The 10 billion complement inhibitor market "triples", Alexion's exclusive position was broken; Novartis, Sanofi...

Key words

Empaveli; Soliris; complement inhibitor; acquisition

Recently, Apellis Pharmaceuticals announced that the FDA has approved its C3 complement inhibitor Empaveli (pegcetacoplan) to be marketed for the treatment of naïve paroxysmal nocturnal hemoglobinuria (PNH) adult patients, as well as previous complement C5 inhibitors Soliris and Ultramiris Treated PNH patients
.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic disease caused by genetic mutations in acquired hematopoietic stem cells
.

PIG-A gene mutation is considered to be the main molecular biological cause of PNH intravascular hemolysis

Except for hematopoietic stem cell transplantation, there is no other effective cure for PNH.
Controlling hemolytic attacks is the main method for clinical treatment of the disease.
The main therapeutic drugs include glucocorticoids, immunosuppressants, and complement pathway inhibitors
.

PNH market is monopolized by Alexion

AstraZeneca has $39 billion in revenue

Prior to this, the only approved complement inhibitors were Alexion's Soliris and Ultomiris, among which Ultomiris was an upgraded version of Soliris
.

Soliris (Eculizumab) is the first C5 complement inhibitor approved in the world.
It is administered once a week or every 2 weeks.
The approved indications include PNH, atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor ( AchR) antibody-positive myasthenia gravis (MG) and anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) with a recurring course
.

       Ultomiris is a long-acting C5 complement inhibitor.
The indications approved since its approval in 2018 include PNH and aHUS (adults and pediatric patients ≥1 month).
Among children and adult patients weighing ≥20 kg, Ultomiris Ultomiris is administered once every 8 weeks.
In children with a body weight of <20 kg, Ultomiris is administered once every 4 weeks
.

And last year, Alexion also launched 100mg/mL Ultomiris, which can reduce the average annual infusion time by 60%

       According to Alexion’s previous financial reports, Soliris’ sales have risen year by year since it was approved for listing in 2007, reaching US$4.
064 billion in 2020
.

In the second year of Ultomiris’s listing, sales exceeded US$1 billion, and EvaluatePharma predicts that its sales in 2024 are expected to reach US$3.

       Break the market monopoly in the PNH field

       Empaveli approved to disrupt the game

       The approved Empaveli is a C3 complement inhibitor.
Its active ingredient, pegcetacoplan, is a synthetic cyclic peptide coupled with polyethylene glycol polymer, which can specifically bind to C3 and C3b and regulate excessive complement activation in many diseases.

.

It is worth mentioning that Empaveli is the first therapy to show superior hemoglobin levels to Soliris

       The approval of Empaveli is based on the results of the head-to-head Phase 3 PEGASUS study (NCT03500549)
.

The study is a multi-center, randomized, open-label, positive drug controlled, head-to-head study in 80 adult patients with PNH to evaluate the efficacy and safety of Empaveli relative to Soliris

       The results showed that the study reached the primary endpoint-at 16 weeks of treatment, the hemoglobin level in the Empaveli group was better than Soliris compared to the baseline change, and the adjusted hemoglobin increased by 3.
84 g/dL on average (p≤0.
0001)
.

Moreover, patients in the Empaveli group were not inferior to the Soliris group in terms of avoiding blood transfusion endpoints, and 85% of patients treated with Empaveli had no blood transfusion within 16 weeks (15% in the Vs Soliris group)

       However, the Empaveli prescription information contains a black box warning that it may increase the risk of meningococcal and other serious infections caused by capsular bacteria.
If not identified and treated early, it may be life-threatening or fatal quickly
.

       Empaveli was developed by Apellis Pharmaceuticals.
In addition to the treatment of PNH, Empaveli was also developed for the treatment of primary cold agglutinin disease (CAD), hematopoietic stem cell transplantation-related thrombotic microangiopathy (HSCT-TMA), and immune complex membrane hyperplasia Glomerulonephritis (IC-MPGN), C3 glomerular disease (C3G), amyotrophic lateral sclerosis (ALS) and other diseases
.

       In November 2020, Apellis Pharmaceuticals and Sobi reached an agreement to jointly develop Empaveli, and at the same time granted Sobi the right to commercialize the drug in markets outside the United States
.

The approval of Empaveli is bound to pose a threat to Soliris and Ultomiris, competing for their market share in the PNH field

       A variety of research varieties are already on the way

       Novartis, Sanofi and others enter the game

       In addition to the three approved complement inhibitor drugs, there are currently many drugs under development, such as Sanofi’s sutimlimab, Novartis’s iptacopan (LNP023), Vifor Pharmaceuticals/ChemoCentryx’s avacopan (CCX168), Akari’s nomacopan, Achillion's danicopan, Annexon company ANX005, Ra's zilucoplan and so on
.

       sutimlimab is a pioneering humanized monoclonal antibody under research.
It is specifically designed to selectively target and inhibit the serine protease C1s in the C1 complex.
It has been developed for the treatment of CAD and immune thrombocytopenic purpura (ITP).
) And other diseases
.

In November 2020, the drug's BLA for the treatment of CAD was rejected by the FDA

       Iptacopan is a first-in-class, oral, potent, selective, small molecule, and 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 being developed for the treatment of other kidney diseases where the complement system is involved and there are significant unmet needs, including IgA nephropathy (IgAN), aHUS, and membranous nephropathy (MN)
.

       Avacopan is an oral small molecule and a selective inhibitor of complement C5a receptor C5aR1
.
By precisely blocking the receptors for the pro-inflammatory complement system fragment C5a (C5aR) present on the surface of destructive inflammatory cells such as neutrophils, avacopan can prevent the ability of these cells to damage the activation of C5a, which is the blood vessel of ANCA The driving factors of inflammation
.
In November 2020, the EU accepted the application for marketing authorization of the drug for the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis (granulomatosis with multiple vasculitis [GPA] and microscopic polyangiitis [MPA]) (MAA)
.
In addition, the drug has also been developed to treat diseases such as C3 glomerulopathy (C3G) and hidradenitis suppurativa (HS)
.

       nomacopan is a small recombinant protein (16740Da), highly soluble and stable, acting on the complement component C5, can prevent the release of C5a and the formation of C5b-9 (also known as membrane attack complex), and can also specifically inhibit Leukotriene B4 (LTB4)
.
Both C5 and LTB4 are important components in the human immune/inflammatory response
.
Nomacopan is clinically developed for the treatment of PNH, bullous pemphigoid, atopic keratoconjunctivitis, thrombotic microangiopathies
.
In January 2020, the Phase III CAPSTONE study of nomacopan in the treatment of PNH achieved positive results
.
Moreover, Akari is also developing a new, room-temperature stable, high-concentration nomacopan formula that allows small volume 0.
3mL, low-viscosity injections, using a syringe similar to an insulin injection pen, which can provide subcutaneous injections once a week
.

       Danicopan inhibits complement factor D with a potent and highly specific target, regulates the alternative pathway of complement, and blocks the production of C3 convertase
.
Moreover, danicopan prevents the deposition of C3b fragments on the RBC of patients, controls the decomposition of red blood cells in patients with PNH, and extravascular hemolysis, thereby improving the treatment effect of patients
.
In September 2019, the drug was granted orphan drug designation by the FDA in combination with C5 complement inhibitor treatment for PNH patients who did not respond well to C5 inhibitor treatment
.

       ANX005 is a clinical-stage research monoclonal antibody that can strongly inhibit the initiation molecule C1q of the classical complement cascade, thereby blocking the activation of the entire classical pathway, including downstream C3 and C5, while retaining other complement pathways ( Lectins 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 status for the treatment of Guillain-Barré Syndrome (GBS) by the FDA
.

       Zilucoplan is a new self-administered macrocyclic peptide complement C5 inhibitor.
It is currently being developed for the treatment of systemic myasthenia gravis (gMG) and other rare tissue-based complement-mediated diseases
.
In September 2019, the drug was granted orphan drug designation for zilucoplan for the treatment of myasthenia gravis (gMG) by the FDA
.

       Optimistic about the blue ocean in the complement drug market

       BD trading keeps on

       In the face of the blue ocean in the complement drug market, domestic and foreign pharmaceutical companies have conducted a number of BD transactions around complement drugs in recent years
.

       In November 2018, Tianjing Biotech reached a strategic cooperation with MorphoSys of Germany on the development of MOR210, and obtained exclusive rights to the drug in Greater China and South Korea.
MOR210 is an antibody against C5aR and has been approved for clinical use in the United States and China.

.

       In October 2019, Alexion acquired Achillion for US$930 million to expand its product pipeline, acquire the latter's oral factor D inhibitor platform, and jointly develop effective therapies for the treatment of rare diseases mediated by PNH, C3G, and other complement replacement pathways
.
In the same month, U-Times acquired Ra Pharmaceuticals for US$2.
1 billion to jointly promote the development of the latter's C5 complement inhibitor zilucoplan in the treatment of rare diseases such as myasthenia gravis
.

       In December 2020, AstraZeneca acquired Alexion Pharmaceuticals for US$39 billion, which is the largest transaction amount in the biomedical industry in 2020.
The industry believes that in addition to supplementing its pipeline, the transaction may be more valued by Alexion Pharmaceuticals in complement drugs.
Development capabilities
.

       In April 2021, Tianchen Biotechnology and AierHealth signed a global authorization cooperation agreement for the complement drug RX-001 for the treatment of ophthalmic diseases.
The total amount of the agreement exceeded RMB 1 billion
.

       With the in-depth research on complement drugs and the close cooperation between companies, it is expected that more and more complement drugs will be approved in the future, and the scope of indications will also increase
.

       "The first new complement drug type in the past 15 years" was approved by the FDA, challenging the US$4 billion blockbuster drug eculizumab; can Empaveli redefine the treatment of PNH patients? Which one are you optimistic about in the future market? Welcome to leave a message to discuss~

       Editor in charge: Sanqi