Methods for achieving safe and sustained control of IL-17-dependent states in subjects responsive to treatment with anti-IL 17A / F nanobodies

Abstract

Disclosed herein are methods of treating psoriasis and other IL-17 dependent conditions with anti-interleukin 17A / F Nanobodies for approximately 24 weeks, followed by discontinuing treatment in responsive patients with anti-interleukin 17A / F Nanobodies for a period of at least 4-20 weeks. Disease modification may be achieved with anti-interleukin 17A / F Nanobodies by no later than 24 weeks, such that responders may demonstrate sustained normalization of peripheral and / or cutaneous biomarkers, e.g., IL-17A, IL-17F, and / or IL-22. Treatment methods contemplated herein that have been paused may be resumed based on the subject's condition. Treatment beyond 24 weeks also achieves unexpectedly high efficacy in responders who have not fully reached complete skin clearance in the initial treatment period.

Description

[Technical field]

[0001] Claiming priority This application claims priority to U.S. Provisional Application No. 63 / 333,920, filed April 22, 2022, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to the field of medical treatment of inflammatory conditions, such as psoriasis and other IL-17 dependent conditions, as well as biologics for use in such treatment. [Background technology]

[0003] Optimal treatment of IL-17-dependent chronic inflammatory conditions, such as psoriasis, not only reduces disease activity during therapy, but also provides safe, long-term maintenance of control in responsive patients after cessation of treatment, sometimes referred to as "disease modifying." Sustained disease improvement has been observed for many months after cessation of IL-23 inhibitors in responsive patients (Blauvelt et al., 2003). et al., JAMA Dermatol 2020; 156:649-58). Models postulating the perceived strength of IL-23 inhibitors in providing drug-free disease control focus on the upstream position of IL-23 in the psoriatic disease cascade and its role in inducing IL-17A production in IL-23-responsive T cell subsets (Hawkes et al., J Immnol 2018; 201:1605-13).

[0004] The proinflammatory cytokine IL-17F is upregulated in psoriasis and other IL-17-dependent chronic inflammatory conditions, with accumulating evidence supporting its preferential production by γδ T cells, group 3 innate lymphoid cells and mucosal-associated invariant T cells (Hinks 2013). (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).

[0005] IL-17A is also upregulated in psoriasis, and as a result, both IL-17A and IL-17F are biologically active as dimers (IL-17A / A, IL-17A / F, and IL-17F / F) that signal through a receptor composed of two IL-17 receptor A chains (IL-17RA) and one IL-17 receptor C chain.

[0006] Biomarkers measured in peripheral blood and / or diseased tissues a) help predict disease course and b) respond to targeted treatment of IL-17-dependent chronic inflammatory conditions, such as psoriasis. These biomarkers reflect the pathways underlying the disease as well as targets of IL-17 inhibitory therapies used for short- and long-term control of inflammation. For example, IL-17 induces in keratinocytes the production of neutrophil chemoattractants such as CXCL8 (formerly IL-8), which enhances and perpetuates inflammation in diseases such as psoriasis and hidradenitis suppurativa, which are characterized by the influx of neutrophils into diseased tissues (Narla S, et al. Br J Dermatol. 2021 Jun;184(6): 1004-1013). Biomarkers relevant for optimizing disease management during treatment with IL-17 inhibitors are shared between dermatological and rheumatic conditions responsive to IL-17 blockade. For example, IL-22 serves as a predictive marker not only in IL-17-dependent skin but also in joint conditions, such as psoriatic arthritis (Miyagawa I, et al. Arthritis Res Ther. 2022 Apr 2020). 15;24(1):86. doi: 10.1186 / s13075-022-02771-4). Biomarkers for the production of antimicrobial peptides, such as the protein encoded by DEFB4A, also identify patients at increased risk of developing side effects during treatment with c) IL-17 inhibitory drugs.

[0007] Monoclonal antibodies targeting IL-17 are known and have been utilized as treatments for plaque-type psoriasis (Gordon et al., N Engl J Med 2016; 375:345-56; Langley et al., N Engl J Med 2014; 371:326-28). However, canonical antibodies have certain disadvantages, including their large size (approximately 150 kDa) and limited tissue penetration, relative instability, as well as their relative expense in production.

[0008] Nanobodies are a class of therapeutic proteins based on single-domain, camelid, heavy-chain-only antibodies that can overcome such limitations by combining the benefits of monoclonal antibody properties with the advantages of small proteins. Nanobodies are not glycosylated, thus allowing alternative expression hosts with substantially higher volumetric yields than monoclonal antibodies. Also, compared to conventional antibodies, nanobodies exhibit high stability in terms of fragmentation, aggregation tendency, and stress sensitivity (Konning et al., Curr Opin Struct Biol 2017; 45:10-16).

[0009] Soneloximab (also known as M1095) is a trivalent nanobody comprising monovalent camelid-derived (i.e., derived from mammals of the camelid family, such as camels, llamas and alpacas) nanobodies specific for human interleukin (IL)-17A, IL-17F, and human serum albumin.

[0010] Long-term treatment with immunomodulatory biologics is not only very expensive, but also involves the risk of infection and other health concerns for patients.17 Conventional antibody treatment of dependent conditions, such as psoriasis, often results in higher doses and longer time periods than necessary.There remains a need for a treatment method that avoids these shortcomings and has the ability to achieve sustained control of such conditions. Summary of the Invention

[0011] Disclosed herein is a method of treating an IL-17 dependent condition, comprising administering a Nanobody that specifically binds to the IL17A / A homodimer, IL17-A / F heterodimer, and / or IL-17F / F homodimer to a subject in need of treatment of an IL-17 dependent condition at a dose of 30-240 mg every 2-4 weeks for up to 24 weeks, followed by discontinuing treatment with the Nanobody for those subjects who respond. In one embodiment, administration is subcutaneous. In one embodiment, discontinuing treatment with the Nanobody is for a period of 4 weeks or more, preferably for a period of 10 weeks or more, even more preferably for a period of 20 weeks or more (e.g., 8, 10, 12, 14, 16, 18, or 20 weeks).

[0012] For example, the methods disclosed herein include methods of treating IL-17-dependent dermatological conditions. In certain embodiments, the methods include methods of treating psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, generalized pustular psoriasis, palmoplantar psoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis, and inverse psoriasis), atopic dermatitis, discoid lupus erythematosus, and psoriasis of the skin. The method may be for treating erythematosus, alopecia areata, autoimmune urticaria, bullous pemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linear IgA dermatosis, morphea, pemphigus vulgaris, or pyoderma gangrenosum.

[0013] In certain embodiments, the method may be a method of treating psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjogren's syndrome, juvenile idiopathic arthritis, granulomatosis, Behcet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu's disease.

[0014] In one embodiment, the method may comprise administering the nanobody at a dose of 30, 60, 120, or 240 mg every 2-4 weeks for up to 24 weeks.

[0015] In one embodiment, the above method includes a method where the dose is increased between weeks 2 and 24 if the subject has an IGA score greater than 1.

[0016] In one embodiment, the nanobody comprises soneloximab.

[0017] In one embodiment, the methods include a method of treating psoriasis that achieves complete skin clearance in a subject by as early as 4-8 weeks.

[0018] Also disclosed herein is a disease-modifying method comprising administering 30-240 mg of a Nanobody every two weeks to a subject suffering from an IL-17-dependent condition, wherein the Nanobody specifically binds to an IL17A / A homodimer, an IL17-A / F heterodimer, and / or an IL-17F / F homodimer; and wherein the treatment is for a period of 4 weeks or more, optionally 8 weeks or more, and preferably for a period of 24 weeks or less. In one embodiment, the disease-modifying method comprises administering the Nanobody every two weeks until week 12, and then every four weeks until week 24. In one embodiment, the disease-modifying method may be a method wherein administration of the Nanobody is paused or permanently stopped at week 24.

[0019] In one embodiment, the disease-modifying 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 a subject by at least 24 weeks.

[0020] In one embodiment, the disease-modifying 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 a subject by at least 24 weeks.

[0021] In one embodiment, normalization is sustained for at least an additional 4, 8, 12, 16, and / or 20 weeks after treatment is paused or stopped.

[0022] Also contemplated herein are disease modifying methods comprising administering a Nanobody for a total of at least 4 weeks, preferably for a total of 24 weeks or less, ceasing treatment for a period of more than 2 weeks, and subsequently resuming treatment if one or more symptoms of the IL-17-dependent condition recur. In one embodiment, administration may be resumed if the subject has an IGA score of 1 or greater. In one embodiment, resuming treatment may comprise administering 30-240 mg of the Nanobody every 2 weeks.

[0023] In certain embodiments, in the disease modifying methods disclosed herein, the IL-17 dependent condition is a dermatological condition.

[0024] For example, the method may be a method of treating psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, generalized 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.

[0025] In one embodiment, in the above disease modifying methods, the nanobody may comprise soneloximab.

[0026] In one embodiment, the disease modifying comprises a method wherein the administration is subcutaneous.

[0027] Also disclosed herein is a method of treating an IL-17 dependent dermatological condition comprising administering a Nanobody that specifically binds to the IL17A / A homodimer, IL17-A / F heterodimer, and / or IL-17F / F homodimer to a subject in need of treatment for an IL-17 dependent dermatological condition at a dose of 30-240 mg every 2-4 weeks consecutively for more than 24 weeks to achieve complete skin clearance. In one embodiment, such a method achieves complete clearance of disease in 40% or more, preferably 50% or more of subjects who still exhibit symptoms of the IL-17 dependent dermatological condition at 24 weeks of treatment.

[0028] Also disclosed herein is the use of a medicament comprising a Nanobody that specifically binds to the IL17A / A homodimer, the IL-17A / F heterodimer, and / or the IL-17F / F homodimer, to a subject in need of use of the medicament at a dose of 30-240 mg every 2-4 weeks for up to 24 weeks, followed by discontinuing treatment with the medicament comprising the Nanobody for subjects responsive to the treatment; the subject is a human or a non-human animal.

[0029] In one embodiment, the subject in need of use of the medicament has a dermatological condition.

[0030] In one embodiment, contemplated herein is the use where the subject in need of use of the medicament has or is at risk of having psoriasis (including but not limited to plaque psoriasis, moderate to severe plaque psoriasis, pustular psoriasis, generalized 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.

[0031] In one embodiment, also disclosed is the use, wherein the subject in need of use of the medicament has or is at risk of having psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjogren's syndrome, juvenile idiopathic arthritis, granulomatosis, Behcet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu's disease.

[0032] In one embodiment, the subject may have psoriasis, hidradenitis suppurativa, psoriatic arthritis, or axial spondyloarthritis, and the subject meets certain clinical thresholds, such as 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 Rheumatologists score of 50-70 (hidradenitis suppurativa), or an American College of Rheumatologists score of 50-70 (hidradenitis suppurativa). Treatment may be discontinued if an American College of Rheumatology criteria (ACR) score (psoriatic arthritis) or an Assessment in SpondyloArthritis International Society (ASAS) score of 40 or higher (axial spondyloarthritis) is reached.

[0033] In one embodiment, a subject responsive to treatment may have a PASI score of 75-100, preferably a PASI score of 90-100, most preferably a PASI score of 100, 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. In such an embodiment, a subject responsive to treatment has or is at risk of having psoriasis, and treatment may be 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.

[0034] In one embodiment, a subject responsive to treatment may have an IGA score of 0 or 1, preferably an IGA of 0, 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. In such an embodiment, a subject responsive to treatment has or is at risk of having psoriasis, and 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, a subject responsive to treatment has a HiSCR score of 75-90, preferably a HiSCR score of 90, 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. In such an embodiment, a subject responsive to treatment has or is at risk of having hidradenitis suppurativa, and 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.

[0036] In one embodiment, a subject responsive to treatment has an ACR score of 50-70, preferably an ACR score of 70, 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. In such an embodiment, a subject responsive to treatment has or is at risk of having psoriatic arthritis, and 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, a subject responsive to treatment has an ASAS score of 40 or greater 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. In such an embodiment, a subject responsive to treatment has or is at risk of having axial spondyloarthritis, and 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]

[0038] [Figure 1] Study design of a placebo-controlled phase 2b study with sonerooxib in psoriasis. The IL-17A inhibitory antibody secukinumab served as the active reference. [Diagram 2] Investigator's Global Assessment (IGA) and Psoriasis Area and Severity Index (PASI) response rates in the intention-to-treat population from baseline to week 24 in the various treatment arms. [Diagram 3] PASI 90 (A) and PASI 100 (B) response rates in participants who were randomized at study baseline to receive 120 mg soneroximab (regular and augmented loading), achieved skin clearance at week 24, discontinued soneroximab and restarted with disease recurrence between weeks 24 and 48 (blue / upper line), or had residual psoriatic lesions at week 24 and received soneroximab continuously every 4 weeks between weeks 24 and 28 (red / lower line). [Figure 4]Drug-free remission and treatment resumption among patients treated with soneloximab 120 mg (boosted loading) who achieved complete skin clearance (IGA=0) at week 24. Soneloximab was discontinued at week 24 in all of these patients and was only resumed if disease control was lost (IGA>1; visit interval=every 4 weeks). The bold percentages indicate patients with complete clearance at each visit without retreatment. Complete clearance was maintained up to week 44 without treatment resumption in 20% of patients (n=5 / 25). The percentage of patients who were resumed at each visit is given next to the blue / curved arrows; *n indicates the number of resumed patients who achieved IGA=0 again. Overall 80% of the 20 patients who were resumed on soneloximab achieved complete clearance again. The green arrowhead indicates the time of the last soneloximab injection before treatment cessation. The orange arrowhead indicates approximately five half-lives of soneroximal endotoxin after the last dose. [Diagram 5] Percentage of patients with skin clearance over time (IGA=0) among patients who achieved skin clearance at week 24. In patients receiving soneroximab (120 mg, boosted loading), the drug was stopped and resumed only in case of recurrence of psoriasis (dotted blue line). In patients receiving the IL-17A inhibitory antibody secukinumab (approved dose), treatment was continuous without discontinuation (solid orange line). Bars represent the percentage of patients receiving injections of soneroximab (light blue bar) or secukinumab (light orange bar) at each visit (every 4 weeks). Similar rates of skin clearance were seen at week 48 for both drugs, with patients in the soneroximab group receiving only 50% more injections per month overall compared to patients in the secukinumab group. [Figure 6] Skin clearance rates over time among patients with active disease (IGA ≥ 1) at week 24 given sequential treatment with secukinumab (solid orange line) or soneroximab (solid blue line). Complete skin clearance at week 48 was achieved in 50.0% of patients treated with soneroximab compared with 30.0% of patients treated with secukinumab (P = 0.166). [Figure 7] Demographics and baseline disease in the intention-to-treat population. Data are mean (SD) or n (%) unless otherwise specified. [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 non-response. PASI<3=numeric PASI score less than 3. PASI 75=at least 75% improvement from baseline. PASI 90=at least 90% improvement from baseline. PASI 100=100% improvement from baseline. *p<0.0001; vs placebo for all groups unless otherwise indicated. †PASI<3 response was not a prespecified endpoint. ‡p=0.0016. §p=0.0003. ¶Included participants receiving soneroximab 120 mg normally loaded once every 4 weeks from week 12 in the placebo group; soneroximab 30 mg and up-loaded soneroximab 120 mg once every 4 weeks after week 12 in the soneroximab 30 mg normally loaded group; soneroximab 60 mg and up-loaded soneroximab 120 mg once every 4 weeks after week 12 in the soneroximab 60 mg normally loaded group; soneroximab 120 mg once every 8 weeks after week 12 in the soneroximab 120 mg normally loaded group; soneroximab 120 mg once every 4 weeks after week 12 in the soneroximab 120 mg up-loaded group; and secukinumab 300 mg once every 4 weeks after week 12 in the secukinumab 300 mg group. [Figure 9]Summary of safety and tolerability results at weeks 0-12 and 12-52 in the safety analysis population. Data are n(%). *For information on specific events, see the Supplement in Papp et al., Lancet 2021; 397:1564-75, incorporated herein by reference in its entirety. †Between weeks 0-12, common treatment-emergent adverse events were considered as adverse events occurring in ≥5% of participants in any of the soneroximab-containing groups; between weeks 12-52, common treatment-emergent adverse events were considered as adverse events occurring in ≥3% of all participants in all soneroximab-containing groups combined. ‡Events under the preferred term for oral candidiasis for weeks 12-24; see adverse events of particular interest for the consolidated Candida assessment. §Includes infections, injection site reactions, liver function test abnormalities, cerebrocardiovascular events, cytopenias, allergic or hypersensitivity reactions, malignancies, depression, and inflammatory bowel disease. ¶Post-hoc pooling 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. [Figure 10] Patient breakdown. [Figure 11] Patient breakdown. [Figure 12] Patient breakdown. [Figure 13] IGA score category shift from baseline to week 12 (ITT population). [Figure 14] DLQI 0 / 1 response rate (NRI) at weeks 12 and 24 (ITT population). [Figure 15] Serious adverse events by preferred term (weeks 0-52). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Detailed Description of the Invention The details set forth herein are by way of example and are merely for purposes of illustrative discussion of the various embodiments, and are presented in a motive to provide what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the methods and compositions described herein. In this regard, it is not intended to provide more detail than is necessary for a fundamental understanding, and the description is provided as a general guide to how some forms may be embodied in practice. This will make clear to one skilled in the art what is required.

[0040] The present invention will now be described by reference to more detailed embodiments. The present invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0041] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The academic terms used in the description herein are only for describing specific embodiments and are not intended to be limiting. When used in this specification and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. All publications, patent applications, patents and other references mentioned herein are expressly incorporated by reference in their entirety.

[0042] Unless indicated to the contrary, the numerical parameters set forth in the following detailed description and attached claims are approximations that may vary depending on the desired properties sought to be obtained and, as such, 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 approaches.

[0043] Although the numerical ranges and parameters describing the broad ranges are approximate, the numerical values ​​described in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in each testing measurement. Every numerical range given throughout this specification includes every narrower numerical range that falls within such broader numerical range, as if such narrower numerical range were all expressly written herein. The applicant also contemplates ranges derived from the data points and specific ranges disclosed herein.

[0044] Nanobodies

[0045] Nanobodies are a novel class of proprietary therapeutic proteins based on the smallest functional fragments of heavy-chain-only antibodies (Vhh) naturally found in camelids. Nanobodies bind to their targets with the specificity and affinity of traditional therapeutic antibodies, but a single Vhh has a size of only about 15 kDa, about 10 times smaller than traditional antibodies. The smaller size has a number of advantages; a) several Vhhs can be linked to more easily form multivalent molecules that overcome the limitations of traditional monospecific antibodies in complex diseases driven by multiple cytokines or in passive immunization against viral diseases (Koenig PA, et al. Science 2021;371(6530):eabe6230). b) The smaller size of nanobodies still allows them to bind and inhibit mutant growth hormone receptors on tumor cells resistant to traditional antibodies, with the same specificity (Tintelnot J, et al. Mol Cancer Ther 2019;18:823-33). c) There is compelling evidence that the smaller size of nanobodies allows for better tissue penetration and specific enrichment at sites of malignant or inflammatory disease compared to traditional antibodies (Kruwel et al. T, et al. Sci Rep 2016;6:21834). The latter phenomenon is further enhanced with nanobodies bearing an albumin-binding moiety, such as soneloximab, which allows preferential accumulation within inflammatory edema, e.g., swollen joints (Coppieters K, et al. Arthritis Rheum 2006;54:1856-66). Soneloximab is a trivalent single-chain monoclonal nanobody consisting of three sequence-optimized Vhhs (each derived from a heavy-chain-only llama antibody) that contain the unique structural and functional properties of naturally occurring heavy-chain-only antibodies. The N-terminal portion binds IL-17F and the C-terminal portion binds IL-17A and IL-17F, allowing inhibition of 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 nine amino acid glycine / serine linker, resulting in a predicted total molecular weight of approximately 40 kDa. The calculated drug tissue permeability of soneloximab, which is 4-6 fold higher compared to traditional antibodies (150 kDa) (Li Z, et al. mAbs 2016;8:1:113-119), is an important consideration, especially in the treatment of inflammatory diseases such as hidradenitis suppurativa, where disease manifestations are often characterized by scar tissue and deep inflammatory skin morphology, e.g., inflammatory lesions surrounded by tunnels.

[0046] Nanobodies for use herein include the nanobodies disclosed in US Pat. No. 10,017,568, which is incorporated herein by reference in its entirety.

[0047] Nanobodies for use herein, including SEQ ID NO: 1, and variants thereof, are envisaged. For example, Nanobodies having a sequence homologous to the amino acid sequence represented by SEQ ID NO: 1 are included, and may be proteins having the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1, except that one or several amino acids have been deleted, substituted, inserted and / or added. In the case of substitutions, insertions or additions, conservative mutations resulting from conservative substitutions, insertions or additions of one or several amino acids are possible.

[0048] As used herein, "one or several amino acids" means 1 to 50, preferably 1 to 20, more preferably 1 to 10, even more preferably 1 to 5 or 1 to 3 amino acids.

[0049] Furthermore, proteins having an amino acid sequence homologous to the amino acid sequence represented by SEQ ID NO: 1 include proteins having an amino acid sequence in its full-length form that has 70% or more identity to the amino acid sequence represented by SEQ ID NO: 1. Proteins include proteins having an amino acid sequence in its full-length form that has preferably 80% or more, more preferably 90% or more, even more preferably 95%, 96%, 97%, 98%, or 99% or more identity to the above-mentioned amino acid sequence.

[0050] "Sequence identity" may refer to the percentage of identical nucleotides or amino acids in a nucleotide or amino acid sequence that are shared between two sequences, as determined by aligning the two sequences in an optimal pairwise alignment, optionally by using conventional or commercially available algorithms.

[0051] disease modification

[0052] Disease modification is commonly used in the context of therapeutic disease management to describe the effect of a treatment that alters the natural history of a disease. For example, the term disease-modifying anti-rheumatic drugs (DMARDs) is used to describe treatments that prevent the development and / or progression of bone degradation that typically characterizes the (untreated) course of a disease, such as rheumatoid or psoriatic arthritis. More recently, disease modification has been argued to be the basis for the maintenance of disease control in responsive patients with psoriasis after cessation of treatment. For example, the prolonged disease control observed after termination of treatment with an antibody that inhibits the cytokine IL-23 in patients with psoriasis where the natural disease course would predict rapid disease recurrence has been classified as representing disease modification (Eyerich K, et al. BMJ Open. 2021 Sep 13;11(9):e049822), as well as in the psoriatic disease cascade, have been linked to an upstream role of IL-23 in specific molecular and cellular events in previously affected skin, such as the reduction of endogenous memory CD8+ T cells (Mehta H, et al. J Invest Dermatol. 2021 Jul;141(7):1707-1718). As an alternative definition of disease modification in the treatment of chronic inflammatory skin conditions, increasing improvement of skin lesions with successive treatments has been described with parallel evidence of molecular and / or cellular normalization of affected tissues (Bieber T, et al. Allergy. 2012 Aug;67(8):969-75). Such a definition may be applicable to diseases such as atopic dermatitis and hidradenitis suppurativa, where complete skin clearance is not achievable with existing treatments.

[0053] The more 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 as to whether inhibitors of IL-17, and in particular IL-17F, might also exhibit disease-modifying phenomena. This is particularly relevant in diseases where IL-17F has been identified as a major driver of inflammation and / or where inhibitors of IL-23 have demonstrated only limited or irrelevant clinical benefits, such as hidradenitis suppurativa, psoriatic arthritis, and ankylosing spondylitis.

[0054] Administration and Dosing

[0055] Nanobodies for the prevention and / or treatment of the diseases and conditions mentioned herein are administered at doses between 30 mg and 240 mg, depending on the disease or condition to be treated, the specific route of administration, and the individualized regime for the subject. A contemplated induction injection scheme includes administration every 2 weeks for up to 8-12 weeks; a contemplated maintenance regime includes administration every 4 weeks to every 8 weeks. An early response to treatment may occur after 2-8 weeks; a complete response, i.e., time to skin clearance, may be up to 48 weeks; thus, the first time point to discontinuation may be after 16-48 weeks.

[0056] Generally, for pharmaceutical use, the Nanobodies of the invention may be formulated as pharmaceutical preparations or compositions comprising the Nanobody and at least one pharma- ceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more further pharma- ceutically active polypeptides and / or compounds. As non-limiting examples, such formulations may be in a form suitable for oral administration, parenteral administration (e.g. by intravenous, intramuscular or subcutaneous injection or intravenous infusion, intracavitary, intraarterial or intrathecal administration), topical (i.e. transdermal or intradermal) administration, inhalation, administration by skin patch, implant, suppository, etc. Such suitable dosage forms, which may be solid, semi-solid or liquid depending on the mode of administration, as well as methods and carriers for use in their preparation will be apparent to the skilled artisan.

[0057] subject

[0058] Patients with increased sensitivity to disease modification induced by treatment with soneloximab include those with a shorter disease duration, e.g., less than 6 months to 2 years; those with an early response in serum and / or tissue biomarkers, e.g., after 2 to 8 weeks; and those with an early clinical response. and high levels of response, e.g., with 50%-90% improvement after 2-8 weeks; and / or patients with high and stable levels of response, e.g., with PASI 100 at week 12 and 1 or 2 consecutive visits 2-6 weeks apart.

[0059] Biomarkers for predicting disease severity, disease course, response to treatment and / or susceptibility to side effects of inhibition of IL-17A and IL-17F may be based on a) analysis of proteins in peripheral blood and / or mRNA in circulating cells and / or surface markers and / or intracellular markers in peripheral cells by flow cytometry; and / or b) measurement of proteins in tissues; mRNA levels in tissues, bulk and / or single cell RNAseq of cells isolated from tissues. Useful biomarkers envisaged 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. EXAMPLES

[0060] Example 1

[0061] In a 48-week phase 2b study in patients (n=313) with moderate-to-severe plaque-type psoriasis, IL-17A- and IL-17F-targeted nanobody neroximab was discontinued at week 24 in patients who achieved complete skin clearance (investigator global assessment [IGA]=0) and resumed if disease control was lost (IGA≥1). Sonelokimab has the following amino acid sequence: Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Val Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ile Gly Ala Ile Ser Gly Ser Gly Glu Ser Ile Tyr Tyr Ala Val Ser Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ala Asp Gln Glu Phe Gly Tyr Leu Arg Phe Gly Arg Ser Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr IleSer Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu S is Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Asp Ala Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Gly Ser Gly Asp Asp Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Arg Arg Gly Leu Tyr Tyr Val Trp Asp Ala Asn Asp Tyr Glu Asn Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser (sequence number 1) included.

[0062] participants

[0063] Adults aged 18-75 years who had stable, moderate-to-severe, plaque-type psoriasis (defined as an Investigator's Global Assessment [IGA] score of ≥ 3, ≥ 10% body surface area involvement, and a Psoriasis Area and Severity Index [PASI] score of ≥ 12) for more than 6 months prior to randomization, were candidates for systemic biologic therapy, and did not have underlying medical conditions that placed them at unacceptable risk for receiving immunomodulatory therapy were eligible for this study. Patients previously treated with more than two biologic therapies or any therapy targeting IL-17 were excluded. All patients provided written informed consent prior to screening.

[0064] Randomization and Masking

[0065] Participants were enrolled by a masked investigator and randomly assigned (1:1:1:1:1:1) to receive either placebo, soneloximab 30 mg, soneloximab 60 mg, soneloximab 120 mg normal loading, soneloximab 120 mg boost loading, or secukinumab 300 mg. Randomization was stratified by body weight (≦90 kg or >90 kg) and prior biologic use (with or without prior use), resulting in four strata with a permuted block size of six within each stratum. Randomization was performed at the study level via a centralized interactive response technology system that provided blinded treatment kit numbers to investigators. Study medication was prepared and administered at the site by a designated unmasked individual at the study site not otherwise involved in the trial. Participants and all other site personnel were masked to treatment assignment throughout the study. The study sponsor was unmasked after all participants had completed 24 weeks of treatment and the database was locked.

[0066] procedure

[0067] All participants underwent a 4-week screening period, a 12-week placebo-controlled run-in period, a 12-week dose maintenance or escalation period (during which all participants received active treatment), a 24-week response evaluation or dose retention period, and a final assessment at week 52 ( Figure 1 ). The use of bland emollients was permitted throughout the study period except during the 24-hour period prior to the clinic visit.

[0068] During the placebo-controlled run-in period (weeks 0–12), participants received placebo (weeks 0, 1, 2, 3, 4, 6, 8, and 10), soneloximab 30 mg, 60 mg, or 120 mg. Patients received either sonerooximab 120 mg standard loading (weeks 0, 2, 4, 6, 8, and 10), sonerooximab 120 mg boost loading (weeks 0, 2, 4, 6, 8, and 10), or secukinumab 300 mg (weeks 0, 1, 2, 3, 4, and 8), with placebo given at weeks 1, 3, 6, and 10 in the sonerooximab 30 mg, 60 mg, and 120 mg standard loading groups, at weeks 1 and 3 in the sonerooximab 120 mg boost loading group, and at weeks 6 and 10 in the secukinumab 300 mg group.

[0069] During the dose maintenance or escalation period (weeks 12 to 24), participants assigned to the placebo group received soneroximab 120 mg (weeks 12, 14, 16, and then every 4 weeks); participants assigned to the soneroximab 30 mg or 60 mg groups with an IGA score higher than 1 were escalated to 120 mg every 4 weeks, and participants assigned to the soneroximab 30 mg or 60 mg groups with an IGA score of 1 or less remained at their assigned dose at week 12 and then every 4 weeks; participants assigned to the soneroximab 120 mg group received soneroximab 120 mg at week 12 and then every 8 weeks (normal loading group) or every 4 weeks (escalation loading); and participants assigned to the secukinumab 300 mg group received secukinumab 300 mg at week 12 and then every 4 weeks. During this period, placebo was given at week 14 in all groups and at week 16 in the sonerooxib 120 mg normally loaded group.

[0070] In the response assessment during the dose retention period (weeks 24–48), participants in the soneloximab 30 mg or 60 mg groups who were dose-escalated to 120 mg remained on the same regimen regardless of their IGA score at week 24. Participants in the secukinumab 300 mg group also remained on the same regimen regardless of their IGA score at week 24. Participants in the soneloximab 30 mg and 60 mg groups without dose escalation, as well as all participants in the two soneloximab 120 mg groups (including placebo rollover participants), were eligible to stop study drug at week 24. Those patients with an IGA score of 0 at week 24 were given placebo; these participants resumed their previous dose of soneloximab every 4 weeks if they had an IGA score (assessed every 4 weeks) of 1 or greater. Participants in these groups with an IGA score of 1 or greater at week 24 continued on the same dosage.

[0071] All study treatments were administered as subcutaneous injections. The final dose in all groups was given at week 44, and key efficacy and safety evaluations 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. al. Dermatologica 1978; 157:238-244; Weisman S., et al. J Dermatolg Treat 2003; 14:158-165) assessments, which were performed by study site personnel familiar with the scoring system and specially trained as part of the study conduct.

[0072] Outcome

[0073] The primary outcome was the proportion of participants in the soneloximab group with an IGA of clearance or near clearance (score 0 or 1) at week 12 compared with the placebo group. Secondary outcomes during the placebo-controlled period were PASI response, change in body surface area of ​​psoriasis, and safety assessments. A 100% improvement in PASI from baseline (PASI 100 response) is 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. A prespecified exploratory endpoint was dose escalation response at week 24. Examination endpoints included efficacy of dose retention 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 are listed in the study protocol). Adverse events reported by participants based on open-ended, non-leading verbal questions posed by the treating physician were collected at each visit.

[0074] statistical analysis

[0075] The sample size calculation was based on feasibility in a phase 2 setting and the assumption that it would allow differentiation between the highest and lowest doses of soneroximab. Controls for multiple comparisons were not performed. The study was not powered for formal comparisons between soneroximab and secukinumab. Response and safety data for the secukinumab 300 mg group were used for qualitative comparisons.

[0076] The primary outcome was analyzed in the intention-to-treat (ITT) population; participants with missing data were considered non-responders (non-responder imputation). Comparison of the primary active treatment (i.e., soneroximab or secukinumab) against placebo was performed using a two-sided Cochran-Mantel-Haenszel test, stratified by actual prior biologic use (yes or no) and weight strata (≦90 kg or >90 kg). Selected sensitivity analyses (missing responses were imputed using the last observation carried forward, using the randomized prior biologic use and weight strata) were performed in the ITT population. The safety population was defined as all patients who received study drug and were identical to the defined ITT population.

[0077] Secondary efficacy and quality of life endpoints were compared between the active treatment and placebo groups, and between the soneloximab groups at each scheduled visit through week 12, as well as between treatment groups at week 24 using the Cochran-Mantel-Haenszel test for analysis of binary endpoints and models of covariance, including planned treatment group, strata of actual prior biologic use combined with weight as factors, and baseline value as a covariate in the model for change from baseline (or percent change from baseline for PASI).

[0078] Exploratory efficacy analyses were performed in all participants who were dose escalated at week 12. At the end of the study, exploratory efficacy analyses were also performed in participants who were discontinued from active treatment (i.e., participants who had an IGA score of 0 at week 24) and participants who were not discontinued from active treatment (i.e., participants who had an IGA score of ≧1 at week 24).

[0079] All statistical analyses were performed using SAS version 9.4.

[0080] A data monitoring committee consisting of three dermatologists from the institution who were not involved in the study but who are knowledgeable in clinical studies of biologics in psoriasis met regularly as mandated by a written statement established at the beginning of the study and reviewed the safety information. The committee did not recommend any changes to the study protocol.

[0081] result

[0082] Between August 15, 2018 and March 27, 2019, 383 patients were evaluated for eligibility and 313 were enrolled and randomized to placebo (n=52), soneroquimab 30 mg (n=52), soneroquimab 60 mg (n=52), soneroquimab 120 mg standard loading (n=53), soneroquimab 120 mg boosted loading (n=51), or secukinumab. Patients were randomly assigned to receive either 100 mg or 300 mg of psoriasis per 100 mg dose (n=53) (see Supplement in Papp et al., Lancet 2021;397:1564-75). Demographic and baseline characteristics were generally similar between treatment groups (Figure 7). Participants' mean age was 46 years (SD 13.1), most participants 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).

[0083] At week 12, none of the 52 participants in the placebo group (0.0% [95% None of the 52 participants had an IGA score of 0 or 1 (CI 0.0-6.8) compared with 25 of 52 participants (48.1% [34.0-62.4], p<0.0001) in the sonerooximab 30 mg group, 44 of 52 participants (84.6% [71.9-93.1], p<0.0001) in the sonerooximab 60 mg group, and 1 of 53 participants in the sonerooximab 120 mg normally loaded group. Forty-one of them (77.4% [63.8 to 87.7], p<0.0001), 45 of 51 participants (88.2% [76.1 to 95.6], p<0.0001) in the sonerooxib 120 mg boost-loading group, and 41 of 53 participants (77.4% [63.8 to 87.7], p<0.0001) in the secukinumab 300 mg group had an IGA score of 0 or 1.

[0084] Of the 313 randomized participants, 302 (97%) completed their assigned treatment through week 12, including week 12 (Papp et al., Lancet 2021;397:1564-75 (see Supplement). Compared with the placebo group, a significantly higher proportion of participants in the soneloximab 120 mg boost-loading group had a PASI 90 response (39 of 51 participants [76.5%; 95% CI 62.5 to 87.2]; p<0.0001) and a PASI 100 response (17 of 51 participants [33.3%; 20.8 to 47.9]; p<0.0001), defined as at least a 90% improvement from baseline (Figure 8). A significantly higher proportion of participants in the soneloximab 120 mg boost-dose group than in the placebo group had an IGA of 0 (Figure 13). The proportion of participants with IGA responses (i.e., IGA scores of 0 or 1) and PASI 90 responses in the active treatment groups began to differ from the placebo group early on, with groups receiving higher doses (i.e., soneroximab 60 mg and 120 mg) mostly outperforming the soneroximab 30 mg group (Figure 2). Onset of response was rapid, with 16 of 51 participants (31.4%) in the soneroximab 120 mg boost-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. Compared with the placebo group, 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 to 76.9]; p<0.0001) and a PASI 100 response (15 of 53 participants [28.3%; 16.8 to 42.3]; p<0.0001) at week 12. One hundred and thirty-one of all 208 participants (63.0%) in the soneloximab group had a DLQI score of 0 or 1 by week 12, compared with only one participant in the placebo group (Figure 14). The change in percentage of body surface area involvement with psoriasis between weeks 0 and 12 in participants who received soneroximbib was consistent with the IGA score and PASI response results (see Supplement in Papp et al., Lancet 2021; 397:1564-75).

[0085] Of the 313 originally randomized participants, 297 (95%) completed week 24 (see Supplement in Papp et al., Lancet 2021; 397:1564-75). At week 12, 27 of 52 patients (51.9%) in the soneloximab 30 mg group and 27 of 52 patients (52.1%) in the soneloximab 60 mg group Seven of the participants (13.5%) did not achieve the primary endpoint of IGA response; these participants had their dosage escalated to soneroximab 120 mg every 4 weeks. Participants in the soneroximab 120 mg regular-loading group received 120 mg at week 12 and every 8 weeks thereafter; patients in the soneroximab 120 mg boost-loading group received 120 mg at week 12 and every 4 weeks thereafter. The proportion of participants in the dose-optimized soneloximab 60 mg and 120 mg groups with IGA responses ranged from 80.4% (95% CI 66.9-90.2) to 94.2% (84.1-98.8); the proportion with PASI 90 responses ranged from 79.2% (65.9-89.2) to 90.4% (79.0-96.8); and the proportion with PASI 100 responses ranged from 40.4% (27.0-54.9) to 56.9% (42.2-70.7) (Figure 8; Figure 2(A-C)). Participants in the placebo group received 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter; at week 24, the proportion of participants with IGA and PASI responses was similar to that observed at week 12 in participants initially receiving this regimen. In participants who received soneloximab 120 mg during the first 12 weeks, the proportion of participants with IGA scores of 0 or 1, PASI 90 responses, and PASI 100 responses generally peaked by week 16 (Figure 2(A-C)). Of note, the proportion of participants on soneloximab once every 8 weeks in weeks 12-24 with IGA, PASI 90, and PASI 100 responses decreased by the time the next dose was to be given (i.e., by week 20). In all groups, the proportion of participants with DLQI scores of 0 or 1 increased by week 24 compared to week 12 (Figure 14). At week 24, 40 of 53 participants (75.5%; 61.7-86.2) in the secukinumab 300 mg group 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).

[0086] PASI scores improved over time during the placebo-controlled period (weeks 0-12) in all active treatment groups, regardless of dose (Figure 2(D)). The mean percentage change from baseline in PASI response scores indicates the rapid effect of treatment in these participants. During the dose maintenance or escalation period, a notable rapid improvement in PASI response scores was observed beginning at week 14 in placebo-group participants who were transitioned to soneroximuab 120 mg.

[0087] Assessment of response at 48 weeks with continued administration of soneloximab was not a goal of the study design. Instead, participants with an IGA score of 0 at week 24 were stopped from soneloximab treatment. Interpretation of the IGA and PASI response scores for each group is complicated by dose adjustments allowed by the study protocol (see Supplement in Papp et al., Lancet 2021; 397:1564-75). Post-hoc analyses were performed in participants randomly assigned to the placebo group who received soneloximab 120 mg after week 12 as well as participants randomly assigned to the soneloximab 120 mg normal-loading group and the soneloximab 120 mg boost-loading group. These participants were combined into a single group of 142 participants, of whom 69 (48.6%) had an IGA of 0 at week 24 and soneloximab was subsequently discontinued. Of these 69 participants, 60 (87.0%) did not maintain an IGA score of 0 over the subsequent 4–12 weeks, but 47 of these 60 participants (78.3%) subsequently achieved an IGA of 0 again when they resumed soneloximab 120 mg. When participants who did not have an IGA score of 0 at week 24 were continued on soneloximab 120 mg, the proportion of participants with PASI 90 and PASI 100 responses continued to increase (Figure 3(A,B)). Safety was assessed during the initial placebo-controlled 12-week run-in period and the dose optimization (secukinumab-controlled) period between weeks 12 and 52 (i.e., the combined dose maintenance or escalation period and the response evaluation or dose hold period). After week 12, soneloximab dosage and exposure were The treatment groups differed. Participants at 30 mg and 60 mg soneroximab with an IGA score higher than 1 at week 12 were given the increased dose. Participants with an IGA score of 0 at week 24 were stopped from soneroximab treatment until this response was lost. Participants in the placebo group were only eligible to receive soneroximab after week 12. Adverse events occurred in 155 of 313 participants (49.5%), with a slightly higher occurrence in the soneroximab-containing group (107 of 208 (51.4%)) than in the placebo group (22 of 52 [42.3%]) at weeks 0 to 12 (Figure 9). There was no clear effect of increasing soneroximab dose on the occurrence of adverse events. During weeks 0–12, the most common adverse events in all participants on soneloximab were nasopharyngitis (28 [13.5%] of 208 participants), pruritus (14 [6.7%] participants), and upper respiratory tract infection (9 [4.3%] participants). Three participants on soneloximab 120 mg (1 in the normal-loading group and 2 in the augmented-loading group) discontinued treatment due to adverse events during weeks 0–12: 1 participant had a pustular rash and did not want to undergo a protocol-mandated biopsy, 1 participant had hypertension, and 1 participant had acute kidney injury. The participant with acute kidney injury was given soneloximab 120 mg for 1 month, then prescribed amoxicillin with clavulanate and clarithromycin for 3 days for an upper respiratory tract infection, and was diagnosed with acute tracheal necrosis with acute drug-induced nephritis. Between weeks 0 and 12, six participants had serious adverse events (one in the placebo group, two in the sonerooximab 30 mg group, one in the sonerooximab 60 mg group, one in the sonerooximab 120 mg normal-loading group, and one in the sonerooximab 120 mg augmented-loading group; Figure 9; Figure 15). No clinically significant signals were identified from laboratory assessments, vital signs, electrocardiograms, or Depression and Suicidality Scale assessments.

[0088] Between weeks 12 and 52, participants on soneloximab were combined into one group due to variability in dosing between groups. Adverse events of particular interest were defined based on known effects of IL-17 modulation. With the possible exception of candidiasis, no dose-response association with toxicity was evident. Most candidal infections were easily managed. Four of 251 participants on soneloximab (1.6%) had absolute neutrophil counts of less than 1000 cells per μL; all cases of neutropenia resolved rapidly without changes to soneloximab dosing. No other clinically significant signals were identified from laboratory assessments, vital signs, electrocardiograms, or Depression and Suicidality Scale assessments.

[0089] One participant in the soneloximab group, who initially received placebo and was crossed over to soneloximab 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 intravenous antifungals. Other notable events were one new diagnosis of Crohn's disease and one death. This Crohn's disease diagnosis was made in one participant who received soneloximab 30 mg and was increased to 120 mg at week 12, who reported a family history of chronic bowel disease. This participant had intermittent diarrhea between months 2 and 9 of the study and underwent a colonoscopy at month 11 of the study. One participant in the soneloximab 60 mg group died in his sleep at home and was reported to have had cardiopulmonary failure due to pulmonary aspiration of gastric contents.

[0090] Consideration

[0091] In this Phase 2b study of soneroximab, doses up to 120 mg demonstrated rapid and significant clinical benefit when compared with placebo. Participants at the highest dose (120 mg boost loading) demonstrated rapid response, 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. Approximately half of participants (69 of 142 [48.6%]) on secukinumab 120 mg had an IGA score of 0 at week 24. A small decrease in response was observed when treatment was discontinued in participants with an IGA score of 0 at week 24; many (47 of 60 [78.3%]) participants achieved a complete response again when treatment was resumed. Some differences in response between the different doses and schedules of soneroximab were evident and were best visualized in the early portion of the mean change in the PASI response curves, and in the mid-to-late portion of the PASI 100 response curves. Soneroximab was generally well tolerated and had a safety profile similar to the secukinumab active control. Overall, a higher incidence of Candida infections was observed in participants on soneroximab compared with placebo; a single incidence of esophageal candidiasis occurred in one participant in the secukinumab 300 mg group. It is possible that the highest dose and schedule of sonerooxib may be used in future clinical studies, although additional evaluation and modeling may aid in the final selection of the optimal dose and schedule.

[0092] The first biologic for the treatment of psoriasis, a T cell-directed therapy, was approved 18 years ago. Since then, the therapeutic mechanism has 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 on IL-17A / F modulators. Each of these innovations has raised questions regarding potential increases in efficacy, benefits of various molecular constructs, and caution regarding the need to fully understand potential toxicities. In particular, with regard to the mechanism of action of IL-17 in psoriasis, IL-17A and IL-17F appear to be the main pro-inflammatory mediators in psoriasis, with IL-17A / A and IL-17F / F homodimers and IL-17A / F heterodimers as biologically active molecules. Secukinumab primarily inhibits IL-17A / A, and ixekizumab primarily inhibits IL-17A / A and IL-17A / F (Eli Lilly and Company. Highlights of prescribing information: TALTZ (ixekizumab) injection, for subcutaneous use. 2020. http: / / pi.lilly.com / us / taltz-uspi.pdf (Accessed: September 17, 2020; Paul C., Br J Dermatol 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 alone has the ability to 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). Furthermore, concomitant IL-17F and IL-17A blockade reduces synoviocyte and fibroblast mediator production induced by supernatants from T helper 17 cells in vitro compared to IL-17A blockade alone. (Glatt S., et al. Ann Rheum Dis 2018; 77:523-532). Brodalumab is a monoclonal antibody that targets IL-17RA, preventing binding by all IL-17 subtypes (Lebwohl M, et al. N Engl J Med 2015; 373:1318-1328) and interfering with both IL-17A and IL-17F.

[0093] Brodalumab also blocks other IL-17 family members, including IL-17E (or IL-25), which are downregulated in lesional psoriatic skin compared to nonlesional psoriatic skin and may have some 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 inhibits human IL-17A and I It is a humanized monoclonal antibody that potently and selectively neutralizes both biological functions of IL-17A and IL-17F. Seven clinical phase 2 data on bimekizumab support the concept that IL-17A and IL-17F blockade is effective in treating psoriasis. (Papp KA, et al. J Am Acad Dermatol 2018; 79:277-86.e10; Ritchlin CT, et al. Lancet 2020; 8:427-440). The rate and extent of responses observed in these phase 2 studies, together with early views of 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. Our phase 2b study of soneloximab is the first to include two different IL-17 modulating agents in the same study. Uniquely, soneloximab is a nanobody that blocks IL-17A, IL-17F, and the IL-17A / F heterodimer. Compared to monoclonal antibodies, the smaller size of soneloximab may allow differential penetration of skin and other tissues. A major limitation of this study is the phase 2 scope and the absence of a formal comparison between soneloximab and secukinumab. Although indications of differences between soneloximab and secukinumab, such as more rapid effects and higher peak responses, are suggested, the study was not powered to allow for a confident distinction. A true comparative approach would require a phase 3 setting, where the optimal dose of soneloximab would be prospectively compared head-to-head with an antibody such as secukinumab. The data presented in this report suggest that the addition of IL-17F modulation may provide a rapid onset of action, a high ceiling of efficacy, and possibly more frequent oral fungal infections. Future studies, such as the bimekizumab and secukinumab trial completed in 2020 (NCT03536884), may contribute to the understanding of IL-17A and IL-17F blockade compared to IL-17A blockade alone. Additionally, it remains to be understood how differences in the precise binding properties of IL-17A / A or IL-17A / F and IL-17F / F inhibitors, such as bimekizumab and soneloximab, affect the benefit-risk profile of these drugs.

[0094] Example 2

[0095] Maintenance Treatment Response

[0096] Individual patient-level clinical response data obtained within the highest soneroximab dose group (120 mg injected every 2 weeks until week 12, every 4 weeks until week 24, and then discontinued or continued every 4 weeks; n=51) and the active reference group treated sequentially with the IL-17A inhibitor secukinumab (300 mg weekly until week 4 and then every 4 weeks; n=53) were analyzed to gain insight into the "disease-modifying" potential of IL-17A and Il-17F inhibition in psoriasis. See Reich et al., Br J Dermatol. 2022 Apr 20. doi: 10.1111 / bjd.21617, incorporated herein by reference in its entirety.

[0097] Analyses using a 5-point IGA scale (Langley RG et al., J Dermatolog Treat 2015; 26:23-31) were performed based on the intention-to-treat (ITT) population through week 24 and on the observed population thereafter. In the soneroximab and secukinumab groups, respectively, n=4 and n=2 patients were discontinued prior to week 24. Between weeks 24 and 48, n=4 patients in the soneroximab group were discontinued (n=2 each lost to follow-up and withdrew consent; n=3 patients left the study with IGA=0) and n=2 patients in the secukinumab group were discontinued (n=2 withdrew consent, both with IGA=2). ). The interval between visits at weeks 24 and 48 was every 4 weeks. Patients who requested resumption of treatment due to disease recurrence (IGA ≥ 1) after discontinuation of soneroximab were given monthly injections until week 48. Analyses were descriptive post-hoc comparisons with nominal P values ​​derived from chi-square tests and no correction for multiple testing was made.

[0098] In the soneroximab 120 mg and secukinumab arms, 56.9% (n=29 / 51) and 34.0% (n=18 / 53) of patients, respectively, achieved complete clearance (Psoriasis Area and Severity Index [PASI] 100) at week 24 (ITT-nonresponder imputation; P=0.019). Of the 25 patients in the soneroximab arm followed to week 48 who had IGA=0 and were discontinued at week 24, 20% (n=5 / 25) maintained complete clearance (IGA=0) to week 44 and did not require treatment resumption (Figure 4). Of the remaining 20 patients, n=16 / 2 / 2 were retreated with disease activity of IGA=1 / 2 / 3, respectively, and 80% of the retreated patients achieved complete clearance at week 48 (n=16 / 20). The proportion of patients with complete clearance at week 48 among patients with IGA=0 at week 24 was similar among patients with discontinuation and re-initiation of soneroximab and patients treated consecutively with secukinumab (72.0% and 73.7%, respectively; Figure 5). Patients in the soneroximab discontinuation / retreatment group received approximately 50% fewer total monthly injections between weeks 24 and 48 compared with patients in the consecutive secukinumab arm. Among patients with active disease (IGA ≥ 1) at week 24, a numerically higher proportion of patients in the soneroximab arm achieved complete clearance at week 48 compared with the secukinumab arm (Figure 6).

[0099] Analysis and comparison of maintenance of treatment response must take into account variability in eligibility for treatment discontinuation (required level of response), duration of treatment prior to discontinuation, and therapeutic half-life. In a phase 2 study, maintenance of skin clearance (IGA=0) over 7 half-lives was observed in approximately 50% of patients after discontinuation from monthly 120 mg soneloximab (half-life 12 days; (Svecova et al., J Am Acad Dermatol 2019; 81:196-203); randomized discontinuation at week 24). This result was consistent with approximately 40% of patients with maintenance of clearance (PASI 100) over 7 half-lives after discontinuation of the IL-17A and IL-17F inhibitor bimekizumab (half-life 26 days; randomized discontinuation at week 16) (Committee for Medicinal Products for Human Use (CHMP). Assessment report: Bimzelx (bimekizumab), 24 June 2021. Available at: https: / / www.ema.europa.eu / en / documents / assessment-report / bimzelx-epar-public-assessment-report_en.pdf (last updated: 24 November 2021; Gordon KB et al., Lancet 2021; 397:475-86), somewhat higher than the approximately 70% of patients with maintenance of clearance (PASI 100) for 7 half-lives after discontinuation of the IL-23 inhibitor risankizumab (half-life 28 days; randomized discontinuation at week 28) (Blauvelt A et al., JAMA Dermatol 2020; 156:649-58; Pang Y et al., Clin Pharmacokinet 2020; 59:311-26). Although comparable data are not available for IL-17A inhibitors; the comparable skin clearance rates observed at week 48 between patients treated sequentially with secukinumab and those who had discontinued and eventually restarted soneloximab may point to a greater maintenance of treatment response with inhibition of IL-17A and IL-17F compared to inhibition of IL-17A alone. The overlap and separation of IL-23 and IL-17-driven inflammation in diseases, such as psoriasis, the main cellular sources of these cytokines, the mechanisms underpinning "disease modification," and the different functions of these pathways are of great importance. Further studies are warranted to understand the differential effects of therapeutics targeting specific molecular members.

Claims

1. A pharmaceutical composition for treating an IL-17-dependent state, comprising nanobodies that specifically bind to an IL-17A / A homodimer, an IL-17A / F heterodimer, and / or an IL-17F / F homodimer, A pharmaceutical composition comprising the nanobody being administered to a subject in need at a dose of 30 to 240 mg every 2 to 4 weeks for a maximum of 24 weeks, followed by discontinuation of treatment with the nanobody for subjects that have responded.

2. The pharmaceutical composition according to claim 1, wherein the administration is performed subcutaneously.

3. The pharmaceutical composition according to claim 1, wherein the discontinuation of treatment at the nanobody is carried out over a period of four weeks or more.

4. The pharmaceutical composition according to claim 1 for treating IL-17-dependent dermatological conditions.

5. The pharmaceutical composition according to claim 4 for treating psoriasis, atopic dermatitis, lupus erythematosus discoid, alopecia areata, autoimmune urticaria, bullous pemphigoid, herpetiform dermatitis, hidradenitis suppurativa, linear IgA dermatopathy, maculoplasty, pemphigus vulgaris, or pyoderma gangrenosum.

6. The pharmaceutical composition according to claim 1 for treating psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjögren's syndrome, juvenile idiopathic arthritis, granulomatous disease, Behçet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu's arteritis.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the nanobody is administered in doses of 30, 60, 120, or 240 mg every 2 to 4 weeks for a maximum of 24 weeks.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the dose is increased between the second and 24th week after the start of administration if the subject has an IGA score higher than 1.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the nanobody comprises sonerokimab.

10. A pharmaceutical composition according to claim 1 for treating psoriasis, wherein complete skin clearance is achieved in the subject within four to eight weeks after the start of administration.

11. A pharmaceutical composition for disease modification comprising nanobodies that specifically bind to an IL-17A / A homodimer, an IL-17A / F heterodimer, and / or an IL-17F / F homodimer, The aforementioned nanobody is administered to subjects suffering from an IL-17-dependent state at a dose of 30 to 240 mg every two weeks. A pharmaceutical composition in which the aforementioned administration is carried out over a period of four weeks or more.

12. The pharmaceutical composition according to claim 11, wherein the nanobody is administered every two weeks until the 12th week after the start of administration, and then every four weeks until the 24th week.

13. The pharmaceutical composition according to claim 11, wherein the administration of the nanobody is suspended or permanently stopped 24 weeks after the start of the administration.

14. The pharmaceutical composition according to claim 11 for achieving 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 24 weeks after the start of the administration.

15. The pharmaceutical composition according to claim 11 for achieving 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 24 weeks after the start of the administration.

16. The pharmaceutical composition according to claim 14 or 15, wherein the normalization is sustained for at least 4, 8, 12, 16, or 20 weeks after the administration is suspended or stopped.

17. The nanobody is administered over a total period of at least 4 weeks and no more than 24 weeks. The pharmaceutical composition according to claim 11, wherein administration is resumed if one or more symptoms of the IL-17-dependent state recur after the administration has been discontinued for a period longer than two weeks.

18. The pharmaceutical composition according to claim 17, wherein administration is resumed when the subject has one or more IGA scores.

19. The pharmaceutical composition according to claim 17, wherein the resumption of administration includes administering 30 to 240 mg of the nanobody every two weeks.

20. The pharmaceutical composition according to claim 11, wherein the IL-17 dependent state is a dermatological condition.

21. The pharmaceutical composition according to claim 20, wherein the dermatological condition is psoriasis, atopic dermatitis, lupus erythematosus discoid, alopecia areata, autoimmune urticaria, bullous pemphigoid, herpetiform dermatitis, hidradenitis suppurativa, linear IgA dermatopathy, maculoplasty, pemphigus vulgaris, or pyoderma gangrenosum.

22. The pharmaceutical composition according to claim 11, wherein the nanobody comprises sonerokimab.

23. The pharmaceutical composition according to claim 11, wherein the administration is performed subcutaneously.

24. A pharmaceutical composition for treating an IL-17-dependent dermatological condition, comprising nanobodies that specifically bind to an IL-17A / A homodimer, an IL-17A / F heterodimer, and / or an IL-17F / F homodimer, A pharmaceutical composition in which the nanobody is administered to a target requiring it at a dose of 30 to 240 mg every 2 to 4 weeks for a period longer than 24 weeks, thereby achieving complete skin clearance.

25. The pharmaceutical composition according to claim 24, which achieves complete clearance of the IL-17-dependent dermatological condition in 40% or more of subjects who still exhibit symptoms of the IL-17-dependent dermatological condition at 24 weeks of the treatment.

26. A pharmaceutical composition comprising nanobodies that specifically bind to IL-17A / A homodimers, IL-17A / F heterodimers, and / or IL-17F / F homodimers, A pharmaceutical composition in which the pharmaceutical composition is used at a dose of 30 to 240 mg every 2 to 4 weeks for a maximum of 24 weeks to a subject in need thereof, and thereafter the use of the pharmaceutical composition containing the nanobody is discontinued for subjects that respond to said use; the subject is human or non-human animal.

27. The pharmaceutical composition according to claim 26, wherein the subject requiring the use of the pharmaceutical has a dermatological condition.

28. The pharmaceutical composition according to claim 26, wherein the subject has or is at risk of having psoriasis, atopic dermatitis, lupus erythematosus discoid, alopecia areata, autoimmune urticaria, bullous pemphigoid, herpetiform dermatitis, hidradenitis suppurativa, linear IgA dermatopathy, maculoplasty, pemphigus vulgaris, or pyoderma gangrenosum.

29. The pharmaceutical composition according to claim 26, wherein the subject has or is at risk of having psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Sjögren's syndrome, juvenile idiopathic arthritis, granulomatous disease, Behçet's disease, antiphospholipid syndrome, giant cell arteritis, scleroderma, polyarteritis nodosa, or Takayasu's arteritis.

30. The pharmaceutical composition according to claim 26 or 27, wherein the subject responsive to the use has a PASI score of 75 to 100 after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

31. The pharmaceutical composition according to claim 30, wherein the subject responsive to the use has or is at risk of having psoriasis, and the use is discontinued after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

32. The pharmaceutical composition according to claim 26 or 27, wherein the subject responsive to the use has an IGA score of 0 or 1 after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

33. The subject responsive to the use has or is at risk of having psoriasis, and the use is discontinued after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks, claim 32 The pharmaceutical composition described above.

34. The pharmaceutical composition according to claim 26 or 27, wherein the subject responsive to the use has a HiSCR score of 75 to 90 after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

35. The pharmaceutical composition according to claim 34, wherein the subject responsive to the use has or is at risk of having hidradenitis suppurativa, and the use is discontinued after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

36. The pharmaceutical composition according to claim 26, wherein the subject responsive to the use has an ACR score of 50 to 70 after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

37. The pharmaceutical composition according to claim 36, wherein the subject responsive to the use has or is at risk of having psoriatic arthritis, and the use is discontinued after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

38. The pharmaceutical composition according to claim 26, wherein the subject responsive to the use has an ASAS score of 40 or more after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

39. The pharmaceutical composition according to claim 38, wherein the subject responsive to the use has or is at risk of having axial spondyloarthritis, and the use is discontinued after a period of use of 4 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 20 weeks or more, or 24 weeks.

40. The pharmaceutical composition according to claim 26, wherein the nanobody comprises SEQ ID NO: 1 or a variant thereof having 70% or more sequence identity thereto.

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