Welcome to pay attention to Gloria Medicine
On December 6, 2023, Novartis ("Novartis") announced that the U.S. Food and Drug Administration (FDA).Fabhalta (iPTACOPAN) was approved as the first oral single** for paroxysmal nocturnal hemoglobinuria (PNH).
FDA approval is:Based on a phase III Apply-PNH trial, which was used in patients who had previously received anti-C5** but still had anemia (haemoglobin < 10 g DL), who switched to fabhalta;Trials have demonstrated superiority in improving hemoglobin without RBC infusion.
Aboutapply-pnh
Apply-PNH is a phase III, randomized, multicenter, active-controlled, open-label trial to evaluate the efficacy and safety of iptacpan**PNH administered orally twice daily.
Primary Endpoint:
1. At week 24, the proportion of patients with hemoglobin levels increased by 2 g DL from baseline after receiving iptacopan** was significantly higher than that in the control group receiving C5 standard ** (P < 0.).0001) and no need to continue blood transfusion** (RBCT).
2. At week 24, the proportion of patients with a hemoglobin level of 12 g dl after receiving iptacopan** was significantly higher than that of the control group receiving standard ** (P < 0.).0001), and there is no need to continue with RBCT.
Secondary Endpoints:
1. At week 24, the proportion of patients without RBCT in the iptacopan** group was 60 62, while the proportion of patients in the standard** group was 14 35.
2. At week 24, iPTAPAN monotherapy** also showed statistically significant differences in the change of hemoglobin level from baseline, FACIT-fatigue score, reticulocyte count (ARC), and incidence of clinical breakthrough hemolysis (BTH).
In terms of safety, there were no deaths and no serious bacterial infections on the capsule.
About iptacopan:
iptacopan is aFirst-in-class, oral, potent, selective, small molecule, reversible complement factor B (FB) inhibitor。FB is a key serine protease in the complement system alternative pathway, and iPTAPAN blocks intravascular hemolysis (IVH) and extravascular hemolysis (EVH) of hemolytic PNH ** by acting upstream of the C5-terminal pathway of the complement systemIt may reduce the risk of infection in patients with diseases caused by dysfunction of multiple alternative pathways without affecting the immune response mediated by other complement pathways to microbial invasion.
Previously, iPTAPAN received Breakthrough Designation from the FDA and EMA for PNH and C3 glomerulopathy (C3G).At the same time, the drug has been recognized by the FDA for rare pediatric diseases, **C3G. In addition, in March 2022 and March 2023, the drug was granted Breakthrough Drug Designation by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) for C3G and PNH, respectively.
About complement factor B
The complement system is part of the innate immune system, and complement is activated by one of three pathways: classical, alternative, and lectin pathways, resulting in a series of proteolytic cleavages to enhance the immune response or form a membrane attack complex (MAC). C1 is upstream of the classical pathway, C3 is the convergence point of the three pathways, and C5 is at the end of the pathway. Under normal conditions, intravascular hemolysis is blocked by CD59, which blocks the last step of the complement response, which is the MAC that blocks the formation of holes on the target cells. In patients with erythrocyte deficiency, intravascular hemolysis occurs by attaching CD59 to a GPI anchor on its surfaceTargeting terminal complement C5 prevents the formation of MAC complexes and blocks intravascular hemolysis.
Complement factor B, a serine protease, is an essential protein that regulates the complement bypass pathway cascade, in which complement factor B is broken down by complement factor D into two subunits, BA and BB. Together with C3B, BB forms the alternative pathway C3 convertase C3BBB, which then forms C5 convertase (C3BBBC3B), which eventually forms the membrane attack complex.
According to incomplete statistics, there are currently more than 17 drugs under development for complement factor B, covering small molecule inhibitors, monoclonal antibodies, antisense **, RNAI, etc.
About PNH
PNH is a type of somatic cell due to XP221. Acquired hematopoietic stem cell clonal disease caused by mutation in the pig-a gene. The pathogenesis includes mutations in the pig-A gene of hematopoietic stem cells, which impairs the synthesis of partial or complete blood cell membrane glycosylated phosphatidylinositol (GPI), resulting in the loss of GPI anchor protein on the surface of blood cells, and the weakening of cell inactivation complement, resulting in cell destruction and hemolysis. The main clinical manifestations are episodic intravascular hemolysis, paroxysmal hemoglobinuria, bone marrow hematopoietic failure and venous thrombosis.
According to statistics,The incidence rate is about 1 to 2 per million, and the incidence rate in Asians is higher than that in Europe and the United States. PNH can occur at any age, common in people aged 30-40 years In addition to bone marrow transplantation, PNH has no other effective means, and the control of hemolytic attacks is the main means of the disease in clinical practice, and the main drugs include glucocorticoids, immunosuppressants, complement pathway inhibitors, etc., of which anti-complement C5 drugs are its current standard.
Currently, the only complement C5 inhibitors approved for **PNH in the world are SoliS (Eculizumab) and Ultomiris (R**Ulizumab), both of which were developed by AstraZeneca and administered intravenously.
soliris：It is the first complement C5 inhibitory device approved worldwide, and in addition to the approved PNH, it is also approved for atypical AHUS, myasthenia gravis (MG) with positive anti-acetylcholine receptor (ACHR) antibody, and neuromyelitis optica spectrum disorder (NMOSD) with positive anti-aquaporin-4 (AQP4) antibody, administered weekly or every 2 weeks. The total revenue in 2022 is as high as 37$6.2 billion.
ultomiris：It is an upgraded version of Soliris and is currently approved for PNH, AHUS (and 1-month-old pediatric patients) and generalized myasthenia gravis (GMG). The total revenue in 2022 is as high as 19$6.5 billion.
Anti-complement C5** is the previously internationally recognized standard for PNH**, but after anti-C5**, most patients still have residual anemia, fatigue and transfusion dependence, which seriously affects the quality of life.
References
1. The company's official website, Guosheng**.
2, Chen Zhi. Expression and significance of complement factor B and factor D in diabetic nephropathy.
3. Hematological tumor consultation, original link:
4. CPHI Pharmaceutical**, original link: