Novartis presents new 48-week results from Phase III APPLY-PNH trial showing sustained efficacy and long-term safety of Fabhalta® (iptacopan) in adults with paroxysmal nocturnal hemoglobinuria (PNH)

Novartis announced results from the extension period of the pivotal Phase III APPLY-PNH trial of oral monotherapy Fabhalta® in adults with paroxysmal nocturnal hemoglobinuria who had residual anemia despite previous anti-C5 therapy.

  • APPLY-PNH extension data show that continuous Fabhalta® (iptacopan) treatment in adults with paroxysmal nocturnal hemoglobinuria (PNH) enabled sustained hemoglobin-level increases to near-normal (≥12 g/dL), blood transfusion avoidance, and improved patient-reported fatigue in the majority of patients, with a safety profile consistent with previously reported data1-5
  • Patients switching from anti-C5s to Fabhalta in the extension period achieved outcomes comparable to the Fabhalta arm in the 24-week randomized controlled period, including transfusion avoidance and near-normal hemoglobin-levels (≥12 g/dL) in the majority of patients1
  • Fabhalta was recently approved by the FDA for adults with PNH, including for both previously treated and treatment-naive patients6

Basel, December 11, 2023 Novartis today announced results from the extension period of the pivotal Phase III APPLY-PNH trial of oral monotherapy Fabhalta® (iptacopan) in adults with paroxysmal nocturnal hemoglobinuria (PNH) who had residual anemia (hemoglobin <10 g/dL) despite previous anti-C5 therapy1,2. Continuous Fabhalta treatment (200 mg twice daily) for 48 weeks enabled sustained hemoglobin-level increases to near-normal (12 g/dL or more), blood transfusion avoidance, and reduced patient-reported fatigue in the majority of patients; comparable benefits emerged in those patients switching from anti-C5 therapy to Fabhalta in the extension1. Data will be presented at the 65th American Society of Hematology Annual Meeting & Exposition (ASH).

“The new APPLY-PNH data are an expansion of the robust outcomes we saw in the randomized phase and demonstrate that patients with PNH who took Fabhalta experienced meaningful hemoglobin improvement over the longer term – nearly a year,” said principal co-investigator 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. “Additionally, the new data confirm that these benefits may occur within weeks after switching from anti-C5s. The APPLY-PNH findings continue to confirm Fabhalta as a promising therapeutic option for people living with PNH.”

Patients completing the 24-week randomized treatment period of APPLY-PNH could elect to enter the extension, continuing Fabhalta (61/62 patients; one patient discontinued due to pregnancy) or switching from anti-C5s to Fabhalta (34/35 patients; one patient discontinued based on investigator decision) through week 481,2.

In the continuous Fabhalta group, outcomes achieved in the randomized period were sustained at 48 weeks: mean hemoglobin level continued to be near-normal (12.2 g/dL), nearly all patients (91.9%) remained free of transfusions (Weeks 2-48), and improvements in patient-reported fatigue were observed (adjusted mean change from baseline: 9.80-point increase in Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F] score)1.

In the anti-C5-to-Fabhalta group, similar benefits emerged after switch: mean hemoglobin levels increased to near-normal (from 9.1 g/dL at 24 weeks to 12.1 g/dL at 48 weeks), transfusion avoidance was achieved for almost all patients (94.1%, Weeks 26-48), and improvements in patient-reported fatigue were observed after switching to Fabhalta (adjusted mean change from baseline between Week 48 and Week 24: 10.79-point increase in FACIT-F score)1.

“Coming on the heels of Fabhalta’s recent approval in PNH, these extended data from the APPLY-PNH phase III trial reinforce Fabhalta’s utility as an important new oral monotherapy for people living with PNH,” said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. “We are eager to bring this novel treatment to even more people living with rare complement-driven disorders as we pursue several additional indications for Fabhalta.”

Fabhalta had a similar safety profile at 48 weeks vs. 24 weeks1,2. Three patients had major adverse vascular events (MAVEs), all considered unrelated to Fabhalta (one serious transient ischemic attack [TIA] occurred in the randomized period and was reported previously)1,2. In the extension, there was one non-serious TIA and one serious portal vein thrombosis (PVT; this patient had a history of PVT and discontinued heparin prior to the MAVE)1. Six patients of 62 receiving continuous Fabhalta for 48 weeks had clinical breakthrough hemolysis (BTH); one patient in the anti-C5-to-Fabhalta extension arm had clinical BTH after switching (compared to six of 35 patients while on anti-C5s prior to switch)1,2. All cases of clinical BTH resolved without changing Fabhalta dosing1. During the 48-week study period, the most frequently reported treatment-emergent adverse events (TEAEs) in the Fabhalta arm were COVID-19 (29.0% of patients), headache (19.4%), and diarrhea (16.1%)1. Throughout the full 48 weeks on Fabhalta, 9.7% of patients experienced any severe TEAE and 14.5% experienced any serious TEAE, none of which was suspected to be related to Fabhalta treatment; there were no serious hemolysis TEAEs on Fabhalta1,2. There were no serious infections caused by N. meningitidis, S. pneumoniae, or H. influenzae and no treatment discontinuations because of TEAEs1,2.

PNH is a rare, chronic, and serious complement-mediated blood disorder, in which a large proportion of patients can remain anemic and some dependent on blood transfusions despite currently available standard of care, anti-C5 treatments7-10.

Full 48-week results from the Phase III APPOINT-PNH trial in treatment-naïve PNH patients will be presented at a congress in 2024.

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 (US-approved and non-US-approved eculizumab or ravulizumab) 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 randomization4,11. 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)4,11.

About paroxysmal nocturnal hemoglobinuria (PNH)
PNH is a rare, chronic and serious complement-mediated blood disorder7. 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 system7,8. 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 symptoms7,8.

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 old12,13,14.

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 transfusions7-10,15.

About Fabhalta® (iptacopan)
Fabhalta (iptacopan) is an oral, Factor B inhibitor of the alternative complement pathway14,16,17. Fabhalta is FDA-approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).

Discovered at Novartis, Fabhalta is currently in development for a range of complement-mediated diseases including immunoglobulin A nephropathy (IgA nephropathy), C3 glomerulopathy (C3G), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS).

Based on disease prevalence, unmet needs and data from Phase II studies, Fabhalta has received FDA approval in PNH, FDA Breakthrough Therapy Designation in C3G, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN6,18-22.

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,” “expectations,” “investigational,” “drives,” “remains,” “ongoing,” “exploring,” “goal,” “expected,” “estimated,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for FABHALTA (iptacopan), 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 FABHALTA (iptacopan) 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 FABHALTA (iptacopan) 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
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  1. Risitano 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
  2. Risitano 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 23-36, 2023; Paris, France.
  3. 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.
  4. 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
  5. Jang H, 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
  6. Novartis receives FDA approval for Fabhalta® (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH. Novartis. Accessed December 6, 2023.
  7. Cançado RD, Araújo A da S, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348. doi:10.1016/j.htct.2020.06.006
  8. 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
  9. Debureaux PE, Kulasekararaj AG, Cacace F, et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant. 2021;56(10):2600-2602. doi:10.1038/s41409-021-01372-0
  10. Debureaux PE, Cacace F, Silva BGP, 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(Supplement_1):3517-3517. doi:10.1182/blood-2019-125917
  11. 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.; 2022. Accessed September 21, 2022.
  12. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primer. 2017;3(1):17028. doi:10.1038/nrdp.2017.28
  13. Schrezenmeier H, Röth A, Araten DJ, et al. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol. 2020;99(7):1505-1514. doi:10.1007/s00277-020-04052-z
  14. Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci. 2019;116(16):7926-7931. doi:10.1073/pnas.1820892116
  15. 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
  16. Barratt J, Rovin B, Zhang H, et al. POS-546 EFFICACY AND SAFETY OF IPTACOPAN IN IgA NEPHROPATHY: RESULTS OF A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2 STUDY AT 6 MONTHS. Kidney Int Rep. 2022;7(2):S236. doi:10.1016/j.ekir.2022.01.577
  17. Rizk DV, Rovin BH, Zhang H, et al. Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. Kidney Int Rep. 2023;8(5):968-979. doi:10.1016/j.ekir.2023.01.041
  18. Novartis Pharmaceuticals. A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Iptacopan (LNP023) in Complement 3 Glomerulopathy.; 2022. Accessed September 20, 2022.
  19. Novartis Pharmaceuticals. A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase III Study to Evaluate the Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients.; 2022. Accessed September 21, 2022.
  20. Novartis announces European Medicines Agency (EMA) has granted orphan drug designation for iptacopan (LNP023) in IgA nephropathy (IgAN). Novartis. Accessed September 22, 2022.
  21. Novartis received European Medicines Agency (EMA) PRIME designation for iptacopan (LNP) in C3 glomerulopathy (C3G). Novartis. Accessed September 22, 2022.
  22. Novartis investigational oral therapy iptacopan (LNP023) receives FDA Breakthrough Therapy Designation for PNH and Rare Pediatric Disease Designation for C3G. Novartis. Accessed September 22, 2022.
  23. Novartis. Data on File.

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