**: Yakudu
Written by: May
On December 1, 2023, Akeso Biopharma (9926.)HK) announced that the pivotal registrational phase clinical study of the company's self-developed novel humanized IL-17 monoclonal antibody, gumochimab (AK111)** in moderate and severe plaque psoriasis, met all efficacy endpoints, including PASI100 and SPGA0 1.
Coincidentally, on the same day, Sansheng Guojian (688336SH) announced that the pivotal registrational phase clinical study of recombinant anti-IL-17A humanized monoclonal antibody injection (608)** in moderate to severe plaque psoriasis developed by the company met the primary efficacy endpoints (PASI 75 and SPGA 0 1), all key secondary efficacy endpoints (PASI 90, PASI 100 and SPGA 0) and all secondary efficacy endpoints.
At present, autoimmunity is the second largest market area after tumors, and according to the Frost & Sullivan report, China's autoimmune disease drug market is expected to grow rapidlyFrom US$2 billion in 2018 to US$2.9 billion in 2022, with a CAGR of 98%, which is estimated to reach $19.9 billion in 2030.
Interleukin-17 (IL-17) is associated with many autoimmune diseases, such as psoriasis and psoriatic arthritis, and is a star target in the field of autoimmunity.
At present, a total of five IL-17-targeting IL-17R drugs have been approved for marketing worldwide, among which secukinumab and ixekizumab are the two best-selling drugs, with combined global sales of more than $7 billion last year.
There are no domestic drugs targeting IL-17 and IL-17R that have been approved for marketing in China, but there are many drugs under development, among which Hengrui and Zhixiang Jintai varieties are being declared for marketing.
Recently, the phase III clinical trials of IL-17 drugs of Akeso Biopharma and Sunshine Guojian have been successful, and the birth of the first domestic IL-17 drug is just around the corner.
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IL-17 and its receptor family
Interleukin 17 (IL-17) is a pro-inflammatory factor secreted by CD4+ T cells, which can induce epithelial cells, endothelial cells, and fibroblasts to synthesize and secrete IL-6, IL-8, G-CSF, and PGE2, and promote the expression of ICAM-1.
There are 6 members of the IL-17 family, including IL-17A (IL-17), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. There are five members of the IL-17 receptor family: IL-17R IL-17RA, IL-17BR IL-17RB, IL-17RC, IL-17RD SEF, and IL-17RE (Figure 1)[1].
Figure 1IL-17 family and receptor family, Ref. 1
Autoimmune diseases are the second most popular area of research after tumors, and it is estimated thatFrom 2019 to 2030, the global autoimmune disease drug market will increase from $116.9 billion to $163.8 billion.
Currently, IL-17 has been shown to play an important role in autoimmune diseases such as psoriasis, bronchial asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis (Fig. 2) [2].
Figure 2IL-17 plays an important role in psoriasis,**Ref. 2
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Approved for marketing
5 IL-17 targeting IL-17R drugs
At present, there are 5 large molecule biologics targeting IL-17 IL-17R on the market worldwide, including secukinumab (cosentyx), ixekizumab (taltz), brodalumab, netakimab (efleira) and bimekizumab. Among them, secukinumab, ixekizumab and brolilumab have been approved in China, and bigelizumab has also been applied for marketing in China (Table 1).
Table 15 IL-17-targeting drugs approved for marketing worldwide.
SecuchinumabIt was developed by NovartisThe first approved monoclonal antibody targeting IL-17A, used for ** psoriasis, psoriatic arthritis and ankylosing spondylitis and other autoimmune diseases, is currently the best-selling IL-17 class of drugs, with sales of 47 in 2022$8.8 billion, sold 23$4.8 billion.
IxekizumabIt is a monoclonal antibody targeting IL-17A developed by Eli LillyIt was the first IL-17A antagonist to outperform adalimumab in a head-to-head study of psoriatic arthritis (PSA)., last year's sales reached 24$8.2 billion, sold $12$3.1 billion.
Recently, UCys'sBimegizumab(bimekizumab) was approved for marketing in the United StatesIt is the first and only dual-target inhibitor of IL-17A and IL-17F approved for moderate to severe plaque psoriasis[3].
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Clinically under investigation
Targeting IL-17 IL-17R drugs
In addition to the 5 drugs that have been approved for marketing, there are many IL-17 and IL-17R drugs under clinical development (Table 2), among which:Hengrui Pharmaceutical's phnakizumab(Vunakizumab, SHR-1314) andZhixiang Jintai's self-developed cerikumab（xeligekimab，gr1501）Both were declared for marketing this year, and the two are expected to become the first batch of domestic IL-17A monoclonal antibody products to be marketed, bringing more choices to domestic psoriasis patients.
Table 2Some IL-17 targeting IL-17R drugs under clinical development.
no.1
Fnuakizumab
Vunakizumab (SHR-1314) is a recombinant humanized IgG1 monoclonal antibody developed by Hengrui, which can target IL-17A and inhibit its interaction with IL-17 receptor.
Previously, Zhang et al. recently reported a 36-week, multicenter, double-blind phase II study (NCT03463187) evaluating the efficacy of venakizumab in moderate to severe plaque psoriasis.
At week 12, there were phnakizumab and 240 mg in the placebo group, respectively. 6% and 865% achieved an improvement in PASI (Psoriasis Lesion Area and Severity Index) 75 (75% improvement in PASI score) compared to 5 in the placebo group4%；Patients with a PGA (Physician's Global Assessment) of 0 1 were also higher with phnakizumab (respectively). 5% and 730%，vs 8.1%）。The PGA is scored on a scale of 0 to 3, with 0 or 1 representing patients with no or mild disease [4].
On April 27 this year, the marketing application of phnakizumab injection was accepted by the Food and Drug Administration, which is intended to be used for **autoimmune diseases related to the IL-17 pathway.
According to the official website of the China Drug Clinical Trial Registration and Information Publicity Platform, Hengrui Pharmaceutical has conducted a number of clinical trials for SHR-1314 in China, covering indications including active moderate to severe gr**e's eye disease, **active psoriatic arthritis, **lupus nephritis, **ankylosing spondylitis, moderate to severe chronic plaque psoriasis, etc. Among them, a phase III clinical study in patients with moderate to severe chronic plaque psoriasis has been completed, and a phase II and III clinical study in active ankylosing spondylitis has completed patient enrollment [5].
no.2
Celikimab
Xeligekimab (GR1501) is a recombinant fully human anti-IL-17A monoclonal antibody developed by Zhixiang Jintai, which can selectively bind to IL-17A, inhibit the downstream signaling of IL-17RA, and inhibit IL-17A-induced inflammation.
Serikimab is the first IL-17 monoclonal antibody submitted a new drug marketing application by a domestic company, and its marketing application was accepted by the NMPA on March 25 this year, and it is expected to become the first domestic IL-17 monoclonal antibody to be approved.
In addition to moderate to severe plaque psoriasis, serikimab is also being developed for lupus nephritis, active axial spondyloarthritis, and other autoimmune diseases.
no.3
Gumoximab
Gumokimab (AK-111) is a new autoimmune disease drug targeting IL-17A independently developed by Akeso, which is intended to be used for psoriasis, ankylosing spondylitis and other diseases.
Gumoqimab inhibits the biological activity of IL-17 by competitively blocking the binding of human IL-17A to IL-17R, so as to achieve the efficacy of clinical ** immune-related diseases.
As mentioned at the beginning of the article,Recently, the Phase III study of Akeso's ancient moximab (IL-17)** moderate to severe plaque psoriasis met all efficacy endpoints. The study is a randomized, double-blind, placebo, parallel-controlled, multicenter phase III clinical study evaluating the efficacy and safety of gumoximab** in subjects with moderate and severe plaque psoriasis. The primary endpoints of the study were the percentage of participants who achieved a response to PASI 75 and the percentage of participants with SPGA 0 1 at week 12;The key secondary endpoints were the percentage of participants who responded to PASI 90 and the percentage of participants who responded to PASI 100 at week 12;Other secondary endpoints include safety throughout the study period [6].
no.4
ssgj-608
SSGJ-608 (608) is a recombinant anti-IL-17A humanized monoclonal antibody injection independently developed by Sunshine Guojian, which can specifically bind to human IL-17A, block the binding of IL-17A to its receptor, and effectively inhibit the release of inflammatory factors.
As mentioned at the beginning of the article,Recently, the phase III study of Sunshine Guojian's recombinant anti-IL-17A humanized monoclonal antibody injection (608)** moderate to severe plaque psoriasis reached all efficacy endpoints. The results showed that, compared with the placebo group, the 608 dose group had significant clinical efficacy, which could significantly improve the skin lesions of patients with moderate to severe plaque psoriasis, and significantly increase the proportion of patients with PASI 75, SPGA 0 1, PASI 90, PASI 100 and SPGA 0, with significant statistical differences and good safety. Compared with marketed products with the same target, 608 has a strong competitive advantage in terms of efficacy and safety. Additional data results will be further analyzed and disclosed as the study progresses [7].
no.5
qx002n
QX002N is a high-affinity monoclonal antibody targeting IL-17A developed by Quanxin Biopharma, which is one of the company's core products, and QX002N has been clinically developed for the indications of ankylosing spondylitis and lupus nephritis, of which the indication of ankylosing spondylitis (AS) has entered phase III clinical trial.
AS is a chronic inflammatory disease of the axial joints of unknown cause, the number of patients with AS in China reached 3.9 million in 2022, and the market for AS drugs also increased from $1.3 billion to $1.8 billion from 2018 to 2022, and is estimated to reach $6.5 billion by 2030.
In current clinical guidelines, IL-17A inhibitors in combination with TNF-inhibitors are recommended for second-line** regimens in patients with AS who have high disease activity despite first-line traditional**.
QX002N has shown promising efficacy in Phase 1B and Phase II clinical trials for AS. In the Phase 1b trial, participants who received QX002N (160 mg) every 2 weeks had 62 ASAS20 and ASAS40 response rates at week 16, respectively5% and 375%, and QX002N is currently in Phase III clinical trial[8].
no.6
sonelokimab
Sonellokimab is a 40 kDa humanized nanobody developed by Moonlake Immunotherapeutics consisting of three VHH domains covalently linked by a flexible glycine-serine spacer.
Sonelokimab has two domains that selectively bind IL-17A and IL-17F with high affinity, thereby inhibiting IL-17A A, IL-17A F, and IL-17F F dimers. The third central domain binds to human albumin and promotes further enrichment of sonelokimab at the site of inflammatory edema.
On November 6, 2023, Moonlake Immunotherapeutics announced positive topline results from its global Phase II ARGO trial, which evaluated the efficacy and safety of the nanobody sonelokimab in patients with active psoriatic arthritis (PSA).
In the ARGO trial (M1095-PSA-201), which enrolled 207 patients, the proportion of patients who received sonelokimab 60 mg or 120 mg (induced)** achieved a statistically significant increase in the proportion of patients who achieved an American College of Rheumatology (ACR) 50 response at week 12 compared with placebo, meeting its primary endpoint.
Specifically, 46% and 47% of patients with sonelokimab** achieved ACR50 (P<001 compared to placebo);78% and 72% of patients achieved ACR20;29% and 26% achieved ACR70.
Both the 60 mg and 120 mg doses were induced to meet all key secondary endpoints. All induction doses met the key secondary endpoint, Psoriasis Area and Severity Index (PASI) of 90;Seventy-seven percent of patients responded to the 60 mg dose at week 12 (ITT-NRI, p<0.)001 compared to placebo)[9].
no.7
DC-806 and DC-853
Compared with monoclonal antibodies, which need to be administered by subcutaneous injection, small molecule drugs can be administered orally, and patients have higher compliance, which is more favored by patients and doctors.
The DC-806 is a product developed by Dice Therapeutics (acquired by Eli Lilly) based on the Delscape technology platformOral small molecule antagonist of IL-17It is currently in phase II clinical trial to explore IL-177 and other IL-17-mediated related diseases, and is expected to obtain phase 2b clinical data in 2024.
DC-853 is also an anti-IL-17 small molecule antagonist, as a follow-up DC-806 pipeline, which is currently in the Phase I clinical stage, and top-line data is expected to be obtained in the second half of 2023.
Figure 5Dice Therapeutics' pipeline of IL-17 drugs.
Summary
At present, most of the domestic self-immune market is still occupied by foreign capital, and the targeted IL-17 IL-17R drug has not yet been approved for marketing, but many domestic companies are speeding up, Zhixiang Jintai and Hengrui applied for listing in March and April this year respectively, who can become the first IL-17 drug, we wait and see.
At present, the drugs approved for marketing are all monoclonal antibodies, which need to be administered by injection, and many pharmaceutical companies have turned their attention to oral small molecule IL-17 inhibitors, such as Eli Lilly's acquisition of Dice Therapeutics, because Eli Lilly has taken a fancy to the company's oral small molecule IL-17 inhibitors DC-806 and DC853, and it will take time to verify whether they can be successfully marketed in the future.
References (swipe up and down):
1.mandy j. mcgeachy, daniel j. cua, and sarah l. gaffen, the il-17 family of cytokines in health and disease, immunity 50, april 16, 2019
3.bimzelx[®]approved by the u.s. fda for the treatment of adults with moderate to severe plaque psoriasis | ucb
4.chunlei zhang, kexiang yan, a multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study evaluating the efficacy and safety of vunakizumab in patients with moderate-to-severe plaque psoriasis, j am acad dermatol. 2022 jul;87(1):95-102.
5.Medical Guanlan: Express!Hengrui Pharmaceutical's Class 1 new drug venakizumab was declared for marketing.
8.BIG Bio Innovation Society: Domestic self-exemption field: The 100 billion market needs to be carved up urgently, and the eight major pharmaceutical companies have laid out.
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