▎WuXi AppTec Content Team Report

Recently, Novartis' oral monotherapy — iptacopan hydrochloride capsules (iptacopan) — has been approved by the National Medical Products Administration (NMPA) of China.Approved for Marketing, for the treatment of patients who have not previously received complement inhibitor therapyAdult patients with paroxysmal nocturnal hemoglobinuria (PNH). Public information shows that this is a "first-in-class" complement pathway Factor B inhibitor,It is also the first oral monotherapy approved by the U.S. FDA for the treatment of adult PNH, and was listed by the industry media Evaluate as one of the 10 potential blockbuster therapies worth watching.。

The approval of Eptinezumab in China has also drawn people's attention toFocus on PNH. PNH is a chronic, progressive, debilitating, and life-threatening disease that has been included in China's "First List of Rare Diseases." The disease often occurs in young and middle-aged populations.Year~40 years old account for about 77%.Studies have found that the 5-year mortality rate of PNH patients is as high as 35%, with a median survival period of approximately 10 years.[1]。The arrival of Ipkepan provides a new targeted treatment option for PNH patients. In today's article, the content team of WuXi AppTec will introduce the century-long history of human efforts against PNH disease based on publicly available information.

——✦Diseases that occur after sleep✦——

Research on PNH disease has a long history. As early as the second half of the 19th century, PNH gradually drew the attention of European physicians. Through the study of this rare disease, scientists progressively uncovered the alternative pathway of complement activation, complement regulatory proteins, mechanisms of protein linkage to cell membrane surfaces, and thePathogenic geneetc.

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In 1882, Dr. Paul Strübing reported that PNH patients experienced hemoglobinuria at night. However, in later studies,He also found that the episodes of hemoglobinuria do not necessarily occur at night, but often after sleep.Moreover, he also observed that red blood cells in PNH patients are sensitive to complement in an acidic environment during sleep.[2]。

In 1939, Dr. Thomas Hale Ham from Harvard Medical School reported evidence of complement-mediated hemolysis of PNH red blood cells in acidified serum, making the acid hemolysis test (known as the Ham test) a specific diagnostic test.[2]。

In the 1950s, Dr. Ham's colleague Louis Pillemer discovered that the hemolysis of PNH red blood cells in acidic serum was mediated by the alternative complement pathway; Professor John V. Dacie from Hammersmith Hospital in London found a close relationship between PNH and aplastic anemia, proposing that PNH results from somatic mutations occurring against a background of bone marrow hypoplasia, and that the mutated cells may possess an unexplained proliferative advantage.[2]。

In 1985, it was recognized that there are anchors on the surface of PNH patients' cells that can connect proteins to the cells. In 1989, complement regulatory proteins (such as CD55, CD59, etc.) in the anchor-connected proteins and their roles in the pathogenesis of PNH were discovered.This discovery also provides a basis for the future use of flow cytometry to detect PNH clones.[2]。

——✦Why Do Humans GetPNH？✦——

In 1993, scientists conducted researchThe confirmation that the loss of glycosylphosphatidylinositol (GPI) anchors on PNH cell surfaces is due to mutations in the phosphatidylinositol glycan class A (PIG-A) gene in hematopoietic stem cells became a watershed event in the history of PNH.[2]。

It is now known that PNH patients are due toPIG-AGene mutations prevent a group of GPI-anchored proteins from being anchored on the cell membrane surface, including CD55 (Decay Accelerating Factor, DAF) and CD59 (Membrane Inhibitor of Reactive Lysis, MIRL). Hematopoietic stem cells with PIG-A somatic mutations can clonally expand, producing many affected peripheral blood cells.

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Cells lacking ankyrin have a reduced ability to resist complement attack. The complement system, consisting of a series of enzymatic cascades of proteins, is part of the innate immune system. Many complement proteins are enzymes that exist in an inactive precursor (zymogen) form in serum and on cell surfaces.The main activation pathways include the classical pathway.（classical pathway）、Bypass Pathway(alternative pathway) andCoagulation Pathway（lectinactivation pathway）。

Under normal circumstances, the complement system can perform multiple functions after activation, including enhancing antibody responses and possessing immunological memory, lysing foreign cells, and clearing immune complexes and apoptotic cells.However, in PNH patients, the complement system attacks their own red blood cells, leading to the lysis of affected red blood cells, hemolysis, and triggering various complications.。

Intravascular hemolysis, potential hematopoietic failure, and thrombotic tendency are the three main clinical manifestations of PNH.Thrombosis can occur in blood vessels throughout the body, damaging vital organs and leading to premature death. Common complications include anemic heart disease, cholelithiasis, renal insufficiency, and even failure. Thromboembolism and infection are common causes of death among patients, with a 5-year mortality rate as high as 35%.

In PNH patients, approximately 40% will experience thrombosis, 64% will suffer from renal impairment, 50% will develop pulmonary hypertension, and 66% will have dyspnea; about 30% may transform into aplastic anemia, and individual PNH patients can progress to myelodysplastic syndrome or acute myeloid leukemia.Moreover, less than half of PNH patients have mild jaundice, about one-quarter of patients have mild hepatomegaly, and less than 15% of patients have mild splenomegaly.

——✦Traditional Treatment Fails to Meet the Demand✦——

The traditional treatment for PNH aims to "protect" the PNH clone, reduce complement attack and destruction, and alleviate hemolysis. The main treatment methods include routine blood transfusions and symptomatic treatments, such as glucocorticoids, blood transfusion, iron supplements, and anticoagulants.

According to the manifestations of different PNH patients, symptomatic treatment plays an important role: for example, adrenal glucocorticoids can be used during acute hemolysis episodes, then gradually tapered to the minimum dose; patients with bone marrow failure can be treated with immunosuppressants such as cyclosporine, or even combined with anti-thymocyte globulin (ATG) therapy. Additionally, androgens such as stanozolol, testosterone propionate, and danazol can be used to promote hematopoiesis.

For the treatment of vascular embolism, acute thrombotic events require heparin anticoagulation; in cases of acute Budd-Chiari syndrome, systemic thrombolytic therapy or direct thrombolytic therapy via catheter placement at the thrombus site can be performed.

However, traditional treatment cannot fully improve the impact of the disease on patients' quality of life, effectively control hemolysis, and long-term use has significant side effects. The 10-year survival rate of patients is about 70%. A considerable proportion of patients face potential life-threatening risks due to accompanying complications, urgently needing to explore new drugs and treatment strategies.

——✦The Arrival of a New Era in Targeted Therapy✦——

The complex signaling pathways of the complement system provide multiple targetable sites for treating complement system abnormalities. The C5 complement protein is located at the terminal end of the complement cascade; thus, targeting this protein can modulate complement signals activated by three different pathways. Inhibiting the activity of C5 can suppress autoimmune attacks and alleviate disease symptoms.

In the research process of PNH,Based on the understanding that PNH red blood cells are sensitive to complement, researchers have developed inhibitors targeting C5 complement, which have become the standard therapy for PNH, bringing the treatment of PNH into the era of targeted therapy.。

C5 complement inhibitors can specifically bind to human C5 complement protein, preventing its cleavage into C5a and C5b, thereby inhibiting the formation of the membrane attack complex (MAC), suppressing intravascular hemolysis, and improving patient survival rates. Studies show that C5 complement inhibitors can effectively reduce thrombosis in PNH, alleviate symptoms such as pain, fatigue, and dyspnea, and to a certain extent, decrease patients' reliance on blood transfusions.

In March 2007, eculizumab, developed by AstraZeneca, was approved by the FDA for marketing to treat PNH and reduce hemolysis.The drug also became the world's first approved C5 complement inhibitor.。

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With the development of targeted complement inhibitors, two more targeted C5 complement inhibitors have been approved for marketing since then, namely: ravulizumab from Alexion Pharmaceuticals (now acquired by AstraZeneca), which was approved inIn December 2018, it was first approved by the FDA for the treatment of adult PNH patients, and in 2021, it was again approved by the FDA for the treatment of pediatric and adolescent PNH patients; andRoche's Crovalimab, obtained in China in February 2024NMPA Approval for TreatmentAdult and Adolescent Patients with PNH。

C5 complement inhibitors can block C5-mediated intravascular hemolysis but cannot block C3-mediated extravascular hemolysis, so patients sometimes still require blood transfusions for treatment. According to a retrospective study of patients receiving C5 inhibitor therapy, at least 72% of patients had persistently low hemoglobin levels, and at least 36% required one or more transfusions per year.

In May 2021, pegcetacoplan, a C3 complement inhibitor, was approved by the FDA for marketing. It is used to treat adult patients with newly diagnosed PNH and PNH patients switching from C5 complement inhibitor therapy to pegcetacoplan therapy. Public information shows,This is the first FDA-approved C3-targeted therapy for the treatment of PNH.。

Pegcetacoplan is a synthetic cyclic peptide conjugated with a polyethylene glycol polymer, which can specifically bind to complement C3 and C3b, thereby inhibiting the cleavage of complement C3 into active fragments to exert its function; it can also bind to the already generated active fragment C3b, inhibiting the production of its downstream effects, mainly manifested as the inhibition of extravascular hemolysis mediated by C3b and intravascular hemolysis mediated by terminal complement.

——✦Proximal Complement Therapy: A New Hope for PNH Patients✦——

Despite C5 complement inhibitors as the standard treatment for PNH improving patient survival, a significant number of patients still experience residual anemia, fatigue, and transfusion dependence after C5 complement inhibitor treatment. Additionally, intravenous administration and frequent dosing pose challenges to patient compliance. These issues limit the efficacy for patients, creating an urgent need for new therapies to break this deadlock.

With continuous breakthroughs in research and development, PNH has entered a new era of proximal complement treatment, such as Factor B (CFB) complement inhibitors.Factor B, also known as C3 activator precursor, is mainly synthesized by the liver and macrophages and is an important component in the activation of the complement alternative pathway.。The alternative pathway is a complement activation pathway initiated by certain bacteria, fungi, bacterial lipopolysaccharides (endotoxins), yeast polysaccharides, dextran aggregates, IgA, and IgG4. These activators directly bind to C3b and, with the participation of factors B, D, and P, sequentially form C3 convertase and C5 convertase, leading to the formation of the membrane attack complex.

The study found,Inhibition of factor B can suppress the activity of C3 convertase and C5 convertase, prevent the formation of the membrane attack complex, and inhibit intravascular and extravascular hemolysis.。

In December 2023, iptacopan, a complement factor B inhibitor developed by Novartis, received FDA approval.Became the first oral monotherapy for the treatment of adult PNH, and this is also the world's first approved complement B factor inhibitor., adding a new option for the treatment of PNH.

According to the Novartis press release, iptacopan acts upstream of the terminal pathway of the complement system C5, simultaneously controlling both intravascular and extravascular hemolysis. It addresses the limitations of C5 complement inhibitors while offering patients an oral monotherapy option, enhancing treatment adherence, improving medication experience, and increasing quality of life.

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The FDA approval was based on the Phase 3 clinical trial APPLY-PNH. The trial included patients with hemoglobin <10 g/dL who had previously received C5 complement inhibitor treatment but still had residual anemia. The results showed,Iptacopan is superior to continuing C5 complement inhibitor treatment in improving hemoglobin levels and avoiding transfusions.. In addition, the approval was supported by the Phase 3 clinical trial APPOINT-PNH, which targeted patients who had not received complement inhibitor treatment.The main findings of the APPLY-PNH and APPOINT-PNH trials at 24 weeks include:

• 82.3% of patients treated with C5 complement inhibitors who did not receive a blood transfusion saw their hemoglobin levels increase continuously by ≥2 g/dL after being treated with Fabhalta, compared to 0% for those who continued receiving C5 complement inhibitors. Among patients who had not received complement inhibitor treatment, 77.5% achieved this result after being treated with iptacopan.

• Without blood transfusion, 67.7% of patients treated with C5 complement inhibitors maintained hemoglobin levels ≥12 g/dL, compared to 0% for those who continued C5 complement inhibitor treatment.

• For patients who have received C5 complement inhibitor treatment, the transfusion avoidance rate after receiving iptacopan was 95.2%, compared to 45.7% in the C5 complement inhibitor group.

Currently, Novartis is expanding the drug's application to other complement-related diseases, such as IgAN (IgA nephropathy) and C3G (C3 glomerulopathy). The FDA has granted iptacopan treatmentC3 GlomerulopathyThe breakthrough therapy designation,The European Medicines Agency (EMA) has granted the drug for the treatment of C3GPriority Drug Designation,Orphan Drug Designation andOrphan Drug Designation for the Treatment of IgA Nephropathy.

In China,Iptacopan (Chinese generic name:IpecacuanhaAlsoIncluded by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of ChinaSuddenBreakthrough therapy designation and priority review for the treatment of PNH.In April 2024, the drug was approved in China for the treatment of adult PNH patients who have not previously received complement inhibitor therapy, also bringing new options to PNH patients in China.A New Option for Oral Monotherapy。

Ipsen inThe approval in China was based on the results of the pivotal Phase 3 APPOINT-PNH global and China subgroup clinical study, wherein 50% of the participants were enrolled in China.. Research data shows,After 24 weeks of treatment, most patients achieved hemoglobin levels of 12 g/dL or higher, nearly all patients avoided the need for transfusions, and patient-reported fatigue also improved.。

Besides Novartis, there are also some other companies currently developing complement factor B inhibitors. Due to space limitations, this article will not introduce them one by one.

——✦A Promising Future✦——

In the field of PNH treatment, the therapeutic goals have been continuously evolving—from initial symptomatic treatment, reducing complement-mediated attacks and destruction, and alleviating hemolysis, to controlling complement activity, preventing severe disease-related complications, and striving for longer survival. Now, the focus has shifted to correcting anemia, eliminating transfusion dependence, alleviating fatigue symptoms, and pursuing a better quality of life.

We believe that with the improvement in disease diagnosis and treatment as well as new drug development, especially the emergence of novel complement inhibitors, more innovative and effective treatment options and a better quality of life will be brought to PNH patients!