Complement drugs are full of smoke! Novartis, AstraZeneca, Sanofi, Roche prepare

Rare diseases have always been the field of onslaught by multinational big pharmaceutical companies, and the market competition around "orphan drugs" has never lacked stories
.

Novartis has announced that the phase III APPOINT-PNH study of oral single-agent Iptacopan (NCT04820530) met the primary endpoint
in adults with paroxysmal nocturnal hemoglobinuria (PNH) who have not received complement inhibitor therapy (including anti-C5 therapy).

PNH is a rare, chronic, life-threatening blood disorder caused by acquired mutations that cause uncontrolled complement activation and destruction of red blood cells
through intravascular and extravascular hemolysis.
Up to now, there are 3 therapeutic drugs for PNH worldwide, including 2 C5 monoclonal antibodies Soliris and Ultomiris from AstraZeneca, and 1 complement C3 monoclonal antibody Empaveli (pegcetacoplan) from Apellis
.

The market view is that Novartis' Iptacopan is expected to be approved for marketing in 2023, which will challenge the market advantages
of AstraZeneca's Soliris (eculizumab, Chinese trade name: Sulliris) and Ultomiris in the segment 。 In the Chinese market, considering that AstraZeneca has announced that it has listed Sullilab as the company's first product in the field of rare diseases, and Roche's C5 inhibitor Crovalimab injection (corolimab) is accelerating its world premiere, competition in the PNH field has begun to ignite
.

Novartis set off direct competition

Can oral drugs break through?

Iptacopan is an orally selective complement bypass factor B inhibitor
.
It acts upstream of the C5 terminal pathway and prevents not only intravascular hemolysis of PNH, but also extravascular hemolysis
.
In addition, Iptacopan may have better therapeutic advantages
over C5 monoclonal antibody therapy by targeting key parts of the biology responsible for PNH while providing oral monotherapy options.

Phase III data show that Novartis' oral drug Iptacopan met the primary endpoint
in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have not been treated with complement inhibitors.
One of the primary endpoints was the proportion of patients who achieved a ≥2 g/dl increase in haemoglobin levels from baseline at 24 weeks without red blood cell transfusion; The other primary endpoint was the proportion of
patients who achieved a sustained haemoglobin level of 12 g/dl at 24 weeks without red blood cell transfusion≥.

Iptacopan also shows clinical potential
in patients with PNH who still have symptoms of anemia after prior treatment with complement C5 therapy.
In October, the Phase III APPLY-PNH study also met two primary endpoints, with 85% and 70% of patients in the Iptacopan group meeting endpoints
, respectively, compared to C5 monoclonal antibodies.
According to Novartis' plan, Iptacopan will file for listing
in 2023.

In the industry's view, if Iptacopan is approved, it will have an impact
on the market share of AstraZeneca Soliris and Ultomiris in the PNH segment.
Soliris was approved for marketing in 2007, the world's first approved C5 complement inhibitor, and also became the first and only drug to treat PNH at that time, and the "orphan drug" became a "blockbuster"
in the field of this super rare disease.
Currently, Soliris has approved a variety of super rare diseases, including: paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), neuromyelitis optica spectrum disorder (NMOSD).

Soliris' upgraded product, the second-generation, long-acting C5 complement inhibitor Ultomiris, was first approved by the FDA in late 2018
.
Compared to Soliris, Ultomiris requires fewer infusions per year and has good efficacy and safety
.
Approved indications include: PNH, aHUS, and the first and only drug
approved by the US FDA and the European Union for children and adolescents with PNH.

Ultomiris also continued Soliris' performance "myth", with sales exceeding $1 billion in its second year on the market, reaching $1.
077 billion in 2020, and EvaluatePharma predicting that its sales are expected to reach $3.
43 billion
in 2024.

Complement drug market

Sanofi, Roche and others joined the fray

It is reported that as a rare and fatal blood system disease, the incidence of PNH is about 1~10 cases per million population, mostly young and middle-aged patients, and about 77%
of patients aged 20~40.
Patients with PNH are prone to fatigue, anemia, bone marrow failure, hemoglobinuria, thrombosis, etc.
, and patients with PNH have a 35% risk of death within five years if left
untreated.

Since the discovery of complement in the 19th century, research into the complement system and its drug development has continued
.
It was not until 2007, when Sorilis, the first C5 complement inhibitor developed by Alexion, was approved for marketing, that complement drugs were truly available
.
However, there are still only a
handful of new drugs on the market in the complement field.

In the face of the blue ocean of the complement drug market, more and more pharmaceutical companies have entered the complement field through their own research and development or external borrowing, hoping to get a piece of the pie
.
AstraZeneca took the lead, and in December 2020, AstraZeneca spent $39 billion to acquire Alexion
, a leader in complement medicines.

However, after anti-C5 therapy, most patients still have residual anemia, fatigue, and transfusion dependence, which seriously affects quality of life
.
In order to make up for the shortcomings of C5 inhibitors, C3 complement therapy came into being
.
In 2021, Apellis' first C3 complement inhibitor, EmpaveliTM, made a stunning appearance, challenging AstraZeneca's C5 complement inhibitors Soliris and Ultomiris
.

AstraZeneca and Alexion will clearly not be waiting for the latecomers
.
In September 2022, Alexion announced positive late results
for potential complementary therapy to PNH.
Alexion announced that danicopan met the primary endpoint
of the Phase III ALPHA study in PNH patients undergoing clinically significant extravascular hemolysis (EVH).
The trial is an investigational oral factor D inhibitor that will be used with
Ultomiris or Soliris in PNH.

Today, in the field of PNH treatment, in addition to Novartis' Novartis' Iptacopan, a number of drugs are also accelerating on the road of research and development, such as Sanofi's sutimlimab, Roche's crovalimab, Vifor Pharma/ChemoCentryx's avacopan (CCX168), Akari's nomacopan, etc.
, are in clinical trials or early stage studies
.

It is worth mentioning that Roche has placed its main research and development resources in the Chinese market
.
In August 2022, Roche officially submitted the Chinese marketing application for crovalimab and was included in the priority review, which not only improved the effectiveness and convenience of existing PNH therapies, but also changed the mode of administration to self-subcutaneous injection, greatly improving accessibility
.
Crovalimab is expected to become the first innovative drug
in Roche's history to use China as the world premiere.

With the deepening of complement drug research and close cooperation between enterprises, it is expected that more and more complement drugs will be approved in the future, and the scope of indications will become larger and larger
.
How will the market structure of PNH drugs change in the future? The new media center of "Medical Economic News" will continue to pay attention
.