From the AstraZeneca subsidiary to see the global C5 target layout

On September 24, the CDE website showed that the application for clinical trial of anti-C5/albumin double-anti-ALXN1720 injection of Alexion, a subsidiary of AstraZeneca, was accepted
.

In 2020, AstraZeneca announced the $39 billion acquisition of Alexion, which focuses on the application of complement-targeted drugs in the field of rare diseases and has been a leader in complement biology
.

01 Complement system

01 Complement system

The complement system is made up of more than 30 proteins and is part of the innate immune system that activates and maintains body balance
through an enzyme cascade.

Disruption or over-activation of the control mechanisms of the complement system can trigger uncontrolled cascading reactions, leading to the development
of many rare diseases and some common autoimmune and inflammatory diseases.

Disorders associated with complement disorders[1]

The complement system has 3 different activation pathways: the classic pathway, the lectin pathway, and the alternative pathway
.

Classic pathway, lectin pathway, and alternative pathway

The classical pathway is activated by C1q when binding to the antibody Fc domain, non-immunoglobulin activator, or other polyionic substances in the antigen-antibody complex, and is the main effector mode
of humoral immune response mediated by the antibody.

Classic pathway

The lectin pathway is very similar to the classical pathway, except that it is activated by identifying components, manna binding lectins (MBL), fibrogelins and collagen lectins, and MBL-associated serine protease MASP1/2 by interacting
with specific carbohydrate structures (usually not present in the host).

Lectin pathway

The alternative pathway is through a membrane material such as a microbial surface, starting from C3, with factors B and D involved in the activation process
.

Alternative pathways

[3]

02 Alexion complement-targeted drug grooming

02 Alexion complement-targeted drug grooming

C5 inhibitors

C5 inhibitors

The terminal pathway begins with the capture and lysis of C5 by C5 convertase, releasing the pro-inflammatory peptide C5a
.

It is worth noting that while MAC is effective at lysing aging red blood cells and susceptible bacteria, when it forms on nucleated autologous cells, it triggers a large number of activation events, many of
which are highly pro-inflammatory.

The terminal pathway is the driving force behind damaging and/or activating target cells in rare diseases, and complement protein C5 is at the end of the cascade reaction, so targeting this protein can regulate all pathways
.

The terminal pathway is the driving force behind damaging and/or activating target cells in rare diseases, and complement protein C5 is at the end of the cascade reaction, so targeting this protein can regulate all pathways
.

There are currently three versions of Alexion's C5 inhibitor pipeline, namely first-generation, second-generation and third-generation inhibitors
.

Alexion pipeline

Alexion III generation C5 inhibitor

In 2007, Alexion's first-generation C5 inhibitor, Eculizumab (trade name Soliris), was approved by the FDA to become the world's first C5 inhibitor to be marketed, and the currently approved indications are paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), optic neuromyelitis spectrum disorder (NMOSD), and systemic myasthenia gravis (gMG
).

Eculizumab (trade name Soliris) Paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), Optic neuromyelitis spectrum disorder (NMOSD), Systemic myasthenia gravis (gMG)

The latest data released this year reflect Soliris' remarkable efficacy in the treatment of systemic myasthenia gravis (gMG).

In 2018, its second-generation C5 inhibitor, Ravulizumab (trade name Ultomiris), was approved by the FDA and the second approved C5 inhibitor, the first-generation long-acting version, with a longer half-life and lower
frequency of administration.

Ravulizumab (trade name Ultomiris) PNH, aHUS and gMG

In May, phase III data for its treatment of NMOSD was published, and the risk of recurrence in the Ultomiris treatment group decreased by 98.
6 percent compared to the control group.

NMOSD had a 98.
6% reduction in the risk of recurrence in the Ultomiris-treated group compared to the control group.

In addition, Ultomiris is expected to be the first drug
to treat transplant-associated thrombotic microangiopathy (HSCT-TMA) and cardiac surgery-related acute kidney injury (CSA-AKI).

ALXN1720 is a third-generation C5 inhibitor, an anti-C5/albumin mini-double antibody with a molecular weight of only 25kDa, with better permeability, and is specifically bound to albumin (albumin) by antibody heavy chain variable region (VH) targeting C5 with a longer
half-life.
The main indications are gMG
.

ALXN1720 has a better permeability half-life and a longer gMG

Other complement-targeting drugs

Other complement-targeting drugs

Although targeting C5 can regulate all of the above pathways, this can also be a disadvantage, resulting in all three pathways being suppressed
.
So Alexion has also developed therapies
that target targets in other complement systems.

Alexion complement-targeted drugs

One of them is a mini antibody with a similar structure design to ALXN1720, ALXN1820
.
It mainly targets rexedin (factor P), which inhibits the C3 complement pathway without affecting the conditioning effect on bacteria, thereby reducing the possibility
of infection in patients.

ALXN1820

03 C5 Targeted Drug Line Layout

03 C5 Targeted Drug Line Layout

At present, there are three C5 targeted drugs on the market worldwide, in addition to Alexion's Soliris and Ultomiris, the third is ChemoCentryx's Tavneos (avacopan
).

SolirisUltomirisTavneos (avacopan)
。

In September 2021, Tavneos was first approved for marketing in Japan, becoming the world's first approved C5a receptor inhibitor for the treatment of two main types of anti-neutrophil cytoplasmic autoantibody (ANCA)-related vasculitis: microscopic polymasculitis (MPA) and granulomas with polyangiitis (GPA).

In addition, domestic Shutaishen is leading the way into phase III clinical, and many other C5 targeted drugs that have been declared for listing or entered phase III are sorted out as follows:

On August 10, 2022, the Drug Review Center undertook the listing application of Roche Pharmaceutical's C5 inhibitor Crovalimab injection (Crovalimab) and included it in the priority review, which is expected to be approved in the first half of next year, becoming the first innovative drug in the history of Roche Pharmaceutical to be launched in China as the world's first launch
.

Crovalimab is a new generation of anti-complement C5 antibodies, developed
by Chugai using Smart-Ig engineering retrofit technology.
It inhibits complement activation by binding to the epitope on the C5 β chain (unlike the eculizumab and ravulizumab binding epitopes), blocking the cleavage of C5a to C5a and C5b, and its indication is PNH
.

Crovalimab mechanism of action

Reference:

Reference:

1.
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2.
https://jneuroinflammation.
biomedcentral.
com/articles/10.
1186/s12974-020-02024-8

2.
https://jneuroinflammation.
biomedcentral.
com/articles/10.
1186/s12974-020-02024-8

3.

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