Complement Inhibitor Market Reaches $10 Billion as Alexion's Monopoly Ends with Empaveli Approval; Novartis and Sanofi Enter the Arena

Keywords

Empaveli; Soliris; Complement Inhibitor; Acquisition

Recently, Apellis Pharmaceuticals announced that the FDA has approved its C3 complement inhibitor Empaveli (pegcetacoplan) for the treatment of treatment-naïve adult patients with paroxysmal nocturnal hemoglobinuria (PNH), as well as adult patients with PNH previously treated with the C5 complement inhibitors Soliris and Ultomiris.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder caused by genetic mutations in hematopoietic stem cells. Mutations in the PIG-A gene are considered the primary molecular basis for intravascular hemolysis in PNH. The PIG-A mutation leads to a defect in glycosylphosphatidylinositol (GPI) anchor synthesis, preventing CD55 and CD59 from binding to the erythrocyte membrane. This results in the loss of their function to inhibit complement pathway activation. Consequently, abnormal complement activation leads to a spectrum of clinical manifestations, including intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. CD55 (also known as decay-accelerating factor) and CD59 (also known as membrane attack complex inhibitory protein) are both GPI-anchored proteins, whose primary function is to protect host cells from complement-mediated lysis.

Except for hematopoietic stem cell transplantation, there are currently no other effective curative treatments for PNH. Controlling hemolytic episodes remains the primary clinical management strategy, with mainstay therapeutic agents including glucocorticoids, immunosuppressants, and complement pathway inhibitors.

The PNH market is monopolized by Alexion.

AstraZeneca's $39 Billion Acquisition

Prior to this, the only approved complement inhibitors were Alexion’s Soliris and Ultomiris, with Ultomiris being the upgraded version of Soliris.

Soliris (eculizumab) is the world's first approved C5 complement inhibitor, administered once weekly or once every two weeks, with approved indications including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG), and anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) with a relapsing course.

Ultomiris is a long-acting C5 complement inhibitor. Since its approval in 2018, its approved indications have included PNH and aHUS (in adults and pediatric patients aged ≥1 month). For pediatric and adult patients weighing ≥20 kg, Ultomiris is administered once every 8 weeks, whereas for pediatric patients weighing <20 kg, it is administered once every 4 weeks. Additionally, last year Alexion introduced a 100 mg/mL formulation of Ultomiris, which reduces the average annual infusion time by 60%.

According to Yaozhi's analysis of Alexion's historical financial reports, sales of Soliris have steadily increased year after year since its market approval in 2007, reaching $4.064 billion in 2020. Meanwhile, sales of Ultomiris surpassed $1 billion in just its second year on the market, with EvaluatePharma forecasting that its sales could reach $3.43 billion by 2024. Notably, given Alexion's leading position in the field of therapeutics for complement-mediated rare diseases, AstraZeneca acquired the company for $39 billion in December 2020.

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Breaking the Monopoly in the PNH Market

Empaveli Approved, Shaking Up the Market

The newly approved Empaveli is a C3 complement inhibitor. Its active ingredient, pegcetacoplan, is a synthetic cyclic peptide conjugated to a polyethylene glycol (PEG) polymer, which specifically binds to C3 and C3b to modulate excessive complement activation in various diseases. Notably, Empaveli is the first therapy to demonstrate superiority over Soliris in terms of hemoglobin levels.

The approval of Empaveli was based on the results of the head-to-head Phase 3 PEGASUS study (NCT03500549). This multicenter, randomized, open-label, active-controlled, head-to-head study was conducted in 80 adult patients with PNH to evaluate the efficacy and safety of Empaveli compared with Soliris.

The results showed that the study met its primary endpoint: at 16 weeks of treatment, the change in hemoglobin levels from baseline in the Empaveli group was superior to that in the Soliris group, with an adjusted mean increase in hemoglobin of 3.84 g/dL (p≤0.0001). Furthermore, the Empaveli group was non-inferior to the Soliris group regarding the transfusion avoidance endpoint, with 85% of patients receiving Empaveli remaining transfusion-free over the 16-week period (vs. 15% in the Soliris group).

However, the prescribing information for Empaveli contains a boxed warning indicating that it may increase the risk of meningococcal and other serious infections caused by encapsulated bacteria, which can rapidly become life-threatening or fatal if not recognized and treated early.

Empaveli, developed by Apellis Pharmaceuticals, is used for the treatment of PNH and is also being developed for the treatment of primary cold agglutinin disease (CAD), hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), immune complex membranoproliferative glomerulonephritis (IC-MPGN), C3 glomerulopathy (C3G), and amyotrophic lateral sclerosis (ALS), among other diseases.

In November 2020, Apellis Pharmaceuticals and Sobi entered into an agreement to co-develop Empaveli, granting Sobi commercialization rights for the drug in markets outside the United States. The approval of Empaveli is poised to challenge Soliris and Ultomiris, as it competes for their market share in the PNH therapeutic landscape.

Multiple pipeline candidates are advancing.

Novartis, Sanofi, and Others Enter the Market

In addition to the three approved complement inhibitor drugs mentioned above, several investigational drugs are currently in development, including Sanofi's sutimlimab, Novartis's iptacopan (LNP023), Vifor Pharma/ChemoCentryx's avacopan (CCX168), Akari Therapeutics' nomacopan, Achillion Pharmaceuticals' danicopan, Annexon Biosciences' ANX005, and Ra Pharma's zilucoplan, among others.

Sutimlimab is a first-in-class investigational humanized monoclonal antibody specifically designed to selectively target and inhibit the serine protease C1s within the C1 complex. It is being developed for the treatment of cold agglutinin disease (CAD), immune thrombocytopenic purpura (ITP), and other indications. In November 2020, the U.S. Food and Drug Administration (FDA) rejected its Biologics License Application (BLA) for the treatment of CAD. In April this year, Sanofi announced that the final results of Part A of the pivotal Phase 3 CARDINAL open-label, single-arm study evaluating sutimlimab in CAD were published in *The New England Journal of Medicine*. Treatment with sutimlimab demonstrated sustained inhibition of classical complement pathway-mediated hemolysis, improved anemia, and reduced fatigue within one week, with sustained therapeutic effects maintained throughout the study.

Iptacopan is a first-in-class, oral, potent, selective, small-molecule, reversible Factor B inhibitor. Factor B is a key serine protease in the alternative pathway of the complement system. In addition to PNH and C3G, iptacopan is currently under development for the treatment of several other complement-mediated kidney diseases with significant unmet medical needs, including IgA nephropathy (IgAN), atypical hemolytic uremic syndrome (aHUS), and membranous nephropathy (MN).

Avacopan is an oral small molecule and a selective inhibitor of the complement C5a receptor C5aR1. By precisely blocking the receptor (C5aR) for the proinflammatory complement system fragment C5a, which is expressed on the surface of destructive inflammatory cells such as neutrophils, avacopan prevents these cells from exerting their damaging effects in response to C5a activation, a key driver of ANCA vasculitis. In November 2020, the European Union accepted the marketing authorization application (MAA) for this drug for the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]). Additionally, the drug is under development for the treatment of other indications, including C3 glomerulopathy (C3G) and hidradenitis suppurativa (HS).

Nomacopan is a recombinant small protein (16.74 kDa) that is highly soluble and stable. It targets complement component C5, preventing the release of C5a and the formation of C5b-9 (also known as the membrane attack complex), while specifically inhibiting leukotriene B4 (LTB4). Both C5 and LTB4 are critical components of human immune and inflammatory responses. Nomacopan is under clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), bullous pemphigoid, atopic keratoconjunctivitis, and thrombotic microangiopathy. In January 2020, the Phase 3 CAPSTONE trial of nomacopan for PNH yielded positive results. Additionally, Akari is developing a novel, room-temperature-stable, high-concentration formulation of nomacopan that enables low-viscosity, 0.3 mL injections via an insulin pen-like device, allowing for once-daily subcutaneous administration for up to one week.

Danicopan potently and highly specifically inhibits complement factor D, modulating the alternative complement pathway and blocking the formation of C3 convertase. Additionally, danicopan prevents the deposition of C3b fragments on patients' red blood cells (RBCs), controls red blood cell destruction and extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH), thereby improving therapeutic outcomes. In September 2019, the drug was granted orphan drug designation by the FDA for use in combination with a C5 complement inhibitor for the treatment of PNH patients with an inadequate response to C5 inhibitor therapy.

ANX005 is a clinical-stage investigational monoclonal antibody that potently inhibits C1q, the initiating molecule of the classical complement cascade, thereby blocking the activation of the entire classical pathway, including downstream C3 and C5, while preserving the protective functions of other complement pathways (lectin and alternative pathways). Currently, ANX005 is being developed for the treatment of autoimmune and neurodegenerative diseases. In September 2019, the drug was granted Fast Track designation by the FDA for the treatment of Guillain-Barré syndrome (GBS).

Zilucoplan is a novel self-administered macrocyclic peptide complement C5 inhibitor currently under development for the treatment of generalized myasthenia gravis (gMG) and other rare, tissue-based complement-mediated diseases. In September 2019, the FDA granted orphan drug designation to zilucoplan for the treatment of generalized myasthenia gravis (gMG).

Bullish on the Blue Ocean Market for Complement Therapeutics

Continuous BD Deals

Facing the blue ocean market for complement therapeutics, domestic and international pharmaceutical companies have conducted multiple BD deals focused on complement drugs in recent years.

In November 2018, I-Mab and Germany's MorphoSys entered into a strategic collaboration for the development of MOR210, securing exclusive rights to the drug in Greater China and South Korea. MOR210 is an antibody targeting C5aR and has currently received clinical trial approval in both the United States and China.

In October 2019, Alexion Pharmaceuticals acquired Achillion Pharmaceuticals for $930 million to expand its product pipeline and obtain the latter's oral factor D inhibitor platform, aiming to co-develop effective therapies for PNH, C3G, and other rare diseases mediated by the alternative complement pathway. In the same month, UCB acquired Ra Pharmaceuticals for $2.1 billion to jointly advance the development of the latter's C5 complement inhibitor, zilucoplan, for the treatment of rare diseases such as myasthenia gravis.

In December 2020, AstraZeneca acquired Alexion Pharmaceuticals for $39 billion, marking the largest transaction in the biopharmaceutical industry in 2020. Industry analysts believe that beyond supplementing its pipeline, the acquisition was primarily driven by AstraZeneca's strategic interest in Alexion's development capabilities in complement therapeutics.

In April 2021, LongBio and RxViosn entered into a global licensing and collaboration agreement for the complement drug RX-001 for the treatment of ophthalmic diseases, with a total agreement value exceeding RMB 1 billion.

With advancing research into complement therapeutics and close collaboration among industry players, an increasing number of complement drugs are expected to gain regulatory approval in the future, accompanied by a continuously expanding range of indications.

“The first new class of complement therapeutics in nearly 15 years” receives FDA approval, challenging the $4 billion blockbuster eculizumab; can Empaveli redefine treatment for PNH patients? Which company do you favor in the future market? Welcome to leave a comment and join the discussion~

Responsible Editor: Sanqi

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