A method of enabling safe and sustained control of IL-17 dependent conditions in subject responsive to treatment with anti-IL17A / F nanoantibody

Abstract

The methods disclosed herein use anti-interleukin 17A / F nanoantibodies to treat psoriasis or other IL-17 dependent conditions for a period of about 24 weeks followed by ceasing treatment with anti-interleukin 17A / F nanoantibodies to a responsive patient for a period of at least 4-20 weeks. The use of anti-interleukin 17A / F nanoantibodies can achieve the effect of disease recuperating up to not later than 24 weeks, so that the responder can exhibit sustained normalization of peripheral and / or skin biomarkers, such as IL-17A, IL-17F and / or IL-22. The treatment methods considered herein that have been suspended can be resumed depending on the condition of the subject. Treatment for more than 24 weeks also achieves an unexpected high therapeutic effect in persons who have not been reacted to complete skin clearance during the initial treatment.

Description

[0001] Priority claim

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 333,920, filed on April 22, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the medical field of inflammatory conditions such as psoriasis or other IL-17 dependent conditions, and biologics for use in such treatment. Background Art

[0004] Optimal treatment of IL-17-dependent chronic inflammatory conditions such as psoriasis not only reduces disease activity during treatment, but also provides safe, long-term maintained control in responding patients after treatment has stopped, sometimes referred to as "disease modification". It has been observed that in responding patients, improvements in the disease are maintained for many months after IL-23 inhibitor discontinuation (Blauvelt et al., JAMA Dermatol 2020; 156: 649-58). Models that assume the perceived strength of IL-23 inhibitors in providing drug-free disease control focus on the upstream position of IL-23 in the disease cascade of psoriasis and its role in inducing the production of L-17A in IL-23-reactive T cell subsets (Hawkes et al., J Immnol 2018; 201: 1605-13).

[0005] The proinflammatory cytokine IL-17F is upregulated in psoriasis and other IL-17-dependent chronic inflammatory conditions, and there is increasing evidence that it is preferentially produced by γδ T cells, group 3 innate lymphoid cells, and mucosal-associated invariant T cells (Hinks TSC and Zhang XW. Front Immunol 2020; 11: 1014; Cole S, et al. Front Immunol 2020; 11: 585134; Domingues RG and Hepworth MR. Front Immunol 2020; 11: 116; Provine NM, et al. Science. 2021; 371: 521–26). There is also strong evidence that IL-17F production in these cells is at least partially independent of IL-23 (Cole et al., Front Immunol 2020; 11: 585134).

[0006] IL-17A is also upregulated in psoriasis, resulting in both IL-17A and IL-17F being biologically active dimers (IL-17A / A, IL-17A / F, and IL-17F / F) that transmit information through a receptor composed of two IL-17 receptor A chains (IL-17RA) and one IL-17 receptor C chain.

[0007] Biomarkers measured in peripheral blood and / or affected tissues will a) help predict the course of the disease and b) respond to targeted therapies for IL-17-dependent chronic inflammatory conditions such as psoriasis. These biomarkers reflect the pathways behind the disease and targets for IL-17 inhibition therapy for short-term and long-term control of inflammatory responses. For example, IL-17 induces keratinocytes to produce neutrophil chemotactic factors such as CXCL8 (formerly known as IL-8), which enhance and sustain inflammatory responses in diseases such as psoriasis and suppurative hidradenitis (Narla S, et al. Br JDermatol. 2021Jun; 184 (6): 1004-1013), characterized by neutrophil influx into diseased tissues. During treatment with IL-17 inhibitors, biomarkers associated with optimized disease management are shared by skin conditions and rheumatic conditions that respond to IL-17 blockade. For example, IL-22 is used as a predictive marker not only in IL-17-dependent skin, but also in joint pathologies such as psoriatic arthritis (Miyagawa I, et al. Arthritis Res Ther. 2022 Apr 15; 24(1): 86. doi: 10.1186 / s13075-022-02771-4). Biomarkers associated with the production of antimicrobial peptides (e.g., proteins encoded by DEFB4A) can also c) identify patients at increased risk of side effects during treatment with IL-17 inhibitory drugs.

[0008] Monoclonal antibodies targeting IL-17 are known and have been used to treat plaque psoriasis (Gordon et al., N Engl J Med 2016; 375:345-56; Langley et al., N Engl J Med 2014; 371:326-28). However, typical antibodies have certain disadvantages, including their large size (about 150 kDa) and limited tissue penetration, relative instability, and their relatively expensive manufacturing costs.

[0009] Nanobodies are therapeutic proteins based on single-domain, camelid, heavy-chain-only antibodies that overcome these limitations by combining the advantages of small proteins with the benefits of monoclonal antibody properties. Nanobodies are not glycosylated and can therefore be used in other expression hosts with much higher volumetric yields than monoclonal antibodies. In addition, compared to traditional antibodies, nanobodies exhibit high stability in terms of fragmentation, aggregation tendency, and pressure sensitivity ( et al., Curr Opin Struct Biol 2017;45:10-16).

[0010] Soneloximab (also known as M1095) is a trivalent nanobody composed of monovalent nanobodies derived from camelids (e.g., from mammals of the family Camelidae, such as camels, llamas, alpacas) that are specific for human interleukin (IL)-17A, IL-17F, and human serum albumin.

[0011] Long-term treatment with immunomodulatory biologics is not only extremely expensive, but also puts patients at risk for infection or other health problems. Conventional antibody treatments for 17-dependent conditions such as psoriasis often result in higher-than-necessary doses and longer-than-necessary durations of administration. Treatments that achieve sustained control of such conditions are therefore needed to avoid these drawbacks. Summary of the invention

[0012] Disclosed herein is a method for treating an IL-17-dependent condition, comprising administering a nanobody that specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers to a subject in need thereof at a dose of 30-240 mg once every two weeks to once every four weeks for a maximum of 24 weeks, followed by discontinuation of treatment with the nanobody for subjects who have responded. In one embodiment, the administration is subcutaneous administration. In one embodiment, the discontinuation of treatment with the nanobody lasts for 4 weeks or longer, preferably 10 weeks or longer, more preferably 20 weeks or longer (e.g., 8, 10, 12, 14, 16, 18 or 20 weeks).

[0013] For example, the methods disclosed herein include methods for treating IL-17-dependent skin conditions. In certain embodiments, the methods can be used to treat psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, systemic pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, inverse psoriasis), atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris, or pyoderma gangrenosum.

[0014] In certain embodiments, the method can be used to treat psoriatic arthritis, axonal spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjögren's syndrome, juvenile idiopathic arthritis, granulomatous disease, Behcet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu disease.

[0015] In one embodiment, the above method may comprise administering the Nanobody at a dose of 30, 60, 120 or 240 mg once every two weeks to once every four weeks for a maximum period of 24 weeks.

[0016] In one embodiment, the above methods include those methods, wherein if the subject's IGA score is greater than 1, the dose is increased at week 2 to week 24.

[0017] In one embodiment, the Nanobody comprises sonelokimab.

[0018] In one embodiment, the above method comprises a method for treating psoriasis, and the method achieves full skin clearance in the subject as early as week 4 to week 8.

[0019] Also disclosed herein is a method of disease regulation, comprising administering 30-240 mg of a nanobody to a subject with an IL-17-dependent condition once every two weeks, wherein the nanobody specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers; and the treatment lasts for no less than 4 weeks, optionally no less than 8 weeks, and preferably no more than 24 weeks. In one embodiment, the method of disease regulation comprises administering the nanobody once every two weeks until week 12, and then administering the nanobody once every four weeks until week 24. In one embodiment, the method of disease regulation may be a method in which administration of the nanobody is suspended or permanently stopped in week 24.

[0020] In one embodiment, the disease modification method achieves normalization of peripheral IL-17A, IL-17F, CCL20, CXCl1, DEFB4A, CXCL8, LCN2, CAMP, KRT16, IL-13, IL-23, IL-31 and / or IL-22 in the subject by no later than week 24.

[0021] In one embodiment, the disease modification method achieves normalization of skin IL-17A, IL-17F, CCL20, CXCl1, DEFB4A, CXCL8, LCN2, CAMP, KRT16, IL-13, IL-23, IL-31 and / or IL-22 in the subject by no later than week 24.

[0022] In one embodiment, the normalization persists for at least an additional 4, 8, 12, 16 and / or 20 weeks after suspension or cessation of treatment.

[0023] Also contemplated herein are methods of conditioning such diseases, comprising: administering the nanobody for a total of at least 4 weeks, and preferably for a total of no more than 24 weeks, suspending the treatment for a period of more than two weeks, and then, if one or more symptoms of the IL-17-dependent condition recur, restarting the treatment. In one embodiment, administration may be restarted when the subject's IGA score is 1 or higher. In one embodiment, restarting treatment may include administering 30-240 mg of the nanobody once every two weeks.

[0024] In certain embodiments, in the methods of disease management disclosed herein, the IL-17 dependent condition is a skin condition.

[0025] For example, the method can be a method for treating psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, systemic pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, inverse psoriasis), atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris, or pyoderma gangrenosum.

[0026] In one embodiment, in the above-mentioned disease treatment method, the Nanobody may include sonelokimab.

[0027] In one embodiment, the disease treatment includes methods wherein the administration is subcutaneous administration.

[0028] Also disclosed herein is a method for treating an IL-17-dependent skin condition, comprising continuously administering to a subject in need thereof a nanobody that specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers at a dose of 30-240 mg once every two weeks to once every four weeks for more than 24 weeks to achieve complete skin clearance. In one embodiment, this method achieves complete clearance of the disease in 40% or more, preferably 50% or more, of subjects who still exhibit symptoms of the IL-17-dependent skin condition at the 24th week of treatment.

[0029] Also disclosed herein is the use of a medicament comprising a Nanobody that specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers for a subject in need thereof, at a dose of 30-240 mg once every two weeks to once every four weeks for a maximum of 24 weeks, followed by discontinuation of the treatment with the medicament comprising the Nanobody in a subject who responds to the treatment, wherein the subject is a human or non-human animal.

[0030] In one embodiment, the subject in need thereof suffers from a skin condition.

[0031] In one embodiment, the present invention contemplates a use wherein the subject in need thereof suffers from or is at risk of suffering from psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, systemic pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, inverse psoriasis), atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris, or pyoderma gangrenosum.

[0032] In one embodiment, the present invention also discloses such a use, wherein the subject in need suffers from or is at risk of suffering from the following diseases: psoriatic arthritis, axonal spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjögren's syndrome, juvenile idiopathic arthritis, granulomatous disease, Behcet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa or Takayasu's disease.

[0033] In one embodiment, the subject may have psoriasis, hidradenitis suppurativa, psoriatic arthritis, or axonal spondyloarthritis, and treatment may be discontinued when the subject reaches a certain clinical threshold, such as, for example, a PASI score of 75-100 (psoriasis), an IGA score of 0 or 1 (psoriasis), a Hidradenitis Suppurativa Clinical Response (HiSCR) score of 75-90 (hidradenitis suppurativa), an American College of Rheumatology criteria (ACR) score of 50 to 70 (psoriatic arthritis), or an International Spondyloarthritis Society (ASAS) assessment score of 40 or higher (axial spondyloarthritis).

[0034] In one embodiment, after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after a period of 24 weeks, the subject who responds to treatment may have a PASI score of 75-100, preferably a PASI score of 90-100, and most preferably a PASI score of 100. In this embodiment, the subject who responds to treatment has or is at risk for psoriasis, and wherein treatment is discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

[0035] In one embodiment, after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment, the subject who responded to treatment may have an IGA score of 0 or 1, preferably an IGA of 0. In this embodiment, the subject who responds to treatment has or is at risk for psoriasis, and wherein treatment is discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 2 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

[0036] In one embodiment, after 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment, subjects who respond to treatment have a HiSCR score of 75 to 90, preferably a HiSCR score of 90. In this embodiment, the subject who responds to treatment has or is at risk for having hidradenitis suppurativa, and wherein treatment is discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

[0037] In one embodiment, after 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment, a subject who responds to treatment has an ACR score of 50 to 70, preferably an ACR score of 70. In this embodiment, the subject who responds to treatment has or is at risk for psoriatic arthritis, and wherein treatment is discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 2 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

[0038] In one embodiment, a subject who responds to treatment has an ASAS score of 40 or greater after 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment. In this embodiment, the subject who responds to treatment has or is at risk for axonal spondyloarthritis, and wherein treatment is discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 Study design of a placebo-controlled phase 2b study of soneloximab in psoriasis. The IL-17A inhibitory antibody secukinumab served as an active control group.

[0040] Figure 2. Investigator's Global Assessment (IGA) and Psoriasis Area and Severity Index (PASI) response rates from baseline to Week 24 in the intention-to-treat population in each treatment group.

[0041] Figure 3 PASI 90 (A) and PASI 100 (B) response rates in participants who were randomized to receive 120 mg of soneliximab (normal load and increased load) at study baseline, who achieved skin clearance at Week 24, discontinued soneliximab, and restarted soneliximab at disease relapse between Weeks 24-48 (blue / top line); or who had residual psoriasis lesions at Week 24 and continued to receive soneliximab every four weeks between Weeks 24-48 (red / bottom line).

[0042] Figure 4 . Drug-free remission rate and treatment restart in patients treated with 120 mg of soneliximab (loading) who achieved complete skin clearance (IGA=0) at week 24. Soneliximab was discontinued in all these patients at week 24 and restarted only in cases of failure of disease control (IGA≥1; visit interval=every four weeks). Percentages in bold refer to patients who had complete clearance at each visit and did not restart treatment. In 20% (n=5 / 25) of patients, complete clearance was maintained until week 44 without treatment restart. The percentage of patients who restarted at each visit is shown next to the blue / curved arrows; *n refers to the number of patients who restarted and achieved IGA=0 again. 80% of the total 20 patients who restarted soneliximab achieved complete clearance again. The green arrow indicates the time point of the last soneliximab injection before stopping treatment. The orange arrow indicates the half-life of soneliximab, which is approximately 5 times after the last dose.

[0043] Figure 5 .Percentage of patients with clear skin (IGA=0) over time among patients who achieved skin clearance at week 24. In patients receiving soneliximab (120 mg, increasing loading), the drug was discontinued and restarted only when psoriasis recurred (blue dotted line). In patients receiving the IL-17A inhibitory antibody secukinumab (licensed dose), treatment continued without discontinuation (orange solid line). The bars represent the percentage of patients who received an injection of soneliximab (light blue bar) or secukinumab (light orange bar) at each visit (once every four weeks). Similar skin clearance rates were observed for the two drugs at week 48, with patients in the soneliximab group receiving only 50% of the total monthly injections compared to patients in the secukinumab group.

[0044] Figure 6Skin clearance rate over time in patients with active disease (IGA ≥ 1) at week 24 who received continuous treatment with secukinumab (solid orange line) or soneloximab (solid blue line). Complete skin clearance was achieved at week 48 in 50.0% of patients treated with soneloximab, compared with 30.0% of patients treated with secukinumab at week 48 (P = 0.166).

[0045] Figure 7 . Demographics and disease baseline of the intention-to-treat population. Data are mean (SD) or n (%) unless otherwise stated.

[0046] Figure 8 .IGA and PASI responses at Weeks 12 and 24 in the intention-to-treat population. Data are n (%; 95% CI). For PASI scores, any missing responses were imputed as no response. PASI <3 = PASI score expressed as a number less than 3. PASI 75 = at least 75% improvement from baseline. PASI 90 = at least 90% improvement from baseline. PASI 100 = at least 100% improvement from baseline. *p < 0.0001, all groups versus placebo, unless otherwise stated. A PASI<3 response was not a predefined endpoint. §p=0.0003. Participants in the placebo group received normal loading of soneliximab 120 mg every 4 weeks starting from week 12; participants in the soneliximab 30 mg normal loading group received soneliximab 30 mg and escalated soneliximab 120 mg every 4 weeks after week 12; participants in the soneliximab 60 mg normal loading group received soneliximab 60 mg and escalated soneliximab 120 mg every 4 weeks after week 12; participants in the soneliximab 120 mg normal loading group received soneliximab 120 mg every 8 weeks after week 12; participants in the soneliximab 120 mg increased loading group received soneliximab 120 mg every 4 weeks after week 12; and participants in the secukinumab 300 mg group received secukinumab 300 mg every 4 weeks after week 12.

[0047] Fig. 9 Summary of safety and tolerability results for the safety analysis population at weeks 0 to 12 and weeks 12 to 52. Data are n (%). *See Supplementary Information in Papp et al., Lancet 2021; 397: 1564-75, which is incorporated herein by reference in its entirety for information on specific events. During weeks 0 to 12, common treatment-emergent adverse events were considered to be those occurring in 5% or more of the participants in any soneliximab-containing group; during weeks 12 to 52, common treatment-emergent adverse events were considered to be those occurring in 3% of the participants in all soneliximab-containing groups combined. Events under the preferred oral candidiasis term during Weeks 12 to 24; see Adverse Events of Special Interest for Comprehensive Assessment of Candida. § Includes: infections, injection site reactions, liver function test abnormalities, cerebrovascular events, cytopenias, allergic or hypersensitivity reactions, malignancies, depression, and inflammatory bowel disease. Post hoc integration of adverse event terms to assess oral, esophageal, and vaginal candidiasis (participants with oral candidiasis, candidal infection, esophageal candidiasis, oropharyngeal candidiasis, or vulvovaginal candidiasis). ** Includes myocardial infarction, cerebrovascular accident, or cardiovascular death.

[0048] Fig.10 .Patient arrangements.

[0049] Fig.11 .Patient arrangements.

[0050] Fig.12 .Patient arrangements.

[0051] Fig.13 . Change in IGA score category from baseline to Week 12 (ITT population).

[0052] Fig.14 .DLQI 0 / 1 responder rate (NRI) at Week 12 and Week 24 (ITT population).

[0053] Fig.15 .Serious adverse events expressed as optional terms (weeks 0 to 52). DETAILED DESCRIPTION

[0054] The details shown herein are for the purpose of describing various embodiments only and are intended to provide the most useful and understandable description of the principles and conceptual aspects of the methods and compositions described herein. In this regard, the present invention does not attempt to present more details than are necessary for a basic understanding, and the description enables those skilled in the art to clearly understand how the various forms of the invention may be embodied in practice.

[0055] The present invention will now be described with reference to more detailed embodiments. However, the present invention can be implemented in different forms and should not be construed as being limited to the embodiments described herein. On the contrary, these embodiments are provided to make the disclosure of the present invention comprehensive and complete, and will fully convey its scope to those skilled in the art.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in this specification are only used to describe specific embodiments and are not intended to be limiting. As used herein and in the appended claims, the singular forms "a", "an" and "the" are also intended to include plural forms, unless the context clearly indicates otherwise. All publications, patent applications, patents and other references mentioned herein are expressly incorporated herein by reference in their entirety.

[0057] Unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained and, therefore, may be modified by the term "about." At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

[0058] Although the numerical ranges and parameters that specify a broad range are approximate, the numerical values ​​described in the specific embodiments are reported as accurately as possible. However, any numerical value includes certain inherent errors that are necessarily caused by the standard deviation in its respective measurement. Each numerical range provided throughout this specification will include each narrower numerical range that falls within this broader numerical range, as if these narrower numerical ranges are all explicitly recorded herein. The applicant also considers the range derived from the data point and describes the range disclosed herein.

[0059] Nanobodies

[0060] Nanobodies are a new class of proprietary therapeutic proteins based on the smallest functional fragment of pure heavy-chain antibodies (Vhh) naturally present in camelids. The binding of nanobodies to their targets has the specificity and affinity of traditional therapeutic antibodies, but the size of a Vhh is only about 15kDa, about one-tenth of a traditional antibody. The smaller size brings some advantages: a) Several Vhh can be connected, making it easier to form multivalent molecules, overcoming the limitations of traditional monospecific antibodies in complex diseases driven by multiple cytokines or in passive immunity against viral diseases (Koenig PA, et al. Science 2021; 371(6530):eabe6230). b) The small size of nanobodies can still bind to and inhibit mutant growth hormone receptors on cancer cells that are resistant to traditional antibodies with the same specificity (Tintelnot J, et al. Mol Cancer Ther 2019; 18:823–33). c) There is strong evidence that the smaller size of nanobodies leads to better tissue penetration and specific enrichment at sites of malignant or inflammatory diseases compared to traditional antibodies (Krüwel T, et al. Sci Rep 2016; 6: 21834). This phenomenon of specific enrichment is further enhanced by nanobodies with albumin binding moieties such as soneloximab, which can preferentially accumulate in inflammatory edemas such as swollen joints (Coppieters K, et al. Arthritis Rheum 2006; 54: 1856–66). Soneloximab is a trivalent single-chain monoclonal nanobody composed of three sequence-optimized Vhhs containing the unique structural and functional properties of naturally occurring pure heavy chain antibodies (each derived from a pure heavy chain llama antibody). The N-terminal portion binds IL-17F, and the C-terminal portion binds IL-17A and IL-17F, allowing it to inhibit the biologically relevant IL-17A / A, IL-17A / F, and IL-17F / F dimers. The central portion binds serum albumin. The subunits are fused head-to-tail with a 9-amino acid glycine / serine linker, resulting in a total predicted molecular weight of approximately 40 kDa. The calculated drug tissue penetration of soneloximab is 4 to 6 times that of conventional antibodies (150 kDa) (Li Z, et al. mAbs 2016; 8:1:113–119), an important consideration in therapy, especially in the treatment of inflammatory diseases such as hidradenitis suppurativa, where disease manifestations are often characterized by inflammatory lesions surrounded by scar tissue and deep inflammatory dermal morphology such as tunnels.

[0061] Nanobodies used herein include those disclosed in US Pat. No. 10,017,568, which is incorporated herein by reference in its entirety.

[0062] Nanobodies used herein, including SEQ ID NO: 1 and variants thereof, are contemplated. For example, Nanobodies having sequences homologous to the amino acid sequence shown in SEQ ID NO: 1 are included, and may be proteins having the same amino acid sequence as the amino acid sequence shown in SEQ ID NO: 1, but with one or more amino acids deleted, substituted, inserted and / or added. In the case of substitution, insertion or addition, conservative substitution, insertion or addition of one or more amino acids leading to conservative mutations is possible.

[0063] Herein, "one or several amino acids" refers to 1 to 50, preferably 1 to 20, more preferably 1 to 10, still more preferably 1 to 5 or 1 to 3 amino acids.

[0064] In addition, proteins having an amino acid sequence homologous to the amino acid sequence shown in SEQ ID NO: 1 include proteins having an amino acid sequence having no less than 70% identity with the amino acid sequence shown in SEQ ID NO: 1 (full-length form thereof). Such proteins include proteins having an amino acid sequence having no less than 80%, more preferably no less than 90%, and still more preferably no less than 95%, 96%, 97%, 98% or 99% identity with the aforementioned amino acid sequence in full-length form.

[0065] "Sequence identity" may refer to the percentage of identical nucleotides or amino acids between two sequences in a nucleotide sequence or an amino acid sequence, as determined by aligning the two sequences with optimized pairwise alignment, optionally using conventional or commercially available algorithms.

[0066] Disease treatment

[0067] Disease modification is often used in the context of therapeutic disease management to describe the effects of treatment that alter the natural course of a disease. For example, the term disease-modifying antirheumatic drug (DMARD) is used to describe treatments that prevent the onset and / or progression of bone destruction, which is often a feature of the (untreated) course of diseases such as rheumatoid arthritis or psoriatic arthritis. Disease modification is recently recognized as the basis for maintaining disease control in responding psoriasis patients after cessation of treatment. For example, long-term disease control observed in psoriasis patients (in whom rapid relapse of the disease would be expected under the natural history) after terminating treatment with antibodies that inhibit the cytokine IL-23 is classified as representing disease modification (Eyerich K, et al. BMJ Open. 2021 Sep 13; 11(9): e049822) and is associated with the upstream role of IL-23 in the psoriasis cascade and specific molecular and cellular phenomena in previously affected skin, such as a reduction in resident memory CD8+ T cells (Mehta H, et al. J Invest Dermatol. 2021 Jul; 141(7): 1707-1718). Another definition of disease modification in the treatment of chronic inflammatory skin conditions is described as continuous improvement of skin lesions with continuous treatment, while molecular and / or cellular normalization of affected tissues can be documented (Bieber T, et al. Allergy. 2012 Aug; 67(8): 969-75). This definition may be applicable to diseases such as atopic dermatitis and hidradenitis suppurativa where complete skin clearance cannot be achieved with currently available treatments.

[0068] The recent identification of other tissue-resident immune cells, such as innate lymphoid cells and γδ T cells, that produce the proinflammatory cytokine IL-17F independently of IL-23 has raised the question of whether inhibitors of IL-17, particularly IL-17F, may also demonstrate phenomena relevant to disease management. This is particularly relevant to diseases where IL-17F has been identified as a major driver of the inflammatory response and / or where IL-23 inhibitors have been shown to have only limited or no relevant clinical effect (e.g., hidradenitis suppurativa, psoriatic arthritis, and ankylosing spondylitis, including arthritis).

[0069] Administration and dosage

[0070] Depending on the disease or condition to be treated, the specific route of administration and the individualized dosing regimen of the subject, the dosage of the Nanobodies for preventing and / or treating the diseases or conditions described herein is 30 mg to 240 mg. The induction injection plan considered herein includes administration once every 2 weeks until the 8th to 12th week; the maintenance regimen considered herein includes administration once every 4 weeks to once every 8 weeks. An early response to treatment may occur after 2 to 8 weeks; a complete response, i.e., skin clearance, may last up to 48 weeks; therefore, the first stop may be after 16 to 48 weeks.

[0071] In general, for medical use, the Nanobodies of the invention can be formulated into a pharmaceutical preparation or composition comprising: a Nanobody, and at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more other pharmaceutically active polypeptides and / or compounds. By way of non-limiting example, such a preparation may be in a form suitable for oral administration, parenteral administration (e.g. intravenous, intramuscular or subcutaneous injection or intravenous infusion, intravascular, intraarterial or intrathecal administration), topical administration (i.e. transdermal or intradermal), inhalation administration, skin patch, implant, suppository, etc. Such suitable administration forms (which may be solid, semisolid or liquid, depending on the mode of administration) as well as methods for their preparation and carriers are clear to those skilled in the art.

[0072] Subjects

[0073] Patients who may be more susceptible to treatment-induced disease resolution with soneliximab may be patients with a shorter duration of illness, e.g., less than 6 months to 2 years, patients with early (e.g., after 2 to 8 weeks) responses in serum and / or tissue biomarkers, patients with an early (e.g., after 2 to 8 weeks) and high level (50% to 90% improvement) clinical response, and / or patients with a high and stable level of response, e.g., a PASI of 100 at Week 12 and at one or two consecutive visits 2 to 6 weeks apart.

[0074] Biomarkers for predicting disease severity, disease course, response to treatment, and / or susceptibility to side effects of inhibiting IL-17A and IL-17F can be based on measuring a) proteins in peripheral blood and / or mRNA in circulating cells and / or surface markers and / or intracellular markers of peripheral cells by flow cytometry; and / or b) proteins measured in tissues; mRNA levels in tissues, bulk and / or single cell RNAseq of cells isolated from tissues. Useful biomarkers contemplated herein include, but are not limited to, IL-17A, IL-17F, CCL20, CXCl1, DEFB4A, CXCL8, LCN2, CAMP, KRT16, IL-13, IL-23, IL-31, and / or IL-22.

[0075] Example

[0076] Example 1

[0077] In a 48-week phase 2b study in patients with moderate-to-severe plaque psoriasis (n=313), the nanobody Soneliximab targeting IL-17A and IL-17F was discontinued at week 24 in patients who achieved complete skin clearance (Investigator Global Assessment [IGA]=0) and restarted when disease control failed (IGA≥1). Soneliximab contains the following amino acid sequence:

[0078] Asp Val Gln Leu Val Glu Ser Glv Gly Gly Leu Val Gln Fro Gly Gly SerLeu Arg Leu Scr Cys Ala Ala Scr Gly Arg Thr Phe Scr Scr Tyr Val Val Gly TrpPhe Arg Gin Ala Pro Gly Lys Glu Arg Glu Phc Ile Gly Ala Ile Ser Gly Ser GlyGlu Scr Ile Tyr Tyr Ala Val Ser Glu Lys Gly Arg Phc Thr Ile Ser Arg Asp AsnSer Lys Ash Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Pro Glu Asp Thr Ala ValTyr Tyr Cys Iht Ala Asp Gin Glu Phc Gly Tyl Leu Arg Phc Gly Arg Ser Glu TyrTrp Gly Gln Gly Thr Lcu Val Thr Val Scr Ser Gly Gly Gly Gly Scr Gly Gly GlySer Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Ash Ser LeuArg Lcu Ser Cys Ala Ala Ser Gly Phc Thr Phc Ser Ser Phc Gly Met Ser Trp ValArg Gln Ala Pro Gly Lys Gly Lcu Glu Trp Val Scr Ser Ile Scr Gly Ser Gly SerAsp Thr Lcu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn AlaLys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val tyrTyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr ValSer Ser Gly Gly Gly Gly Scr GlyGly Gly Ser Glu Val Gln Leu Val Glu Ser GlyGly-Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly ArgThr Tyr Asp Ala Met Gly Trp Lcu Arg Gln Ala Pro Gly Lys Glu Arg Glu Phc ValAla Ala Ile Ser Gly Ser Gly Asp Asp Thr Tyr Tyr Ala Asp Scr Val Lys Gly ArgPhc Thr Ile Scr Arg Asp Ash Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser LeuArg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Arg Arg Gly Lcu Tyr Tyr ValTrp Asp Ala Ash Asp Tyr Glu Ash Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser (SEQ ID NO: 1).

[0079] Participants

[0080] Adults aged 18 to 75 years with stable moderate-to-severe plaque psoriasis (defined as an Investigator Global Assessment [IGA] score ≥3, affected body surface area ≥10%, and Psoriasis Area and Severity Index [PASI] score ≥12) who had had the disease for more than 6 months before randomization were eligible for participation in the study and were candidates for systemic biologic therapy and had no underlying medical conditions that placed them at unacceptable risk for immunomodulatory therapy. Patients who had previously received more than two biologic therapies or any therapy targeting IL-17 were excluded. All patients provided written informed consent before screening.

[0081] Randomization and Blinding

[0082] Participants were recruited by masked investigators and randomly assigned (1:1:1:1:1:1:1) to receive placebo, soneliximab 30 mg, soneliximab 60 mg, soneliximab 120 mg normal loading, soneliximab 120 mg increased loading, or secukinumab 300 mg. Randomization was stratified by body weight (≤90 kg or >90 kg) and prior biologic use (previous use or no prior use), resulting in four strata with a permuted block size of 6 within each stratum. Randomization was performed at the study level by a centralised interactive response technology system that provided blinded treatment drug numbers to the investigators. Study drugs were prepared and administered on-site by unblinded personnel designated by the study institution who did not participate in other phases of the study. Participants and all other study institution personnel were blinded to treatment allocation throughout the study. The trial sponsor was unblinded after all participants had completed week 24 of treatment and the database was locked.

[0083] process

[0084] All participants underwent a 4-week screening period, a 12-week placebo-controlled induction period, a 12-week dose maintenance or escalation period (during which all participants received active treatment), a 24-week response assessment or dose-holding period, and a final assessment at week 52. Figure 1 ). The use of unscented emollients was permitted throughout the study, except during the 24-hour period prior to the clinic visit.

[0085] During the placebo-controlled induction phase (weeks 0 to 12), participants received placebo (at weeks 0, 1, 2, 3, 4, 6, 8, and 10), soneloximab 30 mg, 60 mg, 120 mg normal load (at weeks 0, 2, 4, and 8), soneloximab 120 mg increased load (at weeks 0, 2, 4, 6, 8, and 10), or secukinumab 300 mg (at weeks 0, 1, 2, 3, 4, and 8), with placebo given at weeks 1, 3, 6, and 10 in the soneloximab 30 mg, 60 mg, 120 mg normal load group, at weeks 1 and 3 in the soneloximab 120 mg increased load group, and at weeks 6 and 10 in the secukinumab 300 mg group.

[0086] During the dose maintenance or escalation period (weeks 12 to 24), participants assigned to the placebo group received soneloximab 120 mg (at weeks 12, 14, and 16, then every 4 weeks); participants assigned to the soneloximab 30 mg or 60 mg group with an IGA score greater than 1 were escalated to 120 mg every 4 weeks, and participants with an IGA score of 1 or less maintained their assigned dose at week 12 and then every 4 weeks; participants assigned to the soneloximab 120 mg group received soneloximab 120 mg at week 12, then every 8 weeks (normal loading group) or every 4 weeks (increased loading group); participants assigned to the secukinumab 300 mg group received secukinumab 300 mg at week 12, then every 4 weeks. During this period, placebo was given to all groups at week 14, and soneloximab 120 mg was given to the normal loading group at week 16.

[0087] During the response assessment and dose maintenance period (weeks 24 to 48), participants in the soneliximab 30 mg or 60 mg groups who were dose-escalated to 120 mg remained on the same dosing schedule regardless of their IGA score at week 24. Participants in the secukinumab 300 mg group also remained on the same dosing schedule regardless of their IGA score at week 24. Participants in the soneliximab 30 mg and 60 mg groups who were not dose-escalated and all participants in both soneliximab 120 mg groups (including participants who resumed placebo) were eligible to discontinue study drug at week 24. Patients with an IGA score of 0 at week 24 received placebo; participants with an IGA score of 1 or higher (assessed every 4 weeks) resumed their previous soneliximab dose every 4 weeks. Participants in these groups with an IGA score of 1 or higher at week 24 continued on the same dose.

[0088] All study treatments were administered by subcutaneous injection. The last dose was given at week 44 for all groups, and key efficacy and safety assessments were performed at week 52. Efficacy was assessed by IGA (Langley, RGB et al. J Dermatolg Treat 2015; 261: 23-31) and PASI (Fredriksson T., et al. Dermatologica 1978; 157: 238-244; Weisman S., et al. J Dermatolg Treat 2003; 14: 158-165) assessments, which were performed at the study site by personnel familiar with the scoring system and who were specifically trained as part of the study execution.

[0089] Outcomes

[0090] The primary efficacy endpoint was the proportion of participants in the soneliximab group with clear or almost clear IGA (score of 0 or 1) at 12 weeks compared with the placebo group. Secondary efficacy endpoints during the placebo-controlled period were PASI response, change in body surface area of ​​psoriasis, and safety assessments. A 100% PASI improvement compared with baseline (PASI 100 response) was defined as clinically free of psoriasis. Safety and efficacy were assessed weekly until Week 4, then every 2 weeks until Week 16, and then every 4 weeks until Week 52. Pre-specified exploratory endpoints included dose escalation response at Week 24, the effect of maintaining the dose after Week 24, and the proportion of participants with a Dermatology Life Quality Index (DLQI) score of 0 or 1 (assessed every 12 weeks) (all pre-specified exploratory endpoints were listed in the study protocol). Adverse events reported by participants based on open-ended and non-leading questions asked verbally by the investigator were collected at each visit.

[0091] Statistical analysis

[0092] The sample size was calculated based on feasibility in a phase 2 setting and the assumption that differentiation between the highest and lowest doses of soneloximab could be achieved. Controls for multiple comparisons were not performed. The study was not powered to formally compare soneloximab with secukinumab. Response and safety data from the secukinumab 300 mg group were used for qualitative comparisons.

[0093] The primary efficacy endpoint was analyzed in the intention-to-treat (ITT) population; participants with missing data were considered nonresponders (imputation of nonresponders). Comparisons of the primary active treatment (i.e., soneliximab or secukinumab) with placebo were performed with the use of a two-sided Cochran-Mantel-Haenszel test, stratified by actual previous biologic use (yes or no) and body weight strata (≤90 kg or >90 kg). Selected sensitivity analyses were performed in the ITT population (with randomized previous biologic use and body weight strata, and missing responses were imputed with the last observation carried forward). The safety population was defined as all patients who received study drug, as defined for the ITT population.

[0094] Secondary efficacy and quality of life end points were compared between the active treatment and placebo groups and between the soneliximab groups at each scheduled visit until week 12 and between the treatment groups at week 24 with the use of the Cochran-Mantel-Haenszel test for binary end points and an analysis of covariance model including planned treatment group, strata with combined weight and actual previous biologic use as factors, and baseline value as a covariate in the model for change from baseline (or percent change from baseline for PASI).

[0095] Exploratory analyses of efficacy were performed in all participants who had their dose escalated at Week 12. Exploratory analyses of efficacy were also performed in participants who discontinued active treatment (i.e., participants with an IGA score of 0 at Week 24) and those who did not discontinue active treatment (i.e., participants with an IGA score ≥1 at Week 24) at the end of the study.

[0096] All statistical analyses were performed using SAS version 9.4.

[0097] The data monitoring committee, composed of three dermatologists from institutions not involved in the study who were familiar with clinical studies of biologics in psoriasis, met regularly to review safety information as required by the charter established at the start of the study. The committee did not propose any changes to the study protocol.

[0098] result

[0099] Between August 15, 2018, and March 27, 2019, 383 patients were assessed for eligibility and 313 were enrolled and randomly assigned to placebo (n = 52), soneliximab 30 mg (n = 52), soneliximab 60 mg (n = 52), soneliximab 120 mg normal load (n = 53), soneliximab 120 mg increased load (n = 51), or secukinumab 300 mg (n = 53; see supplementary material in Papp et al., Lancet 2021;397:1564-75). The demographic characteristics and baseline characteristics were generally similar between the treatment groups ( Figure 7 The mean age of participants was 46 years (SD 13.1), most were male (228 [73%] of 313) and white (282 [90%]), the mean duration of psoriasis was 18 years (SD 12.8), and the mean baseline PASI score was 20.8 (8.1).

[0100] At week 12, none of the 52 participants in the placebo group had an IGA score of 0 or 1 (0.0% [95% CI 0.0–6.8]), whereas 25 of 52 participants in the soneliximab 30 mg group had an IGA score of 0 or 1 (48.1% [34.0–62.4], p < 0.0001), 44 of 52 participants in the soneliximab 60 mg group had an IGA score of 0 or 1 (84.6% [71.9–93.1], p < 0.0001), and 41 of 53 participants in the soneliximab 120 mg normal-load group had an IGA score of 0 or 1 (84.6% [71.9–93.1], p < 0.0001). The IGA score was 0 or 1 in 45 of 51 participants in the soneliximab 120 mg loading group (77.4% [63.8–87.7], p<0.0001), 0 or 1 in 41 of 53 participants in the secukinumab 300 mg group (88.2% [76.1–95.6], p<0.0001), and 0 or 1 in 41 of 53 participants in the secukinumab 300 mg group (77.4% [63.8–87.7], p<0.0001).

[0101] Of the 313 randomized participants, 302 (97%) completed the assigned treatment up to and including week 12 (see supplementary material in Papp et al., Lancet 2021;397:1564-75). A significantly higher proportion of participants in the soneliximab 120 mg loading group had a PASI 90 response (defined as at least 90% improvement from baseline) (39 of 51 participants [76.5%; 95% CI 62.5-87.2]; p<0.0001) and a PASI 100 response (17 of 51 participants [33.3%; 20.8-47.9]; p<0.0001; Figure 8 A significantly higher proportion of participants in the soneliximab 120 mg loading group had an IGA score of 0 ( Fig.13 The proportion of participants with IGA responses (i.e., IGA scores of 0 or 1) and PASI 90 responses in the active treatment group began to differ from the placebo group early on, with the higher dose groups (i.e., soneliximab 60 mg and 120 mg) mostly outperforming the soneliximab 30 mg group ( Figure 2). Onset of response was rapid, with 16 of 51 participants (31.4%) in the soneliximab 120 mg loading group achieving a PASI 90 response by week 4. No IGA or PASI responses to placebo were observed in the placebo group at any time point. At week 12, a significantly higher proportion of participants in the secukinumab 300 mg group had a PASI 90 response (34 of 53 participants [64.2%; 49.8–76.9]; p < 0.0001) and a PASI 100 response (15 of 53 participants [28.3%; 16.8–42.3]; p < 0.0001) compared with the placebo group. At week 12, 131 of 208 participants (63.0%) taking soneliximab had a DLQI score of 0 or 1, compared with only one participant in the placebo group ( Fig.14 The percentage change in psoriasis-involved body surface area between week 0 and week 12 in participants given soneliximab was consistent with the IGA score and PASI response results (see supplementary material in Papp et al., Lancet 2021; 397: 1564-75).

[0102] Of the 313 participants initially randomized, 297 (95%) completed week 24 (see supplementary material in Papp et al., Lancet 2021; 397: 1564-75). At week 12, 27 of 52 patients (51.9%) in the soneliximab 30 mg group and 7 of 52 participants (13.5%) in the soneliximab 60 mg group did not reach the primary endpoint of IGA response; these participants were dosed to soneliximab 120 mg every 4 weeks. Participants in the soneliximab 120 mg normal load group received 120 mg at week 12 and every 8 weeks thereafter; patients in the soneliximab 120 mg increased load group received 120 mg at week 12 and every 4 weeks thereafter. Participants in the dose-optimized soneliximab 60 mg and 120 mg groups had an IGA response of 80.4% (95% CI 66.9–90.2) to 94.2% (84.1–98.8), a PASI 90 response of 79.2% (65.9–89.2) to 90.4% (79.0–96.8), and a PASI 100 response of 40.4% (27.0–54.9) to 56.9% (42.2–70.7) ( Figure 8 ; Figure 2 A to Figure 2C). Participants in the placebo group received 120 mg at weeks 12, 14, and 16 and every 4 weeks thereafter; at week 24, the proportions of participants with IGA and PASI responses were similar to those observed at week 12 in participants initially given this dosing regimen. Among participants who received soneliximab 120 mg during the first 12 weeks, the proportions of participants with IGA scores of 0 or 1, PASI 90 responses, and PASI 100 responses generally peaked by week 16 ( Figure 2 A to Figure 2 C). Of note, the proportion of participants who received soneloximab every 8 weeks from weeks 12 to 24 who had IGA, PASI 90, and PASI 100 responses decreased by the time they were due to receive the next dose (i.e., by week 20). In all groups, the proportion of participants with a DLQI score of 0 or 1 increased by week 24 compared with week 12 ( Fig.14 At week 24, 40 of 53 participants in the secukinumab 300-mg group (75.5%; 61.7–86.2) had an IGA score of 0 or 1, 42 (79.2%; 65.9–89.2) had a PASI 90 response, and 18 (34.0%; 21.5–48.3) had a PASI 100 response ( Figure 8 ).

[0103] During the placebo-controlled period (weeks 0 to 12), PASI scores improved over time in all active treatment groups, regardless of dose ( Figure 2 D). The mean percentage change from baseline in PASI response scores demonstrates the rapid onset of treatment efficacy in these participants. During the dose maintenance or escalation phase, starting at Week 14, significantly more rapid improvements in PASI response scores were observed in placebo participants who switched to soneliximab 120 mg.

[0104] It was not the objective of the study design to evaluate the response over 48 weeks in which soneloximab was continuously administered. Instead, participants with an IGA score of 0 at week 24 discontinued soneloximab treatment. The interpretation of the IGA and PASI response scores for each group was complicated by the dose adjustments allowed by the study protocol (see Papp et al., Lancet 2021; Supplementary Materials in 397:1564-75). Post hoc analyses were performed on participants who were randomized to the placebo group and received soneloximab 120 mg after week 12, as well as participants who were randomized to the soneloximab 120 mg normal load group and the soneloximab 120 mg increased load group. These participants were combined into a single group of 142 participants, of whom 69 (48.6%) had an IGA score of 0 at week 24 and subsequently discontinued soneloximab. Of these 69 participants, 60 (87.0%) did not maintain an IGA score of 0 at 4 to 12 weeks, but 47 (78.3%) of these 60 participants subsequently regained an IGA score of 0 when they restarted soneliximab 120 mg. Participants who did not maintain an IGA score of 0 at week 24 continued to receive soneliximab 120 mg, and the proportion of these participants with PASI 90 and PASI 100 responses continued to increase ( Figure 3 A. Figure 3 B). Safety was assessed during an initial 12-week placebo-controlled induction phase and a dose optimization (secukinumab-controlled) phase (i.e., a combined dose maintenance or escalation phase and response assessment or dose retention phase) between weeks 12 and 52. After week 12, soneliximab doses and exposures differed between treatment groups. Participants who received 30 mg and 60 mg soneliximab and had an IGA score greater than 1 at week 12 were given an increased dose. Participants with an IGA score of 0 at week 24 discontinued soneliximab until loss of response. Participants in the placebo group could only receive soneliximab after week 12. Adverse events occurred in 155 of 313 participants (49.5%), with a slightly higher incidence in the soneliximab group (107 of 208 [51.4%)) than in the placebo group (22 of 52 [42.3%]) from weeks 0 to 12 ( Fig. 9Increasing the soneliximab dose had no apparent effect on the incidence of adverse events. The most common adverse events among all participants receiving soneliximab during weeks 0 through 12 were nasopharyngitis (28 of 208 participants [13.5%]), pruritus (14 [6.7%] participants), and upper respiratory tract infection (9 [4.3%] participants). Three participants receiving soneliximab 120 mg (one in the normal-loading group and two in the increased-loading group) discontinued treatment because of adverse events during weeks 0 through 12: one participant who developed pustular rash and refused to undergo a protocol-mandated biopsy; one participant who developed hypertension; and one participant who developed acute kidney injury. The participant who developed acute kidney injury received soneliximab 120 mg for one month and was subsequently prescribed amoxicillin plus clavulanic acid and clarithromycin for 3 days for an upper respiratory tract infection and was diagnosed with acute tubular necrosis with drug-induced acute nephritis. Between weeks 0 and 12, six participants had serious adverse events (one in the placebo group, two in the soneliximab 30-mg group, one in the soneliximab 60-mg group, one in the soneliximab 120-mg normal-load group, and one in the soneliximab 120-mg increased-load group); Fig. 9 ; Fig.15 ). No clinically significant signals were found from laboratory evaluations, vital signs, electrocardiograms, or assessments of depression and suicidality scales.

[0105] Participants who received soneliximab were combined into one group during weeks 12 through 52 because of differences in dosing between the groups. Adverse events of special interest were defined based on known effects on IL-17 regulation. With the possible exception of candidiasis, there was no clear dose-response associated with toxicity. Most candidal infections were easily controlled. Four of 251 participants (1.6%) who received soneliximab had an absolute neutrophil count of less than 1000 cells per microliter; all cases of neutropenia resolved rapidly without a change in soneliximab dose. No clinically significant signals were found on laboratory assessments, vital signs, electrocardiograms, or assessments of depression and suicide scales.

[0106] One participant receiving soneliximab, who was initially given placebo and switched to soneliximab 120 mg at week 12, was hospitalized for oral treatment of oropharyngeal candidiasis. One participant in the secukinumab 300 mg group was hospitalized for esophageal candidiasis and received an intravenous antifungal. Other notable events were 1 new diagnosis of Crohn's disease and 1 death. The Crohn's disease diagnosis was in a participant receiving soneliximab 30 mg and escalated to 120 mg at week 12 who reported a family history of chronic intestinal disease. This participant had intermittent diarrhea at study months 2 and 9 and underwent a colonoscopy at study month 11. One participant in the soneliximab 60 mg group died while sleeping at home, reportedly from cardiopulmonary failure due to pulmonary aspiration of gastric contents.

[0107] discuss

[0108] In this phase 2b study of soneloximab, doses up to 120 mg showed rapid and significant clinical benefit compared with placebo. Participants taking the highest dose (120 mg loading dose) showed rapid responses, with 16 of 51 participants (31.4%) achieving a PASI 90 response by week 4 and 39 of 51 participants (76.5%) achieving a PASI 90 response by week 12. Responses were durable. About half (69 of 142 [48.6%]) of participants taking soneloximab 120 mg had an IGA score of 0 at week 24. A modest attenuation of response was observed when treatment was stopped for participants with an IGA score of 0 at week 24; when treatment was restarted, many (47 of 60 [78.3%]) participants regained a complete response. Some differences in responses between different soneliximab doses and schedules were evident and were most intuitive in the early portion of the mean change in the PASI response curve and in the mid- to late-stage portions of the PASI 100 response curve. Soneliximab was generally well tolerated, with a safety profile similar to that of the active control, secukinumab. Overall, a higher incidence of Candida infections was observed in participants taking soneliximab compared with those taking placebo; one participant in the secukinumab 300-mg group had one episode of esophageal candidiasis. Although the highest dose and schedule of soneliximab may be used in future clinical studies, additional evaluation and modeling will help ultimately select the optimized dose and schedule.

[0109] The first biologic T-cell-directed therapy for the treatment of psoriasis was licensed 18 years ago. Since then, therapeutic mechanisms have evolved from tumor necrosis factor (TNF) inhibition to IL-12 and IL-23 blockade, to IL-17A interference and IL-17 receptor blockers, to IL-23-specific agents, and now data are emerging for IL-17A / F modulators. Each of these innovations has raised concerns related to potential improvements in efficacy, the benefits of various molecular constructs, and the need to fully understand the potential for toxicity. Specifically, with respect to the mechanism of action of IL-17 in psoriasis, IL-17A and IL-17F appear to be the major proinflammatory mediators in psoriasis, with IL-17A / A and IL-17F / F homodimers and IL-17A / F heterodimers as the biologically active molecules. Although secukinumab primarily inhibits IL-17A / A and ixekizumab primarily inhibits IL-17A / A and IL-17A / F (Eli Lilly and Company. Prescribing Information Highlights: TALTZ (ixekizumab) injection, for subcutaneous administration. 2020. http: / / pi.lilly.com / us / taltz-uspi.pdf (accessed September 17, 2020; Paul C., Br JDermatol 2018;178:1003-1005)), there is evidence that IL-17F / F also plays a role in the inflammatory cascade. In the presence of TNFα, IL-17F can independently activate proinflammatory signaling pathways in human keratinocytes and fibroblasts (Glatt S., et al. Ann Rheum Dis 2018; 77: 523-532; Kolbinger F., et al. J Allergy Clin Immunol 2017; 3: 329-32.e8). In addition, compared with blocking IL-17A alone, simultaneous blocking of IL-17F and IL-17A in vitro can reduce the production of mediators induced by T helper 17 cell supernatants in synovial cells and fibroblasts (Glatt S., et al. Ann Rheum Dis 2018; 77: 523-532). Brodalumab is a monoclonal antibody targeting IL-17RA that prevents the binding of all IL-17 isoforms (Lebwohl M, et al. N Engl J Med 2015; 373: 1318-1328) and interferes with both IL-17A and IL-17F.

[0110] Brocitumab also blocks other IL-17 family members, including IL-17E (or IL-25), which is downregulated in lesional and non-lesional psoriatic skin and may have certain anti-inflammatory effects (Monin L., et al. Cold Spring Harb Perspect Biol 2018; 10: a028522; Johnston A., et al. J Immunol 2013; 190: 2252-2262). Bimekizumab is a humanized monoclonal antibody that can effectively and selectively neutralize the biological functions of human IL-17A and IL-17F. Phase 2 clinical data from bemoxetine support the view that IL-17A and IL-17F blockade can effectively treat psoriasis (Papp KA, et al. J Am Acad Dermatol 2018; 79: 277-86.e10; Ritchlin CT, et al. Lancet 2020; 8: 427-440). The speed and extent of response observed in these Phase 2 studies and early observations in Phase 3 data (Reich K., et al. Lancet 2021; 397: 487-498; Gordon KB, et al., Lancet 2021; 397: 475-486) ​​support the clinical relevance of IL-17F interference. The inventors' Phase 2b study of soneloximab is the first study to include two different IL-17 modulators in the same study. Uniquely, soneloximab is a nanobody that blocks IL-17A, IL-17F, and IL-17A / F heterodimers. Compared with monoclonal antibodies, soneloximab of smaller size may be able to achieve differential penetration into the skin and other tissues. The main limitations of this study are the 2-phase scope and the lack of a formal comparison between soneloximab and secukinumab. Although there are teachings pointing out the differences between soneloximab and secukinumab, such as faster action and higher peak response, this study is not enough to present credible differences. A true comparison approach would require a 3-phase setting, in which an optimized dose of soneloximab is prospectively compared head-to-head with an antibody such as secukinumab. The data provided in this report show that the addition of IL-17F regulation may provide rapid onset, high upper limit of effect, and possibly more frequent oral fungal infections. Subsequent studies, such as the trial of bamoxetine plus secukinumab (NCT03536884) completed in 2020, may help to understand IL-17A and IL-17F blockade versus IL-17A blockade alone.Furthermore, it remains to be understood how differences in the exact binding properties of inhibitors of IL-17A / A or IL-17A / F and IL-17F / F (eg, bamoxetine and soneliximab) will affect the benefit-risk profile of these agents.

[0111] Example 2

[0112] Maintaining treatment response

[0113] Individual patient-level clinical response data obtained in the highest soneloximab dose group (120 mg, injected every 2 weeks until week 12, injected every 4 weeks until week 24, then stopped or continued every 4 weeks; n = 51) and in the active control group with continuous treatment with the IL-17A inhibitor secukinumab (300 mg, once a week until week 4, then once every 4 weeks; n = 53) were analyzed to explore the potential of IL-17A and Il-17F inhibition in psoriasis for "disease modification". Reference Reich et al., Br J Dermatol. 2022 Apr 20. doi: 10.1111 / bjd.21617, the entire text of which is incorporated herein by reference.

[0114] Analyses using the 5-point IGA scale (Langley RG et al., J Dermatolog Treat 2015; 26: 23-31) were based on the intention-to-treat (ITT) population until week 24 and on the observational population thereafter. n = 4 and n = 2 patients discontinued treatment before week 24 in the soneloximab group and secukinumab group, respectively. Between weeks 24 and 48, n = 4 patients discontinued treatment in the soneloximab group (n = 2 of each were unable to return and withdrew consent; n = 3 patients withdrew from the study and IGA = 0 at the time of withdrawal) and n = 2 patients discontinued treatment in the secukinumab group (n = 2 withdrew consent, both withdrew IGA = 2 at the time of withdrawal). The visit interval between weeks 24 and 48 was every 4 weeks. Patients who had disease relapse after stopping soneloximab and needed to restart treatment (IGA ≥ 1) received monthly injections until week 48. Analyses were descriptive post hoc comparisons with nominal P values ​​from chi-square tests without correction for multiple testing.

[0115] At Week 24, 56.9% (n=29 / 51) and 34.0% (n=18 / 53) of patients in the soneliximab 120 mg arm and secukinumab arm, respectively, achieved complete clearance (PSI 100) (ITT-nonresponder imputation; P=0.019). Of the 25 patients in the soneliximab arm who were followed to Week 48 and had IGA=0 at Week 24 and discontinued treatment, 20% (n=5 / 25) maintained complete clearance (IGA=0) until Week 44 and did not require treatment restart ( Figure 4 ). Of the remaining 20 patients, n=16 / 2 / 2 were retreated with disease activity IGA=1 / 2 / 3, and 80% of retreated patients achieved complete clearance at week 48 (n=16 / 20). The proportion of patients who achieved complete clearance at week 48 with IGA=0 at week 24 was similar in patients who discontinued and restarted soneliximab and those who continued treatment with secukinumab (72.0% and 73.7%, respectively; Figure 5 At weeks 24 to 48, patients in the soneliximab discontinuation / re-treatment group received approximately 50% fewer total monthly injections compared with patients in the secukinumab continuation arm. Among patients with active disease (IGA ≥ 1) at week 24, a higher proportion of patients in the soneliximab arm achieved complete clearance at week 48 compared with the secukinumab arm ( Figure 6 ).

[0116] Analysis and comparison of maintenance of treatment response must take into account the eligibility for discontinuation of treatment (the required degree of response), the duration of treatment before discontinuation, and the variability in treatment half-life. In a Phase 2 study, skin clearance (IGA = 0) was observed in approximately 50% of patients after discontinuation of monthly 120 mg soneloximab for seven half-lives (half-life 12 days; (Svecova et al., J Am Acad Dermatol 2019; 81: 196-203) randomized discontinuation at week 24). This result is slightly higher than the approximately 40% of patients who maintained clearance (PASI 100) for seven half-lives after stopping the IL-17A and IL-17F inhibitor bimzelx (half-life 26 days; randomized discontinuation at week 16) (Committee for Medicinal Products for Human Use (CHMP). Assessment report: Bimzelx (bimzelx), June 24, 2021. Available at: https: / / www.ema.europa.eu / en / documents / assessment-report / bimzelx-epar-public-assessment-report_en.pdf (last accessed November 24, 2021; Gordon KB et al., Lancet 2021;397:475-86)) and slightly lower than the approximately 40% of patients who maintained clearance (PASI 100) after stopping the IL-23 inhibitor risankizumab ( 100) for seven half-lives (half-life 28 days; randomized discontinuation at week 28) in approximately 70% of patients (Blauvelt A et al., JAMA Dermatol 2020; 156: 649-58; Pang Y et al., Clin Pharmacokinet 2020; 59: 311-26). Equivalent data are not available for IL-17A inhibitors; however, comparable skin clearance rates observed at week 48 between patients who continued to receive secukinumab and those who discontinued and eventually restarted soneloximab may indicate that the treatment response is better maintained by inhibiting IL-17A and IL-17F than by inhibiting IL-17A alone. Further research is needed to understand the overlapping and independent roles of IL-23 and IL-17 driven inflammatory responses in diseases such as psoriasis, the major cellular sources of these cytokines, the mechanisms behind “disease modulation,” and the differential efficacy of therapies targeting different molecular members of these pathways.

Claims

1. A method for treating an IL-17-dependent condition, comprising administering to a subject in need thereof a nanobody that specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers at a dose of 30-240 mg once every two weeks to once every four weeks for a maximum period of 24 weeks, followed by discontinuation of treatment with the nanobody for subjects who have responded.

2. The method of claim 1, wherein: The administration is subcutaneous.

3. The method of claim 1, wherein: The cessation of treatment with the Nanobody lasts for 4 weeks or more, preferably for 10 weeks or more, more preferably for 20 weeks or more (e.g. 8, 10, 12, 14, 16, 18 or 20 weeks).

4. A method as claimed in any one of the preceding claims, wherein: The method is a method for treating IL-17 dependent skin conditions.

5. The method of claim 4, wherein: The method is a method for treating psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, systemic pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, invertebral psoriasis), atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris or pyoderma gangrenosum.

6. The method of claim 1, wherein: The method is a method for treating psoriatic arthritis, axonal spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjögren's syndrome, juvenile idiopathic arthritis, granulomatous disease, Behcet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu's disease.

7. A method as claimed in any one of the preceding claims, wherein: The method comprises administering the Nanobody at a dose of 30, 60, 120 or 240 mg once every two weeks to once every four weeks for a maximum period of 24 weeks.

8. A method as claimed in any one of the preceding claims, wherein: If the subject's IGA score is greater than 1, the dose will be increased from Week 2 to Week 24.

9. A method as claimed in any one of the preceding claims, wherein: The nanobodies include soneliximab.

10. The method of claim 1, wherein: The method includes a method for the treatment of psoriasis wherein complete skin clearance is achieved in the subject as early as week 4 to week 8.

11. A method of disease conditioning, comprising administering 30-240 mg of a nanobody to a subject suffering from an IL-17-dependent condition once every two weeks, wherein: The Nanobody specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers; and The treatment continues for a period of not less than 4 weeks, optionally not less than 8 weeks, and preferably not more than 24 weeks.

12. The method of claim 11, wherein: The method comprises administering the Nanobody once every two weeks until week 12, and then administering the Nanobody once every four weeks until week 24.

13. The method of claim 11, wherein: Administration of the Nanobody was suspended or permanently stopped at week 24.

14. The method according to any one of claims 11 to 13, wherein: The method achieves normalization of peripheral IL-17A, IL-17F, CCL20, CXCl1, DEFB4A, CXCL8, LCN2, CAMP, KRT16, IL-13, IL-23, IL-31 and / or IL-22 in the subject by no later than week 24.

15. The method according to any one of claims 11 to 13, wherein: The method achieves normalization of skin IL-17A, IL-17F, CCL20, CXCl1, DEFB4A, CXCL8, LCN2, CAMP, KRT16, IL-13, IL-23, IL-31 and / or IL-22 in the subject by no later than week 24.

16. The method according to claim 14 or 15, wherein: This normalization persists for at least an additional 4, 8, 12, 16 and / or 20 weeks following suspension or cessation of treatment.

17. The method of claim 11, wherein: The method includes: administering the Nanobody for a total of at least 4 weeks, and preferably for a total of no more than 24 weeks, pausing the treatment for a period of more than two weeks, and then, If one or more symptoms of the IL-17-dependent condition recur, treatment is resumed.

18. The method of claim 17, wherein: When the subject's IGA score was 1 or higher, administration was restarted.

19. The method of claim 17, wherein: Restarting treatment consisted of administering 30-240 mg of the Nanobody once every two weeks.

20. The method according to any one of claims 11 to 19, wherein: The IL-17 dependent condition is a skin condition.

21. The method of claim 20, wherein: The method is a method for treating psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, systemic pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, invertebral psoriasis), atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris or pyoderma gangrenosum.

22. The method of any one of claims 11 to 21, wherein: The nanobodies include soneliximab.

23. The method of any one of claims 11 to 22, wherein: The administration is subcutaneous.

24. A method for treating an IL-17-dependent skin condition, comprising continuously administering to a subject in need thereof a Nanobody that specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers at a dose of 30-240 mg once every two weeks to once every four weeks for more than 24 weeks to achieve complete skin clearance.

25. The method of claim 24, wherein: The method achieves complete clearance of the disease in 40% or more, preferably 50% or more of subjects still exhibiting symptoms of the IL-17-dependent skin condition at week 24 of treatment.

26. Use of a medicament comprising a Nanobody that specifically binds to IL17A / A homodimers, IL17-A / F heterodimers and / or IL-17F / F homodimers for use in a subject in need thereof, at a dose of 30-240 mg once every two weeks to once every four weeks for a maximum of 24 weeks, followed by discontinuation of the treatment with the medicament comprising the Nanobody in a subject who responds to the treatment, wherein the subject is a human or non-human animal.

27. The use of a drug as claimed in claim 26, wherein: The subject in need thereof suffers from a skin condition.

28. The use of a drug as claimed in claim 26, wherein: The subject in need suffers from or is at risk of suffering from the following diseases: psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, systemic pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, invertebrate psoriasis), atopic dermatitis, discoid lupus erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpeticum, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris or pyoderma gangrenosum.

29. The use of a drug as claimed in claim 26, wherein: The subject in need thereof has or is at risk of having psoriatic arthritis, axonal spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjögren's syndrome, juvenile idiopathic arthritis, granulomatous disease, Behcet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu's disease.

30. The use of a drug as claimed in claim 26 or 27, wherein: After 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment, a subject who responds to treatment has a PASI score of 75-100, preferably a PASI score of 90-100, and most preferably a PASI score of 100.

31. The use of a drug as claimed in claim 30, wherein: The subject who responded to treatment had or was at risk for psoriasis and wherein treatment was discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

32. The use of a drug as claimed in claim 26 or 27, wherein: After 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment, a subject who responds to treatment has an IGA score of 0 or 1, preferably an IGA of 0.

33. The use of a drug as claimed in claim 32, wherein: The subject who responds to treatment has psoriasis or is at risk for psoriasis and wherein treatment is discontinued after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 2 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

34. The use of a drug as claimed in claim 26 or 27, wherein: After 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment, a subject who responds to treatment has a HiSCR score of 75 to 90, preferably a HiSCR score of 90.

35. The use of a drug as claimed in claim 34, wherein: The subject who responds to treatment has or is at risk for having hidradenitis suppurativa, and wherein: Discontinue treatment after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

36. The use of a drug as claimed in claim 26, wherein: After 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment, a subject who responds to treatment has an ACR score of 50 to 70, preferably an ACR score of 70.

37. The use of a drug as claimed in claim 36, wherein: The subject who responds to treatment has or is at risk for having psoriatic arthritis, and wherein: Discontinue treatment after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

38. The use of a drug as claimed in claim 26, wherein: A subject who responded to treatment had an ASAS score of 40 or greater after 4 weeks of treatment or more, after 8 weeks of treatment or more, after 10 weeks of treatment or more, after 12 weeks of treatment or more, after 14 weeks of treatment or more, after 16 weeks of treatment or more, after 18 weeks of treatment or more, after 20 weeks of treatment or more, or after 24 weeks of treatment.

39. The use of a drug as claimed in claim 38, wherein: The subject who is responsive to treatment has or is at risk of having axonal spondyloarthritis, and wherein: Discontinue treatment after 4 weeks or more of treatment, after 8 weeks or more of treatment, after 10 weeks or more of treatment, after 12 weeks or more of treatment, after 14 weeks or more of treatment, after 16 weeks or more of treatment, after 18 weeks or more of treatment, after 20 weeks or more of treatment, or after 24 weeks of treatment.

40. The use of a drug as claimed in claim 26, wherein: The Nanobody comprises SEQ ID NO: 1 or a variant thereof having 70% or higher sequence identity with SEQ ID NO: 1.

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