoma

Misetionamide is effective in targeting and killing BRAF-mutated melanoma cells while preserving normal cellsBRAF-mutated melanoma accounts for approximately 50% of all melanomas BERWYN, PA, Nov. 21, 2023 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed International Journal of Molecular Sciences in a manuscript titled, “In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes.”1 The publication by Gambichler, et al. (2023) details the anti-tumor activity of the GAPDH inhibitor misetionamide (GP-2250) in BRAF-mutated melanoma cell lines and benign melanocytes. Mutated BRAF is a potent oncogene involved in sending signals inside cells which are involved in directing cell growth and is overexpressed in melanomas, non-small cell lung cancer, and other tumor types. Misetionamide is a tumor cell selective drug that is broadly active in multiple cancer models with a unique mechanism of action that suppresses cancer by disrupting its energy metabolism, leading to cancer cell death while not affecting normal cells. This activity occurs due to misetionamide’s targeting at least 3 key enzymes in the aerobic glycolysis pathway as well as downstream effects on other enzymes, transcription factors and tumor suppressor genes. Misetionamide’s inhibition of hexokinases, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), and PVD (pyruvate dehydrogenase) during aerobic glycolysis greatly inhibits ATP production for cancer cells, setting up oxidative, metabolic and hypoxic stresses within the cancer cell. Additionally, misetionamide’s inhibition of key transcription factors such as NFkB and enzymes further impair the ability for the cancer cell to provide sufficient energy for cellular reproduction for proliferation and survival. It also induces tissue hypoxia by inhibiting new blood vessel development in tumors.2 This study demonstrated that misetionamide may be a promising add-on therapy in BRAF-mutated melanomas, which account for approximately 50% of all melanomas. “Given the anti-tumor activity observed in misetionamide as recently published from our studies in Merkel cell carcinoma cells as well as in cutaneous squamous cell carcinoma cell lines, I was eager to study the impact in BRAF-melanoma due to its GAPDH inhibition. The results demonstrated that misetionamide is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines and could represent a promising therapy for tumors such as melanoma,” said Prof. Thilo Gambichler, former Head of the Skin Cancer Center of the Ruhr-University Bochum. This research was conducted at Skin Cancer Center Ruhr-University, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, Germany with support from the Company. Results of this preclinical study showed misetionamide has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. These findings also extend the mechanism of action activity of misetionamide to include STAT, COX2, and NOTCH 1,2, and 3 in melanoma cells in addition to the known effects on GAPDH, Hexokinases, NFkB, and others. The team studied three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4, and ATCC-PCS-200-013, respectively) which were exposed to different misetionamide doses. All three melanoma cell lines (Ma-Mel-62a, Ma-Mel-86a, SH-4) showed a dose-dependent response to misetionamide during BrDU testing and the MTT viability assays, whereas proliferation as well as viability were drastically reduced by a misetionamide concentration of 500 μmol/L. “We are very excited to see the cancer cell killing benefits of misetionamide demonstrated in this study. These results further broaden the mechanism of action into yet another potential oncology target in BRAF-mutated melanoma. The high incidence of BRAF-mutated melanoma of approximately 50% indicates that it could be an attractive therapeutic target in addition to the company’s current focus on pancreatic and ovarian cancers,” said Greg Bosch, Chairman and CEO. About Panavance TherapeuticsPanavance Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company developing a novel oncology asset, GP-2250 (also known as misetionamide). Panavance was formed in 2021 as a US-based, wholly-owned carve out of Geistlich group, a family owned Swiss company, to focus on GP-2250 and the oncology business. GP-2250 is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which effects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company is advancing towards the initiation of two registration directed clinical studies expected: a Phase 2/3 study of GP-2250 for the treatment of platinum resistant ovarian cancer and a pivotal Phase 3 clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients. Extensive preclinical studies have demonstrated that GP-2250’s broadly anti-neoplastic MOA has the potential to be effective in additional indications, including melanoma, squamous cell, breast, and colorectal cancers. For more information, please visit panavance.com and connect with the Company on Twitter, LinkedIn, and Facebook. Corporate and Investor Relations Contact Lisa DeScenzaLaVoieHealthScience(978) 395-5970ldescenza@lavoiehealthsceince.com Media ContactSara KraneLaVoieHealthScience(617) 865-2197skrane@lavoiehealthscience.com ________________________________________1Gambichler, Thilo & Harnischfeger, Friederike & Skrygan, Marina & Majchrzak-Stiller, Britta & Buchholz, Marie & Müller, Thomas & Braumann, Chris. (2023). In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes. International Journal of Molecular Sciences. 24. 15336. 10.3390/ijms242015336. 2Majchrzak-Stiller, B.; Buchholz, M.; Peters, I.; Waschestjuk, D.; Strotmann, J.; Höhn, P.; Hahn, S.; Braumann, C.; Uhl, W.; Müller, T.; et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J. Cell. Mol. Med. 2023, 27, 2082–2092.

Ad hoc announcement pursuant to Art. 53 LR Transformation into a “pure-play” innovative medicines business is complete, with the spin-off of Sandoz; commentary below is on continuing operations2Q3 sales grew +12% (cc, +12% USD) with core operating income growing +21% (cc, +17% USD) Growth driven by continued strong performance from Kesimpta (+124% cc), Entresto (+31% cc), Kisqali (+76% cc), Pluvicto (+217% cc) and Scemblix (+157% cc) Q3 operating income grew +13% (cc, -4% USD) driven by higher sales and lower restructuring charges, partly offset by higher impairments through discontinuation of early stage development projects Q3 net income grew +37% (cc, +14% USD) mainly due to higher operating incomeQ3 free cash flow3 was USD 5.0 billion (+24% USD) driven by higher net cash flows from operating activitiesQ3 core EPS grew +29% (cc, +24% USD) to USD 1.74Strong nine months performance with sales growing +10% (cc, +8% USD) and core operating income growing +19% (cc, +13% USD)Q3 key innovation milestones, including positive Ph3 data for multiple pipeline assets with blockbuster potential: Cosentyx – FDA approval for intravenous formulation in three indications (PsA, AS, nr-axSpA)Demonstrated clinically meaningful and statistically significant Ph3 data for: 1) Pluvicto (mCRPC pre-taxane), 2) iptacopan (IgAN), 3) remibrutinib (CSU), 4) Lutathera (GEP-NETs) Kisqali – Ph3 NATALEE iDFS 500 event analysis complete; file submitted in EU, US submission planned for Q4 2023 Initiated previously announced, up-to USD 15 billion share buyback to be completed by year-end 2025Full-year 2023 guidance raised for core operating income based on strong momentum4 Net sales expected to grow high single digitCore operating income expected to grow mid to high teens (from low double digit to mid teens) Basel, October 24, 2023 – commenting on the quarter, Vas Narasimhan MD, CEO of Novartis, said: “Novartis delivered a very strong quarter, with double-digit sales and core operating income growth leading to a further upgrade to 2023 guidance. We have successfully executed the spin-off of Sandoz, allowing us to fully focus on high-value innovative medicines. Our growth drivers, including Kesimpta, Entresto, Kisqali and Pluvicto, continue to perform well in the market. Our robust pipeline also continues to deliver, and we have achieved important innovation milestones for Pluvicto, iptacopan, remibrutinib and Lutathera. We are confident in our mid-term growth outlook and remain committed to creating value for our shareholders.” Key figures1 Continuing operations2 Q3 2023 Q3 2022 % change 9M 2023 9M 2022 % change USD m USD m USD cc USD m USD m USD cc Net sales 11 782 10 492 12 12 34 017 31 630 8 10 Operating income 1 762 1 826 -4 13 7 187 6 191 16 31 Net income 1 513 1 330 14 37 5 934 4 734 25 41 EPS (USD) 0.73 0.61 20 45 2.84 2.16 31 49 Free cash flow 5 043 4 054 24 11 019 8 661 27 Core operating income 4 405 3 772 17 21 12 551 11 149 13 19 Core net income 3 585 3 035 18 23 10 320 8 983 15 22 Core EPS (USD) 1.74 1.40 24 29 4.95 4.09 21 28 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 48 of the Condensed Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year. 2 As defined on page 37 of the Condensed Interim Financial Report, Continuing operations include the retained business activities of Novartis, comprising the Innovative Medicines Division and the continuing Corporate activities and Discontinued operations include operational results from the Sandoz business. 3 Effective January 1, 2023, Novartis revised its definition of free cash flow, to define free cash flow as net cash flows from operating activities less purchases of property, plant and equipment. To aid in comparability, the prior year free cash flow amounts have been revised to conform with the new free cash flow definition. See page 48 of the Condensed Interim Financial Report. 4 Please see detailed guidance assumptions on page 8. Strategy update Our focus Novartis has completed its transformation into a “pure-play” innovative medicines business, with the successful spin-off of Sandoz. Our focus is now centered on four core therapeutic areas (cardiovascular, renal and metabolic; immunology; neuroscience, and oncology). In each of these areas, we have multiple significant in-market and pipeline assets, all of which address diseases with a high 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. Financials Following the September 15, 2023, shareholders’ approval of the spin-off of the Sandoz business the Company reported its consolidated financial statements for the current and prior years as “continuing operations” and “discontinued operations.” Continuing operations include the retained business activities of Novartis, comprising the Innovative Medicines Division 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. With the spin-off of the Sandoz business, Novartis operates as a single global operating segment, being a focused innovative medicines company. The commentary below focuses on continuing operations. We also provide information on discontinued operations, which mainly includes Sandoz and allocated corporate activities. Continuing operations Third quarter Net sales were USD 11.8 billion (+12%, +12% cc) driven by volume growth of 17 percentage points. Pricing had a negative impact of 1 percentage point and generic competition had a negative impact of 4 percentage points. Operating income was USD 1.8 billion (-4%, +13% cc), mainly driven by higher sales and lower restructuring charges, partly offset by higher impairments through discontinuation of early stage development projects. Net income was USD 1.5 billion (+14%, +37% cc), mainly due to higher operating income and lower tax rate driven by non-recurring items. EPS was USD 0.73 (+20%, +45% cc), growing faster than net income, benefiting from lower weighted average number of shares outstanding. Core operating income was USD 4.4 billion (+17%, +21% cc), mainly driven by higher sales. Core operating income margin was 37.4% of net sales, increasing by 1.4 percentage points (+2.7 percentage points cc). Core net income was USD 3.6 billion (+18%, +23% cc), mainly due to higher core operating income. Core EPS was USD 1.74 (+24%, +29% cc), growing faster than core net income, benefiting from lower weighted average number of shares outstanding. Free cash flow amounted to USD 5.0 billion (+24% USD), compared with USD 4.1 billion in the prior year quarter driven by higher net cash flows from operating activities. Nine months Net sales were USD 34.0 billion (+8%, +10% cc) driven by volume growth of 16 percentage points. Pricing had a negative impact of 2 percentage points and generic competition had a negative impact of 4 percentage points. Operating income was USD 7.2 billion (+16%, +31% cc), mainly driven by higher sales, other income from legal matters, lower restructuring charges, partly offset by higher impairments through discontinuation of early stage development projects. Net income was USD 5.9 billion (+25%, +41% cc), mainly due to higher operating income. EPS was USD 2.84 (+31%, +49% cc), growing faster than net income, benefiting from lower weighted average number of shares outstanding. Core operating income was USD 12.6 billion (+13%, +19% cc), mainly driven by higher sales. Core operating income margin was 36.9% of net sales, increasing by 1.7 percentage points (+2.9 percentage points cc). Core net income was USD 10.3 billion (+15%, +22% cc), mainly due to higher core operating income. Core EPS was USD 4.95 (+21%, +28% cc), growing faster than core net income, benefiting from lower weighted average number of shares outstanding. Free cash flow amounted to USD 11.0 billion (+27% USD), compared with USD 8.7 billion in the prior year period driven by higher net cash flows from operating activities. Discontinued operations Results for discontinued operations in the third quarter and nine-months 2023 include the results of the Sandoz Division and selected portions of corporate activities attributable to Sandoz business, as well as certain expenses related to the spin-off. In connection with the Sandoz spin-off on October 4, 2023, the Company will report as part of its Q4 discontinued operations results a one-time non-cash non-taxable IFRS gain of approximately USD 5.9 billion. This IFRS gain represents mainly the excess amount of the IFRS distribution liability, which is the estimated fair value of the Sandoz business distributed to Novartis AG shareholders, over the then carrying value of Sandoz business net assets. Third quarter Discontinued operations net sales were USD 2.5 billion (+8%, +6% cc), mainly driven by ex-US growth. Operating loss amounted to USD 86 million, compared to an operating income of USD 342 million in the previous year. The operating loss in third quarter was driven by the discontinued corporate transaction cost related to spin-off of the Sandoz business, which were core adjustments. Core operating income was USD 250 million (-51%, -38% cc), mainly driven by lower gross margin and higher SG&A expenses. Net income from discontinued operations amounted to USD 250 million, compared to USD 245 million in the previous year. Nine months Discontinued operations net sales were USD 7.4 billion (+6%, +8% cc), mainly driven by ex-US growth. Operating income amounted to USD 265 million, compared to USD 1.1 billion in the previous year. The current year period includes the discontinued corporate transaction cost related to spin-off of the Sandoz business, which were core adjustments. Core operating income was USD 1.2 billion (-20%, -11% cc), mainly driven by higher SG&A expenses and R&D investments. Net income from discontinued operations amounted to USD 440 million, compared to USD 755 million in the previous year. Total company Third quarter Total company net income was USD 1.8 billion, mainly due to higher operating income and lower tax rate driven by non-recurring items compared to USD 1.6 billion in the prior year. EPS increased to USD 0.85 from USD 0.73 in prior year. Cash flows from operating activities amounted to USD 5.4 billion compared to USD 4.7 billion in the prior year. Free cash flow amounted to USD 5.0 billion compared to USD 4.4 billion in the prior year. Nine months Total company net income was USD 6.4 billion, mainly due to higher operating income compared to USD 5.5 billion in the prior year. EPS increased to USD 3.05 from USD 2.50 in prior year. Cash flows from operating activities amounted to USD 11.9 billion compared to USD 10.1 billion in the prior year. Free cash flow amounted to USD 11.0 billion compared to USD 9.3 billion in the prior year. Q3 key growth drivers Underpinning our financial results in the quarter is a continued focus on key growth drivers including: Kesimpta (USD 657 million, +124% cc) sales growth was driven by increased demand, strong access and benefitting from a one-time revenue deduction adjustment in Europe Entresto (USD 1 485 million, +31% cc) sustained robust demand-led growth, benefitting from the adoption of guideline-directed medical therapy across regions Kisqali (USD 562 million, +76% cc) sales grew strongly across all regions, based on increasing recognition of consistent overall survival and quality of life benefits Pluvicto (USD 256 million, +217% cc) continued sales growth in the US. Supply now unconstrained, focusing on initiating new patients Ilaris (USD 335 million, +24% cc) sales grew across all regions Scemblix (USD 106 million, +157% cc) sales grew across all regions, demonstrating the high unmet need in CML Leqvio (USD 90 million, +165% cc) launch in the US and other markets ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education Cosentyx (USD 1 329 million, +4% cc) continued demand growth across key regions, partly offset by US revenue deduction fluctuations across periods. Ex-US sales grew +15% (cc) Promacta/Revolade (USD 576 million, +10% cc) grew across all regions, driven by increased use in chronic ITP and severe aplastic anemia Xolair (USD 369 million, +13% cc) sales grew across most regions Jakavi (USD 427 million, +9% cc) sales grew in Emerging Growth Markets, Europe and Japan, driven by strong demand in both myelofibrosis and polycythemia vera Tafinlar + Mekinist (USD 482 million, +8% cc) sales grew in the US and Emerging Growth Markets, driven by demand in BRAF+ adjuvant melanoma and NSCLC indications Lutathera (USD 159 million, +19% cc) sales grew mainly in the US, Japan and Europe due to increased demand Emerging Growth Markets* Overall, grew +17% (cc). Growth in China (+14% cc, USD 848 million) *All markets except the US, Canada, Western Europe, Japan, Australia, and New Zealand Net sales of the top 20 products in 2023 Q3 2023 % change 9M 2023 % change USD m USD cc USD m USD cc Entresto 1 485 31 31 4 400 31 33 Cosentyx 1 329 4 4 3 677 -1 1 Promacta/Revolade 576 10 10 1 706 10 12 Kesimpta- excl. revenue deduction adjust.* 657 12787 124 86 1 530 112 95 112 96 Kisqali 562 72 76 1 470 68 74 Tafinlar + Mekinist 482 7 8 1 436 10 13 Tasigna 464 -5 -5 1 402 -3 -1 Jakavi 427 11 9 1 276 9 11 Lucentis 363 -20 -22 1 174 -20 -19 Xolair 369 15 13 1 085 4 6 Sandostatin 338 15 15 998 7 8 Ilaris 335 23 24 979 18 20 Zolgensma 308 -3 -2 928 -13 -11 Gilenya 270 -47 -48 771 -54 -53 Pluvicto 256 220 217 707 nm nm Exforge Group 187 1 3 557 -5 -1 Galvus Group 181 -15 -4 539 -17 -10 Diovan Group 153 -4 -1 466 -9 -4 Lutathera 159 20 19 458 34 34 Gleevec/Glivec 144 -19 -17 433 -24 -21 Top 20 brands total 9 045 13 13 25 992 9 11 nm= not meaningful* Sales growth benefiting from a one-time revenue deduction adjustment in Europe R&D update - key developments from the third quarter New approvals Leqvio Approved in China and Japan as the first and only small interfering RNA (siRNA) therapy for LDL-C reduction Cosentyx In October, FDA approved the intravenous formulation in three indications: Psoriatic Arthritis, Ankylosing Spondylitis, and non-radiographic axial SpA Regulatory updates Kisqali EU file submission in adjuvant early breast cancer setting; US submission planned for Q4 2023 Adakveo EC adopts decision endorsing CHMP recommendation to revoke conditional marketing authorization Results from ongoing trials and other highlights iptacopan In October, Ph3 APPLAUSE-IgAN study interim analysis demonstrated clinically meaningful and highly statistically significant proteinuria reduction in patients with IgA nephropathy. The trial met its pre-specified interim analysis (9 months) primary endpoint, demonstrating superiority vs. placebo in proteinuria reduction, with safety consistent with previously reported data. Novartis plans to review interim data with regulatory authorities for accelerated approval; study continues with final readout at 24 months remibrutinib Ph3 REMIX-1 and REMIX-2 studies met all primary and secondary endpoints, showing fast, clinically meaningful improvements across urticaria disease activity scores. Remibrutinib demonstrated a favorable safety profile with rates of adverse events comparable to placebo and balanced liver function tests across both studies.Final (52 weeks) readout and submissions to health authorities are expected in 2024. Full data will be presented at upcoming medical meetings Pluvicto Ph3 PSMAfore study demonstrated clinically meaningful and statistically significant rPFS benefit in patients with PSMA+ mCRPC in the pre-taxane setting. Per updated analysis presented at ESMO, median rPFS more than doubled compared to ARPI switch. Patients on Pluvicto showed improved quality of life compared to daily oral ARPI, along with improvements in other clinically meaningful efficacy endpoints including PSA response, ORR, DOR and time to symptomatic skeletal event, with favorable safety. Pre-specified crossover-adjusted OS analysis demonstrated a HR of 0.80 (0.48, 1.33); the unadjusted ITT OS analysis was confounded by a high rate of crossover. Novartis is continuing to collect OS data, regulatory filings are anticipated in 2024 Lutathera Ph3 NETTER-2 study demonstrated clinically meaningful and statistically significant improvement in PFS (primary endpoint) in patients with newly diagnosed somatostatin receptor (SSTR)-positive, Grade 2 and 3, advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) vs. high-dose long-acting octreotide alone. The trial also met its key secondary endpoint of ORR. No new or unexpected safety findings were observed and data are consistent with the already well-established safety profile of Lutathera.Data to be presented at an upcoming medical meeting and discussed with regulatory authorities, with submissions to follow Kisqali Ph3 NATALEE iDFS 500 event analysis complete. Updated data is consistent with the interim analysis results announced in March 2023 and will be communicated at an upcoming medical meeting.Health-related quality of life (HRQoL) analyses from Ph3 NATALEE trial demonstrated that patients with early breast cancer receiving adjuvant Kisqali plus ET for up to 3 years maintained physical and social functioning; psychological well-being; and overall health scores, compared to baseline. Data was presented at the ESMO Virtual Plenary 2023 Leqvio Long-term data from Ph3 ORION-8 demonstrated that Leqvio, in addition to statin therapy, provides consistent low-density lipoprotein cholesterol (LDL-C) reduction beyond six years of treatment in patients with atherosclerotic cardiovascular disease (ASCVD), increased risk of ASCVD or heterozygous familial hypercholesterolemia. Efficacy and safety were consistent with previously reported Ph3 results. Data was presented at ESC 2023 GT005 (PPY988) Development in Geographic Atrophy secondary to dry-Age-related Macular Degeneration discontinued based on benefit-risk assessment. No new safety signals identified. Patients treated will be provided with long term safety follow up Tislelizumab Novartis and BeiGene mutually agreed to terminate the collaboration and license agreement for tislelizumab for certain markets. With the termination, BeiGene will re-assume all development and commercialization rights for tislelizumab, and Novartis will manufacture tislelizumab for certain markets. BeiGene will also provide Novartis with ongoing clinical supply of tislelizumab to support its clinical trials ‘Front of Eye’ Assets Divestment completed of ‘front of eye’ ophthalmology assets to Bausch + Lomb 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 2023, Novartis repurchased a total of 74.9 million shares for USD 7.2 billion on the SIX Swiss Exchange second trading line. These repurchases included 52.8 million shares (USD 4.9 billion) under the USD 15 billion share buyback (announced in December 2021 and completed in June 2023) and 10.4 million shares (USD 1.1 billion) under the new up-to USD 15 billion share buyback announced in July 2023. In addition, 11.7 million shares (USD 1.2 billion) were repurchased to mitigate dilution related to participation plans of associates. Furthermore, 1.4 million shares (for an equity value of USD 0.1 billion) were repurchased from associates. In the same period, 12.2 million shares (for an equity value of USD 0.8 billion) were delivered as a result of options exercised and share deliveries related to participation plans of associates. Consequently, the total number of shares outstanding decreased by 64.1 million versus December 31, 2022. These treasury share transactions resulted in an equity decrease of USD 6.5 billion and a net cash outflow of USD 7.3 billion. As of September 30, 2023, net debt excluding net debt related to discontinued operations increased to USD 10.8 billion compared to USD 7.2 billion total net debt at December 31, 2022. The increase was mainly due to the USD 7.3 billion annual dividend payment, net cash outflow for treasury share transactions of USD 7.3 billion and net M&A / intangible assets transactions of USD 2.9 billion. This increase in net debt was partially offset by USD 11.0 billion free cash flow. As part of the spin-off, Sandoz incurred total bank debt of approximately USD 3.7 billion and paid approximately USD 3.0 billion in cash, including payment in satisfaction of certain intercompany indebtedness owed by Sandoz and its subsidiaries to Novartis and its affiliates as of September 30, 2023. This reduced the net debt position of Novartis by USD 3.0 billion. As of Q3 2023, the long-term credit rating for the company is A1 with Moody’s Investors Service and AA- with S&P Global Ratings. 2023 outlook raised due to strong momentum Barring unforeseen events; growth vs prior year in cc Previous Guidance Net sales Expected to grow high single digit Unchanged Core operating income Expected to grow mid to high teens (from low double digit to mid teens) Key assumptions: No US Entresto Gx at risk launch in 2023No Sandostatin LAR generics enter in the US in 2023 Entresto patent update Novartis has appealed to reverse the negative US District Court decision and to uphold the validity of its combination patent covering Entresto and other combinations of sacubitril and valsartan, which expires in 2025 (with pediatric exclusivity). No generics have tentative or final approval in the US. Any US commercial launch of a generic Entresto product prior to the final outcome of Novartis combination patent appeal, or ongoing litigations involving other patents, may be at risk of later litigation developments. Foreign exchange impactIf late-October exchange rates prevail for the remainder of 2023, the foreign exchange impact for the year would be negative 2 percentage point on net sales and negative 6 percentage points on core operating income. The estimated impact of exchange rates on our results is provided monthly on our website. Key figures1 Continuing operations2 Q3 2023 Q3 2022 % change 9M 2023 9M 2022 % change USD m USD m USD cc USD m USD m USD cc Net sales 11 782 10 492 12 12 Net sales 34 017 31 630 8 10 Operating income 1 762 1 826 -4 13 Operating income 7 187 6 191 16 31 As a % of sales 15.0 17.4 As a % of sales 21.1 19.6 Net income 1 513 1 330 14 37 Net income 5 934 4 734 25 41 EPS (USD) 0.73 0.61 20 45 EPS (USD) 2.84 2.16 31 49 Cash flows from operating activities 5 304 4 275 24 Cash flows from operating activities 11 673 9 271 26 Non-IFRS measures Non-IFRS measures Free cash flow 5 043 4 054 24 Free cash flow 11 019 8 661 27 Core operating income 4 405 3 772 17 21 Core operating income 12 551 11 149 13 19 As a % of sales 37.4 36.0 As a % of sales 36.9 35.2 Core net income 3 585 3 035 18 23 Core net income 10 320 8 983 15 22 Core EPS (USD) 1.74 1.40 24 29 Core EPS (USD) 4.95 4.09 21 28 Discontinued operations2 Q3 2023 Q3 2022 % change 9M 2023 9M 2022 % change USD m USD m USD cc USD m USD m USD cc Net sales 2 476 2 286 8 6 Net sales 7 428 6 998 6 8 Operating (loss)/income -86 342 nm nm Operating income 265 1 057 -75 -60 As a % of sales nm 15.0 As a % of sales 3.6 15.1 Net income 250 245 2 79 Net income 440 755 -42 -18 Non-IFRS measures Non-IFRS measures Core operating income 250 510 -51 -38 Core operating income 1 185 1 486 -20 -11 As a % of sales 10.1 22.3 As a % of sales 16.0 21.2 Total company Q3 2023 Q3 2022 % change 9M 2023 9M 2022 % change USD m USD m USD cc USD m USD m USD cc Net income 1 763 1 575 12 44 Net income 6 374 5 489 16 33 EPS (USD) 0.85 0.73 16 51 EPS (USD) 3.05 2.50 22 40 Cash flows from operating activities 5 378 4 721 14 Cash flows from operating activities 11 911 10 125 18 Non-IFRS measures Non-IFRS measures Free cash flow 5 043 4 435 14 Free cash flow 11 038 9 325 18 Core net income 3 784 3 419 11 16 Core net income 11 209 10 101 11 18 Core EPS (USD) 1.83 1.58 16 22 Core EPS (USD) 5.37 4.60 17 24 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 48 of the Condensed Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year.2 As defined on page 37 of the Condensed Interim Financial Report, Continuing operations include the retained business activities of Novartis, comprising the Innovative Medicines Division 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 Condensed Interim Financial Report at the link below:https://ml-eu.globenewswire.com/resource/download/1a97fd38-edbc-49ea-9350-8042dc006c1c/ Disclaimer This 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 “guidance,” “expected,” “momentum,” “continue,” “drivers,” “confident,” “outlook,” “remain,” “committed,” “prioritized,” “prioritizing,” “continued,” “growing,” “growth,” “plans,” “on-track,” “continuing,” “anticipated,” “to follow,” “will,” “outlook,” “may,” “upcoming,” “ongoing,” “focus,” “pipeline,” “potential,” “estimated,” “launch,” “to deliver,” “transformation,” “transformative,” “address,” “planned,” “focusing,” “accelerated,” “long-term,” “innovation,” “priority,” “can,” “awaiting,” 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 potential future, pending or announced transactions; or regarding potential future sales or earnings of Novartis; or regarding discussions of strategy, priorities, plans, expectations or intentions, including our transformation into a “pure-play” innovative medicines business; or regarding our liquidity or cash flow positions and our ability to meet our ongoing financial obligations and operational needs; or regarding our USD 15 billion share buyback; or regarding our appeal of the negative decision of the US District Court for the District of Delaware on the validity of our patent covering Entresto and combinations of sacubitril and valsartan. 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: liquidity or cash flow disruptions affecting our ability to meet our ongoing financial obligations and to support our ongoing business activities; the impact of a partial or complete failure of the return to normal global healthcare systems including prescription dynamics; 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 potential significant breaches of data security or data privacy, or disruptions of our information technology systems; regulatory actions or delays or government regulation generally, including potential regulatory actions or delays with respect to the development of the products described in this press release; the potential that the benefits and opportunities expected from our planned spin-off of Sandoz may not be realized or may be more difficult or take longer to realize than expected; the uncertainties in the research and development of new healthcare products, including clinical trial results and additional analysis of existing clinical data; 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; safety, quality, data integrity, or manufacturing issues; uncertainties involved in the development or adoption of potentially transformational technologies and business models; uncertainties regarding actual or potential legal proceedings, investigations or disputes; our performance on environmental, social and governance measures; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; uncertainties regarding future global exchange rates; uncertainties regarding future demand for our products; 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 as a result of new information, future events or otherwise. All product names appearing in italics are trademarks owned by or licensed to Novartis AG and its subsidiaries. BAUSCH + LOMB is a registered trademark of Bausch & Lomb Incorporated. About Novartis Novartis is a focused 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 8:00 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 Novartis divisions and pipeline of selected compounds in late stage development and a copy of today's earnings call presentation can be found at https://www.novartis.com/investors/event-calendar. Important dates November 13, 2023 Impact and Health Equity Annual Event November 28, 2023 R&D Day Please find full media release in English attached and on the following link: Media release (PDF) German version is available through the following link: Medienmitteilung (PDF) French version is available through the following link: Communiqué aux médias (PDF)

Ad hoc announcement pursuant to Art. 53 LR Q2 sales grew +9% (cc3, +7% USD) with core operating income growing +17% (cc, +9% USD) Innovative Medicines (IM) sales grew +9% (cc, +7% USD) and core operating income +20% (cc, +12% USD), with core margin reaching 39.0%, (+340 bps cc)Growth driven by continued strong performance from Entresto, Kesimpta, Pluvicto and KisqaliSandoz sales grew +8% (cc, +5% USD) and core operating income +6% (cc, -5% USD) Q2 operating income grew +50% (cc, +31% USD) mainly driven by higher sales and lower restructuring charges. Net income grew +54% (cc, +37% USD) mainly due to higher operating income. Free cash flow4 was USD 3.3 billion (-6% USD) Q2 core EPS grew +25% (cc, +17% USD) to USD 1.83 Strong H1 performance with sales growing +8% (cc, +5% USD) and core operating income growing +16% (cc, +9% USD) IM sales grew +8% (cc, +5% USD) and core operating income +19% (cc, +12% USD), with core margin reaching 38.9%, (+360 bps cc)Sandoz sales grew +8% (cc, +4% USD) and core operating income +5% (cc, -3% USD) Q2 key innovation milestones: Cosentyx – EU approval for moderate to severe hidradenitis suppurativa Entresto – EU approval for pediatric heart failure; RDP extends to November 2026Kisqali – demonstrated clinically meaningful data in eBC presented at ASCO (NATALEE) Continuing strategic rationalization of development portfolio including proposed acquisition of Chinook and divestment of front of eye assets5 Initiating up-to USD 15 billion share buyback to be completed by year-end 2025, following completion of previously announced share buyback in June 2023 Board of Directors endorses the separation of Sandoz, by way of a 100% spin-off2 Full-year 2023 Group guidance raised based on strong H1 momentum6 Group sales expected to grow high single digit (from mid)Group core operating income expected to grow low double digit (from high single) Basel, July 18, 2023 - commenting on the quarter, Vas Narasimhan MD, CEO of Novartis, said: “Novartis delivers another strong quarter of sales growth and robust margin expansion, supporting an upgrade to Group guidance for 2023. The performance was broad-based across core therapeutic areas and key geographies. Our growth drivers and rich pipeline continue to provide confidence in our mid-term growth outlook, highlighted by upcoming milestones for Kisqali, Pluvicto and iptacopan. Novartis robust balance sheet and expected future growth allow us to initiate an up-to USD 15 billion share buyback while maintaining the flexibility for continued strategic bolt-on acquisitions.” Key figures3 Q2 2023 Q2 2022 % change H1 2023 H1 2022 % change USD m USD m USD cc USD m USD m USD cc Net sales 13 622 12 781 7 9 26 575 25 312 5 8 Operating income 2 920 2 228 31 50 5 776 5 080 14 28 Net income 2 317 1 695 37 54 4 611 3 914 18 32 EPS (USD) 1.11 0.77 44 62 2.20 1.77 24 39 Free cash flow4 3 275 3 498 -6 5 995 4 890 23 Core operating income 4 668 4 270 9 17 9 081 8 353 9 16 Core net income 3 811 3 431 11 19 7 425 6 682 11 19 Core EPS (USD) 1.83 1.56 17 25 3.54 3.02 17 25 Strategy Update Our focus With our new focused strategy unveiled in 2022, Novartis is transforming into a “pure-play” Innovative Medicines business. We focus on five core therapeutic areas (cardiovascular, immunology, neuroscience, solid tumors and hematology), 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. Sandoz planned spin-off The Novartis Board of Directors has unanimously endorsed the proposed separation of Sandoz to create an independent company by way of a 100% spin-off. As a next step, shareholders of Novartis will be invited to vote on the proposed spin-off and a related reduction of the share capital of Novartis AG at an Extraordinary General Meeting, planned to be held on Friday, 15 September 2023. The invitation to the EGM, a Shareholder Brochure and listing prospectus, which will be published by Sandoz, are planned to be distributed in August 2023. Sandoz is planned to be listed on the SIX Swiss Exchange, with an American Depositary Receipt (ADR) program in the US. The proposed spin-off is planned to occur early in the fourth quarter of 2023. In addition to Novartis shareholder approval, completion of the proposed Sandoz spin-off is subject to satisfaction of certain conditions, including obtaining the necessary approvals for the listing of the Sandoz shares, no order prohibiting (and no other event outside the control of Novartis preventing) the spin-off and no material adverse change.2 Entresto patent update (July) Following a negative decision from the U.S. District Court for the District of Delaware, Novartis will appeal to the U.S. Court of Appeals for the Federal Circuit to uphold validity of Novartis patent covering Entresto and combinations of sacubitril and valsartan. No generics have tentative or final approval in the US. Any commercial launch of a generic Entresto product prior to the final outcome of Novartis combination patent appeal, or ongoing litigations involving other patents, may be at risk of later litigation developments. Financials Second quarter Net sales were USD 13.6 billion (+7%, +9% cc) in the second quarter driven by volume growth of 14 percentage points, price erosion of 2 percentage points and the negative impact from generic competition of 3 percentage points. Operating income was USD 2.9 billion (31%, +50% cc), mainly driven by higher sales and lower restructuring charges. Net income was USD 2.3 billion (+37%, +54% cc), mainly due to higher operating income. EPS was USD 1.11 (+44%, +62% cc), growing faster than net income, benefiting from lower weighted average number of shares outstanding. Core operating income was USD 4.7 billion (+9%, +17% cc), mainly driven by higher sales. Core operating income margin was 34.3% of net sales, increasing by 0.9 percentage points (+2.5 percentage points cc). Core net income was USD 3.8 billion (+11%, +19% cc), mainly due to higher core operating income. Core EPS was USD 1.83 (+17%, +25% cc), growing faster than core net income, benefiting from lower weighted average number of shares outstanding. Free cash flow amounted to USD 3.3 billion (-6% USD), compared with USD 3.5 billion in the prior year quarter. This decrease was driven by the lower net cash flows from operating activities. Innovative Medicines net sales were USD 11.2 billion (+7%, +9% cc), with volume contributing 15 percentage points to growth. Sales growth was mainly driven by continued strong performance from Entresto, Kesimpta, Pluvicto and Kisqali partly offset by generic competition mainly for Gilenya. Generic competition had a negative impact of 4 percentage points. Pricing had a negative impact of 2 percentage points. Sales in the US were USD 4.5 billion (+14%) and in the rest of the world USD 6.7 billion (+3%, +7% cc). Sandoz net sales were USD 2.4 billion (+5%, +8% cc), with volume contributing 9 percentage points to growth. Pricing had a negative impact of 1 percentage point. Sales growth was mainly driven by Europe USD 1.3 billion (+11%, +13% cc), which benefited from strong volume growth driven by continued momentum from prior year launches, a strong cough and cold season and the biosimilars business. Global sales of Biosimilars grew to USD 531 million (+12%, +13% cc), also driven by growth ex-US. First half Net sales were USD 26.6 billion (+5%, +8% cc) in the first half driven by volume growth of 15 percentage points, price erosion of 3 percentage points and the negative impact from generic competition of 4 percentage points. Operating income was USD 5.8 billion (14%, +28% cc), mainly driven by higher sales. Net income was USD 4.6 billion (+18%, +32% cc), mainly due to higher operating income. EPS was USD 2.20 (+24%, +39% cc), growing faster than net income, benefiting from lower weighted average number of shares outstanding. Core operating income was USD 9.1 billion (+9%, +16% cc), mainly driven by higher sales. Core operating income margin was 34.2% of net sales, increasing by 1.2 percentage points (+2.4 percentage points cc). Core net income was USD 7.4 billion (+11%, +19% cc), mainly due to higher core operating income. Core EPS was USD 3.54 (+17%, +25% cc), growing faster than core net income, benefiting from lower weighted average number of shares outstanding.Free cash flow amounted to USD 6.0 billion (+23% USD), compared with USD 4.9 billion in the prior year period driven by higher net cash flows from operating activities. Innovative Medicines net sales were USD 21.8 billion (+5%, +8% cc), with volume contributing 16 percentage points to growth. Sales growth was mainly driven by continued strong performance from Entresto, Kesimpta, Pluvicto and Kisqali partly offset by generic competition mainly for Gilenya. Generic competition had a negative impact of 5 percentage points. Pricing had a negative impact of 3 percentage points. Sales in the US were USD 8.6 billion (+12%) and in the rest of the world USD 13.2 billion (+1%, +6% cc). Sandoz net sales were USD 4.8 billion (+4%, +8% cc), with volume contributing 12 percentage points to growth. Pricing had a negative impact of 4 percentage points. Sales growth was mainly driven by Europe USD 2.7 billion (+11%, +14% cc), which benefited from strong volume growth driven by continued momentum from prior year launches, a strong cough and cold season and the biosimilars business. Global sales of Biosimilars grew to USD 1.0 billion (+12%, +15% cc), also driven by growth ex-US. Q2 key growth drivers Underpinning our financial results in the quarter is a continued focus on key growth drivers including: Entresto (USD 1,516 million, +37% cc) sustained robust demand-led growth, benefitting from the adoption of guideline-directed medical therapy across regions Kesimpta (USD 489 million, +105% cc) sales growth across all regions driven by increased demand and strong access Pluvicto (USD 240 million) continues to see strong demand in the US, with approval received in Q2 for expanded manufacturing capacity at Millburn, NJ Kisqali (USD 493 million, +66% cc) sales grew strongly across all regions, based on increasing recognition of consistent overall survival and quality of life benefits Scemblix (USD 106 million, +248% cc) sales grew across all regions, demonstrating the high unmet need in CML Lutathera (USD 150 million, +75% cc) sales grew mainly in the US and Japan due to increased demand and prior year low base Promacta/Revolade (USD 583 million, +11% cc) grew across all regions, driven by increased use in chronic ITP and as first-line and/or second-line treatment for severe aplastic anemia Tafinlar + Mekinist (USD 496 million, +13% cc) sales grew across all regions, driven by demand in BRAF+ adjuvant melanoma and NSCLC indications Leqvio (USD 78 million, +249%cc) launch in the US and other markets ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education Piqray/Vijoice (USD 130 million, +54% cc) sales grew mainly in the US and Europe, benefiting from indication expansion into PIK3CA-related overgrowth spectrum (PROS) Jakavi (USD 435 million, +11% cc) sales grew in Emerging Growth Markets, Europe and Japan, driven by strong demand in both myelofibrosis and polycythemia vera Ilaris (USD 316 million, +17% cc) sales grew in in the US, Emerging Growth Markets and Japan Cosentyx (USD 1,272 million, +1% cc) sales stabilized with continued demand growth across key regions, offset by US revenue deduction. Ex-US sales grew +18% (cc) Sandoz Biosimilars (USD 531 million, +13% cc) with growth driven ex-US Emerging Growth Markets* Overall, grew +15% (cc). Growth in China (+14% cc, USD 895 million) outpaced the multi-national corporation market, with Innovative Medicines growing +16% *All markets except the US, Canada, Western Europe, Japan, Australia, and New Zealand Net sales of the top 20 Innovative Medicines products in 2023 Q2 2023 % change H1 2023 % change USD m USD cc USD m USD cc Entresto 1 516 35 37 2 915 31 35 Cosentyx 1 272 0 1 2 348 -4 -1 Promacta/Revolade 583 9 11 1 130 10 13 Tafinlar + Mekinist 496 10 13 954 12 15 Tasigna 476 -4 -3 938 -2 1 Kisqali 493 60 66 908 66 73 Kesimpta 489 105 105 873 101 103 Jakavi 435 9 11 849 8 12 Lucentis 395 -21 -20 811 -21 -17 Xolair 362 3 5 716 -1 3 Sandostatin 331 4 5 660 3 5 Ilaris 316 15 17 644 15 18 Zolgensma 311 -18 -16 620 -16 -15 Gilenya 269 -52 -52 501 -57 -56 Pluvicto 240 nm nm 451 nm nm Exforge Group 184 -8 -4 370 -7 -3 Galvus Group 175 -21 -15 358 -18 -12 Diovan Group 155 -3 2 313 -11 -5 Lutathera 150 74 75 299 42 43 Gleevec/Glivec 142 -27 -24 289 -26 -23 Top 20 brands total 8 790 9 11 16 947 7 10 nm= not meaningful R&D update - key developments from the second quarter New approvals Cosentyx EC approved Cosentyx for use in adults with active moderate to severe hidradenitis suppurativa (HS) and an inadequate response to conventional systemic HS therapy based on positive readouts from two Ph3 trials FDA approved the Cosentyx​ UnoReady​​ pen, a 300 mg dosage strength for subcutaneous administration to treat moderate-to-severe plaque psoriasis, active psoriatic arthritis and active ankylosing spondylitis Entresto EU approval for pediatric heart failure, which supports extension of regulatory data protection in Europe to November 2026 Regulatory updates Iptacopan PNH – regulatory submissions completed in the US and Europe C3 glomerulopathy - granted FDA Breakthrough Therapy designation Leqvio In July, FDA expanded the label. Indication updated to primary hyperlipidemia including Heterozygous Familial Hypercholesterolemia, less restrictive language for use for statin therapy, broader population from ORION-11 and removal of several adverse reactions from safety section Denosumab biosimilar EMA accepted the marketing authorization applications for proposed biosimilar denosumab for regulatory review. The two applications include all indications covered by the reference medicines Prolia® and Xgeva® Adakveo CHMP recommended revocation of the conditional marketing authorization, based on the results of the confirmatory Ph3 STAND study, which were not consistent with the pivotal SUSTAIN trial. Final decision is expected in Q3 2023 Results from ongoing trials and other highlights Kisqali Ph3 NATALEE trial showed that ribociclib plus a non-steroidal aromatase inhibitor (NSAI), compared to NSAI alone, significantly lowered the risk of cancer recurrence in a broad population of patients with HR+/HER2- early breast cancer regardless of stage, menopausal or nodal status. Results were also consistent across all secondary efficacy endpoints, , with a trend for improvement in overall survival. The safety profile was favorable at 400 mg with low rates of symptomatic adverse events. Data was presented at ASCO 2023. Novartis plans to submit data from NATALEE to regulatory authorities (in Europe, the US, and other countries) in Q3/Q4 2023 iptacopan APPOINT-PNH trial in adult PNH patients naive to complement-inhibitors (including anti-C5 therapies) met its primary endpoint with an estimated 92.2% of patients (95% CI: 82.5, 100) achieving a 2 g/dL or more hemoglobin-level increase from baseline without the need for blood transfusions after the 24-week core treatment period. Secondary endpoints also showed clinically meaningful benefits. Data was presented at EBMT 2023. Additional iptacopan data in PNH was also presented at EHA 2023 Kesimpta Up to five year data from the ALITHIOS open-label extension study showed that patients treated earlier and continuously with Kesimpta had fewer disability worsening events and low brain volume change versus those who started on teriflunomide and were later switched to Kesimpta. Treatment with Kesimpta continued to be well tolerated with no new safety signals identified over the treatment period. Data was presented at AAN 2023 NIS793 Program in metastatic pancreatic ductal adenocarcinoma (mPDAC) to be discontinued based on benefit-risk assessment. Ongoing Ph2 study in colorectal cancer is continuing MBL949 GDF-15 discontinued due to lack of efficacy Chinook Therapeutics Novartis announced that it has entered into an agreement to acquire Chinook Therapeutics, a clinical-stage biopharmaceutical company with two high-value, late-stage assets in development for IgA nephropathy: atrasentan (an oral endothelin A receptor antagonist, in Phase 3) and zigakibart (an anti-APRIL monoclonal antibody, entering Phase 3). Closing anticipated in H2 2023 and subject to customary conditions ‘Front of Eye’ assets Agreement to divest ‘front of eye’ ophthalmology assets to Bausch + Lomb. Deal includes: Xiidra (dry eye disease), SAF312 (libvatrep) in development for chronic ocular surface pain, OJL332 (TRPV1 antagonist in pre-clinical development) and rights for use of the AcuStream delivery device. Closing anticipated in H2 2023 and subject to customary conditions DTx Pharma Novartis announced that it has acquired DTx Pharma. Deal includes: DTx-1252 a potential therapy for Charcot-Marie-Tooth disease type 1A (CMT1A), two additional preclinical programs for other neuroscience indications and DTx's fatty acid ligand-conjugated oligonucleotide (FALCON) platform Sandoz / Just-Evotec Biologics Sandoz and Just-Evotec Biologics announced a partnership to develop and manufacture multiple biosimilars, supporting the expansion of the current Sandoz pipeline to 24 assets and the continued development of the early-stage pipeline ociperlimab(TIGIT inhibitor) BeiGene and Novartis entered into a Mutual Termination and Release Agreement to terminate the Option, Collaboration and License Agreement for ociperlimab effective July 10 2023 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 half of 2023, Novartis repurchased a total of 61.3 million shares for USD 5.8 billion on the SIX Swiss Exchange second trading line. These repurchases included 52.8 million shares (USD 4.9 billion) under the USD 15 billion share buyback (announced in December 2021 and completed in June 2023 with a total of 170.7 million shares repurchased over this period). In addition, 8.5 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 Q3 2023. Furthermore, 1.3 million shares (for an equity value of USD 0.1 billion) were repurchased from associates. In the same period, 11.3 million shares (for an equity value of USD 0.6 billion) were delivered as a result of options exercised and share deliveries related to participation plans of associates. Consequently, the total number of shares outstanding decreased by 51.3 million versus December 31, 2022. These treasury share transactions resulted in an equity decrease of USD 5.3 billion and a net cash outflow of USD 5.7 billion. As of June 30, 2023, net debt increased to USD 15.4 billion compared to USD 7.2 billion at December 31, 2022. The increase was mainly due to the USD 7.3 billion annual dividend payment and net cash outflow for treasury share transactions of USD 5.7 billion, partially offset by USD 6.0 billion free cash flow during the first half of 2023. As of Q2 2023, the long-term credit rating for the company is A1 with Moody’s Investors Service and AA- with S&P Global Ratings. 2023 outlook raised due to strong H1 momentum Barring unforeseen events; growth vs prior year in cc Previous Guidance Innovative Medicines Sales expected to grow high single digitCore OpInc expected to grow low double digit to mid-teens (from mid)(from high single to low double) Novartis ex. Sandoz(IM + Corporate) Sales expected to grow high single digitCore OpInc expected to grow low double digit to mid-teens (from mid)(from high single to low double) Novartis incl. Sandoz (IM + Sandoz + Sales expected to grow high single digit Core OpInc expected to grow low double digit (from mid)(from high single) * Novartis Group guidance, assuming Sandoz would remain within the Group for the entire FY 2023 Barring unforeseen events; growth vs prior year in cc Sandoz Sales expected to grow mid-single digitCore OpInc expected to decline low double digit, reflecting required stand-up investments to transition Sandoz to a separate company and continued inflationary pressures Key assumptions: No US Entresto Gx at risk launch in 2023No Sandostatin LAR generics enter in the US in 2023 Sandoz spin-off completed in early Q4 2023 Foreign exchange impactIf mid-July exchange rates prevail for the remainder of 2023, the foreign exchange impact for the year would be 0 to negative 1 percentage point on net sales and negative 5 percentage points on core operating income. The estimated impact of exchange rates on our results is provided monthly on our website. Key figures1 Group Q2 2023 Q2 2022 % change USD m USD m USD cc Net sales 13 622 12 781 7 9 Operating income 2 920 2 228 31 50 As a % of sales 21.4 17.4 Net income 2 317 1 695 37 54 EPS (USD) 1.11 0.77 44 62 Cash flows from operating activities 3 576 3 755 -5 Non-IFRS measures Free cash flow2 3 275 3 498 -6 Core operating income 4 668 4 270 9 17 As a % of sales 34.3 33.4 Core net income 3 811 3 431 11 19 Core EPS (USD) 1.83 1.56 17 25 Innovative Medicines Q2 2023 Q2 2022restated3 % change USD m USD m USD cc Net sales 11 243 10 525 7 9 Operating income 2 999 2 206 36 52 As a % of sales 26.7 21.0 Core operating income 4 387 3 911 12 20 As a % of sales 39.0 37.2 Sandoz Q2 2023 Q2 2022restated3 % change USD m USD m USD cc Net sales 2 379 2 256 5 8 Operating income 212 357 -41 -27 As a % of sales 8.9 15.8 Core operating income 429 451 -5 6 As a % of sales 18.0 20.0 Corporate Q2 2023 Q2 2022restated3 % change USD m USD m USD Cc Operating loss -291 -335 13 16 Core operating loss -148 -92 -61 -63 Group H1 2023 H1 2022 % change USD m USD m USD cc Net sales 26 575 25 312 5 8 Operating income 5 776 5 080 14 28 As a % of sales 21.7 20.1 Net income 4 611 3 914 18 32 EPS (USD) 2.20 1.77 24 39 Cash flows from operating activities 6 533 5 404 21 Non-IFRS measures Free cash flow2 5 995 4 890 23 Core operating income 9 081 8 353 9 16 As a % of sales 34.2 33.0 Core net income 7 425 6 682 11 19 Core EPS (USD) 3.54 3.02 17 25 Innovative Medicines H1 2023 H1 2022restated3 % change USD m USD m USD cc Net sales 21 813 20 755 5 8 Operating income 5 674 4 833 17 30 As a % of sales 26.0 23.3 Core operating income 8 475 7 583 12 19 As a % of sales 38.9 36.5 Sandoz H1 2023 H1 2022restated3 % change USD m USD m USD cc Net sales 4 762 4 557 4 8 Operating income 531 751 -29 -19 As a % of sales 11.2 16.5 Core operating income 933 964 -3 5 As a % of sales 19.6 21.2 Corporate H1 2023 H1 2022restated3 % change USD m USD m USD cc Operating loss -429 -504 15 17 Core operating loss -327 -194 -69 -71 1Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 48 of the Condensed Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year.2To aid in comparability, the prior year free cash flow amounts have been revised to conform with the new free cash flow definition that was effective as of January 1, 2023.3 Restated to reflect the transfers of the Sandoz division’s biotechnology manufacturing services to other companies’ activities and the Coartem brand to the Innovative Medicines division that was effective as of January 1, 2023 (see Note 9 of the Condensed Interim Financial Report). Detailed financial results accompanying this press release are included in the Condensed Interim Financial Report at the link below:https://ml-eu.globenewswire.com/resource/download/3861d4a9-4d81-4e59-be60-a18eeeeb8bd7/Disclaimer This 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 “anticipated,” “continue,” “remain,” “growth,” “confidence,” “upcoming,” “expect,” “ongoing,” “outlook,” “planned” “focus,” “pipeline,” “potential,” “will,” “guidance,” “continuing,” “estimated,” “launch,” “to deliver,” “transformation,” “transforming,” “address,” “growing,” “accelerate,” “remains,” “scaling,” “expected,” “driven,” “long-term,” “innovation,” “transformative,” “priority,” “can,” “to develop,” “to experience,” “look forward,” “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 potential future, pending or announced transactions, including the acquisitions of Chinook Therapeutics or DTx Pharma, or our divestiture of ‘front of eye’ ophthalmology assets; or regarding potential future sales or earnings of the Group or any of its divisions; or regarding discussions of strategy, priorities, plans, expectations or intentions, including our transforming into a “pure-play” Innovative Medicines business; or regarding the Group’s liquidity or cash flow positions and its ability to meet its ongoing financial obligations and operational needs; or regarding our planned spin-off of Sandoz; or regarding the new share buyback; or regarding the impact of the decision of the US District Court for the District of Delaware on the validity of our patent covering Entresto and combinations of sacubitril and valsartan. 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: liquidity or cash flow disruptions affecting our ability to meet our ongoing financial obligations and to support our ongoing business activities; the impact of a partial or complete failure of the return to normal global healthcare systems including prescription dynamics; 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 potential significant breaches of data security or data privacy, or disruptions of our information technology systems; regulatory actions or delays or government regulation generally, including potential regulatory actions or delays with respect to the development of the products described in this press release; the potential that the benefits and opportunities expected from our planned spin-off of Sandoz may not be realized or may be more difficult or take longer to realize than expected; the uncertainties in the research and development of new healthcare products, including clinical trial results and additional analysis of existing clinical data; 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; safety, quality, data integrity, or manufacturing issues; uncertainties involved in the development or adoption of potentially transformational technologies and business models; uncertainties regarding actual or potential legal proceedings, investigations or disputes; our performance on environmental, social and governance measures; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; uncertainties regarding future global exchange rates; uncertainties regarding future demand for our products; 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 as a result of new information, future events or otherwise. All product names appearing in italics are trademarks owned by or licensed to Novartis Group companies. Chinook Therapeutics and Chinook are registered trademarks of Chinook Therapeutics, Inc. DTx Pharma is a registered trademark of DTx Pharma, Inc. BAUSCH + LOMB is a registered trademark of Bausch & Lomb Incorporated. About Novartis Novartis 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 103,000 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 will conduct a conference call with investors to discuss this news release today at 14:00 Central European time and 8:00 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 Novartis divisions and pipeline of selected compounds in late stage development and a copy of today's earnings call presentation can be found at https://www.novartis.com/investors/event-calendar. Important dates September 15, 2023 Extraordinary General Meeting (related to Sandoz Spin-off) October 24, 2023 Third quarter & Nine months 2023 results November 28, 2023 R&D Day 1 Up-to USD 15 billion share buyback to be completed by year-end 2025. 2 Sandoz spin-off - there can be no assurance regarding the ultimate timing of the proposed transaction or that the transaction will be completed. Further details of the proposed spin-off will be provided at a later date. 3 Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 48 of the Condensed Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year. 4 Effective January 1, 2023, Novartis revised its definition of free cash flow, to define free cash flow as net cash flows from operating activities less purchases of property, plant and equipment. To aid in comparability, the prior year free cash flow amounts have been revised to conform with the new free cash flow definition. See page 48 of the Condensed Interim Financial Report. 5 Closing anticipated in H2 2023 and subject to customary conditions. 6 Please see detailed guidance assumptions on page 8. Please find full media release in English attached and on the following link: Media release (PDF) German version is available through the following link: Medienmitteilung (PDF) French version is available through the following link: Communiqué aux médias (PDF)