Atypical Hemolytic Uremic Syndrome

AstraZeneca’s Ultomiris (ravulizumab-cwvz) gained approval from the FDA for the treatment of adults with AQP4 antibody-positive (Ab+) neuromyelitis optica spectrum disorder (NMOSD). The agency had rejected the long-acting C5 complement inhibitor in this indication last year, calling for modifications to the risk evaluation and mitigation strategy (REMS).Specifically, the FDA requested changes to the REMS to further validate patients' meningococcal vaccination status or prophylactic administration of antibiotics prior to treatment. AstraZeneca said Monday that approval of Ultomiris was based on findings from the Phase III CHAMPION-NMOSD trial. The study achieved its primary endpoint of time to first on-trial relapse, with no relapses observed among Ultomiris patients with a median treatment duration of 73 weeks.Marc Dunoyer, CEO of the company’s Alexion unit, noted that Ultomiris “has the potential to eliminate relapses with a convenient dosing schedule every eight weeks.” The intravenous therapy is currently approved to treat AQP4 Ab+ NMOSD in the EU, Japan and Canada, with regulatory reviews ongoing in additional countries.In addition, Ultomiris is authorised in the US for the treatment of: certain adults with generalised myasthenia gravis; certain adults and children with paroxysmal nocturnal haemoglobinuria; and certain adults and children with atypical haemolytic uraemic syndrome to inhibit complement-mediated thrombotic microangiopathy.

First and only long-acting C5 complement inhibitor offers patients with AQP4 Ab+ NMOSD the potential to live relapse-free Unprecedented relapse risk reduction observed in CHAMPION-NMOSD trial underscores how ULTOMIRIS may redefine patient journey for rare neurological disease WILMINGTON, Del.--(BUSINESS WIRE)-- ULTOMIRIS® (ravulizumab-cwvz) has been approved in the United States (US) as the first and only long-acting C5 complement inhibitor for the treatment of adult patients with anti-aquaporin-4 (AQP4) antibody-positive (Ab+) neuromyelitis optica spectrum disorder (NMOSD).1 The approval by the US Food and Drug Administration (FDA) was based on positive results from the CHAMPION-NMOSD Phase III trial, which were published in the Annals of Neurology.2 In the trial, ULTOMIRIS was compared to an external placebo arm from the pivotal SOLIRIS® PREVENT clinical trial. ULTOMIRIS met the primary endpoint of time to first on-trial relapse as confirmed by an independent adjudication committee. Zero relapses were observed among ULTOMIRIS patients with a median treatment duration of 73 weeks (relapse risk reduction: 98.6%, hazard ratio (95% CI): 0.014 (0.000, 0.103), p<0.0001).2 NMOSD is a rare and debilitating autoimmune disease that affects the central nervous system (CNS), including the spine and optic nerves.3-5 Most people living with NMOSD experience unpredictable relapses, characterized by a new onset of neurologic symptoms or worsening of existing neurologic symptoms, which tend to be severe and recurrent and may result in permanent disability.6-8 The diagnosed prevalence of adults with NMOSD in the US is estimated at approximately 6,000.9-11 Sean J. Pittock, MD, Director of Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology and of Mayo's Neuroimmunology Laboratory and lead primary investigator in the CHAMPION-NMOSD trial, said: “C5 inhibition has been proven to offer efficacy in reducing the risk of NMOSD relapses by blocking the complement system, a part of the immune system, from attacking healthy cells in the spinal cord, optic nerve and brain. With today’s FDA approval, patients now have the option of a long-acting C5 inhibitor treatment that showed zero relapses in the pivotal CHAMPION-NMOSD trial, supporting the primary goal of relapse prevention in treating NMOSD.” Marc Dunoyer, Chief Executive Officer, Alexion, said: “Alexion has been at the forefront of innovation in NMOSD, striving to offer patients a future without fear of life-altering or even fatal relapses. Building on the established efficacy of C5 inhibition for people living with AQP4 Ab+ NMOSD, we are proud to deliver a transformative, long-acting treatment option that has the potential to eliminate relapses with a convenient dosing schedule every eight weeks. We are grateful to the NMOSD community for their ongoing collaboration and input, which enables us to advance science for rare diseases.” Overall, the safety and tolerability of ULTOMIRIS in the CHAMPION-NMOSD trial were consistent with previous clinical studies and real-world use, and no new safety signals were observed. The most common adverse events (AEs) were COVID-19, headache, back pain, arthralgia and urinary tract infection.2 ULTOMIRIS is also approved for certain adults with NMOSD in Japan and the European Union (EU). Regulatory reviews are ongoing in additional countries. INDICATION(S) & IMPORTANT SAFETY INFORMATION INDICATION(S) What is ULTOMIRIS? ULTOMIRIS is a prescription medicine used to treat: adults and children 1 month of age and older with a disease called Paroxysmal Nocturnal Hemoglobinuria (PNH). adults and children 1 month of age and older with a disease called atypical Hemolytic Uremic Syndrome (aHUS). ULTOMIRIS is not used in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). adults with a disease called generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive. adults with a disease called Neuromyelitis Optica Spectrum Disorder (NMOSD) who are anti-aquaporin 4 (AQP4) antibody positive. It is not known if ULTOMIRIS is safe and effective in children younger than 1 month of age. It is not known if ULTOMIRIS is safe and effective for the treatment of gMG or NMOSD in children. IMPORTANT SAFETY INFORMATION What is the most important information I should know about ULTOMIRIS? ULTOMIRIS is a medicine that affects your immune system and may lower the ability of your immune system to fight infections. ULTOMIRIS increases your chance of getting serious meningococcal infections that may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update meningococcal vaccine(s) at least 2 weeks before your first dose of ULTOMIRIS. If you have not completed your meningococcal vaccines and ULTOMIRIS must be started right away, you should receive the required vaccine(s) as soon as possible. If you have not been vaccinated and ULTOMIRIS must be started right away, you should also receive antibiotics for as long as your healthcare provider tells you. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting ULTOMIRIS. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a meningococcal infection: fever, fever with high heart rate, headache and fever, confusion, muscle aches with flu-like symptoms, fever and a rash, headache with nausea or vomiting, headache with a stiff neck or stiff back, or eyes sensitive to light. Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 8 months after your last ULTOMIRIS dose. Your risk of meningococcal infection may continue for several months after your last dose of ULTOMIRIS. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. ULTOMIRIS is only available through a program called the ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy (REMS). Before you can receive ULTOMIRIS, your healthcare provider must: enroll in the REMS program; counsel you about the risk of serious meningococcal infections; give you information about the signs and symptoms of serious meningococcal infection; make sure that you are vaccinated against serious infections caused by meningococcal bacteria, and that you receive antibiotics if you need to start ULTOMIRIS right away and are not up to date on your vaccines; give you a Patient Safety Card about your risk of meningococcal infection. ULTOMIRIS may also increase the risk of other types of serious infections, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. Your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) if treated with ULTOMIRIS. Certain people may be at risk of serious infections with gonorrhea. Who should not receive ULTOMIRIS? Do not receive ULTOMIRIS if you have a serious meningococcal infection when you are starting ULTOMIRIS. Before you receive ULTOMIRIS, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever, are pregnant or plan to become pregnant, and are breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS will harm your unborn baby or if it passes into your breast milk. You should not breastfeed during treatment and for 8 months after your final dose of ULTOMIRIS. Tell your healthcare provider about all the vaccines you receive and medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements which could affect your treatment. If you have PNH and you stop receiving ULTOMIRIS, your healthcare provider will need to monitor you closely for at least 16 weeks after you stop ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: drop in your red blood cell count, tiredness, blood in your urine, stomach-area (abdomen) pain, shortness of breath, blood clots, trouble swallowing, and erectile dysfunction (ED) in males. If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 months after stopping treatment for signs of worsening aHUS or problems related to a type of abnormal clotting and breakdown of your red blood cells called thrombotic microangiopathy (TMA). Symptoms or problems that can happen with TMA may include: confusion or loss of consciousness, seizures, chest pain (angina), difficulty breathing and blood clots or stroke. What are the possible side effects of ULTOMIRIS? ULTOMIRIS can cause serious side effects including infusion-related reactions. Symptoms of an infusion-related reaction with ULTOMIRIS may include lower back pain, abdominal pain, muscle spasms, changes in blood pressure, tiredness, feeling faint, shaking chills (rigors), discomfort in your arms or legs, bad taste, or drowsiness. Stop treatment of ULTOMIRIS and tell your healthcare provider right away if you develop these symptoms, or any other symptoms during your ULTOMIRIS infusion that may mean you are having a serious infusion-related reaction, including: chest pain, trouble breathing or shortness of breath, swelling of your face, tongue, or throat, and feel faint or pass out. The most common side effects of ULTOMIRIS in people treated for PNH are upper respiratory tract infection and headache. The most common side effects of ULTOMIRIS in people treated for aHUS are upper respiratory tract infection, diarrhea, nausea, vomiting, headache, high blood pressure and fever. The most common side effects of ULTOMIRIS in people with gMG are diarrhea and upper respiratory tract infections. The most common side effects of ULTOMIRIS in people with NMOSD are COVID-19 infection, headache, back pain, urinary tract infection, and joint pain (arthralgia). Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of ULTOMIRIS. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider right away if you miss an ULTOMIRIS infusion or for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Please see the accompanying full Prescribing Information and Medication Guide for ULTOMIRIS, including Boxed WARNING regarding serious meningococcal infections. Notes NMOSD NMOSD is a rare disease in which the immune system is inappropriately activated to target healthy tissues and cells in the CNS.3,4 Approximately three-quarters of people with NMOSD are anti-AQP4 Ab+, meaning they produce antibodies that bind to a specific protein, aquaporin-4 (AQP4).5,12 This binding can inappropriately activate the complement system, which is part of the immune system and is essential to the body’s defense against infection, to destroy cells in the optic nerve, spinal cord and brain.3,13,14 It most commonly affects women and begins in the mid-30s. Men and children may also develop NMOSD, but it is even more rare.15,16 People with NMOSD may experience vision problems, intense pain, loss of bladder/bowel function, abnormal skin sensations (e.g., tingling, prickling or sensitivity to heat/cold) and impact on coordination and/or movement.5-7,17,18 Most people living with NMOSD experience unpredictable relapses, also known as attacks. Each relapse can result in cumulative disability including vision loss, paralysis and sometimes premature death.6-8 NMOSD is a distinct disease from other CNS diseases, including multiple sclerosis. The journey to diagnosis can be long, with the disease sometimes misdiagnosed.19-21 CHAMPION-NMOSD CHAMPION-NMOSD is a global Phase III, open-label, multicenter trial evaluating the safety and efficacy of ULTOMIRIS in adults with NMOSD. The trial enrolled 58 patients across North America, Europe, Asia-Pacific and Japan. Participants were required to have a confirmed NMOSD diagnosis with a positive anti-AQP4 antibody test, at least one attack or relapse in the twelve months prior to the screening visit, an Expanded Disability Status Scale Score of 7 or less and body weight of at least 40 kilograms at trial entry. Participants could stay on stable supportive immunosuppressive therapy for the duration of the trial.22 Due to the potential long-term functional impact of NMOSD relapses and available effective treatment options, a direct placebo comparator arm was precluded for ethical reasons. The active treatment was compared to an external placebo arm from the pivotal SOLIRIS PREVENT clinical trial. Over a median treatment duration of 73 weeks, all enrolled patients received a single weight-based loading dose of ULTOMIRIS on Day 1, followed by regular weight-based maintenance dosing beginning on Day 15, every eight weeks. The primary endpoint was time to first on-trial relapse, as confirmed by an independent adjudication committee. The end of the primary treatment period could have occurred either when all patients completed or discontinued prior to the Week 26 visit and two or more adjudicated relapses were observed, or when all patients completed or discontinued prior to the Week 50 visit if fewer than two adjudicated relapses were observed. In the trial, there were zero adjudicated relapses, so the end of the primary treatment period occurred when the last enrolled participant completed the 50-week visit. Patients who completed the primary treatment period were eligible to continue into a long-term extension period, which is ongoing. ULTOMIRIS® (ravulizumab-cwvz) ULTOMIRIS® (ravulizumab-cwvz), the first and only long-acting C5 complement inhibitor, provides immediate, complete and sustained complement inhibition. The medication works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system. When activated in an uncontrolled manner, the complement cascade over-responds, leading the body to attack its own healthy cells. ULTOMIRIS is administered intravenously every eight weeks in adult patients, following a loading dose. ULTOMIRIS is approved in the US, EU, Japan and other countries for the treatment of certain adults with generalized myasthenia gravis (gMG). ULTOMIRIS is also approved in the US, EU, Japan and other countries for the treatment of certain adults with paroxysmal nocturnal hemoglobinuria (PNH) and for certain children with PNH in the US and EU. Additionally, ULTOMIRIS is approved in the US, EU, Japan and other countries for certain adults and children with atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy (aHUS). Further, ULTOMIRIS is approved in the US, EU and Japan for the treatment of certain adults with neuromyelitis optica spectrum disorder (NMOSD). As part of a broad development program, ULTOMIRIS is being assessed for the treatment of additional hematology and neurology indications. Alexion Alexion, AstraZeneca Rare Disease, is the group within AstraZeneca focused on rare diseases, created following the 2021 acquisition of Alexion Pharmaceuticals, Inc. As a leader in rare diseases for more than 30 years, Alexion is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialization of life-changing medicines. Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on hematology, nephrology, neurology, metabolic disorders, cardiology and ophthalmology. Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in 70 countries. For more information, please visit . AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit and follow the Company on social media @AstraZeneca. References Ultomiris (ravulizumab-cwvz) US prescribing information; 2024. Pittock, SJ, et al. Ravulizumab in aquaporin-4–positive neuromyelitis optica spectrum disorder. Ann Neurol, 2023; 93: 1053-1068. Wingerchuk DM, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815. Wingerchuk DM. Diagnosis and treatment of neuromyelitis optica. Neurologist. 2007;13(1):2-11. Hamid SHM, et al. What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients. J Neurol. 2017;264(10):2088-2094. Wingerchuk DM, et al. Neuromyelitis optica. Curr Treat Options Neurol. 2008;10(1):55-66. Kitley J, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain. 2012;135(6):1834-1849. Jarius S, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation. 2012;9:14. Papp V, et al. A population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary. Eur J Neurol. 2020;27(2):308-317. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79:775–783. Bukhari W, et al. Incidence and Prevalence of NMOSD in Australia and New Zealand. J Neurol Neurosurg Psychiatry. 2017;88(8):632-638. Wingerchuk DM, et al. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53(5):1107-1114. Cossburn M, et al. The Prevalence of Neuromyelitis Optica in South East Wales. Eur J Neurol. 2012;19(4): 655-659. Papadopoulos MC, et al. Treatment of neuromyelitis optica: state-of-the-art and emerging therapies. Nat Rev Neurol. 2014;10(9):493. Takata K, et al. Aquaporins: water channel proteins of the cell membrane. Prog Histochem Cytochem. 2004;39(1):1-83. Mori M, et al. Worldwide prevalence of neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry. 2018;89(6):555-556. Quek AML, et al. Effects of age and sex on aquaporin-4 autoimmunity. Arch Neurol. 2012;69:1039–43. Tüzün E, et al. Enhanced complement consumption in neuromyelitis optica and Behcet’s disease patients. J Neuroimmunol. 2011;233(1-2):211-215. Kuroda H, et al. Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica. J Neuroimmunol. 2013;254(1-2):178-182. Jarius S, et al.. The History of Neuromyelitis Optica. J Neuroinflammation. 2013;10, 797. Mealy MA, et al. Assessment of Patients with Neuromyelitis Optica Spectrum Disorder Using the EQ-5D. Int J MS care. 2019;21(3), 129–134. ClinicalTrials.gov. An Efficacy and Safety Study of Ravulizumab in Adult Participants With NMOSD. NCT Identifier: NCT04201262. Available here. Accessed March 2024. Dr. Pittock has provided consulting services to Alexion.

Positive CHMP opinion based on robust Phase III data, including APPLY-PNH, demonstrating superior hemoglobin improvement in the absence of transfusions with Fabhalta compared to anti-C5 therapy1-5 If approved, Fabhalta® will be the first oral monotherapy available in Europe for the treatment of PNH, a chronic and rare blood disorder, in both complement inhibitor-treated and -naive PNH patients with hemolytic anemia1Despite anti-C5 therapy, a large proportion of patients remain anemic, fatigued and dependent on blood transfusions6,7 Late-stage Fabhalta development program is ongoing in multiple complement-mediated diseases Basel, March 22, 2024 – Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion and recommended granting a marketing authorization for Fabhalta® (iptacopan) for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH) who have hemolytic anemia1. “With a robust body of evidence and a demonstrated safety profile, Fabhalta could be practice-changing for patients, helping relieve burdens experienced by people living with PNH,” said Antonio Risitano, M.D., Ph.D., President of the International PNH Interest Group and Head of the Hematology and Hematopoietic Transplant Unit, Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria at the AORN San Giuseppe Moscati, Avellino, Italy. “In clinical studies, oral iptacopan demonstrated superior hemoglobin improvement without the need for red blood cell transfusions compared to anti-C5 therapies, leading to normalization of hemoglobin in the majority of patients—a potentially groundbreaking benefit for those living with this chronic blood disorder.” PNH is a rare and debilitating chronic blood disorder that occurs when blood cells which are intrinsically susceptible to a part of the immune system called the complement system expand over normal blood cells due to a permissive immune environment8-11. PNH is characterized by hemolysis, bone marrow failure, and thrombosis in varying combinations and levels of severity6,7,12. Current anti-C5 treatments are administered via infusion or subcutaneous injection and may leave PNH symptoms uncontrolled. Up to 50% of patients on anti-C5 treatment may have persistent anemia with 23-39% remaining dependent on blood transfusions, and the majority (75-89%) of patients on anti-C5 treatment remain fatigued7,13-17. The positive CHMP decision is based on robust data from the Phase III APPLY-PNH study in patients with residual anemia despite prior anti-C5 treatment who switched to Fabhalta vs. patients who stayed on anti-C5 treatment, and the Phase III APPOINT-PNH study in complement-inhibitor naïve patients1. In APPLY-PNH, at 24 weeks, 82.3% of anti-C5-experienced Fabhalta patients achieved a sustained increase of Hb levels ≥2 g/dL from baseline in the absence of transfusions vs. 2.0% for anti-C5 (difference of 80.2%, P<0.0001); in APPOINT-PNH, 92.2% of complement inhibitor-naïve patients using Fabhalta achieved this outcome2,3. Similarly, in APPLY-PNH, results highlighted a transfusion avoidance rate of 94.8% for anti-C5-experienced Fabhalta patients vs. 25.9% for those on anti-C5 (difference of 68.9%, P<0.0001)18. In both studies, Fabhalta was also shown to control the destruction of red blood cells (RBCs) within the blood vessels, known as intravascular hemolysis (IVH), with mean lactate dehydrogenase (LDH) levels maintained at <1.5 x upper limit of normal2,3,19. In APPLY-PNH, patients reported improvements in fatigue as measured by Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F] scores2,19. The safety profile of iptacopan was consistent across both APPLY-PNH and APPOINT-PNH studies2,3. “If approved by the European Commission, Fabhalta would be the first oral monotherapy available to PNH patients in Europe,” said Patrick Horber M.D., President, International, Novartis, Basel. “With current standard of care, PNH symptoms are often uncontrolled, while patients endure regular and time-consuming infusions. This oral therapy could provide a much-needed alternative to support many people living with PNH who often have to structure their lives around managing their condition.’’ Following the CHMP’s recommendation to approve Fabhalta in adult patients with PNH who have hemolytic anemia, the European Commission (EC) will take a final decision within approximately two months. About APPLY-PNH APPLY-PNH (NCT04558918) was a Phase III, randomized, multinational, multicenter, active-comparator controlled, open-label trial to evaluate the efficacy and safety of twice-daily, oral Fabhalta monotherapy (200 mg) for the treatment of PNH by assessing if switching to Fabhalta was superior to continuing on anti-C5 therapies in adult patients presenting with residual anemia (Hb <10 g/dL) despite a stable regimen of anti-C5 treatment in the last six months prior to randomization 2,20. The trial enrolled 97 patients who were randomized in an 8:5 ratio to either twice-daily, oral Fabhalta monotherapy, or intravenous anti-C5 therapies (continuing with the same regimen as they were on prior to randomization)2,20. About APPOINT-PNH APPOINT-PNH (NCT04820530) was a Phase III, multinational, multicenter, open-label, uncontrolled single-arm study to evaluate the efficacy and safety of twice-daily, oral Fabhalta monotherapy (200 mg) in adult PNH patients who are naïve to complement inhibitor therapy, including anti-C5 therapies (eculizumab or ravulizumab)3,21. The trial enrolled 40 patients who received twice-daily, oral Fabhalta monotherapy3,21. About paroxysmal nocturnal hemoglobinuria (PNH)   PNH is a rare, chronic and serious complement-mediated blood disorder12. People with PNH have an acquired mutation in some of their hematopoietic stem cells (which are located in the bone marrow and can grow and develop into RBCs, white blood cells and platelets) that causes them to produce RBCs that are susceptible to premature destruction by the complement system7,12. This leads to intravascular hemolysis (destruction of RBCs within blood vessels) and extravascular hemolysis (destruction of RBCs mostly in the spleen and liver), which cause anemia (low levels of circulating RBCs), thrombosis (formation of blood clots), fatigue and other debilitating symptoms7,12.   It is estimated that approximately 10-20 people per million worldwide live with PNH7. Although PNH can develop at any age, it is often diagnosed in people between 30-40 years old8,21,22. PNH has a significant unmet need not addressed by anti-C5 therapies (eculizumab or ravulizumab); despite treatment with anti-C5s, a large proportion of people with PNH remain anemic, and some dependent on blood transfusions6,7,13-17. About Fabhalta® (iptacopan)    Fabhalta (iptacopan) is an oral, Factor B inhibitor of the alternative complement pathway1. Fabhalta was approved by the US Food and Drug Administration (FDA) in December 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). Discovered at Novartis, Fabhalta is currently in development for a range of other complement-mediated diseases including immunoglobulin A nephropathy (IgAN), C3 glomerulopathy (C3G), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS). 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. References Committee for Medicinal Products for Human Use (CHMP). Available at https://www.ema.europa.eu/en/committees/committee-medicinal-products-human-use-chmp. Accessed March 2024. Ristanio AM, Rӧth A, Kulasekararaj A, et al. Oral Iptacopan Monotherapy Has Superior Efficacy to Anti-C5 Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia. Results from the Phase III APPLY-PNH Study. Presented at 49th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT); April 23-26, 2023; Paris, France. Risitano AM, Han B, Ueda Y, et al. Oral Complement Factor B Inhibitor Iptacopan Monotherapy Improves Hemoglobin to Normal/Near-Normal Levels in Paroxysmal Nocturnal Hemoglobinuria Patients Naïve to Complement Inhibitors: Phase III APPOINT-PNH Trial. Presented at: 49th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT); April 23-36, 2023; Paris, France. Risitano AM, Röth A, Soret J, et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021;8(5):e344-e354. doi:10.1016/S2352-3026(21)00028-4 Jang JH, Wong L, Ko BS, et al. Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Blood Adv. 2022;6(15):4450-4460. doi:10.1182/bloodadvances.2022006960 McKinley CE, Richards SJ, Munir T, et al. Extravascular Hemolysis Due to C3-Loading in Patients with PNH Treated with Eculizumab: Defining the Clinical Syndrome. Blood. 2017;130(Supplement 1):3471. doi:10.1182/blood.V130.Suppl_1.3471.3471 Dingli D, Matos JE, Lehrhaupt K, et al. The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey. Ann Hematol. 2022;101(2):251-263. doi:10.1007/s00277-021-04715-5 Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria Nat Rev Dis Primers. 2017;3:17028. doi:10.1038/nrdp.2017.28Shah N, Bhatt H. 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Semin Hematol. 2009;46(1 Suppl 1):S1-S16. doi:10.1053/j.seminhematol.2008.11.004Novartis. Data on fileRisitano AM, Kulasekararaj A, Rӧth A, et al. Factor B Inhibition with Oral Iptacopan Monotherapy Demonstrates Sustained Long-Term Efficacy and Safety in Anti-C5-Treated Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia: Final 48-Week Results from the Multicenter, Phase III APPLY-PNH Trial. Presented at: 65th American Society of Hematology Annual Meeting & Exposition (ASH); December 9-12, 2023; San Diego, CA.Novartis Pharmaceuticals. A Randomized, Multicenter, Active-Comparator Controlled, Open-Label Trial to Evaluate Efficacy and Safety of Oral, Twice Daily LNP023 in Adult Patients With PNH and Residual Anemia, Despite Treatment With an Intravenous Anti-C5 Antibody. clinicaltrials.gov. Accessed February 14, 2024. https://clinicaltrials.gov/ct2/show/NCT04558918 Novartis Pharmaceuticals. 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