Take the "unusual" road, IL-17A inhibitors all the way to the thorns, the pursuit of excellence!

*It is only for medical professionals to read for reference.
IL-17A inhibitors help the reform and upgrade of AS treatment.

In April 2020, Skuchyumumab was approved by the National Food and Drug Administration for the treatment of adult patients with ankylosing spondylitis (AS) whose conventional treatment is not effective.
This is currently the first and only approved AS indication in China.
The interleukin-17A (IL-17A) inhibitor, which has injected new impetus into the innovation and upgrade of AS treatment.

On December 28, 2020, the new version of the medical insurance catalog was released, and scocilizumab was officially included in the scope of medical insurance.
The new catalog will be launched on March 1 this year.
By then, the new treatment plan of scocilizumab will benefit more The Chinese patients bring hope of health to them.

So, how exactly was the innovative drug IL-17A inhibitor for the treatment of AS developed? What clinical research has it gone through? How does it exert its effects in diseases.
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Only by understanding the story behind IL-17A inhibitors and understanding its preciousness can we better use it to fight against diseases.

Today, we are going to review the history and progress of the clinical development of IL-17A inhibitor Skuchiyuumab, and invite Professor Sun Li from the First Affiliated Hospital of Wenzhou Medical College to comment.

Figure 1: The development history of Recukuzumab 1 The discovery of the key target IL-17A and verification of the selection of suitable targets are critical to the development of innovative drugs.

With the advancement of science and technology, our understanding of diseases has gradually deepened, and the path of potential disease occurrence and drug targets have become more and more clear.

AS is an autoimmune disease, which is closely related to disorders of the immune system.

Early studies have found that tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis of AS.
TNF-α inhibitors can effectively reduce disease activity, relieve disease symptoms and signs, and improve patients' physical function [1-2]. Therefore, TNF-α inhibitors have become the first biological agents to be used in the treatment of AS.

However, the search for key targets for AS treatment has never stopped, and relying on TNF-α inhibitors alone cannot fully meet the clinical diverse and complex treatment needs [3].

IL-17A is a newly discovered key target for AS treatment.

In 1993, Rouvier's team discovered CTLA-8 (IL-17A) from rodent T-cell hybridoma transcripts [4]; in 1996, the observation results of Fossiez et al.
showed that IL-17A may be T-cell-dependent The early initiation factor of inflammatory response has established a close relationship between IL-17A and inflammatory response and related diseases [5].

Subsequent reports on the mechanism of IL-17A further confirmed its pleiotropic and potential therapeutic value: it acts on a variety of downstream cells and produces different biological effects, such as inducing inflammation and promoting excessive proliferation of keratinocytes.
, Mediates the process of matrix destruction and vascular activation, and regulates bone metabolism [6-9], and participates in the regulation of chronic inflammation of AS, the occurrence and progression of enthesitis, pain response and new bone formation [10-13].

Figure 2: IL-17A acts on a variety of downstream cells to produce biological effects.
Can inhibiting IL-17A play an effective therapeutic role? This requires preclinical studies (such as studies in cells or using animal models) to verify the effectiveness of the target: In the collagen-induced arthritis (CIA) mouse model, IL- is completely knocked out through genetic engineering technology.
17A or the use of IL-17A polyclonal antibody can prevent the onset of arthritis and reduce the severity of inflammation, which proves that targeting IL-17A can inhibit persistent destructive joint inflammation [14-15]; in spontaneous arthritis ( In the SKG) mouse model, the loss of IL-17A can attenuate arthritis, spondylitis and enthesitis, proving that it has a key role in the pathological process of related rheumatic diseases [16]; in experimental spondyloarthritis rats In the model (HLA-B27 transgenic rat), IL-17A antibody treatment can block the inflammatory response, inhibit pathological new bone formation and structural damage [17-18].

Therefore, IL-17A is a key target for the treatment of AS, and treatments targeting IL-17A have therefore received extensive attention.

2 Formulation development: The development of fully human monoclonal antibody preparations targeting IL-17A is an important link in drug development.

In early preclinical studies, polyclonal antibodies extracted from the serum of immunized animals are often used to target IL-17A, but the uniformity and specificity of the antibodies prepared by this method are insufficient, and the application in humans is limited.

 Monoclonal antibodies are a major trend in the development of biological preparations, and have many advantages such as strong specificity, long-lasting efficacy, and small side effects.

From murine origin to humanization, and then to fully human origin, the monoclonal antibody preparation technology is continuously refined and optimized, and the immunogenicity is successively reduced.
When the composition of the antibody is completely human, the production of anti-drug antibodies can be minimized.
Probability, higher safety in clinical applications [19].

 Skukuzumab is the world's first fully human IL-17A inhibitor.

In 1999, the birth of Medarex mice made it possible to use transgenic mice to prepare fully human antibodies.
Compared with the fully human monoclonal antibodies produced by phage display technology, the antibody drugs developed through transgenic mice have better druggability.
Good [20].

In 2001, researchers injected human IL-17A into transgenic mice and isolated B cells that can produce human antibodies from immunized mice.
Using classic hybridoma technology, they screened out hybrids that can produce specific antibodies.
Tumor, through separation and purification, the final preparation of Skuchiyuumab (Figure 3).

 Figure 3: The preparation process of IL-17A inhibitor Skukuzumab has shown low immunogenicity and good safety in subsequent series of in vitro tests and clinical studies [21-24], which is good Performance has a great relationship with the optimization of formulation development methods.

 3 Rely on strength to get through clinical research verification of effectiveness and safety.
Clinical research is the longest and also the most critical stage in the development of new drugs.
It shoulders the important mission of verifying the effectiveness and safety of candidate drugs in humans.
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Only through the verification of clinical research, the drug can really be used for the treatment of patients.

 The MEASURE study is the most classic series of studies to verify the efficacy and safety of Recucciumab in the treatment of AS.

From 2011 to 2014, the MEASURE1-4 clinical research projects were launched one after another, with the longest research duration being up to 5 years.

The results of a series of studies have shown that, regardless of whether the patient has previously received TNF-α inhibitor treatment, Skucilizumab can bring long-term therapeutic benefits to patients [25].

Figure 4: MEASURE clinical study: classic series of studies on the treatment of AS with scocilizumab 1 rapid improvement of symptoms and long-lasting efficacy.
Under the treatment of scocilizumab, AS patients can relieve back pain in 1 week and relieve morning in 4 weeks.
Stiffness and fatigue, 16 weeks quickly and significantly reduce disease activity, and the effect lasts for 4 years [26-28].

In the extended phase study of MEASURE1, nearly 80% of patients experienced sustained relief of symptoms and signs within 5 years of treatment with Skuchiyuumab [29].

 Figure 5: 80% of patients with Skucilizumab treatment have sustained relief of symptoms and signs within 5 years.
2 Inhibition of new bone formation and improvement of structural function.
During 2 years of Skucilizumab treatment, 97% of the patients were osteophyte-free and 73% at baseline, respectively.
% Of AS patients with osteophytes at baseline have no new osteophytes, and nearly 80% of patients have no imaging progression within 4 years of treatment with Skucilumab [30-32].

Compared with the placebo group, the Bath Ankylosing Spondylitis Measurement Index (BASMI) and Bath Ankylosing Spondylitis Function Index (BASFI) scores of AS patients treated with Skuchiyuumab were significantly improved, and the structural function was maintained well within 5 years [ 29].

 Figure 6: MEASURE1 shows that nearly 80% of patients have no imaging progress within 4 years of Skucilizumab treatment.
In addition, the 2018 SUPERSS study was launched, which is the first to compare biosimilar drugs with Skucilizumab and adalimumab The head-to-head superiority clinical trial mainly evaluates the 104-week mSASSS score results of the two treatments for AS patients, and the main end point is to slow the progression of the spine imaging structure of AS [33].

The research results are expected to be announced in 2022, which may help clinicians and patients make better treatment decisions.

3 Good tolerability and safety.
The incidence of serious adverse events in the Skuchiyuumab treatment group and the placebo group were 0-6% and 1%-4%, respectively.
Among them, the common tuberculosis infection and Reactivation of hepatitis B, treatment with Skuchiyuumab did not increase its risk.

During the five-year clinical study period, Skucilizumab showed good and consistent safety, and no new safety issues appeared [25].

 4Applicable to the Chinese population in September 2020, the results of the 52-week MEASURE 5 study are released.

Among the population enrolled in the MEASURE 5 study, 71.
3% of patients were from China.

The results of the study showed that scocilizumab can also quickly improve symptoms and maintain long-term efficacy in treating Chinese AS patients, and its safety data are basically consistent with previous studies [34], indicating that scocilizumab is suitable for Chinese AS patients.
Of biological agents.

 Figure 7: The MEASURE5 study showed that the response rate of ASAS20 in the Chinese patient population was nearly 80% after 52 weeks of treatment with Skucilizumab.
4 Evidence-based medicine continues to accumulate, and it is on the guideline recommendation list.
In 2016, Skucilizumab was awarded the U.
S.
Food and Drugs.
The Supervision Bureau (FDA) approved for the treatment of AS; in April 2020, it was approved for AS indications in China.

Globally, Skuchiyuumab has 100 large-scale clinical trials, and more than 300,000 patients have been treated with Skuchiyuumab.
The accumulation of real-world drug experience has strongly proved the effectiveness of Skuqiyuumab.
Sex and safety.

 Before the advent of IL-17A inhibitors, TNF-α inhibitors were the only biologics available for patients with AS.
For patients with poor efficacy or intolerance to the use of TNF-α inhibitors, clinically they were almost helpless.
The mechanism of drugs is constantly selected and tried.

The emergence of IL-17A inhibitors has improved this situation, and its multi-level regulation of the pathological process of AS makes up for the clinical deficiency of TNF-α inhibitors.

With the continuous accumulation of evidence-based medicine, IL-17A inhibitors have been listed in the drug recommendations of major diagnosis and treatment guidelines.

 In 2016, the guidelines issued by the International Association for the Assessment of Spondyloarthritis (ASAS) and the European Union Against Rheumatism (EULAR) included IL-17A inhibitors in the guidelines for the first time, and the "interleukin era" for AS treatment officially opened [35]; 2019 In the same year, the AS treatment guidelines issued by the American College of Rheumatology (ACR) and the American Spondylitis Association (SAA) strongly recommend that tracuzumab be used for non-steroidal anti-inflammatory drugs (NSAIDs) who are still in the active stage of disease Patients, who are contraindicated with TNF-α inhibitors or who do not respond well to the first TNF-α inhibitor treatment, are conditionally recommended to use skuziumab for treatment [36].

 At present, according to the guidelines issued by the National Institute of Health and Clinical Optimization (NICE), the French Society of Rheumatology (SFR), the Taiwan Rheumatology Society of China and the expert review published on Lancet, IL-17A inhibitors are clearly recommended as First-line biological agents for the treatment of AS or axial spondyloarthritis (ax-SpA) [37-40].

It is promoting the progress and upgrading of AS treatment and entering a new era.

 Figure 8: The recommended timing of Skuchiyuumab in the treatment of AS is gradually moving forward.
5 Summary From the discovery of the target to the development of preparations, from clinical research to real-world applications, the IL-17A inhibitor Skuchiyudan The resistance has been along the way and has won widespread attention and support with its outstanding performance.

Its application in the AS field will bring a comprehensive innovation and upgrade of concepts and treatment methods, and bring new treatment plans and health hopes for AS patients.
Let us wait and see! It is self-evident that Professor Sun Li's successful research and development and launch of an innovative drug will help patients, and some even enjoy a milestone in the history of medicine.

But the process has not been smooth sailing.
There are many cases of failing in a certain link, and the stories behind it are often twists and turns.

For example, AS, the current treatment drugs are very limited, especially in axial spondyloarthritis.

TNF-ɑ inhibitors have brought dawn to AS.
Innovative treatments can control inflammation.
There are also more positive research results in preventing the progress of imaging.
However, the required duration of treatment and cost-effectiveness still need to be explored. However, there are still some patients with poor efficacy of TNF-ɑ inhibitors, or have intolerance and contraindications.

The introduction of IL-17A inhibitors has gone through three stages: 1.
In 1996, IL-17A targets were found to be related to inflammation and bone metabolism, and they were verified in in vivo and in vitro experiments.

2.
The use of monoclonal antibody technology to prepare fully humanized antibodies 3.
Through a number of clinical studies (including MEASURE1-5) to verify its effectiveness and safety.

After decades of unremitting efforts, AS patients finally brought treatment options other than TNF-ɑ inhibitors.

In recent years, more and more experience has been accumulated in the real-world medication of Skucilizumab, and it has also been recommended by many countries’ guidelines.
It is clearly stated that patients with spondyloarthritis who have failed the treatment of NSAIDs and TNF-ɑ inhibitor treatment have failed Patients with AS can use IL-17A inhibitors.

Therefore, as mentioned in the article, the "interleukin era" of AS treatment has officially begun, ending the only choice of TNF-ɑ antagonists in the past, and avoiding the dilemma of repeated conversion among multiple TNF-ɑ antagonists.

At the same time, due to its multi-level regulation of the pathological process of AS, in clinical trials we found that IL-17A inhibitors have considerable advantages in delaying the progress of imaging.

I hope that in the near future, with the accumulation of medication experience and the deepening of clinical research, we can see more breakthroughs, put the brakes on the disability process of AS, and obtain a better quality of life.

D,et al.
Joint Bone Spine.
2018 May;85(3):275-284.
[39]Wei JC, et al.
Int J Rheum Dis.
2020 Jan;23(1)7-23.
[40]Sieper J, et al.
Lancet.
2017 Jul 1; 390(10089):73-84.
Looking back on the past and embarking on a journey of "treasure" discovery: IL-17A How does IL-17A, the "three-headed and six-armed" IL-17A, exert its diverse biological functions? Explore the key role of IL-17A in ankylosing spondylitis.
Why can it be a key target for treatment? Looking back at the story of monoclonal antibodies, and seeing how to continue to write the legend, how to know horsepower, and to explore the truth about the secondary failure of biological preparations, do biological preparations need to use loading doses? The clinical evidence has the final say!