NOVARTIS AG
'Currently, 20-50% of PNH patients treated with standard-of-care anti-C5 therapies remain transfusion-dependent due to persistent extravascular hemolysis, and an additional 20-40% exhibit varying degrees of residual anemia,' said lead author Professor
All patients completing at least 12 weeks of iptacopan treatment (n=11) achieved the primary endpoint of at least a 60% reduction in their lactate dehydrogenase (LDH) levels, a biomarker of intravascular hemolysis1. Importantly, with the exception of one patient receiving a single red blood cell (RBC) transfusion, all patients remained transfusion-free through 12 weeks of study1. Patients also showed improvement in other biomarkers of hemolysis and a marked increase in the proportion of PNH-type RBCs, indicating overall control of both intra- and extravascular hemolysis1.
No serious adverse events or thromboembolic events were reported during the 12-week treatment period and the study yielded no unexpected safety results1. Two participants discontinued iptacopan treatment before completing 12 weeks of treatment: one due to a non-serious headache, the other by physician decision due to worsening of pre-existing neutropenia1. The most common adverse events were headache (31% of patients), abdominal discomfort (15%), blood alkaline phosphatase increase (15%), cough (15%), oropharyngeal pain (15%), pyrexia (raised body temperature; 15%), and upper respiratory infection (15%)1.
'PNH is a rare and life-threatening blood disorder with often debilitating symptoms,' said
PNH, which is characterized by complement-driven hemolysis, thrombosis and impaired bone marrow function11,12, results in anemia, fatigue and other debilitating symptoms that can impact patients' quality of life13-15. Despite treatment with current anti-C5 standard-of-care therapies, a large proportion of PNH patients remain anemic and dependent on transfusions2,3,11,13,15.
In results from the separate open-label Phase II study (NCT03439839), published in The Lancet Haematology, iptacopan improved hematological response and biomarkers of disease activity in PNH patients with active hemolysis despite treatment with the anti-C5 eculizumab4. This benefit was maintained in patients who stopped eculizumab treatment4.
About iptacopan
Iptacopan is an investigational first-in-class, orally administered targeted factor B inhibitor of the alternative complement pathway7,8. It acts upstream of the C5 terminal pathway, preventing not only intravascular but also extravascular hemolysis in PNH1. In doing so, iptacopan may have a therapeutic advantage over current standard-of-care by targeting a key part of the biology responsible for PNH7,8.
Discovered at the
Based on disease prevalence and the positive interim data from Phase II studies, iptacopan has received orphan drug designations from the FDA and EMA in C3G and PNH6, FDA Breakthrough Therapy Designation in PNH5,
About the Study
NCT03896152 is a Phase II, multinational, multicenter, open-label, randomized, 2-cohort, dose-ranging trial to evaluate the efficacy, safety and pharmacokinetics/pharmacodynamics of iptacopan monotherapy in adult PNH patients with active hemolysis and no complement inhibition in the prior 3 months1. The primary objective of the study was to assess the percentage of patients with 60% reduction in LDH or LDH below upper limit of normal (ULN) up to 12 weeks of treatment1.
The study assessed four iptacopan doses in two separate cohorts with two sequential treatment periods each1. A total of 13 patients were randomized to receive either 25 mg iptacopan twice daily up to week four, rising to 100 mg iptacopan twice daily from weeks five to 12 (cohort 1; n=7), or 50 mg iptacopan twice daily up to week four, rising to 200 mg iptacopan twice daily from weeks five to 12 (cohort 2; n=6)1. Two participants discontinued iptacopan treatment before completing 12 weeks of treatment: one due to a non-serious headache, the other by physician decision due to worsening of pre-existing neutropenia1.
After the 12-week main treatment period, patients responding to iptacopan treatment had the option to enter an approximately two-year treatment extension period1.
Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as 'potential,' 'can,' 'will,' 'plan,' 'may,' 'could,' 'would,' 'expect,' 'anticipate,' 'seek,' 'look forward,' 'believe,' 'committed,' 'investigational,' 'pipeline,' 'launch,' or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in
About Novartis
Novartis is reimagining medicine to improve and extend people's lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world's top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 110,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com.
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References
1. Jang JH, et al. Iptacopan Effectively Controls Intra- And Extravascular Hemolysis And Leads To Durable Hemoglobin Increase In Patients With Treatment-Naive PNH. Abstract presented at the 26th Annual Congress of the
2. Risitano AM. Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going. Transl Med UniSa 2014;8:43-52.
3. Debureaux P, et al. Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals. Blood 2019;134(Suppl 1):3517.
4. Risitano AM, Roth 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. Published online 2021. doi:10.1016/S2352-3026(21)00028-4..
5. Novartis. Novartis investigational oral therapy iptacopan (LNP023) receives FDA Breakthrough Therapy Designation for PNH and Rare Pediatric Disease Designation for C3G. Available at: https://www.novartis.com/news/media-releases/novartis-investigational-oral-therapy-iptacopan-lnp023-receives-fda-breakthrough-therapy-designation-pnh-and-rare-pediatric-disease-designation-c3g. Accessed
6. Novartis. Data on file.
7. Schubart A, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A 2019;116(16):7926-7931.
8. Merle NS, et al. Complement system part II: role in immunity. Front Immunol 2015;6:257.
9. Novartis press release. Novartis announces iptacopan met Phase II study primary endpoint in rare kidney disease IgA nephropathy (IgAN). Available at: https://www.novartis.com/news/media-releases/novartis-announces-iptacopan-met-phase-ii-study-primary-endpoint-rare-kidney-disease-iga-nephropathy-igan. Accessed
10. Novartis press release. Novartis announces new interim analysis Phase II data for iptacopan in rare kidney disease C3 glomerulopathy (C3G). Available at: https://www.novartis.com/news/media-releases/novartis-announces-new-interim-analysis-phase-ii-data-iptacopan-rare-kidney-disease-c3-glomerulopathy-c3g. Accessed
11. Hill A, et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017;3:17028.
12. Risitano AM. Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies.
13. Risitano AM and Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics 2008;2(2):205-222.
14. Hill A, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010;95(4):567-573.
15. Schrezenmeier H, et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 2014;99(5):922-929.
16. Novartis. Novartis received
17. Novartis. Novartis announces
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