Focus on drug targets: TNF-α inhibitor wars, who is in charge of ups and downs?

Tumor necrosis factor (TNF) is an inflammatory cytokine that can coordinate tissue homeostasis by co-regulating the production of other cytokines, cell survival and death
.

Originally, TNF was named for its ability to induce rapid hemorrhagic necrosis of tumors in humans and mice

Yisaipu (recombinant human type II tumor necrosis factor receptor antibody fusion protein) is the first fully human antibody drug on the market in China and the first TNF-α inhibitor on the market in the field of rheumatism in China.
It is mainly used for the treatment of Rheumatoid arthritis (approved in 2005), ankylosing spondylitis and psoriasis (approved in 2007)
.

Yisaipu covers more than 3,700 hospitals, including nearly 1,700 tertiary hospitals

Monthly treatment costs of five TNF-α inhibitors included in the National Medical Insurance List (Source: Huajin Securities)

Monthly treatment costs of five TNF-α inhibitors included in the National Medical Insurance List (Source: Huajin Securities)

Market size forecast of TNF-α inhibitors in China (Source: Huajin Securities)

Market size forecast of TNF-α inhibitors in China (Source: Huajin Securities)

1.
The latest research progress

The latest research progress

1.
According to incomplete statistics, there are currently 40 TNF-α drugs approved and marketed in the world , of which adalimumab is the most approved TNF-α drug, followed by infliximab
.

According to the domestic TNF-α market situation in 2020, the sales volume of Yisaipu of China Health is about 616 million, accounting for about 46% of the market share; the sales volume of Cilag’s gram is about 334 million, accounting for about 25% of the market share; AbbVie The sales volume of Humira is about 120 million, accounting for about 9% of the market share; the sales volume of Qiangke of Saikin Bio is about 107 million, accounting for about 8% of the market share; the sales volume of Embryo produced by Zhejiang Hisun is about 80 million, About 6% of the market share

Approved for listing

2.
There are 161 TNF-α-related drugs under development , including 40 on the market, 7 on the market, 14 in Phase III, 1 in Phase II/III, 17 in Phase II, and 1 in Phase I/II.
2, 23 Phase I clinical trials, 12 clinical trials, and 45 pre-clinical trials
.

in research stage

3.
Indications: The most studied indications are autoimmune diseases (52), tumors (19), sepsis (3), novel coronavirus infection (3), dry eye syndrome (3), uveal disease inflammation (3), osteoarthritis (3), diabetic peripheral neuralgia (2), hidradenitis suppurativa (2),
etc.

4.

3.

5.
The statistics of the drugs in the research stage II and above are as follows:

II and above in the research stage

2.
Introduction of key drugs

Introduction of key drugs

At present, TNF inhibitors marketed in China are mainly divided into two types: fusion protein and monoclonal antibody.
The representative drug of fusion protein TNFi is etanercept, which is a receptor-type TNFi and is composed of human TNFR2 (p75 TNF) receptor cells.
The outer part is composed of the Fc part (CH2 and CH3 domains) of human IgG1; the representative drugs of monoclonal antibodies are infliximab, adalimumab, etc.
, including fully human, human, human-mouse chimeric and mouse-derived etc.
, the molecular structure includes two parts of the variable region Fab and the constant region Fc, both of which can specifically bind to the pathogenic factor TNF-α
.

1.
Etanercept , including Pfizer's Enli, Guojian's Yisaipu, and Saijin Bio's Qiangke, are all humanized receptor-antibody fusion proteins, that is, proteins expressed through human DNA, which can be injected subcutaneously.
Yes
.

The fusion protein TNFi is less bound to tmTNF, and the binding is reversible.

1.

2.
Infliximab

2.
Infliximab

Infliximab, a classic TNF-α inhibitor, has been around for more than 20 years, it binds with high affinity to both the soluble form (sTNF-α) and the transmembrane form (tmTNF-α) of TNF-α , inhibit the binding of TNF-α and receptors, thereby making TNF lose its biological activity
.

The sales of the original Johnson & Johnson Leike peaked in 2014, but in recent years, due to the successive listing of biosimilars after the patent expired and the challenges of various interleukin inhibitors, the global market sales of Leike continued to decline.

3.
Adalimumab

3.
Adalimumab

Adalimumab is developed by AbbVie and is the world's largest TNF-α inhibitor biological drug by sales.
Since 2012, the sales of its original research Merlot has ranked first in the world for 9 consecutive years of prescription drugs.
In 2020, the global drug The sales amounted to 20.
39 billion yuan
.

Since listing, approved therapeutic areas include rheumatoid arthritis, ankylosing spondylitis, psoriasis (including childhood plaque psoriasis), psoriatic arthritis, juvenile idiopathic arthritis, Crohn's Disease (including childhood Crohn's disease), ulcerative colitis, hidradenitis suppurativa, uveitis and other seventeen diseases

4.
Golimumab Golimumab was developed by Johnson & Johnson and was approved by the US FDA in April 2009; in 2011, Merck signed a cooperation agreement with Johnson & Johnson to obtain the distribution rights of these two varieties in other markets outside North America
.
In December 2017, golimumab was officially approved in China for the indications of rheumatoid arthritis (combined with methotrexate) and ankylosing spondylitis
.
Despite being included in medical insurance, the price of golimumab is still higher than that of adalimumab, infliximab and Yisaipu, but with the advantages of excellent efficacy and less frequent injections, the market penetration rate is expected to further increase
.
At present, only Bio-Thera is in the clinical stage of biosimilars of golimumab, and an international multi-center phase 3 clinical trial has been launched
.
According to the latest study data published in Rheumatology and Therapy in July 2021, in patients with RA, PsA and AS, the use of golimumab significantly reduced disease activity at both weeks 12 and 24; at week 24 Weekly, 71.
4% of PsA patients had an ACR20 response, and 72.
9% of AS patients had an ASAS20 response
.

4.
Golimumab

5.
ozoralizumab Ablynx's ozoralizumab (ATN-103) is a humanized, trivalent bispecific nanobody, and Eddingpharm has the right to develop ozoralizumab in Greater China
.
Ozoralizumab contains three nanobody domains, two of which target TNF and one that binds to albumin to prolong drug half-life and is currently being developed for the treatment of inflammatory diseases
.
In a phase II study evaluating the clinical activity and safety of ozoralizumab in patients worldwide and in Japan, the study showed higher clinical activity and better safety when 80 mg of ozoralizumab was injected
.

5.
ozoralizumab

Image credit: Frontiers

6.
Tenacept Tenacept (HBM9036) is a molecularly engineered TNF receptor-1 fragment with a molecular weight of only 19kDa.
It was developed as an eye drop ophthalmic topical drug for relieving dry eye symptoms.
It has the characteristics of good eye permeability, strong TNF-α neutralizing activity, high stability, small side effects, and high comfort
.
The product was developed by HanAll Corporation, and Harbin Pharmaceutical holds the exclusive development and commercialization rights to Tenacept in mainland China, Taiwan, Hong Kong and Macau
.
In January 2022, Harbin Pharmaceutical announced that the Phase III registration clinical trial of Tenacept in China was progressing smoothly, and the first interim analysis had been completed as planned
.

6.
Tenacept

Image source: Hebo Pharmaceutical official website