Brief comment on domestic orthopedics product line

A few days ago, Haisco introduced Lorecivivint, a long-acting FIC drug developed by Biosplice to treat osteoarthritis
.

According to reports, an estimated 303 million people worldwide were affected by osteoarthritis in 2017, of which the knee is the most common site of osteoarthritis
.

The agreement reached with Biosplice this time means that Hisco has expanded from the pain management field to the orthopedics field
.

Brief introduction of domestic orthopedic drugs

The main orthopedic diseases that can be treated with drugs in clinic are rheumatoid arthritis, osteoarthritis and osteoporosis
.

At present, there are four main drugs for treating osteoporosis in China: 1) Inhibition of absorption, that is, bisphosphonate drugs that inhibit osteoblasts, such as Novartis’s zoledronic acid; 2) Selective estrogen receptor modulators, such as Eli Lilly’s raloxifene; 3) osteosynthetic parathyroid hormone analogs, such as Eli Lilly’s teriparatide; and 4) monoclonal antibody drugs, such as Amgen’s RANKL receptor agonist desulumab
.

The main domestic drugs for treating osteoporosis are teriparatide and desulumab
.

At present, a total of 9 domestic biosimilars of Disumab are in clinical trials, 2 have been approved for clinical trials but have not yet started clinical trials, and 1 is in clinical application
.

The drug treatment of osteoarthritis mainly includes non-steroidal anti-inflammatory analgesics, hyaluronic acid drugs and glucosamine sulfate drugs
.

Rheumatoid arthritis is a kind of autoimmune diseases.
The pathogenesis is studied in depth and the targets are clear: such as TNF-α, RANKL, IL-17 and JAK1
.

In 2020, the global cumulative sales of autoimmune disease drugs represented by rheumatoid arthritis will be approximately US$50 billion
.

With the rise of biological drug R&D and promotion, domestic pharmaceutical companies' R&D for orthopedic products is mainly concentrated in the field of rheumatoid arthritis
.

01 TNF-α monoclonal antibody

Mainly used for rheumatoid arthritis, ankylosing spondylitis, psoriasis and Crohn's disease
.
There are 5 TNF-α inhibitors on the global market
.
Including Infliximab, Adalimumab, Certuzumab, Golimumab and Etanercept
.
From 2016 to 2018, the global sales of TNF-α inhibitors were 36.
316 billion U.
S.
dollars, 36.
2 billion U.
S.
dollars and 36.
746 billion U.
S.
dollars, respectively, becoming the world's best-selling drugs
.
Among them, Adalimumab, as the first humanized TNF-α monoclonal antibody, has been approved for dozens of clinical indications, with global sales of nearly 20 billion U.
S.
dollars
.

At present, domestic anti-TNF-α monoclonal antibodies are mainly adalimumab biosimilars.
The companies that have been approved for listing include Biotech, Hisun Pharmaceuticals, Cinda Biologicals and Fuhong Henlius, and Junshi Biologicals and Zhengda Fangqing.
It has also been NDA, and there will be many companies in the clinic in the future, and the competitive landscape is very fierce
.

02 RANKL monoclonal antibody

Disulumab is an FIC anti-RANKL monoclonal antibody developed by Amgen, with global sales of approximately US$5 billion in 2020
.

In June 2020, Prolyx was approved in China for the treatment of osteoporosis in postmenopausal women with a high risk of fracture
.
Proliz should be administered by subcutaneous injection every 6 months at a dose of 60 mg
.

Many domestic biosimilar drugs of disulumab are under development, such as: Qilu Pharmaceutical, Luye Pharmaceutical/Boan Biological, Hausen Pharmaceutical, CSPC/Zinmante, Jiahe Biological, Fuhong Henlius, Kunyao Group , Maiwei Biology/Jiangsu Taikang Biology and so on
.

03 IL-17A monoclonal antibody

As the second largest treatment area after cancer, autoimmune diseases have spawned many blockbuster products
.
The target of interleukin family members is also a research and development hotspot in the field of autoimmunity.
Domestic companies seem to be particularly optimistic about the therapeutic prospects of IL-17A targets for rheumatoid arthritis
.
Companies that have made arrangements in advance include Hengrui Pharmaceutical, Sansheng Guojian, Kangfang Bio, Zhixiang Jintai, Junshi Biology, Livzon and Quanxin Bio, etc.
The current progress is Zhixiang Jintai’s IL-17A monoclonal antibody GR1501 And Hengrui Medicine IL-17A monoclonal antibody vunakizumab (SHR1314), both have entered the phase III clinical stage
.

04 JAK1 inhibitor

Tofacitinib, a JAK1 inhibitor developed by Pfizer, was approved for marketing in the United States in November 2012 and was approved for the treatment of rheumatoid arthritis
.
In 2018, global sales of tofacitinib reached US$1.
774 billion, a year-on-year increase of 32%, and it is still in a period of rapid increase in volume
.

JAK1 inhibitors that have been approved by the FDA for marketing include tofacitinib, rocotinib and barexitinib
.
On March 29, 2019, Astellas’ Smyraf was approved by Japan PMDA for listing
.

At present, many foreign companies are conducting the research and development of JAK-related target inhibitors, and most of them have reached phase III clinical trials
.
In China, in addition to Novartis's international multi-center phase III clinical trial for polycythemia vera, only SHR0302 independently developed by Hengrui is currently undergoing phase III clinical trials in China and the United States
.
According to Microchip's 2021 Interim Report, its JAK inhibitor CS12192 has entered phase I clinical trials, and its indication is rheumatoid arthritis
.
In general, there is still a lot of room in the domestic market, and the competition pattern is good
.

A listed company with a representative domestic orthopedics layout

After Haisco introduced FIC products for osteoarthritis, it has become a new force in this field
.
There are still many domestic companies that have already deployed in this field
.
Below we briefly introduce a few representative listed pharmaceutical companies
.

Hengrui Medicine

Hengrui will become a leading domestic enterprise in the field of rheumatology/orthopedics (rheumatoid arthritis and ankylosing spondylitis) in the future by virtue of its advanced layout in the two targets of IL-17 and JAK1
.

At present, the domestic oncology field has become a red sea, with large indication companies getting together, and small indications cannot support revenue growth
.
Therefore, although Hengrui has a complete tumor pipeline layout, it is facing considerable competitive pressure
.
If there are only me-too drugs, medical insurance negotiations will be a difficult point (the revenue of Karelizol is not as expected as an example)
.

With the regulation of medication and the increasing availability of orthopedic medicines, biological medicines for orthopedic treatment in China will surely shine in the future (currently, more than 3/4 of the medicines for rheumatoid arthritis in China are traditional Chinese medicines and chemical medicines)
.
While many companies are still rushing for the first imitations of adalimumab and desulumab biosimilar drugs, Hengrui has already pushed its new drug to market soon
.
At present, the domestic competition pattern of the two targets of Hengrui IL-17 and JAK1 is very good, and the potential for heavy volume is not even inferior to PD-1.

Xinlitai

According to the disclosure of Xinlitai's 2020 annual report: In terms of orthopedic products, the company's first biopharmaceutical production approval, teriparatide powder injection, has been approved for marketing.
At the same time, the developed water injection has been declared for production, and long-acting teriparatide preparations are in progress.
The PK comparison test is about to enter Phase III clinical trials, and monoclonal antibody products for the treatment of osteoporosis are also in progress
.

Recombinant teriparatide for injection is currently the only drug that can stimulate bone formation and bone resorption.
The original manufacturer was Eli Lilly and was approved for marketing by the FDA in 2002
.
Teriparatide can reduce the incidence of fractures in postmenopausal women.
Depending on the method of administration, it can also increase or decrease bone density
.

At present, only Xinlitai and United Purcell have been on the market of teriparatide biosimilars in China.
In addition, Kangchen Pharmaceuticals used US$22.
5 million to purchase the rights and interests of teriparatide biosimilars in the United States
.
With the joint layout of short-acting and long-acting teriparatide, Xinlitai is expected to create a new one billion variety, but the follow-up will still depend on the development of innovative drugs to evaluate its influence in the field of orthopedics
.

Yifan Pharmaceutical

In July 2021, Yifan Pharmaceutical announced that the cross-linked sodium hyaluronate injection of the company's subsidiary has been approved for listing by NMPA (introduced by the original Korean product), and the indication is knee osteoarthritis
.
According to the sample data of Minai.
com, the market size of sodium hyaluronate injection in China in 2020 is about 1.
27 billion yuan, mainly ordinary sodium hyaluronate
.
At present, only Sanofi’s Xinweico is the only domestic cross-linked sodium hyaluronate, which has a small market share
.
The pattern of duopoly competition is conducive to the rapid increase in volume of Yifan Pharmaceutical in this field, but the overall market for sodium hyaluronate is limited, which is not enough to support a large single product of 1 billion
.

Summarize

Orthopedic drugs are chronic disease drugs, with longer clinical cycles and slower doses
.
At present, most domestic pharmaceutical companies still focus their research and development efforts on the field of oncology.
Among the listed pharmaceutical companies, only Hengrui, Xinlitai, Yifan Pharmaceutical and Haisco have pharmaceutical products in the field of orthopedics
.
However, as competition in the oncology field intensifies, differentiated competition will be an important factor for innovative pharmaceutical companies to consider the layout of R&D pipelines in the future
.

Rheumatoid arthritis caused by autoimmunity and osteoporosis and osteoarthritis of the elderly still have urgent clinical needs in China, and the market is no less than a large tumor target; and chronic disease drugs With a long tail effect, many original research products that have passed the patent period can still bring considerable cash flow to the enterprise
.

With a vast market, a good competitive landscape, and a long product life cycle, it is believed that more domestic pharmaceutical companies will enter the field of orthopedics drugs in the future
.