ATP2A1 inhibitors(Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 inhibitors), SERCA2 inhibitors(Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 inhibitors)

Therapeutic Areas

Infectious Diseases

Active Indication

Acute MalariaMalaria

Inactive Indication

Malaria, Falciparum

Originator Organization

Novartis Pharma AG

Active Organization

Novartis Pharmaceuticals Corp.

KPC Pharmaceuticals, Inc.Chodang Pharm Co., Ltd.

Inactive Organization

Novartis AG

Drug Highest PhaseApproved

First Approval Date

CN (01 Jan 1992),

Malaria

RegulationOrphan Drug (US)

Structure

Molecular FormulaC46H58Cl3NO6

InChIKeyZVAQGQOEHFIYMQ-UGOKYLLISA-N

CAS Registry141204-94-6

213

Clinical Trials associated with Artemether/Lumefantrine

NCT04704999 / RecruitingPhase 4IIT

Optimizing the Dose of Tafenoquine for the Radical Cure of Plasmodium Vivax Malaria in Southeast Asia

Tafenoquine was recently approved by regulatory authorities in the USA and Australia. Tafenoquine is an alternative radical curative treatment to primaquine acting against the dormant liver stage of Plasmodium vivax (the hypnozoite). Tafenoquine (an 8-aminoquinoline) has the substantial advantage of single dosing as compared to a 14-day course of primaquine to achieve radical cure. The recommended tafenoquine dose is 300 mg, which was shown to be significantly worse in radical curative efficacy to a total primaquine dose of 3.5 mg/kg in Southeast Asia. The cure rate of tafenoquine 300 mg in Southeast Asian study sites was only 74%. The comparator 3.5 mg/kg total primaquine dose is the standard and most commonly used dose globally, but in Southeast Asia and the Western Pacific, higher doses of primaquine are needed for radical cure. This study aims to determine the optimal dose of tafenoquine in Southeast Asia.

Start Date22 Jul 2024

Sponsor / Collaborator

University of Oxford

NCT06424002 / Not yet recruitingPhase 4IIT

The Impact, Feasibility Acceptability and Cost Effectiveness of the RTS,S/AS01 Malaria Vaccine in School Aged Children

Across sub-Saharan Africa, school-age children bear an under-appreciated burden of malaria. An estimated 200 million school-age children are at risk of malaria and in many areas prevalence of infection exceeds 50%. The high infection rates in this group serves as a source of onward parasite transmission, undermining elimination and control efforts. Furthermore, malaria illness and malaria-induced anemia in this age group lead to school absenteeism, and impaired cognitive function and classroom attention, ultimately resulting in reduced academic achievement. Although universal malaria interventions, such as insecticide treated nets (ITNs) and access to prompt diagnosis and treatment are available to school-age children, this age group is the least likely to benefit from these interventions. Furthermore, efficacy of these approaches may be compromised by increasing anti-malarial drug and insecticide resistance. A malaria vaccine could help to avert the burden of malaria in this age group.
The RTS,S/AS01 malaria vaccine has recently been recommended for vaccination of young children (< 24 months) by the World health organization (WHO) after a Phase 3 trial and an implementation trial showed that the vaccine had moderate but significant efficacy to prevent clinical and severe malaria in young children. Previous randomized trials suggest that the vaccine is safe for older children. However, efficacy of the vaccine has never been assessed in school age children. Kamuzu University of Health Sciences in partnership with the Malawian Ministry of Health seeks to evaluate the efficacy of the newly introduced RTSS/AS01 malaria vaccine in school aged children. The study hypothesizes that vaccination will decrease the morbidity and transmission of malaria, as well as improve school absenteeism and educational outcomes.

Start Date01 Jun 2024

Sponsor / Collaborator

Michigan State University

[+2]

NCT06294912 / RecruitingPhase 1

A Controlled Human Malaria Infection Study to Evaluate the Antimalarial Activity of MK-7602 Against Plasmodium Falciparum Blood Stage Infection in Healthy Adult Participants

The purpose of this study is to assess the antimalarial activity, pharmacokinetics, and safety of MK-7602 in healthy adults following Plasmodium falciparum (P. falciparum) infection.

Start Date18 Apr 2024

Sponsor / Collaborator

Merck Sharp & Dohme LLC

100 Clinical Results associated with Artemether/Lumefantrine

100 Translational Medicine associated with Artemether/Lumefantrine

100 Patents (Medical) associated with Artemether/Lumefantrine

747

Literatures (Medical) associated with Artemether/Lumefantrine

01 Dec 2024·Lancet Microbe

Artemether–lumefantrine–amodiaquine or artesunate–amodiaquine combined with single low-dose primaquine to reduce Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a five-arm, phase 2, single-blind, randomised controlled trial

Article

Author: Sinaba, Youssouf ; Dicko, Alassane ; Dondorp, Arjen ; Dembele, Adama ; Dicko, Yahia ; Maguiraga, Seydina O ; Mahamar, Almahamoudou ; Stone, William ; Keita, Sekouba ; Dicko, Oumar M ; Sanogo, Koualy ; Vanheer, Leen N ; Samake, Siaka ; Traore, Sekou F ; Teelen, Karina ; Niambele, Sidi M ; Youssouf, Ahamadou ; Diarra, Richard S ; Drakeley, Chris ; Smit, Merel J ; Diallo, Makonon ; Sacko, Adama

BACKGROUND:

Triple artemisinin-based combination therapies (TACTs) can delay the spread of antimalarial drug resistance. Artesunate-amodiaquine is widely used for uncomplicated Plasmodium falciparum malaria. We therefore aimed to determine the safety and efficacy of artemether-lumefantrine-amodiaquine and artesunate-amodiaquine with and without single low-dose primaquine for reducing gametocyte carriage and transmission to mosquitoes.

METHODS:

We did a five-arm, single-blind, phase 2 randomised controlled trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Sciences, Techniques and Technologies of Bamako in Mali. Eligible participants were aged 10-50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage. Eligible participants were randomly allocated (1:1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine-amodiaquine, artemether-lumefantrine-amodiaquine plus primaquine, artesunate-amodiaquine, or artesunate-amodiaquine plus primaquine. Treatment regimens were administered on days 0, 1, and 2; primaquine was given as a single dose on day 0. All staff except the trial pharmacist and participants were masked to the treatment allocation. The primary outcome was the median percentage change in mosquito infection rate between pretreatment and 2 days after treatment initiation, assessed by direct membrane feeding assay. Data were analysed using a per-protocol analysis. This study is registered with ClinicalTrials.gov, NCT05550909.

FINDINGS:

Between Oct 16, 2022, and Dec 28, 2022, a total of 1249 individuals were screened; of whom, 100 were enrolled and randomly assigned to one of the five treatment groups (20 per group). Before treatment, 61 (61%) of 100 participants were infectious to mosquitoes, with a median of 7·3% (IQR 3·2 to 23·5) of mosquitoes becoming infected. Among infectious participants, the median percentage reduction in mosquito infection rate between pretreatment and 2 days after treatment was 100% (IQR 100 to 100) in the artemether-lumefantrine (p=0·0018), artemether-lumefantrine-amodiaquine (p=0·0018), and artemether-lumefantrine-amodiaquine plus primaquine (p=0·0009) treatment groups. In the artesunate-amodiaquine group the median percentage reduction in mosquito infection rate was only 32% (IQR -10·9 to 79·4; p=0·19), whereas a 100% median reduction was seen in the artesunate-amodiaquine plus primaquine group (IQR 100 to 100; p=0·0009). At day 2, two (10%) of 20 participants in the artemether-lumefantrine group, two (11%) of 19 in the artemether-lumefantrine-amodiaquine group, and 15 (75%) of 20 in the artesunate-amodiaquine group infected any number of mosquitoes whereas no infected mosquitoes were observed at this timepoint in the groups with primaquine. 85 (85%) of 100 participants had a total of 262 adverse events during follow-up; of which, 181 (69%) were categorised as mild and 81 (31%) as moderate. No serious adverse events were reported.

INTERPRETATION:

Our findings support the effectiveness of artemether-lumefantrine alone or as part of TACT for preventing nearly all human-mosquito malaria parasite transmission within 48 h. By contrast, substantial transmission was observed following treatment with artesunate-amodiaquine. The addition of a single low dose of primaquine blocks transmission to mosquitoes rapidly regardless of schizonticide.

FUNDING:

Bill & Melinda Gates Foundation.

01 Dec 2024·LANCET INFECTIOUS DISEASES

Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials

Article

Author: Issiaka, Djibrilla ; Dicko, Alassane ; Doan, Viyada ; Doritchamou, Justin Y A ; Wang, Jing ; Richie, Thomas L ; Rausch, Kelly M ; Hoffman, Stephen L ; Soumbounou, Ibrahim H ; Kc, Natasha ; Billingsley, Peter F ; Traore, Seydou ; Dolo, Amagana ; Mwakingwe-Omari, Agnes ; Gaoussou, Santara ; Fried, Michal ; Duffy, Patrick E ; Mahamar, Almahamoudou ; Sim, B Kim Lee ; Murshedkar, Tooba ; Attaher, Oumar ; Hu, Zonghui ; Diawara, Halimatou ; Healy, Sara A ; Morrison, Robert D ; Diallo, Aye ; Zeguime, Amatigue ; Zaidi, Irfan ; Mohan, Rathy ; Wylie, Blair J

BACKGROUND:

Plasmodium falciparum parasitaemia during pregnancy causes maternal, fetal, and infant mortality. Poor pregnancy outcomes are related to blood-stage parasite sequestration and the ensuing inflammatory response in the placenta, which decreases over successive pregnancies. A radiation-attenuated, non-replicating, whole-organism vaccine based on P falciparum sporozoites (PfSPZ Vaccine) has shown efficacy at preventing infection in African adults. Here, we aimed to examine vaccine safety and efficacy of the PfSPZ Vaccine in adults and women who anticipated conception.

METHODS:

Two randomised, double-blind, placebo-controlled trials (phase 1 MLSPZV3 and phase 2 MLSPZV4) were conducted at a clinical research centre in Mali. MLSPZV3 included adults aged 18-35 years and MLSPZV4 included non-pregnant women aged 18-38 years who anticipated conception within a year of enrolment. In MLSPZV3, participants were stratified by village and randomly assigned (2:1) using block randomisation to receive three doses of 9 × 10⁵ PfSPZ Vaccine or saline placebo at weeks 0, 1, and 4 (4-week schedule) or at weeks 0, 8, and 16 (16-week schedule) and a booster dose around 1 year later. In MLSPZV4, women received presumptive artemether-lumefantrine twice per day for 3 days 2 weeks before dose one and were randomly assigned (1:1:1) using block randomisation to receive three doses of 9 × 10⁵ or 1·8 × 10⁶ PfSPZ Vaccine or saline placebo all administered at weeks 0, 1, and 4 (4-week schedule). Participants in both studies received artemether-lumefantrine 2 weeks before dose three and additionally 2 weeks before dose four (booster dose) in MLSPZV3. Investigators and participants were masked to group assignment. The primary outcome, assessed in the as-treated population, was PfSPZ Vaccine safety and tolerability within 7 days after each dose. The secondary outcome, assessed in the modified intention-to-treat population, was vaccine efficacy against P falciparum parasitaemia (defined as the time-to-first positive blood smear) from dose three until the end of transmission season. In exploratory analyses, MLSPZV4 evaluated incidence of maternal obstetric and neonatal outcomes as safety outcomes, and vaccine efficacy against P falciparum parasitaemia during pregnancy (defined as time-to-first positive blood smear post-conception). In MLSPZV4, women were followed at least once a month with human chorionic gonadotropin testing, and those who became pregnant received standard of care (including intermittent presumptive sulfadoxine-pyrimethamine antimalarial drugs after the first trimester) during routine antenatal visits. These studies are registered with ClinicalTrials.gov, NCT03510481 and NCT03989102.

FINDINGS:

Participants were enrolled for vaccination during the onset of malaria seasons for two sequential studies conducted from 2018 to 2019 for MLSPZV3 and from 2019 to 2021 for MLSPZV4, with follow-up during malaria seasons across 2 years. In MLSPZV3, 478 adults were assessed for eligibility, of whom 220 were enrolled between May 30 and June 12, 2018, and then between Aug 13 and Aug 18, 2018, and 210 received dose one. 66 (96%) of 69 participants who received the 16-week schedule and 68 (97%) of 70 who received the 4-week schedule of the 9 × 10⁵ PfSPZ Vaccine and 70 (99%) of 71 who received saline completed all three doses in year 1. In MLSPZV4, 407 women were assessed for eligibility, of whom 324 were enrolled from July 3 to July 27, 2019, and 320 received dose one of presumptive artemether-lumefantrine. 300 women were randomly assigned with 100 per group (PfSPZ Vaccine 9 × 10⁵, 1·8 × 10⁶, or saline) receiving dose one. First trimester miscarriages were the most commonly reported serious adverse event but occurred at a similar rate across study groups (eight [15%] of 54 with 9 × 10⁵ PfSPZ Vaccine, 12 [21%] of 58 with 1·8 × 10⁶ PfSPZ Vaccine, and five [12%] of 43 with saline). One unrelated maternal death occurred 425 days after the last vaccine dose in the 1·8 × 10⁶ PfSPZ Vaccine group due to peritonitis shortly after childbirth. Most related adverse events reported in MLSPZV3 and MLSPZV4 were mild (grade 1) and frequency of adverse events in the PfSPZ Vaccine groups did not differ from that in the saline group. Two unrelated serious adverse events occurred in MLSPZV3 (one participant had appendicitis in the 9 × 10⁵ PfSPZ Vaccine group and the other in the saline group died due to a road traffic accident). In MLSPZV3, the 9 × 10⁵ PfSPZ Vaccine did not show vaccine efficacy against parasitaemia with the 4-week (27% [95% CI -18 to 55] in year 1 and 42% [-5 to 68] in year 2) and 16-week schedules (16% [-34 to 48] in year 1 and -14% [-95 to 33] in year 2); efficacies were similar or worse against clinical malaria compared with saline. In MLSPZV4, the PfSPZ Vaccine showed significant efficacy against parasitaemia at doses 9 × 10⁵ (41% [15 to 59]; p=0·0069 in year 1 and 61% [36 to 77]; p=0·0011 in year 2) and 1·8 × 10⁶ (54% [34 to 69]; p<0·0001 in year 1 and 45% [13 to 65]; p=0·029 in year 2); and against clinical malaria at doses 9 × 10⁵ (47% [20 to 65]; p=0·0045 in year 1 and 56% [22 to 75]; p=0·0081 in year 2) and 1·8 × 10⁶ (48% [22 to 65]; p=0·0013 in year 1 and 40% [2 to 64]; p=0·069 in year 2). Vaccine efficacy against post-conception P falciparum parasitaemia during first pregnancies that arose in the 2-year follow-up was 57% (14 to 78; p=0·017) in the 9 × 10⁵ PfSPZ Vaccine group versus 49% (3 to 73; p=0·042) in the 1·8 × 10⁶ PfSPZ Vaccine group. Among 55 women who became pregnant within 24 weeks after dose three, vaccine efficacy against parasitaemia was 65% (23 to 84; p=0·0088) with the 9 × 10⁵ PfSPZ Vaccine and 86% (64 to 94; p<0·0001) with the 1·8 × 10⁶ PfSPZ Vaccine. When combined in a post-hoc analysis, women in the PfSPZ Vaccine groups had a non-significantly reduced time-to-first pregnancy after dose one compared with those in the saline group (log-rank test p=0·056). Exploratory maternal obstetric and neonatal outcomes did not differ significantly between vaccine groups and saline.

INTERPRETATION:

PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9 × 10⁵ and 1·8 × 10⁶ doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy.

FUNDING:

National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.

01 Dec 2024·Journal of parasitic diseases : official organ of the Indian Society for Parasitology

Antiplasmodial evidence, host mitochondrial biology and possible mechanisms of action of a composite extract of Azadiractha indica and Curcuma longa in Plasmodium berghei-infected mice

Article

Author: Oderinde, Solomon Obaloluwa ; Olorunsogo, Olufunso Olabode ; Olanlokun, John Oludele ; Owolabi, Bunmi Adesola ; Koorbanally, Neil Anthony ; Odedeyi, Aminat

Azadirachta indica A. Juss (Meliaceae) (AI) and Curcuma longa L. (Zingiberaceae) (CL) are used for malaria treatment but their anti-glycolytic and host mitochondrial effects have not been studied. The AI stem-bark and CL rhizomes were extracted with methanol. Methanol extract of CL (Turmeric) was partitioned to yield methanol fraction (MF). Swiss mice infected with Plasmodium berghei (NK 65 strain) were treated with 200 and 400 mg/kg of AI and turmeric for seven days. Turmeric and MF (200 and 400 mg/kg) were combined with 400 mg/kg AI to treat mice infected with Plasmodium berghei (ANKA strain) for four days. Drug and infected controls mice were treated with artemether lumefantrine (10 mg/kg) and distilled water (10 mL/kg), respectively. Serum lactate dehydrogenase (LDH) and aldolase activities were determined. Liver mitochondria were obtained for mitochondrial permeability transition (mPT) pore opening and F_oF₁ ATPase assays. The curcumin content of turmeric was determined using HPLC while LD₅₀ of Turmeric and AI was also determined. The AI, and its combination with turmeric decreased parasite load and increased chemosuppression in both sensitive and resistant studies while MF and its combinations with AI induced mPT pore opening. In the resistant experiment, AI + Turmeric 400 mg/kg decreased F_oF₁ ATPase, LDH and aldolase activities against the infected control. The LD₅₀ values of both extracts were above 2000 mg/kg while the MF had the highest curcumin content. Antiplasmodial mechanisms of action of AI, CL and their combinations involve anti-glycolytic effects. Their composite formulations are more potent in malaria treatment.

News (Medical) associated with Artemether/Lumefantrine

18 Jul 2024

·www.globenewswire.com

Novartis continues to deliver strong sales growth and core margin expansion in Q2; raises FY 2024 bottom-line guidance

Ad hoc announcement pursuant to Art. 53 LR Q2 net sales grew +11% (cc1, +9% USD) with core operating income up +19% (cc, +17% USD) Sales growth driven by continued strong performance from Entresto (+28% cc), Kesimpta (+65% cc), Cosentyx (+22% cc), Kisqali (+50% cc), Leqvio (+134% cc) and Pluvicto (+44% cc)Core operating income margin 39.6%, +270 basis points (cc), mainly driven by higher net sales Q2 operating income grew +47% (cc, +43% USD) and net income up +49% (cc, +43% USD)Q2 core EPS grew +21% (cc, +17% USD) to USD 1.97Q2 free cash flow1 of USD 4.6 billion (+40% USD) driven by higher net cash flows from operating activitiesH1 sales up +11% (cc, +9% USD) and core operating income up +21% (cc, +16% USD)Q2 selected innovation milestones: Fabhalta (iptacopan) received EU, Japan and China approval for the treatment of PNH Lutathera approved by FDA for pediatric GEP-NET patients (≥12 years) Scemblix filing for 1L CML accepted by FDA; received Breakthrough Therapy designationAtrasentan FDA filing accepted for the treatment of adult patients with IgANKisqali NATALEE updated data showed continued clinical benefit with median follow-up ~4 years Full-year 2024 guidance raised for core operating income based on strong momentum2 Net sales expected to grow high-single to low double-digit (unchanged)Core operating income expected to grow mid- to high teens (from low double-digit to mid-teens) Basel, July 18, 2024 – commenting on Q2 2024 results, Vas Narasimhan, CEO of Novartis, said: “Novartis delivered a strong Q2, with net sales up 11% and core operating income margin approaching 40%. Our performance reflects continued strong momentum of our key growth drivers, both in the US and ex-US, which has allowed us to upgrade our FY2024 guidance. We also advanced our pipeline in Q2, completing submissions to the FDA for Scemblix in first-line CML and atrasentan in IgAN, generating updated data in the NATALEE study to support the strong profile of Kisqali in eBC, and executing multiple deals to expand our pipeline in RLT and prostate cancer. We remain on track to achieve our mid-term sales growth (+5% cc CAGR 2023-2028) and margin (40%+ by 2027) guidance.” Key figuresContinuing operations3 Q2 2024Q2 2023% changeH1 2024H1 2023% change USD m USD mUSDcc USD m USD mUSDccNet sales12 51211 437911 24 34122 235911Operating income4 0142 8074347 7 3875 4253643Net income3 2462 2714349 5 9344 4213443EPS (USD)1.601.094752 2.912.123747Free cash flow4 6153 29240 6 6535 97611 Core operating income4 9534 2401719 9 4908 1461621Core net income4 0083 5021418 7 6896 7351419Core EPS (USD)1.971.691721 3.773.231722 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 43 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 33 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. Strategy Our 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 Second quarter Net sales were USD 12.5 billion (+9%, +11% cc), with volume contributing 15 percentage points to growth. Generic competition had a negative impact of 2 percentage points and pricing had a negative impact of 2 percentage points. Operating income was USD 4.0 billion (+43%, +47% cc), mainly driven by higher net sales and lower impairments, partly offset by higher R&D investments. Net income was USD 3.2 billion (+43%, +49% cc), mainly driven by higher operating income. EPS was USD 1.60 (+47%, +52% cc), benefiting from the lower weighted average number of shares outstanding. Core operating income was USD 5.0 billion (+17%, +19% cc), mainly driven by higher net sales, partly offset by higher R&D investments. Core operating income margin was 39.6% of net sales, increasing 2.5 percentage points (+2.7 percentage points cc). Core net income was USD 4.0 billion (+14%, +18% cc), mainly due to higher core operating income. Core EPS was USD 1.97 (+17%, +21% cc), benefiting from the lower weighted average number of shares outstanding. Free cash flow from continuing operations amounted to USD 4.6 billion (+40% USD), compared with USD 3.3 billion in the prior-year quarter, driven by higher net cash flows from operating activities from continuing operations. First half Net sales were USD 24.3 billion (+9%, +11% cc), with volume contributing 15 percentage points to growth. Generic competition had a negative impact of 2 percentage points and pricing had negative impact of 2 percentage points. Operating income was USD 7.4 billion (+36%, +43% cc), mainly driven by higher net sales and lower impairments and restructuring charges, partly offset by a prior-year one-time income from legal matters. Net income was USD 5.9 billion (+34%, +43% cc), mainly driven by higher operating income. EPS was USD 2.91 (+37%, +47% cc), benefiting from the lower weighted average number of shares outstanding. Core operating income was USD 9.5 billion (+16%, +21% cc), mainly driven by higher net sales, partly offset by higher R&D investments. Core operating income margin was 39.0% of net sales, increasing 2.4 percentage points (+3.1 percentage points cc). Core net income was USD 7.7 billion (+14%, +19% cc), mainly due to higher core operating income. Core EPS was USD 3.77 (+17%, +22% cc), benefiting from the lower weighted average number of shares outstanding. Free cash flow from continuing operations amounted to USD 6.7 billion (+11% USD), compared with USD 6.0 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. Second quarter As the Sandoz spin-off was completed on October 3, 2023, there were no operating results in the second quarter of 2024 related to discontinued operations. In the second quarter of 2023, discontinued operations net sales were USD 2.4 billion, operating income amounted to USD 113 million and net income from discontinued operations was USD 46 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. First half As the Sandoz spin-off was completed on October 3, 2023, there were no operating results in the first half 2024 related to discontinued operations. In the first half 2023, discontinued operations net sales were USD 5.0 billion, operating income amounted to USD 351 million and net income from discontinued operations was USD 190 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 Second quarter Total Company net income was USD 3.2 billion in 2024, compared to USD 2.3 billion in 2023 and basic EPS was USD 1.60 compared to USD 1.11 in prior year quarter. Net cash flows from operating activities for total Company amounted to USD 4.9 billion and free cash flow amounted to USD 4.6 billion. First half Total Company net income was USD 5.9 billion in 2024, compared to USD 4.6 billion in 2023 and basic EPS was USD 2.91 compared to USD 2.20 in prior year. Net cash flows from operating activities for total Company amounted to USD 7.1 billion and free cash flow amounted to USD 6.7 billion. Q2 key growth drivers Underpinning our financial results in the quarter is a continued focus on key growth drivers (ranked in order of contribution to Q2 growth) including: Entresto(USD 1 898 million, +28% 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 hypertensionKesimpta(USD 799 million, +65% cc) sales grew across all regions reflecting increased demand and strong access for a high efficacy product with convenient self-administered dosingCosentyx(USD 1 526 million, +22% cc) sales grew mainly in the US, driven by recent launches (including the HS indication and the IV formulation in the US) in addition to volume growth in core indicationsKisqali(USD 717 million, +50% 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 recommendation Leqvio(USD 182 million, +134% cc) continued to show steady growth, with a focus on increasing account and patient adoption, growing customer confidence in acquisition and access, and continuing medical educationPluvicto(USD 345 million, +44% cc) grew in the US and Europe. With supply now unconstrained, the focus is on increasing share in established RLT sites, opening new sites and referral pathways, and initiating new patientsXolair(USD 427 million, +22% cc) growth was driven mainly by emerging growth markets and Europe Ilaris(USD 368 million, +20% cc) sales grew across all regions, mainly US and EuropeScemblix(USD 164 million, +56% cc) sales grew across all regions, demonstrating the high unmet need in later lines of CML Jakavi(USD 471 million, +13% cc) sales grew across all regions, with strong demand in both myelofibrosis and polycythemia vera indicationsTafinlar + Mekinist(USD 523 million, +9% cc) sales grew in all regions, led by emerging growth markets Lutathera(USD 175 million, +17% cc) sales grew across all regions due to increased demand, following the presentation of NETTER-2 results in 1L GEP-NET Fabhalta(USD 22 million) continued to show encouraging early launch indicators in the US, as the first oral monotherapy approved for PNH patientsEmerging Growth Markets*Grew +16% (cc) overall. China grew +27% (cc) to USD 1.1 billion, mainly driven by Entresto and Xolair *All markets except the US, Canada, Western Europe, Japan, Australia, and New Zealand Net sales of the top 20 brands in Q2 2024 Q2 2024 % changeH1 2024 % change USD mUSDccUSD mUSD ccEntresto1 89825283 7773032Cosentyx1 52620222 8522123Kesimpta79963651 4366466Kisqali71745501 3444852Promacta/Revolade544-7-51 064-6-4Tafinlar + Mekinist5235999757Jakavi4718139491215Tasigna446-6-4841-10-9Xolair42718228261518Ilaris36816207241217Sandostatin Group313-5-466813Pluvicto34544446554545Zolgensma349121464446Lucentis275-30-28589-27-26Exforge Group178-3137003Lutathera17517173441516Leqvio182133134333135137Gilenya138-49-47313-38-36Scemblix16455563006567Diovan Group16039300-41Top 20 brands total9 998151819 3261618 R&D update - key developments from the second quarter New approvals Fabhalta(iptacopan)EU, Japan and China approval for the treatment of adults with the rare blood disorder paroxysmal nocturnal hemoglobinuria (PNH).Lutathera(lutetium Lu 177 dotatate)FDA approval for the treatment of pediatric patients (≥12 years) with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Regulatory updates Scemblix(asciminib)FDA granted Breakthrough Therapy designation to Scemblix for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). FDA submission for first-line CML is completed and under Real-Time Oncology Review.AtrasentanFDA filing accepted for the treatment of adult patients with IgA nephropathy (IgAN).Lutathera(lutetium Lu 177 dotatate)EU filing accepted for the treatment of newly diagnosed, unresectable or metastatic, well-differentiated (G2 and G3), somatostatin receptor-positive GEP-NETs in adults. Results from ongoing trials and other highlights Scemblix(asciminib)In the Phase III ASC4FIRST study, Scemblix demonstrated superior major molecular response rates at week 48 vs investigator-selected standard-of-care tyrosine kinase inhibitors (TKIs) (67.7% vs 49.0%) and vs imatinib alone (69.3% vs 40.2%) in adults with newly diagnosed Ph+ CML-CP. Scemblix also demonstrated a favorable safety and tolerability profile. These results have been submitted to the FDA under Real-Time Oncology Review. Data presented at ASCO and EHA 2024 and published in the New England Journal of Medicine. Kisqali(ribociclib)New analyses following the end of Kisqali treatment for all patients in the Phase III NATALEE study in HR+/HER2- early breast cancer showed a continued clinically meaningful benefit with a consistent safety profile. Results to be presented at an upcoming medical meeting. In addition, a subgroup analysis from the NATALEE study at the time of final iDFS data cut-off showed the addition of Kisqali to endocrine therapy in patients with high-risk node-negative (N0) disease resulted in a 28% risk reduction in iDFS. The efficacy, safety and tolerability profile observed in the high-risk N0 subgroup is consistent with the overall NATALEE study population. Data presented at ASCO 2024.Fabhalta(iptacopan)Phase III APPEAR-C3G data showed a 35.1% proteinuria reduction vs placebo at 6 months for C3G patients treated with Fabhalta in addition to supportive care. Secondary endpoint data for estimated glomerular filtration rate showed numerical improvement over 6 months vs placebo. The study also showed Fabhalta has a favorable safety profile with no new safety signals. Submissions to the FDA and EMA for the adult C3 glomerulopathy indication are planned for H2 2024. Data presented at ERA 2024. Phase III APPLAUSE-IgAN data showed a 38.3% proteinuria reduction at nine months vs placebo for patients with IgAN. Fabhalta was well tolerated with a favorable safety profile consistent with previously reported data. Data presented at WCN 2024.AtrasentanResults from a pre-specified interim analysis of Phase III ALIGN data showed patients treated with atrasentan, in addition to supportive care with a renin-angiotensin system inhibitor, achieved a statistically significant 36.1% reduction in proteinuria vs placebo on top of supportive care at 36 weeks. Results presented at ERA 2024.RemibrutinibPhase III REMIX-1 and REMIX-2 data showed sustained efficacy and long-term safety of oral remibrutinib in chronic spontaneous urticaria (CSU) patients, with improvements in weekly urticaria activity scores observed as early as week 1 and sustained to week 52. Across both studies, remibrutinib demonstrated a favorable and consistent safety profile up to one year, including balanced liver function tests vs placebo. Novartis plans to submit remibrutinib for regulatory approval in 2025. Data presented at EAACI 2024.Coartem (artemether- lumefantrine)Phase II/III CALINA study data demonstrated that an optimized dose of Coartem developed for babies weighing <5kg with malaria has the required pharmacokinetic profile and good efficacy and safety. Data presented at the Multilateral Initiative on Malaria Pan-African Malaria Conference 2024.Deals In line with our strategic focus on oncology, Novartis acquired >90% of the total share capital of MorphoSys AG, adding to our pipeline pelabresib, a late-stage investigational BET inhibitor for myelofibrosis, and tulmimetostat, an early-stage investigational dual inhibitor of EZH2 and EZH1 for solid tumors or lymphomas. Novartis acquired Mariana Oncology, a biotech company focused on developing novel radioligand therapies (RLTs) across a range of solid tumors. The acquisition brings a robust portfolio of RLT programs, including MC-339, an actinium-based RLT being investigated in small cell lung cancer. Novartis expanded its peptide discovery collaboration with PeptiDream. Under the multi-program agreement, PeptiDream will identify and optimize novel macrocyclic peptides against targets selected by Novartis, for potential application in RLT. Novartis signed an exclusive strategic license agreement with Arvinas for the worldwide development and commercialization of ARV-766, a second generation PROTAC® androgen receptor (AR) degrader, complementing our RLT platform in prostate cancer. 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 2024, Novartis repurchased a total of 26.7 million shares for USD 2.7 billion on the SIX Swiss Exchange second trading line. These purchases included 25.9 million shares (USD 2.6 billion) under the up-to USD 15 billion share buyback announced in July 2023 (with up to USD 10.1 billion still to be executed). In addition, 0.8 million shares (USD 0.1 billion) were repurchased to mitigate dilution related to participation plans of associates, with the remainder of repurchases for this purpose to be executed in H2 2024. Further, 1.1 million shares (for an equity value of USD 0.1 billion) were repurchased from associates. In the same period, 8.4 million shares (for an equity value of USD 0.5 billion) were delivered as a result of share deliveries related to participation plans of associates. Consequently, the total number of shares outstanding decreased by 19.4 million versus December 31, 2023. These treasury share transactions resulted in an equity decrease of USD 2.3 billion and a net cash outflow of USD 2.7 billion. As of June 30, 2024, net debt increased to USD 18.8 billion compared to USD 10.2 billion net debt at December 31, 2023. The increase was mainly due to the USD 7.6 billion annual dividend payment, net cash outflow for M&A / intangible assets transactions of USD 5.0 billion and cash outflow for treasury share transactions of USD 2.7 billion, partially offset by USD 6.7 billion free cash flow. As of Q2 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 high single to low double-digit(unchanged)Core operating incomeExpected to grow mid- to high teens(from low double-digit to mid-teens) Key assumptions: Our guidance assumes that no Entresto generics and no Promacta generics launch in the US in 2024 Foreign exchange impact If mid-July exchange rates prevail for the remainder of 2024, the foreign exchange impact for the year would be negative 2 to negative 1 percentage points on net sales and negative 3 percentage points on core operating income. The estimated impact of exchange rates on our results is provided monthly on our website. 2025 Annual General Meeting Nomination for election to the Board of Directors The Novartis Board of Directors announced today that it is nominating Elizabeth M. McNally, MD, PhD, for election to the Board. Dr. McNally is Director of the Center for Genetic Medicine at Northwestern University, Feinberg School of Medicine, and as a practicing cardiologist and renowned research leader specializing in the genetics of cardiovascular and neuromuscular disorders, her clinical and scientific expertise will add greatly to the Novartis Board of Directors. Dr. McNally completed her MD and PhD at the Albert Einstein College of Medicine, and trained in Internal Medicine and Cardiology at the Brigham and Women’s Hospital at Harvard Medical School. She is a member of the National Academy of Medicine, serves on the Board of the Muscular Dystrophy Association, and is also the Founder and CEO of Ikaika Therapeutics. Board of Directors announcements The Board also noted Charles L. Sawyers and William T. Winters will not stand for re-election at the AGM 2025 in accordance with the 12-year term limit. The Board of Directors and the Executive Committee of Novartis thank them for their outstanding contributions and many years of distinguished service. Key figures1 Continuing operations2Q2 2024Q2 2023% change H1 2024H1 2023% change USD m USD mUSDcc USD m USD mUSDccNet sales12 51211 437911 24 34122 235911Operating income4 0142 8074347 7 3875 4253643As a % of sales32.124.5 30.324.4 Net income3 2462 2714349 5 9344 4213443EPS (USD)1.601.094752 2.912.123747Cash flows from operating activities4 8753 51739 7 1406 36912 Non-IFRS measures Free cash flow 4 6153 29240 6 6535 97611 Core operating income4 9534 2401719 9 4908 1461621As a % of sales39.637.1 39.036.6 Core net income4 0083 5021418 7 6896 7351419Core EPS (USD)1.971.691721 3.773.231722 Discontinued operations2Q2 2024Q2 2023% change H1 2024H1 2023% change USD m USD mUSDcc USD m USD mUSDccNet sales 2 449nmnm 4 952nmnmOperating income 113nmnm 351nmnmAs a % of sales 4.6 7.1 Net income 46nmnm 190nmnmNon-IFRS measures Core operating income 428nmnm 935nmnmAs a % of sales 17.5 18.9 Total CompanyQ2 2024Q2 2023% change H1 2024H1 2023% change USD m USD mUSDcc USD m USD mUSDccNet income3 2462 317nmnm 5 9344 611nmnmEPS (USD)1.601.11nmnm 2.912.20nmnmCash flows from operating activities4 8753 576nmnm 7 1406 533nmnmNon-IFRS measures Free cash flow 4 6153 275nmnm 6 6535 995nmnmCore net income4 0083 811nmnm 7 6897 425nmnmCore EPS (USD)1.971.83nmnm 3.773.54nmnm 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 43 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 33 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/a9652d15-40e9-4a4b-b225-32014f48e99e/ 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,” “will,” “continue,” “ongoing,” “grow,” “launch,” “expect,” “deliver,” “focus,” “address,” “accelerate,” “deliver,” “remain,” “scaling,” “guidance,” “outlook,” “long-term,” “priority,” “potential,” “can,” “trajectory” 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, including completion of the acquisition of MorphoSys AG; 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. This communication is neither an offer to purchase nor a solicitation of an offer to sell shares of MorphoSys. The final terms and further provisions regarding the delisting purchase offer are available in the offer document published by Novartis BidCo AG (formerly known as Novartis data42 AG) (the “Bidder”). The offer document has been approved by the BaFin and has been filed with the U.S. Securities and Exchange Commission (the “SEC”). The solicitation and offer to buy shares of MorphoSys is only being made pursuant the offer document. In connection with the Offer, the Bidder and Novartis AG have filed Tender Offer Statement on Schedule TO with the SEC (together with the offer document, an Offer to Purchase including the means to tender and other related documents, the “Offer Documents”), the management board and supervisory board of MorphoSys have issued a joint reasoned statement in accordance with sec. 27 of the German Securities Acquisition and Takeover Act and MorphoSys has filed a Solicitation/Recommendation Statement on Schedule 14D-9 with the SEC (together with the joint reasoned statement, the “Recommendation Statements”). THE MORPHOSYS SHAREHOLDERS AND OTHER INVESTORS ARE URGED TO READ THE OFFER DOCUMENTS AND THE RECOMMENDATION STATEMENTS BECAUSE THEY CONTAIN IMPORTANT INFORMATION WHICH SHOULD BE READ CAREFULLY BEFORE ANY DECISION IS MADE WITH RESPECT TO THE OFFER. The Offer Documents and the Recommendation Statements have been distributed to all stockholders of MorphoSys in accordance with German and U.S. securities laws. The Tender Offer Statement on Schedule TO and the Solicitation/Recommendation Statement on Schedule 14D-9 are available for free at the SEC’s website at www.sec.gov. Additional copies may be obtained for free by contacting the Bidder or MorphoSys. Free copies of these materials and certain other offering documents are available on the Bidder’s website at www.novartis.com/investors/morphosys-acquisition or by contacting the Bidder’s investor relations department at +41 61 324 7944. 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 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 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 October 29, 2024 November 20-21, 2024 January 31, 2025 Third quarter & nine months 2024 resultsMeet Novartis Management 2024 (London, UK)Fourth quarter & full year 2024 results Please find full media release in English attached and on the following link:Media Release (PDF) Further language versions are available through the following links: German version is available through the following link:Medienmitteilung (PDF) French version is available through the following link:Communiqué aux médias (PDF)

Clinical ResultDrug ApprovalPhase 3Breakthrough TherapyFinancial Statement

24 Apr 2024

·www.globenewswire.com

Novartis and Medicines for Malaria Venture announce positive efficacy and safety data for a novel treatment for babies <5 kg with malaria

There is currently no evidence-based treatment for the smallest babies with malaria The CALINA study tested a new ratio and dose of Coartem® (artemether- lumefantrine) to account for metabolic differences in babies under 5 kg The CALINA trial indicated that the new formulation has good efficacy and safety, and the data have been submitted for regulatory review Basel, April 24, 2024 – Novartis and Medicines for Malaria Venture (MMV) announce positive data from their phase II/III CALINA study, demonstrating that a novel formulation of Coartem® (artemether-lumefantrine) developed for babies weighing less than 5kg with malaria has the required pharmacokinetic profile and good efficacy and safety. The trial was conducted in several African countries. The data, which will be presented this week at the Multilateral Initiative on Malaria (MIM Society) 8th Pan-African Malaria Conference in Kigali, have been submitted for regulatory review. Malaria exerts a massive burden on public health across the world, particularly in Africa1. Huge strides have been made in recent decades in the treatment of malaria. However, to date, little data has been generated in the smallest children – babies less than 5 kg. “We are pleased with the positive outcomes from our CALINA study and to be one step closer to bringing an effective malaria treatment to all age groups, including vulnerable newborn babies," said Shreeram Aradhye, President, Development and Chief Medical Officer at Novartis. “We have been committed to the fight against malaria for more than two decades, and this successful trial represents another milestone towards ensuring that all people have access to an appropriate antimalarial therapy.” The CALINA study is led by Novartis, with the scientific and financial support of Medicines for Malaria Venture (MMV), and as part of the PAMAfrica consortium, which is funded by the European & Developing Countries Clinical Trials Partnership (EDCTP2). It is the first evidence-based trial conducted to evaluate a new antimalarial dose and regimen for all infants weighing under 5 kg with acute uncomplicated malaria. If approved, Novartis and MMV aim to make the treatment available as soon as possible to the youngest infants, who currently lack access to evidence-based treatment options. The new formulation, known as Coartem <5 kg Baby, uses a new ratio and dose of artemether-lumefantrine to account for metabolic differences in babies under 5kg. Infants under 5 kg can be affected by placental malaria, leading to poor birth outcomes, or contract malaria from the bite of an infected mosquito. The prevalence of the disease in this age and weight group is poorly understood, and it is therefore often misdiagnosed. Current antimalarials have not been developed specifically for infants weighing under 5 kg. There is no approved treatment available for them, and they are treated with tablets meant for children above 5 kg adjusted by weight2. Yet, these tiny patients handle drugs differently due to the immaturity of their metabolizing organs, which can lead to overdose and toxicity. Coartem <5 kg Baby provides optimized dosing specifically tailored to the needs of these vulnerable patients. If approved, the treatment will close a significant treatment gap. “Infants below 5 kg make up a critical neglected group, and developing antimalarials specifically suited to their needs is essential to malaria control efforts,” said Wiweka Kaszubska, Executive Vice President, Head of Product Development, MMV. “The success of the CALINA trial brings us one step closer to ensuring that all patients have access to appropriate and effective treatments.” “The CALINA trial is an example of the type of Europe-Africa collaboration we need to close malaria treatment gaps for vulnerable groups, and EDCTP is proud to be part of this endeavor,” said Pauline Beattie, Operations Manager and Scientific Advisor, EDCTP Association. This year's theme for World Malaria Day – Health Equity, Gender, and Human Rights – serves as a stark reminder of our collective responsibility to protect every child from malaria. It underscores the need to ensure that the youngest and most vulnerable among us also have access to the right treatment. About the CALINA studyPharmacokinetics, Safety, Tolerability and Efficacy of a New Artemether-lumefantrine Dispersible Tablet in Infants and Neonates <5 kg Body Weight With Acute Uncomplicated Plasmodium Falciparum Malaria (CALINA) is an open-label, single-arm, multicenter phase II/III study in young infants < 5 kg with uncomplicated Plasmodium falciparum malaria, which evaluated the PK, safety, tolerability and efficacy of a new dose regimen (5mg:60mg). The study consists of a core segment (treatment and follow-up for 43 days) and long-term follow-up at 12 months of age to assess neurodevelopmental status. The trial was conducted in Burkina Faso, DRC, Kenya, Mali, Nigeria, and Zambia. The primary PK endpoint of the study was met for patients > 28 days of age. For neonates <= 28 days of age, although the sample size was too small for a conclusive statistical evaluation, the required value of the PK endpoint was also within the calculated interval. The key secondary endpoint of lumefantrine C168 concentration was also met for cohort 1 and within range for cohort 2. This indicates that the new dose regimen/formulation delivers exposures to artemether and lumefantrine proven to be safe and effective in paediatric patients of higher body weight. More information about the trial can be found here. DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About 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. About MMVMMV is a leading product development partnership (PDP) in the field of antimalarial drug development and delivery. Its mission is to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating delivery of new, effective and affordable antimalarial drugs. Since its foundation in 1999, MMV and partners have built the largest portfolio of antimalarial R&D and access projects ever assembled, have brought forward 15 medicines that are treating patients. An estimated 15.4 million deaths have been averted by these MMV co-developed medicines. MMV’s vision is a world in which innovative medicines will cure and protect the vulnerable and under-served populations at risk of malaria and help to ultimately eradicate this terrible disease. References World malaria report 2023 (who.int)WHO guidelines for malaria - 16 October 2023 (magicapp.org) # # # Novartis Media RelationsE-mail: media.relations@novartis.com Central North America Richard Jarvis+41 79 584 2326Michael Meo+1 862 274 5414Anja von Treskow+41 79 392 9697Marlena Abdinoor+1 617 335 9525Anna Schäfers+41 79 801 7267 Switzerland Satoshi Sugimoto+41 79 619 2035 Novartis Investor RelationsCentral investor relations line: +41 61 324 7944E-mail: investor.relations@novartis.com Central North America Isabella Zinck+41 61 324 7188Sloan Simpson+1 862 345 4440Nicole Zinsli-Somm+41 61 324 3809Jonathan Graham+1 201 602 9921Imke Kappes+41 61 324 8269Parag Mahanti+1 973 876 4912

Clinical StudyClinical Result

14 Dec 2023

·www.prnewswire.com

Fosun Pharma's Global Multi-Center Phase III Clinical Trial Project for A New Antimalarial Drug Receives 500 Million Japanese Yen Investment from GHIT Fund to Jointly Improve the Global Accessibility of Antimalarial Drugs

SHANGHAI, Dec. 14, 2023 /PRNewswire/ -- The Japan-based Global Health Innovative Technology Fund (GHIT Fund) announced today that it will invest approximately US$3.3 million (approximately 500 million yen[1]) in a global multicenter Phase III clinical trial project (the "Program") led by Fosun Pharma for a triple artemisinin combination drug (Artemether-Lumefantrine-Amodiaquine fixed-dose formulation) against malaria in Africa and Southeast Asia, to accelerate the development and commercialization of this new drug. The Project will be jointly conducted by Fosun Pharma, a major Chinese pharmaceutical and healthcare company, Marubeni, a leading Japanese integrated trading and investment business conglomerate, a Thailand-based research collaboration of universities, Mahidol-Oxford Tropical Medicine Research Unit (MORU), and the product development partnership Medicines for Malaria Venture (MMV), which provides technical support and market access expertise. This is the first time GHIT Fund has invested in a research project led by a Chinese pharmaceutical company. This drug candidate should have a significant public health benefit as it is expected to play an important role in the fight against artemisinin partial resistance (ART-R) which is now observed widely in the Greater Mekong Subregion (GMS) of Southeast Asia[2] and to some extent in several African countries, including Rwanda and Uganda. Importantly, the project includes the development of a co-formulated child-friendly version, given that most malaria cases are in children[3]. Malaria is an infectious parasitic disease transmitted by mosquitos that affects approximately 250 million people annually and was responsible for approximately 620,000 deaths in 20213. Infection in the African region constitutes 95% of the total global malaria cases, and children under the age of 5 account for 80% of all malaria deaths in this region. The GHIT Fund invests in innovative drug development with the aim of contributing to global health through facilitating collaboration between Japanese and global institutions' technology and innovation to address these neglected infectious diseases. Wen Deyong, CEO of Fosun Pharma, said, "We are very pleased to work with GHIT Fund to promote the clinical research on this antimalarial innovator drug. The collaboration will accelerate the launch of this new drug so as to actively respond to the threat of artemisinin partial resistance and partner drug resistance of Plasmodium falciparum parasites and save more lives from malaria. Fosun Pharma is committed to further improving the accessibility and affordability of antimalarial drugs through continuous innovation and our global operational capabilities, so as to continuously strive for a malaria-free world." Dr. Osamu Kunii, CEO of the GHIT Fund, said "We are very excited to have Marubeni and FOSUN PHARMA as our new product development partners. It is an important step forward to invest in the development of antimalarial drugs in late-phase clinical trials to advance commercialization. The number of malaria cases and deaths in children under 5 years old is an urgent issue. This investment will make a significant contribution to reducing the burden of malaria globally, especially among young children." The antimalarial drug independently developed by Fosun Pharma has been used to treat more than 60 million patients with severe malaria worldwide The artemisinin based antimalaria medicines originated from China have made significant contributions to global malaria prevention and control. In Sub-Saharan Africa alone, about 240 million people benefit from artemisinin-based combination therapies every year. The artesunate for injection (Artesun®) independently developed by Fosun Pharma is the first-line treatment of severe malaria for both adults and children recommended by the WHO since 2011. It has become a well-known Chinese innovator drug in Africa and the world. So far, Artesun® has been used to treat more than 60 million patients with severe malaria worldwide, most of whom were African children under five years old. In June 2023, the second-generation artesunate for injection (Argesun®) independently developed by Fosun Pharma was prequalified by the WHO (WHO-PQ), becoming the first injectable artesunate presented with a single solvent system approved by WHO-PQ. It greatly improves the convenience of clinical use and is particularly practicable for remote areas in Africa with backward medical conditions to save more lives. Up to now, the product has been registered and marketed in 18 countries. The deployment of Fosun Pharma's new generation Argesun® has further improved the accessibility of high-quality antimalarial innovator drugs in Africa, providing a convenient solution for primary medical institutions to treat sever malaria patients and save lives. Fosun Pharma was therefore recognized on Fortune 2023 China's Most Admired Company List. Effectively reduce the incidence rate of severe malaria in children from treatment to prevention As an innovation-driven global pharmaceutical and health industry group, Fosun Pharma has independently developed innovative antimalarial products covering malaria prevention and treatment, as well as the rescue of critically ill patients. From "treatment" to "prevention", Fosun Pharma continues to provide more prevention and treatment solutions for malaria patients, especially children. In August 2018, Fosun Pharma's SPAQ-CO® Disp (co-packed sulfadoxine-pyrimethamine dispersible tablets and amodiaquine dispersible tablets), for the prevention of malaria in children, was prequalified by WHO. Fosun Pharma has actively carried out community-oriented "Child Malaria Prevention Knowledge Popularization Projects" in 14 malaria-endemic countries in Africa. These projects aim to enhance local awareness of malaria prevention among African populations, thus helping to reduce the incidence of malaria and interrupt community transmission of the disease. By the end of June 2023, more than 245 million children in Africa had benefited from the "Seasonal Malaria Chemoprevention Program", for which SPAQ-CO® Disp is used as the core drug, effectively reducing the incidence of malaria in children under five years old in Africa. About GHIT Fund The GHIT Fund is a Japan-based international public-private partnership (PPP) fund that was formed between the Government of Japan, multiple pharmaceutical companies, the Bill & Melinda Gates Foundation, Wellcome, and the United Nations Development Programme (UNDP). The GHIT Fund invests in and manages an R&D portfolio of development partnerships aimed at addressing neglected diseases, such as malaria, tuberculosis, and neglected tropical diseases, which afflict the world's vulnerable and underserved populations. In collaboration with global partners, the GHIT Fund mobilizes Japanese industry, academia, and research institutes to create new drugs, vaccines, and diagnostics for malaria, tuberculosis, and neglected tropical diseases. About Fosun Pharma Founded in 1994, Shanghai Fosun Pharmaceutical (Group) Co., Ltd.* ("Fosun Pharma"; stock code: 600196. SH, 02196. HK) is a global innovation-driven pharmaceutical and healthcare industry group. Fosun Pharma directly operates businesses including pharmaceuticals, medical devices, medical diagnosis, and healthcare services. As a shareholder of Sinopharm Co., Ltd., Fosun Pharma expands its areas in the pharmaceutical distribution and retail business. Fosun Pharma is patient-centered and clinical needs-oriented. The company continuously enriches its innovative product pipeline through independent research and development, cooperative development, license-in, and in-depth incubation. Fosun Pharma improves the research and clinical development capabilities of FIC (First-in-class) and BIC (Best-in-class) new drugs as well as accelerates the R&D and launch of innovative technologies and products. Guided by the 4IN strategy (Innovation, Internationalization, Intelligentization, and Integration), Fosun Pharma will uphold the development model of "Innovation Transformation, Integrated Operation and Steady Growth", with the mission of creating shareholder values through strengthening its independent R&D and external cooperation and enriching its product pipelines, as well as promoting the global networks and enhancing operational efficiency. Fosun Pharma will actively promote the digital and physical business layout in the pharmaceutical and healthcare industry and is committed to becoming a first-class enterprise in the global pharmaceutical and healthcare markets. For more information, please visit our official website: . SOURCE Fosun Pharma

Phase 3Drug Approval

100 Deals associated with Artemether/Lumefantrine

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KEGG	Wiki	ATC	Drug Bank
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R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Acute Malaria	US	Novartis Pharmaceuticals Corp.	07 Apr 2009
Malaria	CN	KPC Pharmaceuticals, Inc.	01 Jan 1992

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria, Falciparum	Phase 3	KE	Novartis AG	01 Jul 2002
Malaria, Falciparum	Phase 3	NG	Novartis AG	01 Jul 2002
Malaria, Falciparum	Phase 3	TZ	Novartis AG	01 Jul 2002

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04300309 (CALINA, CTgov)	Phase 2/3	Malaria, Falciparum	28	artemether-lumefantrine (Cohort 1)	cfbjddhivy(gvjgawvuew) = eegxqcooys dzsrkzypxy (tvcwkvyfkf, pkzojrlusx - mhvnlwtcll) View more	-	03 Oct 2024
				artemether-lumefantrine (Cohort 2)	cfbjddhivy(gvjgawvuew) = doxiqztopz dzsrkzypxy (tvcwkvyfkf, sjmwrqspzv - kncyohkoxp) View more
NCT05070520 (Pubmed) Manual	Phase 4	Malaria, Falciparum First line	255	Artemether/lumefantrine	rcxbguqkqn(jxethvcbmn) = tjhotdbzlj nrdbssbbmz (owfjsgrptg, 96.4 - 101.0)	Positive	13 May 2024
				Artemether/lumefantrine (Tessaoua)	rcxbguqkqn(jxethvcbmn) = lkqvzgxujk nrdbssbbmz (owfjsgrptg, 85.0 - 98.5)
NCT03453840 (Pubmed)	Phase 4	Malaria HIV \| 18S rRNA \| SBP1	303	3-day artemether-lumefantrine regimen	ejhrriqwkj(xjoiucuapk) = zwnmgvgdhp iijeacgaha (tdjppxrufe )	Positive	07 May 2024
				5-day artemether-lumefantrine regimen	ejhrriqwkj(xjoiucuapk) = qzsfuirara iijeacgaha (tdjppxrufe )
NCT04300309 (CALINA, GlobeNewswire) Manual	Phase 2/3	Malaria	-	artemether-lumefantrine	-	Positive	24 Apr 2024
NCT04944966 (Pubmed) Manual	Phase 1	Malaria	12	Maytenus senegalensis	dxjjpfnufe(kxbcqgfdgv) = qxifoboodu sahkqlabps (csihrgqlwz ) View more	Positive	12 Apr 2024
NCT04041973 (Pubmed \| Lancet Infect Dis)	Not Applicable	-	1,480	Artemether-lumefantrine	kyylzckazk(uplabenehx) = Overall prevalence of adverse events was 1·9% (355 events in 18 806 doses) in the artemether-lumefantrine group and 1·1% (207 events in 19 132 doses) in the multivitamin group (p<0·0001) vcgylmzktb (ofsonyouno ) View more	Positive	26 Sep 2022
				Antimalarial chemoprophylaxis (Multivitamin)
NCT03453840 (Pubmed \| Clin Infect Dis)	Not Applicable	Malaria	177	3-day AL regimen	lkpnhbnbba(gitwhyithf) = tpvhidgqpt mzaaklpdke (gbhpfikkas ) View more	-	20 Sep 2022
				5-day AL regimen	lkpnhbnbba(gitwhyithf) = dqcyfhkouh mzaaklpdke (gbhpfikkas ) View more
NCT03355664 (TACT-CV, CTgov)	Phase 3	Malaria, Falciparum	310	Artemether-lumefantrine+Primaquine (Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24)	ngdigctfte(htqnjepdmy) = yodxwfcggn btoeeptkhk (urmiyxlmqq, kitaexjnlj - adfmhzhtxl) View more	-	15 Jul 2022
				Artemether-lumefantrine+Primaquine+Amodiaquine (Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24)	ngdigctfte(htqnjepdmy) = odntgisufp btoeeptkhk (urmiyxlmqq, ovocnglcdo - vltbvtdgkf) View more
NCT03952650 (CTgov)	Phase 1/2	Malaria	252	PYR+PfSPZ (1a - Pilot/Safety: Dosing Interval on Days: 1)	ysnjoxoqka(vaxrpjqjmu) = smucfaeayl odzmfjlzqt (lycdhlafse, hszyjpkqms - zqdmrqcggi) View more	-	12 Jul 2022
				PYR+PfSPZ (2a - Pilot/Safety: Dosing Interval on Days: 1)	ysnjoxoqka(vaxrpjqjmu) = hvpivwajcl odzmfjlzqt (lycdhlafse, xhkiymahur - nwlokdttfu) View more
ACTRN12616001422415 (Pubmed \| Malar J)	Phase 4	Malaria	994	Artemether-lumefantrine (AL)	uzoathbnmc(hdnpfwmbmw) = jwcnndwnkl nfvrbtuiri (zufiyywcxu )	-	02 May 2022
				Artesunate-amodiaquine (ASAQ)	uzoathbnmc(hdnpfwmbmw) = dxsxojvnjp nfvrbtuiri (zufiyywcxu )

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