Methods of treatment of uveitis

Abstract

The disclosure related to methods of treatment of uveitis. In certain embodiments, the disclosure provides compositions and dosing regimen of an IL-17A inhibitor for the treatment of uveitis.

Description

Patent Application METHODS OF TREATMENT OF UVEITIS FIELD OF DISCLOSURE

[0001] The disclosure is related to methods, compositions, and formulations thereof for treatment of uveitis. BACKGROUND

[0002] Uveitis is a type of eye inflammation, which traditionally described a type of inflammation in the uvea, which includes the iris, ciliary body, and the choroid. Overtime, Uveitis has become used to describe this type of inflammation in any area of the eye. Uveitis results from a heterogeneous collection of disorders with diverse etiologies and pathogenic mechanisms (Prete et al, 2016). Uveitis can be classified, according to the primary anatomical location of the inflammation, into anterior and non-anterior uveitis.

[0003] Non-anterior uveitis can be further classified into intermediate-, posterior- or pan-uveitis (affecting more than 1 eye segment). Symptoms include severe intraocular inflammation, vision impairment with blurred or cloudy vision, floaters-spots in the eye and eye pain.

[0004] Infectious uveitis may occur as a result of an infection by bacterial and spirochetal diseases, viral diseases, fungal and parasitic infections (Lin, 2015). Non-infectious uveitis has been associated with systemic immune mediated diseases such as spondylarthritis (i.e., ankylosing spondylitis and reactive arthritis), psoriatic arthritis and inflammatory bowel disease (IBD) (Rosenbaum, 2015), multiple sclerosis and Bechet’s disease (Chi et al, 2008). Non-infectious uveitis can also occur without extraocular involvement (Rosenbaum et al, 2019).

[0005] The prevalence of non-infectious uveitis in the United States (US) was estimated to be 121 / 100,000 people based on administrative claims from 14 million privately insured individuals. Anterior non-infectious uveitis made up 81% (prevalence of 98 / 100,000 adults) versus 0.9% (prevalence of 1 / 100,000), 8.6% (prevalence of 10 / 100,000) and 9.6% (12 / 100,000) for non- infectious intermediate-, posterior- and pan-uveitis, respectively (Thorne et al, 2016). In Europe, up to 26% of total uveitis cases are intermediate-, posterior- or pan-uveitis (Wakefield and Chang, 2005). 1  Patent Application

[0006] Patients affected by uveitis are at risk of developing permanent visual impairment and blindness affecting 1 or both eyes. Cystoid macular edema was identified as the leading cause of visual impairment (41%) and blindness (29%) in patients with uveitis. Other eyesight-threatening complications include cataract and glaucoma (Durrani et al, 2004). All anatomical sites of inflammation of uveitis have the potential to lead to visual impairment and blindness, but the risk of visual impairment and blindness is highest in patients with posterior- or pan-uveitis (Rothova et al, 1996). Furthermore, patients with non-infectious, intermediate-, posterior- or pan-uveitis have a worse prognosis compared to those with anterior uveitis (Wakefield and Chang, 2005; Barisani-Asenbauer et al, 2012).

[0007] Uveitis is a rare disease; nevertheless, it is the fourth most common cause of blindness among the working-age population in the developed world (Barisani-Asenbauer et al, 2012). In the US and other Western countries, it is estimated that approximately 10% to 20% of preventable blindness is caused by non-infectious, intermediate-, posterior- or pan-uveitis and associated complications (Rothova et al, 1996;Rothova et al, 1996; Miserocchi et al, 2013; Nguyen et al, 2011; Gritz and Wong, 2004). ; Miserocchi et al, 2013; Nguyen et al, 2011; Gritz and Wong, 2004).

[0008] Accordingly, if left untreated, uveitis carries a very high risk of progression to severe visual impairment, with a substantial impact on day-to-day functioning and overall quality of life. Vision loss due to non-infectious, intermediate-, posterior- or pan-uveitis can negatively affect patients’ mental and physical health (Schiffman et al, 2001; Murphy et al, 2005; Miserocchi et al, 2010). Disability associated with visual impairment also can adversely affect patients’ ability to work and may lead to absenteeism or early exit from the workforce.

[0009] Topical and systemic corticosteroids remain the cornerstone of treatment in patients with uveitis. Patients may require persistent high-dose systemic corticosteroids, high-dose systemic corticosteroids bursts or rapid systemic corticosteroids dose escalation. Conventional non biologic systemic immunosuppressant therapies (e.g., antimetabolites and alkylating agents) are mostly older, not well tolerated, and their efficacy has usually not been well-evidenced; presumably, at least one-third of patients still fail to achieve therapeutic remission with such agents.

[0010] The tumor necrosis factor-alpha (TNF-α) inhibitor adalimumab is the only approved biologic for the treatment of uveitis. In the US, adalimumab is indicated for the treatment of adult patients with non-infectious intermediate-, posterior- and pan-uveitis. In Europe, adalimumab is indicated for the treatment of adult patients with non-infectious intermediate-, posterior- and pan- 2  Patent Application uveitis who have had an inadequate response to corticosteroids, in patients in need of corticosteroid sparing or in whom corticosteroid treatment is inappropriate (Humira SmPC EMA).

[0011] However, there remains an unmet medical need for the treatment of non-infectious, intermediate-, posterior-, or pan-uveitis. These types of uveitis are at a higher risk for vision loss compared to anterior uveitis. Disease management often requires chronic corticosteroid use, whether in an oral or injectable form, which presents with predictable and damaging long-term side effects, whereas in general, anterior uveitis may be managed with topical corticosteroids.

[0012] Immunosuppressive agents have been used as corticosteroid-sparing or additive therapy in noninfectious, intermediate-, posterior- or pan-uveitis, although there is a lack of robust clinical evidence to support their use. These immunosuppressive agents are not effective in all patients and carry risks of known adverse effects.

[0013] The TNF-α inhibitor adalimumab is the only approved biologic for the treatment of uveitis. Nevertheless, a large proportion of patients are also refractory to these treatments and can experience reduction of vision. SUMMARY OF THE DISCLOSURE

[0014] The current disclosure provides methods and compositions for treating inflammation of the eye, and in particular, uveitis. In certain aspects, the disclosure provides methods for treating uveitis by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep, and preferably about or exactly 160 mg izokibep or a salt thereof per dose. Unexpectedly, the present Inventors discovered that such a relatively high dose of izokibep, when provided once weekly, once every two weeks, or twice a week is well tolerated and provides efficacious treatment of uveitis. In a related aspect, the disclosure also provides a composition comprising between about 150 mg and 170 mg of izokibep or a salt thereof for use in the treatment of uveitis. In another related aspect, the disclosure provides use of a composition comprising between about 150 mg and 170 mg of izokibep or a salt thereof in the manufacture of a medicament for the treatment of uveitis.

[0015] In certain aspects, the disclosure provides a method of treatment of uveitis by administration to a patient a composition comprising izokibep or a salt thereof. Preferably, the composition comprises between about 150 mg and about 170 mg of izokibep or a salt thereof. 3  Patent Application More preferably, the composition comprises between about 155 mg and about 165 mg of izokibep or a salt thereof. In more preferred aspects, the composition comprises about 157 mg of izokibep or a salt thereof or does comprise 162 mg of izokibep or a salt thereof. In even more preferred aspects, the composition comprises 160 mg of izokibep or a salt thereof.

[0016] In certain methods, the composition further comprises one or more of sodium phosphate, NaCl, and EDTA. Preferably, composition comprises about 10 mM sodium phosphate, about 150 mM NaCl, and / or about 0.5 mM EDTA.

[0017] In certain methods, the composition is administered to the patient subcutaneously. In such methods, in preferred aspects, the composition is administered in an arm, upper thigh, and / or abdomen of the patient. Preferably, the composition is administered to the patient once weekly. In alternative or supplementary methods, the composition is administered to patient twice weekly. In certain aspects, composition is administered once a week to a patient for between 1 and 52 weeks.

[0018] In preferred methods, the uveitis is one or more of the group consisting of an intermediate- uveitis, a posterior-uveitis, and a pan-uveitis. In some methods, the uveitis is an intermediate- uveitis. In some methods the uveitis is a posterior-uveitis. In some methods the uveitis is a pan- uveitis. In preferred methods, the uveitis is a non-infectious uveitis.

[0019] In methods of the disclosure, the treatment reduces IL-17 expression in the patient. Accordingly, the treatment provides quiescence at between about 1 week and 15 weeks.

[0020] In certain methods of the disclosure, prior to administration, the patient has received a corticosteroid treatment. In such methods, preferably the patient tapers use of the corticosteroid during the administration. In methods of the disclosure, the patient may discontinue use of the corticosteroid by a fifteenth week of administration.

[0021] In certain methods of the disclosure, the patient receives one or more doses of prednisone or prednisolone. In exemplary methods, the patient receives one dose of prednisone or prednisolone daily for a first fourteen days of the administration. In some methods of the disclosure, prior and / or during the administration, the patient receives an immunosuppressant.

[0022] The present disclosure further provides a medicament for the treatment of uveitis in a human subject comprising izokibep or a salt thereof. Preferably, the medicament comprises between about 150 mg and about 170 mg of izokibep or a salt thereof. More preferably, the medicament comprises between about 155 mg and about 165 mg of izokibep or a salt thereof. Even more preferably, the medicament comprises about 157 mg to about 162 mg of izokibep or a salt 4  Patent Application thereof. In exemplary aspects of the disclosure, the medicament comprises 160 mg of izokibep or a salt thereof.

[0023] In certain aspects, the medicament further comprises one or more of sodium phosphate, NaCl, and EDTA. In preferred aspects, the medicament comprises 10 mM sodium phosphate, 150 mM NaCl, and 0.5 mM EDTA.

[0024] In preferred embodiments, the medicament is formulated for subcutaneous administration. The medicament may be formulated for subcutaneous administration in an arm, upper thigh, and / or abdomen of the subject. Preferably, the medicament is administered to the subject one weekly. Alternatively, the medicament is administered to subject twice weekly.

[0025] In certain aspects, the medicament is administered to a subject for between 1 and 52 weeks.

[0026] Exemplary medicaments of the disclosure may be used to treat a uveitis selected from one or more of the group consisting of an intermediate-uveitis, a posterior-uveitis, and a pan-uveitis. Preferably, the uveitis is a non-infectious uveitis.

[0027] In aspects of the disclosure, administration of the medicament to the subject reduces IL-17 expression in the subject. Consequently, administration of the medicament to the subject provides quiescence at between about 1 week and 15 weeks.

[0028] In some aspects, prior to administration of the medicament, the subject received corticosteroid treatment. The subject may taper use of the corticosteroid during the administration of the medicament. Preferably, the subject discontinues use of the corticosteroid by a fifteenth week of administration of the medicament.

[0029] In certain aspects, the subject further receives one or more doses of prednisone or prednisolone during administration of the medicament. The subject may receive one dose of prednisone or prednisolone daily for a first fourteen days of the administration. In some aspects, prior and / or during the administration of the medicament to the subject, the subject further receives an immunosuppressant.

[0030] In certain embodiments, a composition administered to a patient comprises 160 mg of izokibep or a salt thereof. In certain aspects, patients receiving such a composition have uveitis despite prior treatment with a corticosteroid or equivalent, e.g., prednisone / prednisolone. In certain methods, the izokibep composition is provided in conjunction with a corticosteroid or equivalent regimen. In certain aspects, the patient tapers and / or eliminates use of the corticosteroid while receiving the izokibep composition. 5  Patent Application

[0031] In certain embodiments, the disclosure provides a composition comprising 160 mg of izokibep or a salt thereof for administration once weekly (QW) for the treatment of Uveitis. In certain embodiments, the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once weekly (QW) or twice weekly for the treatment of Uveitis. In certain embodiments, the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once every two weeks (Q2W) for the treatment of Uveitis.

[0032] In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as an injection for treatment of uveitis. In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as an intravenous infusion for treatment of uveitis. In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as a subcutaneous for treatment of uveitis.

[0033] In certain aspects, the methods of the disclosure provide that the composition comprising izokibep is administered for a duration for which the therapeutic effect is observed. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of uveitis for a duration of at least 15 weeks. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of uveitis for a duration of at least 52 weeks. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of uveitis for a duration of at least 14 weeks.

[0034] The disclosure provides novel and efficacious compositions comprising at least 160 mg izokibep or a salt thereof are safe and efficacious for the treatment of uveitis. The methods of the disclosure provide a clear benefit and utility in treating uveitis, including via complete quiescence, especially compared with existing therapies used to treat inflammatory conditions of the eye. Moreover, unexpectedly, the izokibep compositions and methods disclosed herein are able to treat uveitis in patients undergoing, or have undergone, corticosteroid and / or immune suppression treatment to treat uveitis. The disclosure also recognizes that it is unexpected that a composition comprising 160 mg izokibep or a salt thereof would not have significant adverse events and will be generally well tolerated. Surprisingly, administration of compositions comprising 160 mg 6  Patent Application izokibep or a salt thereof, administered either QW or Q2W, are well-tolerated, and have better efficacy in the treatment of uveitis.

[0035] The disclosure also recognizes that, in particular, subcutaneous administrations of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, are well-tolerated. This provides a benefit for patients experiencing uveitis, as subcutaneous may be self-administered by patients or less-technical medical staff, obviating the need to visit a doctor to receive the QW or Q2W dose, depending on the regiment.

[0036] In certain embodiments, the methods of the disclosure alleviate the symptoms of uveitis via administration of the izokibep compositions and dosing regimes disclosed herein, which may improve the time to treatment failure compared to placebo in subjects with active non-infectious intermediate-, posterior- or pan-uveitis, despite previous systemic corticosteroid therapy. Further, due to its small molecular size as compared to monoclonal antibodies and its binding to albumin, izokibep may have the potential to better reach inflamed tissues and may provide higher exposure relative to monoclonal antibodies developed to treat uveitis. Consequently, treatment with izokibep, as described herein, may lead to quiescence of ongoing uveitis, an improvement in the best corrected visual acuity (BVCA) of a patient, improvements in vision as revealed through the National Eye Institute (NEI) visual function questionnaire-25 (VFQ-25), and improvements in central retinal thickness. BRIEF DESCRIPTION OF DRAWINGS

[0037] Fig. 1 shows observed exposure of 10 mg / kg secukinumab IV Q2W (administered on 4 occasions) with the 160 mg QW SC dose of izokibep.

[0038] Fig.2 provides a liver safety protocol of the disclosure. DETAILED DESCRIPTION

[0039] The current disclosure provides methods and compositions for treating inflammation of the eye, and in particular, uveitis. In certain aspects, the disclosure provides methods for treating uveitis by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep, and preferably about or exactly 160 mg izokibep or a salt thereof per dose. Unexpectedly, the present Inventors discovered that such a relatively high dose of izokibep, when provided once weekly, once every two weeks, or twice a week is well tolerated and provides efficacious treatment of uveitis. 7  Patent Application

[0040] In certain aspects, the disclosure provides a method of treatment of uveitis by administration to a patient a composition comprising izokibep or a salt thereof. Preferably, the composition comprises between about 150 mg and about 170 mg of izokibep or a salt thereof. More preferably, the composition comprises between about 155 mg and about 165 mg of izokibep or a salt thereof. In more preferred aspects, the composition comprises about 157 mg of izokibep or a salt thereof or does comprise 162 mg of izokibep or a salt thereof. In even more preferred aspects, the composition comprises 160 mg of izokibep or a salt thereof.

[0041] Uveitis results from a heterogeneous collection of disorders with diverse etiologies and pathogenic mechanisms (Prete et al, 2016). Uveitis is classified, according to the primary anatomical location of the inflammation, into anterior and non-anterior uveitis. Non-anterior uveitis can be further classified into intermediate-, posterior- or pan-uveitis (affecting more than 1 eye segment). Symptoms include severe intraocular inflammation, vision impairment with blurred or cloudy vision, floaters-spots in the eye and eye pain. Non-infectious uveitis can be associated with systemic immune mediated diseases such as spondylarthritis (i.e., ankylosing spondylitis and reactive arthritis), psoriatic arthritis and inflammatory bowel disease (IBD) (Rosenbaum, 2015), multiple sclerosis and Behcet’s disease (Chi et al, 2008). Non-infectious uveitis can also occur without extraocular involvement (Rosenbaum et al, 2019).

[0042] Uveitis is a major risk factor in developing permanent visual impairment and blindness affecting 1 or both eyes. Other eyesight-threatening complications caused by uveitis include cataract and glaucoma (Durrani et al, 2004). Anatomical sites of uveitis inflammation may cause visual impairment and blindness, but the risk of visual impairment and blindness is highest in patients with posterior- or pan-uveitis (Rothova et al, 1996). Furthermore, patients with non- infectious, intermediate-, posterior- or pan-uveitis have a worse prognosis compared to those with anterior uveitis (Wakefield and Chang, 2005; Barisani-Asenbauer et al, 2012).

[0043] Topical and systemic corticosteroids remain the cornerstone of treatment in patients with uveitis. Patients may require persistent high-dose systemic corticosteroids, high-dose systemic corticosteroids bursts or rapid systemic corticosteroids dose escalation. Unfortunately, conventional non biologic systemic immunosuppressant therapies are not well tolerated, and their efficacies have not been well-evidenced. Accordingly, at least one-third of patients still fail to achieve therapeutic remission with such agents. 8  Patent Application

[0044] The immunopathology of uveitis is thought to be driven by autoreactive T cells targeting ocular tissues and acting in concert with cells of the innate immune system (Lee and Dick, 2012). Interleukin-17A, which is produced by T-helper (Th) 17 and other immune cells, is one of the major proinflammatory cytokines that contributes to the pathogenesis of several inflammatory disorders (Miossec and Kolls, 2012). Circulating Th17 cell levels are elevated during active uveitis and reduced following effective treatment (Amadi-Obi et al, 2007). Under normal conditions, circulating IL-17A levels are extremely low or undetectable, but in patients with active uveitis associated with systemic immune disorders such as Behçet’s disease, increased serum and ocular IL-17A concentrations are seen (Chi et al, 2008). Moreover, IL-17A is produced in experimental models of T-cell-mediated uveitis and blocking IL-17A reduces ocular inflammation in these models (Amadi-Obi et al, 2007; Zhang et al, 2009Amadi-Obi et al, 2007; Zhang et al, 2009).; Zhang et al, 2009). These clinical and experimental observations suggest that IL-17A may be an attractive therapeutic target in patients with non-infectious uveitis.

[0045] The efficacy of secukinumab, a human monoclonal antibody against IL‐17, was evaluated in a Phase 3 SHIELD study for the treatment of chronic non-infectious uveitis (Dick et al, 2013). However, secukinumab administered at SC doses of 150 or 300 mg every 2 or 4 weeks did not meet primary efficacy endpoints of reduction of uveitis occurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication. The secondary efficacy data from the study suggest a beneficial effect of secukinumab in reducing the use of concomitant immunosuppressive medications (Dick et al, 2013). These findings raised the possibility that insufficient exposure to secukinumab may have led to the study not meeting its primary endpoint.

[0046] The importance of adequate exposures was demonstrated in a small dose-ranging Phase 2 study with secukinumab intravenous (IV) or SC in patients with active non-infectious intermediate, posterior- or pan-uveitis who required corticosteroid-sparing immunosuppressive therapy. In this study, 37 patients were randomized to secukinumab 300 mg SC every 2 weeks (Q2W) for 4 doses, secukinumab 10 mg / kg IV Q2W for 4 doses or secukinumab 30 mg / kg IV every 4 weeks for 2 doses. Secukinumab IV doses (30 mg / kg IV and 10 mg / kg IV) produced higher responder rates at 72.7% and 61.5% versus the 33.3% response rate seen with secukinumab 300 mg SC Q2W dosing. Other measures, including time to response onset, change in visual acuity and change in vitreous haze score, showed numeric trends favoring IV dosing (Letko et al, 2015). 9  Patent Application

[0047] As disclosed herein, administering izokibep 160 mg once weekly (QW) SC provides a very similar exposure level as that of the secukinumab 10 mg / kg IV dose. Safety and tolerability of izokibep compositions and dosing regimes of the disclosure

[0048] Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal in terms of blocking the biological activity of IL 17A. Izokibep has the potential to be an efficacious treatment for a variety of IL 17A-related diseases. The smaller size of izokibep compared to monoclonal antibodies offers advantages in terms of required dosing volumes and potential for alternative pharmacological formulations.

[0049] Izokibep is based on a small protein binding to and blocking the biological effect of the cytokine IL-17A. The izokibep protein molecule contains an albumin-binding domain which confers specific binding to a single site on endogenous serum albumin and thereby a prolonged half-life (t½) in the circulation and in tissues after parenteral administration.

[0050] In certain embodiments of the disclosure, the izokibep protein comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% similarity with the amino acid sequence of: AEAKYAKEADDAAVEIASLPNLTWDQWYAFIQKLRDDPSQSSELLSEAKKLNDSQAPK ASGSLAEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALPGTGGGGSA EAKYAKEADDAAVEIASLPNLTWDQWYAFIQKLRDDPSQSSELLSEAKKLNDSQAPK (SEQ ID NO.1), or a fragment thereof.

[0051] Though not in the context of uveitis, IL-17 inhibitors have demonstrated efficacy and a favorable safety profile in different inflammatory diseases, including psoriasis, psoriatic arthritis and axial spondylarthritis. These include secukinumab (Cosentyx®) and ixekizumab (Taltz®) in the US, Canada, and the European Union.

[0052] Assessments of target-binding specificity have demonstrated high specificity and affinity of izokibep to IL-17A and to albumin. Prior in vitro and in vivo pharmacodynamic evaluations reveal that izokibep has a 3- to 5-fold higher potency than the anti-IL-17A monoclonal antibody secukinumab on a molar basis, and that it also appears to be equipotent to ixekizumab on a molar basis.

[0053] Pharmacokinetic data for IV- and SC-administered izokibep have been obtained in rat and monkey. Pharmacokinetic assessments in rat and monkey indicate that the time course of izokibep 10  Patent Application concentrations after a bolus IV injection and SC injection is well described by a 2- or 3 compartment model. Pharmacokinetic assessments indicate that the elimination rate of izokibep is similar to that of albumin in the respective species.

[0054] Repeated (10 days to 3 months) SC or IV administration of izokibep to cynomolgus monkeys was well tolerated with no observed adverse effect levels (NOAELs) of 40 mg / kg / dose administered every third day (IV, 28-day study) and 20 mg / dose administered every third day (SC, 28-day) and 20 mg / kg / week (SC, 3-month study), being the highest dose levels tested in the respective studies.

[0055] In the 26-week repeated dose toxicity study in cynomolgus monkeys, weekly SC injection of 10, 20 or 40 mg / kg / week izokibep to monkeys for 26 weeks was generally well-tolerated. However, due to the presence of local abscessation and systemic sequelae in 1 female administered 40 mg / kg / week, which was considered adverse, the NOAEL for SC administration was considered to be 20 mg / kg / week.

[0056] In the enhanced pre- and post-natal developmental toxicity study in cynomolgus monkeys, SC izokibep administration of up to 40 mg / kg / week to pregnant monkeys for approximately 21 weeks was well tolerated. The NOAEL was 40 mg / kg / week.

[0057] Surprisingly, Izokibep entered healthy cynomolgus monkeys’ eyes in a dose-dependent manner that parallels systemic exposures of izokibep when delivered via inhalation.

[0058] The results from the immunotoxicity screening assays do not suggest that izokibep has an intrinsic capacity for immune system activation. Further, metabolism and genotoxicity are expected to be satisfactory for human treatment as izokibep is a protein molecule and contains only naturally occurring amino acids.

[0059] The present disclosure provides a preferred 160 mg izokibep dose, administered once a week, twice a week, or once every two weeks based on the safety profile deduced by the present inventors. Briefly, a first-in-human multipart clinical study (Study ABY-035-001, EudraCT number 2015 004531 13, NCT02690142) was conducted with the parenteral formulation of izokibep. Izokibep was administered IV and SC to healthy subjects and plaque psoriasis patients, in doses ranging from 2 mg to 40 mg in a single or multiple dose regimen.

[0060] Moreover, a Phase 2 dose-finding study in subjects with moderate to severe plaque psoriasis was recently completed with up to 3 years of exposure (Study ABY-035-002, EudraCT number 2017-001615-36, NCT03591887). One hundred eight subjects were randomized into 5 11  Patent Application dose groups: 2 mg, 20 mg, 80 mg, and 160 mg izokibep or placebo. The treatment period consisted of an induction period (12 weeks), an optimization period (12 weeks), and an individualization period including 4 weeks follow-up (28 weeks), and 2 further years of extension. The induction period was double blind and placebo controlled.

[0061] The primary endpoint of the study was the proportion of patients that achieved a Psoriasis Area and Severity Index response of 90% (PASI90) after 12 weeks of treatment. PASI90 at 12 weeks was 71.4% and 59.1% in subjects treated with 80 mg and 160 mg Q2W of izokibep, respectively. In the lower dose groups, 2 mg and 20 mg izokibep, only 5.0% and 19.0% of subjects, respectively, reached the primary endpoint. None of the subjects receiving placebo reached PASI90 response at week 12. At week 24, PASI90 responses were comparable between the initial 80 mg and 160 mg treatment groups. The safety and efficacy data obtained from the 52-week core period of the study with izokibep suggest a favorable benefit-risk profile in plaque psoriasis (Investigator’s Brochure).

[0062] The results from a dose-ranging Phase 2 study comparing secukinumab dosed IV versus SC suggest that higher exposures may be necessary to achieve adequate therapeutic concentrations in this patient population (Letko et al, 2015). As disclosed herein, there are no dose-limiting adverse events (AEs) for izokibep moving from the 2 mg, 20 mg, 80 mg and 160 mg SC dosing, which support the testing of the 160 mg QW and 160 mg Q2W dosing.

[0063] Additionally, in the first-in-human study in healthy subjects and subjects with psoriasis (Study ABY 035-001), doses of up to 40 mg IV and SC of izokibep (n = 62) were well tolerated, with no deaths or treatment-related serious AEs (SAEs).

[0064] Intravenous administration (single doses up to 40 mg in 46 subjects in total) resulted in the following treatment-emergent AEs (TEAEs) by preferred term: oropharyngeal pain (10.9%), nasopharyngitis (6.5%), diarrhea (4.3%) and headache (4.3%). A further 9 TEAEs were reported, and affected 1 subject each (2.2% each). Subcutaneous administration (single and multiples doses up to 40 mg in 21 subjects in total) resulted in the following TEAEs by preferred term: injection site reaction (61.9%) and injection site pain (28.6%). A further 11 TEAEs were reported, and affected 1 subject each (5.2% each). The majority of the injection site reactions were of mild intensity and required no treatment or limited therapy.

[0065] In the Phase 2, 52-week core period in subjects with plaque psoriasis (ABY-035-002), multiple doses of up to 160 mg SC of izokibep (n = 108) were well tolerated with no deaths or 12  Patent Application treatment related SAE. A total of 65 subjects (60.2%) experienced at least 1 izokibep-related TEAE. The most common izokibep-related TEAEs (n / %) were injection site reaction (42 / 38.9%), nasopharyngitis (13 / 12%), diarrhea (7 / 6.5%) and fatigue (6 / 5.6%) consistent with the first-in- human study.

[0066] Following SC administration of single izokibep doses in the first-in-human study (Study ABY-035-001), median time to maximum observed concentration (tmax) was 60 hours post- dose. After reaching maximum observed plasma concentration (Cmax), plasma levels of izokibep declined in an apparent mono- or bi-phasic manner with the geometric mean t½being 278 hours which was similar to that after IV administration (288 hours). Individual t½ estimates ranged from 199 to 464 hours and 220 to 340 hours for SC and IV treatments, respectively. The absolute bioavailability after a 40 mg dose of izokibep was estimated to 77%. In general, as assessed by the geometric percent coefficient of variation (CV%) low between-subject variability was noted for area under the concentration-time curve (AUC) extrapolated to infinity (AUC0-∞) and Cmax for both dose routes, with values ranging from 20% to 22% and 14% to 15%, respectively.

[0067] Following 40 mg repeated SC doses, maximum plasma concentrations occurred at a median tmax of 48.0 hours post-dose on days 1 and 29 (individual range: 24.0 to 71.0 hours post- dose). On day 85, median tmaxwas slightly later at 71.6 hours post-dose (individual range: 66.6 to 73.1 hours post-dose). After reaching Cmaxon day 85, plasma concentrations of izokibep declined in an apparent mono- or bi-phasic manner with a geometric mean t½ of 279 hours with individual patients ranging from 229 to 423 hours. Pre-dose trough izokibep plasma concentrations showed that steady state was achieved by day 71, following 5 doses of izokibep administered Q2W. There was evidence of accumulation following repeated dosing by day 85 with geometric mean accumulation ratio, based on AUC over the dose interval (AUC0-τ) of 1.95, and individual patients ranging from 1.35 to 5.09. Between-patient variability, based on geometric CV%, was moderate on the monitored study days for AUC0-τ with values ranging from 29.4% to 36.0%, and low to moderate for Cmax with values ranging from 20.4% to 28.8%.

[0068] Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A.

[0069] IL-17A inhibitors, including secukinumab and ixekizumab as well as izokibep, do not appear to have dose-limiting AEs. Class effects and potential risks seen with other IL-17 inhibitors 13  Patent Application have not been identified with izokibep. Given the small numbers of subjects treated to date, class effects and potential risks of IL-17 inhibitors will be explicitly monitored (i.e., events of special interest) and have been taken into consideration in the development of inclusion and exclusion criteria. These events include candida infections, IBD, suicidal ideation, malignancies, major cardiovascular and cerebrovascular events, TB, opportunistic infections and serious infections.

[0070] No genotoxicity or carcinogenicity is foreseen as izokibep is a protein consisting of natural amino acids. However, since no data are available at this stage of clinical development on possible effects on the reproductive system, precautionary measures are taken. For example, females of childbearing potential as well as reproductive female partners of male patients must use an adequate method of contraception while participating in the clinical study until 8 weeks after the last dose of study drug. Pregnancy testing will be performed at regular intervals prior to, during treatment and after the end of treatment.

[0071] Accordingly, as described, the preferred 160 mg dose of izokibep provides a favorable safety and efficacy profile for the targeted treatment of uveitis. Benefit of disclosed compositions in treating uveitis

[0072] As described, there is an urgent, unmet medical need for the treatment of non-infectious, intermediate-, posterior- or pan-uveitis and this represents the focus of the present disclosure. These types of uveitis are at a higher risk for vision loss compared to anterior uveitis. Disease management often requires chronic corticosteroid use, whether in an oral or injectable form, that presents with predictable long-term side effects, whereas in general, anterior uveitis may be managed with topical corticosteroids.

[0073] Immunosuppressive agents have been used as corticosteroid-sparing or additive therapy in non-infectious, intermediate-, posterior- or pan-uveitis, although there is a lack of robust clinical evidence to support their use. These immunosuppressive agents are not effective in all patients and carry risks of known adverse effects. The TNF-α inhibitor adalimumab is the only approved biologic for the treatment of uveitis. Nevertheless, a large proportion of patients are also refractory to these treatments and can experience reduction of vision.

[0074] The benefit of the compositions and methods of the disclosure that treat uveitis with izokibep is in that they may improve the time to treatment failure compared to placebo in subjects with active non-infectious intermediate-, posterior- or pan-uveitis despite systemic corticosteroid 14  Patent Application therapy. Thus, izokibep is shown to be effective in controlling uveitis while also allowing for the discontinuation of systemic corticosteroids.

[0075] Given the known possibility of progression to severe visual impairment if uveitis goes untreated, subjects may be initiated on high-dose systemic corticosteroids which is tapered over the first 15 weeks of izokibep administration. The use of concomitant background steroids is shown to mitigate the risk of progression of disease in a placebo group, justifying the placebo cohort to reveal the actual efficacy of izokibep. In certain aspects, expected time to treatment failure in the placebo and corticosteroid arm is informed by results seen in a similarly-designed Phase 3 interventional study of adalimumab in active non-infectious uveitis, where subjects in both arms were given bursts of high-dose systemic corticosteroids, tapered over 15 weeks. In the adalimumab study, time to treatment failure in the placebo group was 13 weeks (Jaffe et al, 2016).

[0076] Based on the safety, efficacy and PK data obtained in clinical izokibep inhealthy subjects and in patients with psoriasis, a favorable benefit-risk profile in uveitis emerges. Based on published data showing efficacy and safety for other IL-17 inhibitors in other inflammatory disease and in proof-of-concept studies in patients with non-infectious, intermediate-, posterior- or pan-uveitis, the benefit-risk relationship in patients with uveitis also appears favorable and justifies treatment of uveitis using izokibep as disclosed herein. Due to its small molecular size as compared to monoclonal antibodies and its binding to albumin, izokibep may have the potential to better reach inflamed tissues and may provide higher exposure relative to monoclonal antibodies. Methods and compositions of the disclosure

[0077] The current disclosure provides methods and compositions for treating inflammation of the eye, and in particular, uveitis. In certain aspects, the disclosure provides methods for treating uveitis by administration to a patient a composition comprising izokibep or a salt thereof.

[0078] In certain aspects, the disclosure provides a method of treatment of uveitis by administration to a patient a composition comprising izokibep or a salt thereof. Preferably, the composition comprises between about 100 and about 200 mg of izokibep or a salt thereof. More preferably, the composition comprises between about 150 and about 170 mg of izokibep or a salt thereof. In more preferred aspects, the composition comprises about 160 mg of izokibep or a salt thereof or does comprise 160 mg of izokibep or a salt thereof. 15  Patent Application

[0079] In certain methods, the composition further comprises one or more of sodium phosphate, NaCl, and EDTA. Preferably, composition comprises about 10 mM sodium phosphate, about 150 mM NaCl, and / or about 0.5 mM EDTA.

[0080] In certain methods, the composition is administered to the patient subcutaneously. In such methods, in preferred aspects, the composition is administered in an arm, upper thigh, and / or abdomen of the patient. Preferably, the composition is administered to the patient once weekly. In alternative or supplementary methods, the composition is administered to patient twice weekly. In certain aspects, composition is administered once a week to a patient for between 1 and 52 weeks.

[0081] In preferred methods, the uveitis is one or more of the group consisting of an intermediate- uveitis, a posterior-uveitis, and a pan-uveitis. In some methods, the uveitis is an intermediate- uveitis. In some methods the uveitis is a posterior-uveitis. In some methods the uveitis is a pan- uveitis. In preferred methods, the uveitis is a non-infectious uveitis.

[0082] In methods of the disclosure, the treatment reduces IL-17 expression in the patient. Accordingly, the treatment provides quiescence at between about 1 week and 15 weeks.

[0083] In certain methods of the disclosure, prior to administration, the patient has received a corticosteroid treatment. In such methods, preferably the patient tapers use of the corticosteroid during the administration. In methods of the disclosure, the patient may discontinue use of the corticosteroid by a fifteenth week of administration.

[0084] In certain methods of the disclosure, the patient receives one or more doses of prednisone or prednisolone. In exemplary methods, the patient receives one dose of prednisone or prednisolone daily for a first fourteen days of the administration. In some methods of the disclosure, prior and / or during the administration, the patient receives an immunosuppressant.

[0085] The present disclosure further provides a medicament for the treatment of uveitis in a human subject comprising izokibep or a salt thereof. Preferably, the medicament comprises between about 100 mg and about 200 mg of izokibep or a salt thereof. More preferably, the medicament comprises between about 150 mg and about 170 mg of izokibep or a salt thereof. Even more preferably, the medicament comprises about 160 mg of izokibep or a salt thereof. In exemplary aspects of the disclosure, the medicament comprises 160 mg of izokibep or a salt thereof. 16  Patent Application

[0086] In certain aspects, the medicament further comprises one or more of sodium phosphate, NaCl, and EDTA. In preferred aspects, the medicament comprises 10 mM sodium phosphate, 150 mM NaCl, and 0.5 mM EDTA.

[0087] In preferred embodiments, the medicament is formulated for subcutaneous administration. The medicament may be formulated for subcutaneous administration in an arm, upper thigh, and / or abdomen of the subject. Preferably, the medicament is administered to the subject one weekly. Alternatively, the medicament is administered to subject twice weekly.

[0088] In certain aspects, the medicament is administered to a subject for between 1 and 52 weeks.

[0089] Exemplary medicaments of the disclosure may be used to treat a uveitis selected from one or more of the group consisting of an intermediate-uveitis, a posterior-uveitis, and a pan-uveitis. Preferably, the uveitis is a non-infectious uveitis.

[0090] In aspects of the disclosure, administration of the medicament to the subject reduces IL-17 expression in the subject. Consequently, administration of the medicament to the subject provides quiescence at between about 1 week and 15 weeks.

[0091] In some aspects, prior to administration of the medicament, the subject received corticosteroid treatment. The subject may taper use of the corticosteroid during the administration of the medicament. Preferably, the subject discontinues use of the corticosteroid by a fifteenth week of administration of the medicament.

[0092] In certain aspects, the subject further receives one or more doses of prednisone or prednisolone during administration of the medicament. The subject may receive one dose of prednisone or prednisolone daily for a first fourteen days of the administration. In some aspects, prior and / or during the administration of the medicament to the subject, the subject further receives an immunosuppressant.

[0093] In certain embodiments, a composition administered to a patient comprises 160 mg of izokibep or a salt thereof. In certain aspects, patients receiving such a composition have uveitis despite prior treatment with a corticosteroid or equivalent, e.g., prednisone / prednisolone. In certain methods, the izokibep composition is provided in conjunction with a corticosteroid or equivalent regimen. In certain aspects, the patient tapers and / or eliminates use of the corticosteroid while receiving the izokibep composition.

[0094] In certain embodiments, the disclosure provides a composition comprising 160 mg of izokibep or a salt thereof for administration once weekly (QW) for the treatment of Uveitis. In 17  Patent Application certain embodiments, the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once weekly (QW) or twice weekly for the treatment of Uveitis. In certain embodiments, the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once every two weeks (Q2W) for the treatment of Uveitis.

[0095] In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as an injection for treatment of uveitis. In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as an intravenous infusion for treatment of uveitis. In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as a subcutaneous for treatment of uveitis.

[0096] In certain aspects, the methods of the disclosure provide that the composition comprising izokibep is administered for a duration for which the therapeutic effect is observed. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of uveitis for a duration of at least 15 weeks. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of uveitis for a duration of at least 52 weeks. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of uveitis for a duration of at least 14 weeks.

[0097] The disclosure provides novel and efficacious compositions comprising at least 160 mg izokibep or a salt thereof are safe and efficacious for the treatment of uveitis. The methods of the disclosure provide a clear benefit and utility in treating uveitis, including via complete quiescence, especially compared with existing therapies used to treat inflammatory conditions of the eye. Moreover, unexpectedly, the izokibep compositions and methods disclosed herein are able to treat uveitis in patients undergoing, or have undergone, corticosteroid and / or immune suppression treatment to treat uveitis. The disclosure also recognizes that it is unexpected that a composition comprising 160 mg izokibep or a salt thereof would not have significant adverse events and will be generally well tolerated. Surprisingly, administration of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, are well-tolerated, and have better efficacy in the treatment of uveitis. 18  Patent Application

[0098] The disclosure also recognizes that, in particular, subcutaneous administrations of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, are well-tolerated. This provides a benefit for patients experiencing uveitis, as subcutaneous may be self-administered by patients or less-technical medical staff, obviating the need to visit a doctor to receive the QW or Q2W dose, depending on the regiment.

[0099] In certain embodiments, the methods of the disclosure alleviate the symptoms of uveitis via administration of the izokibep compositions and dosing regimes disclosed herein, which may improve the time to treatment failure compared to placebo in subjects with active non-infectious intermediate-, posterior- or pan-uveitis, despite previous systemic corticosteroid therapy. Further, due to its small molecular size as compared to monoclonal antibodies and its binding to albumin, izokibep may have the potential to better reach inflamed tissues and may provide higher exposure relative to monoclonal antibodies developed to treat uveitis. Consequently, treatment with izokibep, as described herein, may lead to quiescence of ongoing uveitis, an improvement in the best corrected visual acuity (BVCA) of a patient, improvements in vision as revealed through the National Eye Institute (NEI) visual function questionnaire-25 (VFQ-25), and improvements in central retinal thickness.

[0100] As used herein, a "pure isomeric" compound or "isomerically pure" compound is substantially free of other isomers of the compound. The term "pure isomeric" compound or "isomerically pure" denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified structure. In certain embodiments, the weights are based upon total weight of all isomers of the compound.

[0101] As used herein, a "pure stereoisomeric" compound or "stereoisomerically pure" compound is substantially free of other stereoisomers of the compound. Thus, the composition is substantially free of isomers that differ at any chiral center. If the compound has multiple chiral centers, a substantial majority of the composition contains compounds having identical stereochemistry at all of the chiral centers. The term "pure stereoisomeric" compound or "stereoisomerically pure" denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the 19  Patent Application compound with the specified stereochemistry. In certain embodiments, the weights are based upon total weight of all stereoisomers of the compound.

[0102] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0103] Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; N may be any isotopic form, including14N and15N; O may be in any isotopic form, including16O and18O; and the like.

[0104] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.

[0105] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0106] "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- 20  Patent Application disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0107] "Solvate" refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate"), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution- phase and isolable solvates.

[0108] As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be2H / D, any carbon may be13C, or any nitrogen may be15N, and that the presence and placement of such atoms may be determined within the skill 21  Patent Application of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon- 14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as11C,18F,15O, and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.

[0109] "Stereoisomers": It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers", and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, and an atom, such as a carbon atom, is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

[0110] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0111] A "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, 22  Patent Application e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0112] Disease, disorder, and condition are used interchangeably herein.

[0113] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").

[0114] In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a cancer. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound, composition, or formulation of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0115] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent, i.e., to produce a reduction in the amount and / or severity of the symptoms associated with that disorder. Therapeutically effective amounts vary with the type and extent of brain damage, and can also vary depending on the overall condition of the subject.

[0116] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence. A 23  Patent Application prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0117] The izokibep compositions of the disclosure may be formulated for administration by a particular mechanism. The compositions may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration. The compositions may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug- eluting stent or balloon equivalents). Preferably, the compositions are formulated for subcutaneous administration.

[0118] The compositions may be formulated a single weekly, bi-weekly, or twice-weekly dosage. The compositions may be formulated to provide the weekly dose of izokibep split up in multiple daily doses, e.g., two, three, four, five, six or more daily doses. The compositions may be provided to the subject according to any dosing schedule, but is preferably once weekly as described herein.

[0119] The methods of treating a subject of the present disclosure include providing an izokibep composition, as described above, to the subject. Providing may include administering the composition to the subject. The composition may be administered by any suitable route or means, such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).

[0120] The composition may be provided as a single unit dosage. The composition may be provided as a divided dosage.

[0121] The composition may be provided under any suitable dosing regimen. For example, the composition may be provided as a single dose or in multiple doses. Doses may be provided once a week or twice a week over a duration of 1 week, 2 weeks, 3 weeks, 4 weeks, 4 weeks to 8 weeks, 8 weeks to 12 weeks, 12 weeks to 16 weeks, 16 weeks to 20 weeks, 20 weeks to 24 weeks, 24 weeks to 28 weeks, 28 weeks to 32 weeks, 32 weeks to 36 weeks, 36 weeks to 40 weeks, 40 weeks to 44 weeks, 44 weeks to 48 weeks, 48 weeks to 52 weeks, or more than 52 weeks. Multiple doses may be provided within a period of time. For example, multiple doses may be provided over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. The 24  Patent Application compositions may be provided repeatedly for a specified duration. For example and without limitation, the compositions may be provided for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months or more.

[0122] A pharmaceutical composition containing the izokibep, preferably at 160 mg / dose, may be in a form suitable for oral use, such as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No. 6,214,841 and U.S. Pub. No. 2003 / 0232877, the contents of which are incorporated herein by reference.

[0123] Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0124] An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating. 25  Patent Application

[0125] Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0126] Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0127] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present.

[0128] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters 26  Patent Application with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0129] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and / or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0130] ACC means herein the anterior chamber cell; ADAs mean herein anti-drug antibodies. BCVA means herein best corrected visual acuity. CST means herein central subfield thickness. EQ-5D means herein European Quality of Life-5 Dimensions. IL means herein interleukin. NEI means herein National Eye Institute. PRO means herein patient-reported outcome. SAE means herein serious adverse event. SD-OCT means herein Spectral-Domain Optical Coherence Tomography. SF-12 means herein 12-Item Short Form Survey. SUN means herein Standardization of Uveitis Nomenclature. TEAE means herein treatment-emergent adverse event. TNF means herein tumor necrosis factor. VFQ-25 means herein Visual Function Questionnaire-25. Examples

[0131] Example 1 – Administration of 160 mg izokibep in exemplary doses and schedules

[0132] Patients are administered 160 mg izokibep compositions in according with the following protocol for effective and safe treatment of uveitis.

[0133] Overall Benefit Risk Conclusion

[0134] The following considerations are important for the benefit-risk assessment. 27  Patent Application

[0135] First, only subjects with active non-infectious, intermediate-, posterior- or pan-uveitis in at least 1 eye despite at least 2 weeks of prednisone / prednisolone (7.5 mg / day to 40 mg / day) or corticosteroid equivalent are enrolled in the protocol.

[0136] The inclusion and exclusion criteria ensure that subjects who might be predisposed to a higher risk of drug-related TEAEs are either excluded or identified and treated with caution. Class effects seen with other IL-17 inhibitors have been taken into account when designing the eligibility criteria. Subjects with active infections and with a history of autoimmune, chronic inflammatory or connective tissue disease are excluded from participating in the study.

[0137] Subjects are monitored at the study site for at least 1 hour after the first 2 dose administrations of izokibep.

[0138] Participation in the study is voluntary. Each subject may refuse to participate or withdraw from the study, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.

[0139] Taking into account the measures taken to minimize risk to subjects participating in this study, the lack of clear dose-limiting AEs associated with izokibep, and the pre-existing data on the effects of IL-17 inhibitors in non-infectious, intermediate-, posterior- or pan-uveitis, the potential risks identified in association with izokibep are justified by the anticipated benefits that are afforded to subjects with uveitis.

[0140] A benefit-risk assessment related to severe acute respiratory syndrome coronavirus (SARS CoV 2) has been considered for this study and concluded that the coronavirus disease of 2019 (COVID-19) pandemic does not alter the overall benefit-risk for conducting this study. Risk mitigation measures will be implemented based on the prevailing situation during study conduct, at the investigator’s discretion and in accordance with local and institutional guidelines as applicable. The benefit-risk of the study in relation to the COVID-19 pandemic will continue to be assessed during the study and additional or revised measures may be implemented based on any updates to the benefit-risk assessment.

[0141] Objectives, Endpoints, and Estimands

[0142] Table 1 provides a summary of the primary and secondary objectives of the protocol for treating patients with uveitis with izokibep at the 160 mg dose in accordance with the protocol described herein. 28  Patent Application Table 1 Objectives Endpoints P i Ob ti atsubject protocol and study. Table 229  Patent Application Inflammatory, chorioretinal New active, inflammatory New active, inflammatory and / or inflammatory retinal lesions, or worsening of lesions, or worsening of oTable 3y p g

[0146] Overall design

[0147] The study is a Phase 2b pivotal multi-center, dose-finding, randomized, double-blind, placebo controlled study. The study investigates the efficacy, safety, and immunogenicity of izokibep in subjects with active non-infectious, intermediate-, posterior- or pan-uveitis in at least 1 eye despite treatment with at least 2 weeks of prednisone / prednisolone 7.5 mg / day to 40 mg / day inclusive (or corticosteroid equivalent). Subjects may continue treatment with 1 non biologic (non- corticosteroid) immunosuppressive therapy as long as the dose has been stable for ≥ 4 weeks prior to day 1.

[0148] Approximately 100 subjects with active non-infectious, intermediate-, posterior- or pan- uveitis despite at least 2 weeks of prednisone / prednisolone 7.5 mg / day to 40 mg / day (or corticosteroid equivalent) are enrolled. The study consists of up to a 28-day (4 weeks) screening period, a 51-week treatment period and a follow-up period with visits at 8 weeks and 14 weeks after the last dose of study drug to assess safety and immunogenicity.

[0149] Eligible subjects will be randomized into 1 of 2 groups in a 1:1 ratio as follows: Group 1: placebo SC QW Group 2: izokibep SC 160 mg QW

[0150] Of the approximately 100 subjects enrolled, approximately 20 are attributed to those enrolled under previous versions of the protocol (i.e., previously included Q2W arm), with an additional approximately 80 subjects (40 / arm) are enrolled in the QW arms.

[0151] The first dose of study drug (i.e., izokibep or placebo) is administered on day 1 (week 0). 30  Patent Application

[0152] Randomization is stratified by any prior treatment with a systemic TNF-α inhibitor (yes / no) and concomitant systemic inflammatory disease (yes / no).

[0153] All subjects receive a standardized prednisone / prednisolone burst of 60 mg / day from day 1 up to day 14 (week 0 to week 1). By week 2, subjects undergo a protocol-defined mandatory taper schedule which decreases their dosage until all subjects are off oral prednisone / prednisolone by week 15. Subjects who enter the study on topical corticosteroids (eye drops) undergo a standardized taper schedule beginning at week 1 until all subjects have completely discontinued topical corticosteroids no later than week 10.

[0154] Subjects complete study assessments according to the study visits outlined in the Schedule of Activities (SoA) described herein. From week 4 up to but not including week 10, subjects are assessed for non-response, as described herein. At or after week 10, subjects are assessed for treatment failure as described herein. Subjects who meet the criteria for non-response must complete the early termination visit (week 52) within 2 weeks. Subjects who meet treatment failure criteria may receive rescue medications at the investigator’s discretion. If the rescue medication is a biologic, the subject discontinues study drug and completes the early termination visit (week 52) within 2 weeks. If the rescue medication is a non-biologic, the subject can continue on study and continue receiving study drug. Assessments as outlined in the Schedule of Activities are followed, with the exception of efficacy assessments. Only efficacy assessments of BCVA and VFQ-25 will be completed at weeks 24 and 52, and no other efficacy assessments will be completed. Refer to Section 7.1 for discontinuation of study drug.

[0155] Both of the subject’s eyes are evaluated for the purpose of determining eligibility based on inclusion and exclusion criteria, and for the purpose of assessing treatment failure. There is no designated “study eye”.

[0156] Subjects assigned to receive placebo or active, administered QW, are randomized in a 1:1 ratio. Study drug doses are fixed and not adjusted for individual subjects during the study.

[0157] The last dose of study drug is administered at week 51. Analysis of the primary efficacy endpoint occurs after all subjects have had the opportunity to complete the week 24 visit or terminate early from the study.

[0158] Independent Data Monitoring Committee 31  Patent Application

[0159] Data Monitoring Committee (DMC) is established to monitor data on an ongoing basis to ensure the continuing safety of the subjects enrolled in this study.

[0160] The DMC consists of at least 1 medical expert with the relevant therapeutic area expertise and at least 1 statistician and has a minimum of 3 members, 1 of whom serves as the Chair. The DMC responsibilities, authorities and procedure are documented in the DMC charter. The committee meets approximately every 6 months to review interim data. After each review, the DMC makes recommendations regarding the continuation of the study based on safety. The DMC may review unblinded efficacy data when all subjects have had the opportunity to complete the week 10 visit. The DMC may make a recommendation on further development activities for izokibep based on this data review.

[0161] The DMC is not empowered to recommend stopping this study or changing the sample size due to a demonstration of positive efficacy. The study team operationalizing the day-to-day of the study, the subjects and the investigators remain blinded to these interim results until after the study is completed.

[0162] Number of Sites

[0163] Approximately 60 sites across North America and Europe participate in this study. Additional sites and regions may be added. Sites that do not screen subjects within 2 months of site initiation may be closed.

[0164] Number of Subjects

[0165] Participants in this clinical investigation shall are referred to as “subjects”. Approximately 100 subjects are enrolled / randomized. Subjects who are withdrawn or removed from treatment or the study are not be replaced.

[0166] Study Duration for Subjects

[0167] The maximum planned length of participation in the study for an individual subject is up to 69 weeks, which includes the following: 1) Screening period of up to 28 days (4 weeks); 2) 51- week treatment period; and 3) Follow-up visit at 8 weeks and 14 weeks after the last dose of study drug 32  Patent Application

[0168] Scientific Rationale for Study Design

[0169] The design of this clinical study was chosen to evaluate izokibep in subjects with active non-infectious, intermediate-, posterior- or pan-uveitis in at least 1 eye. The primary aim of the study is to provide approximately 1-year placebo-controlled data demonstrating the safety and efficacy of izokibep administered SC at a dose of 160 mg QW for the treatment of active non-infectious, intermediate-, posterior- or pan-uveitis. The primary endpoint of time to treatment failures is evaluated after all subjects have the opportunity to complete the week 24 study visit. Long-term efficacy beyond week 24 is explored up to week 52 and safety is explored up to the end of study.

[0170] Standard statistical procedures are utilized in this study. Efficacy measurements in this study have been selected or designed to assess disease activity in subjects with non-infectious, intermediate-, posterior- or pan-uveitis. All clinical and laboratory procedures in this study are standard and generally accepted.

[0171] Males and females ≥ 18 years and ≤ 75 years with active non-infectious, intermediate-, posterior- or pan-uveitis in at least 1 eye despite treatment with at least 2 weeks of prednisone / prednisolone 7.5 mg / day to 40 mg / day, inclusive (or corticosteroid equivalent), who meet all inclusion criteria and who do not meet any of the exclusion criteria are eligible for this study. The population being studied represents a population normally seen in clinical practice. This ensures the activity of izokibep can be evaluated across a distribution of disease severity in the study.

[0172] Justification for Dose

[0173] The dose of izokibep is 160 mg SC QW administered from day 1 (week 0) through week 51 in subjects randomized to izokibep.

[0174] The selection of the dosing regimen is informed by the following facts. In the clinical setting, izokibep has not demonstrated dose-limiting safety / tolerability up to 160 mg Q2W with multiple doses. A dose of 160 mg QW has 10-fold margin for Cmaxand 9-fold margin for AUC0-τbased on the NOAEL from non-clinical cynomolgus monkey toxicity studies (Table 4). Furthermore, IV administration of secukinumab at doses of 10 mg / kg (approximately 800 mg; Q2W on 4 occasions) or 30 mg / kg (2400 mg; Q4W on 2 occasions) in subjects with uveitis did not identify any dose-related safety / tolerability concerns (Letko et al, 2015). Finally, based on PK 33  Patent Application modeling of the izokibep and secukinumab plaque psoriasis data and the available data with secukinumab in uveitis, the sponsor aimed to approximate the observed exposure of 10 mg / kg secukinumab IV Q2W (administered on 4 occasions) with the 160 mg QW SC dose of izokibep as shown in Figure 1 and Table 5.

[0175] Table 4. Cmaxand AUC0-τat NOAEL in Cynomolgus Monkey Versus Predicted Exposure Levels in Man and Respective Margins Parameter NOAEL Predicted in Subjects Margin 20 / k / k S d S 160once a week Table 5: predicted Exposure at Steady State for 160 mg Izokibep SC QW Parameter Unit Value Unit Valuepmaxpm nminimum observed plasma concentration; QW = once a week; SC = subcutaneous

[0176] The dose of izokibep used in this study supports the maximum likelihood of demonstrating the potential efficacy for izokibep in subjects with non-infectious, intermediate-, posterior- or pan-uveitis within an acceptable safety profile. Measures have also been taken to ensure the well-being of subjects by applying appropriate inclusion and exclusion criteria to recruit a broad population that is most likely to benefit from treatment, while excluding subjects with an unacceptable risk to enter the study. Further, during the study, measures are in place to monitor the safety of subjects on a regular basis. An independent DMC reviews the data on an ongoing basis, as detailed herein. 34  Patent Application

[0177] End of Study Definition

[0178] The primary completion for the study is the date the last subject completes the week 24 assessment for the purpose of the primary endpoint.

[0179] The end of the study is defined as the date of the last scheduled procedure including the last follow-up visit (i.e., week 65) shown in the SoAfor the last subject in the study globally.

[0180] A subject is considered to have completed the study if the subject has completed all periods of the study including the last scheduled procedure shown in the SoA (i.e., week 65 follow-up visit).

[0181] Study Population

[0182] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, are not permitted.

[0183] Inclusion Criteria

[0184] Subjects are eligible to be included in the study only if all of the following criteria apply, as set forth in Table 6. Table 6 e o n35  Patent Application reading center assessment using FA, fundus photography and / or SD-OCT is required to confirm eligibility prior to day 1). .Patent Application Plus either: o Be abstinent from heterosexual intercourse as their preferred and usual lifestyle e in

[0185] Exclusion criteria are set forth in Table 7 and subjects are excluded from the study if any of the following criteria apply. Disease-related Medical Conditions37  Patent Application History of prior refractive laser surgery, laser surgery of the macula (including photodynamic therapy or focal laser photocoagulation), retinal laser photocoagulation, re or fPatent Application History of demyelinating disease (including myelitis) or neurological symptoms suggestive of demyelinating disease r nd us lPatent Application Subject has received Ozurdex®(dexamethasone implant) ≤ 6 months prior to the first dose of study drug t re ePatent Application 44. Any other laboratory abnormality that in the opinion of the investigator will pose a risk to subject safety or interfere with the study evaluation, procedures or completion e, er[ ] festy e ons erat ons

[0187] The investigator encourages the subject to limit alcohol consumption to < 2 per day, < 7 alcoholic drinks per week. An alcoholic drink is defined as a 6 oz (177 mL) glass of wine, a 1 oz (30 mL) glass of hard liquor (eg, whiskey) or an 8 oz (237 mL) glass of beer.

[0188] Screen Failures

[0189] A screen failure occurs when a subject who consents to participate in the clinical study is not subsequently enrolled / randomized to the study. A minimal set of screen failure information is collected to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography (i.e., age, sex), screen failure reason and any SAE.

[0190] Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened up to 2 times (i.e., total of 3 screens including initial screen).

[0191] Criteria for Temporarily Delaying

[0192] Subjects should be dosed within the window as detailed in the SoA. 41  Patent Application

[0193] All missed or delayed doses should be documented. If the investigator determines a subject should not be dosed within the defined window for a safety reason (e.g., an AE, SAE), then a missed dose is recorded.

[0194] COVID-19-related Precautions

[0195] Risk mitigation measures, including COVID-19-related precautions and procedures (including SARS-CoV-2 testing / screening) are implemented based on the prevailing situation during the study conduct, at the investigator’s discretion and in accordance with local and institutional guidelines as applicable.

[0196] Subjects are routinely monitored for any AEs at every visit, including signs or symptoms of infection. Should subjects demonstrate any symptoms or AEs (including known COVID-19 symptoms or tested positive for COVID-19), the symptoms or AEs will be reported to the site as per study procedures and assessed by the investigator. As with any AEs, AE data will be collected on the appropriate case report form (CRF).

[0197] If a subject has received or is planning to receive COVID-19 vaccination, the investigator refers to vaccine considerations in eligibility criteria and concomitant medications requirements in the protocol.

[0198] Study Drug(s) and Concomitant Therapy

[0199] Study drug is defined as any investigational drug(s), marketed product(s), placebo or medical device(s) intended to be administered to a study subject according to the study protocol.

[0200] Study Drug(s) Administered

[0201] The study drugs include izokibep and matching placebo. In addition, prednisone / prednisolone (or corticosteroid equivalent) is used as a non-investigational medicinal product.

[0202] Table 8 provides the Study Drug(s) Administered: Izokibep and Placebo used in the subject protocol. Table 842  Patent Application Form Solution for injection Solution for injection Active ingredient per form Each 2R (2 mL) glass vial Not applicable d

[0203] Non-investigational Medicinal Product

[0204] Commercially available prednisone / prednisolone (or corticosteroid equivalent) is sourced locally. Prednisone / prednisolone is administered orally daily for the first 15 weeks of the study.

[0205] Dosage, Administration and Schedule: Izokibep and Placebo

[0206] Study drug (izokibep 160 mg QW or placebo) is dosed by SC injection. Study drug vials for placebo and izokibep are visually indistinguishable.

[0207] Study drug doses are fixed and not adjusted for individual subjects during the study. Throughout the treatment period, 2 SC injections are to be given for each study drug administration. The anatomical sites for administration of study drug are the upper arm, upper thigh or abdomen.

[0208] At the study site, only authorized investigational site study staff members are to administer study drug. Subjects are monitored for 1 hour after the first 2 doses of study drug.

[0209] Subjects are randomized to 1 of 4 dosing groups as follows: Group 1: placebo QW from day 1 / week 0 to week 51 Group 2: izokibep 160 mg QW from day 1 / week 0 to week 51 43  Patent Application

[0210] Dosage, Administration and Schedule: Prednisone / Prednisolone

[0211] Subjects entering the study are on a stable dose of oral prednisone / prednisolone ≥ 7.5 mg / day to ≤ 40 mg / day or equivalent, for at least 2 weeks prior to day 1 / randomization. After randomization, oral prednisone / prednisolone is taken daily as commercially available oral tablets.

[0212] From day 1 (week 0), all subjects receive a burst of 60 mg / day oral prednisone / prednisolone. By week 2 (day 15), subjects begin a mandatory stepwise tapering such that the subject is off prednisone / prednisolone by the start of week 15.

[0213] The prednisone / prednisolone taper is completed as follows: By week 5, dose must be ≤ 20 mg / day; By week 10, dose must be ≤ 5 mg / day; and By week 15, subjects are completely come off prednisone / prednisolone.

[0214] An example of the tapering scheduled for oral prednisone / prednisolone is provided in Table 9. Corticosteroid equivalent doses are provided in Table 10. Table 9 r44  Patent Application Table 9 rab e 0 g g g g g g g g

[0215] Preparation, Handling, Storage and Accountability

[0216] The investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all study drug received, and any discrepancies are reported and resolved before use of the study drug.

[0217] Only subjects randomized in the study may receive study drug. All study drug must be stored prior to dispensing in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff. 45  Patent Application

[0218] The investigator, institution or the head of the medical institution (where applicable) is responsible for study drug accountability, reconciliation and record maintenance (ie, receipt, reconciliation and final disposition records).

[0219] Further guidance and information for the final disposition of unused study drugs are provided in the Pharmacy Manual.

[0220] Measures to Minimize Bias: Randomization and Blinding

[0221] Subject Enrollment

[0222] Before subjects begin participation in any study-specific activities / procedures, the sponsor or designee requires a copy of the site’s written Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approval of the protocol, ICF, and all other subject information and / or recruitment material, if applicable. All subjects personally sign and date the ICF before commencement of study-specific activities / procedures.

[0223] A subject is considered enrolled when the investigator decides that the subject has met all eligibility criteria and registered the subject as enrolled / randomized within the Interactive Response Technology (IXRS) system. The investigator documents this decision and date in the subject’s medical record. The screening period starts when the subject signs and dates the ICF and ends when the subject is enrolled / randomized, or screen failed. The screening period is up to 28 days. Certain initial screening period procedures may be repeated during the original initial screening period. (Note: Repeating procedures during the original initial screening period is a part of screening and is not considered “rescreening”). These procedures include laboratory assessments due to value(s) out of range due to sampling error or that could be within range with repeat sampling.

[0224] All subjects entering the screening period for the study receive a unique subject identification number assigned by the IXRS system. This number identifies the subject throughout the clinical study and is used on all study documentation related to that subject. The subject identification number remains constant throughout the entire clinical study; it is not changed after initial assignment, including if a subject is rescreened.

[0225] The subject identification number consists of 12 digits that correspond to the site number (9 digits) plus the sequential number (3 digits) as follows:

[0226] Site number (first 9 digits) 46  Patent Application First 3 digits correspond to the last 3 digits of the study protocol number (i.e., 103 in the example below); Middle 3 digits correspond to the 3-digit ISO 3166-1 number code for the country (e.g., US country code = 840; for country codes with only 2 digits, a lead “0” is added); Last 3 digits are sequential numbers given to sites within a country (e.g., for a US site = 103840001).

[0227] Sequential numbering of subjects within a site (last 3 digits): The last 3 digits are sequential numbers assigned by IXRS within a site (e.g., for US Site 103840001, their first subject = 103840001001)

[0228] A subject who is determined to be ineligible is registered as a screen fail in the IXRS system.

[0229] Rescreening

[0230] Investigators may rescreen a subject if the investigator is reasonably certain that reasons for screen failure will be resolved prior to or during a repeat screening attempt. Reasons to rescreen may include but are not limited to the following:

[0231] Laboratory value(s) out of range due to sampling error or that might be within range after medically appropriate supplementation. (Note: Before screen failing and then rescreening the subject, efforts should be made to repeat the laboratory assessment(s) during the original initial screening period).

[0232] The subject has a medical condition that can be stabilized or resolved prior to the repeat screening / rescreening attempt, or

[0233] Additional time is required following the subject’s last dose of an excluded medication.

[0234] Investigators are encouraged to consult with the medical monitor prior to rescreening subjects for other reasons.

[0235] A subject provides informed consent prior to the initiation of any rescreening procedures only if 30 or more days have elapsed since the date of the subject’s initial informed consent. The subject enters into rescreening in the IXRS system, and all screening procedures are repeated except as noted in the inclusion / exclusion criteria. A subject is screened up to 3 times (i.e., no more than 2 rescreens). Near to the end of study enrollment, sites are or may be notified when no additional subjects will be screened or rescreened. 47  Patent Application

[0236] If a subject rescreens, a chest x-ray does not need to be repeated if a previous chest x-ray was performed < 3 months prior to day 1.

[0237] If a subject rescreens, hepatitis, TB, HIV, urinalysis, and electrocardiogram (ECG) tests do not need to be repeated if a previous test was performed < 60 days prior to day 1.

[0238] Randomization

[0239] Subjects are randomized to the study drug (izokibep or placebo; QW) on day 1 by the IXRS system. Randomization is based on a schedule generated by the sponsor or sponsor designee before the start of the study and is centrally executed using the IXRS system. The subject, site personnel and sponsor / Contract Research Organization (CRO) study personnel and designees are blinded to the randomization treatment group assignment (ie, izokibep or placebo). The randomization dates are to be documented in the subject’s medical record.

[0240] Randomization is stratified by any prior treatment with a systemic TNF-α inhibitor (yes / no) and concomitant systemic inflammatory disease (yes / no).

[0241] Izokibep and matching placebo are visually indistinguishable to prevent unblinding during preparation or administration of study material.

[0242] Subjects assigned to receive placebo are randomized in a 1:1 ratio to receive placebo administered QW. This allows for blinding of test material.

[0243] Site Personnel Access to Individual Treatment Assignments

[0244] Subject’s treatment assignment is unblinded only when knowledge of the treatment is essential for the further management of the subject on this study. Unblinding at the study site for any other reason is considered a protocol deviation. In case of an emergency, the investigator has the sole responsibility for determining if unblinding of a subject’s drug assignment is warranted. Subject safety is always the first consideration in making such a determination. If the investigator decides that unblinding is warranted, the investigator is strongly encouraged to contact the sponsor to discuss the situation prior to unblinding a subject’s drug assignment unless this could delay emergency treatment for the subject. If a subject’s drug assignment is unblinded, the sponsor must be notified within 24 hours of this occurrence. The date and reason for the unblinding must be recorded. 48  Patent Application

[0245] If an SAE requires an expedited regulatory report be sent to 1 or more regulatory agencies, sponsor / designee’s safety staff may unblind the drug assignment for the subject. A copy of the report, identifying the subject’s drug assignment, is sent to that regulatory agency in accordance with local regulations.

[0246] Study Drug Compliance

[0247] When subjects are dosed at the site, they receive study drug directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic is recorded in the source documents.

[0248] When study drug(s) is administered at home by the subject / caregiver, compliance with study drug is assessed at each visit. Compliance is assessed by review of the subject dosing diary, during the site visits and documented in the source documents and relevant form. Deviation(s) from the prescribed dosage regimen are recorded.

[0249] A record of the quantity of study drug dispensed and administered to each subject is maintained and reconciled with study drug and compliance records. Intervention dose dates, including study drug delays are also recorded. Partial dose administration is explained herein.

[0250] Dose Modification

[0251] No dose modifications are allowed in the study.

[0252] Continued Access to Study Drug after the End of the Study

[0253] There is no plan to continue access to study drug after the end of study. The choice of further therapy for non-infectious, intermediate-, posterior- or pan-uveitis at the end of the clinical study depends on the subject’s individual needs and is left at the physician's discretion.

[0254] Overdose

[0255] Excessive dosing of study drug or prednisone / prednisolone (beyond that prescribed in the protocol and including overdose) is recorded in the CRF. Any SAE or nonserious AE associated with excessive dosing must be followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if there are associated clinical signs and symptoms or if the act of taking the excess medicine itself is an AE or SAE (e.g., suicide attempt). 49  Patent Application

[0256] Prior and Concomitant Therapy

[0257] Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, vitamins, and / or herbal supplements) that the subject is receiving at the time of enrollment or receives during the study is recorded along with: Reason for use; Dates of administration including start and end dates; and Dosage information including route, dose and frequency.

[0258] Concomitant medications are used in alignment with the approved label in the respective country, and per doses as outlined below. The medical monitor is contacted if there are any questions regarding concomitant or prior therapy.

[0259] Prior Therapies

[0260] Treatments for uveitis since initial diagnosis (as determined through medical history records or through subject interview) prior to study entry are recorded in the source documents and on the CRF, along with the reason for discontinuation.

[0261] The following information on prior uveitis treatments is captured: 1) Any prior biological therapy or Janus kinase inhibitor. 2) Any immunosuppressants other than systemic corticosteroids within 4 weeks prior to day 1. In addition, the highest previously administered dose and the date range should also be recorded if it is beyond 4 weeks of first dose. 3) For prior systemic corticosteroids, record the dose administered within the 2 weeks prior to day 1. In addition, the highest previously administered dose and the date range should also be recorded if it is beyond 2 weeks of day 1. In addition, the date of the last uveitis flare and the dosage of corticosteroid treatment at the time of the flare isrecorded. If the subject was completely off corticosteroids when the flare occurred, the date of the last dose of corticosteroid prior to flare is recorded. 4) For topical uveitis therapies, record the dose administered within 2 weeks prior to day 1. In addition, the highest previously administered dose and the date range is recorded if it is beyond 2 weeks of first dose. The medication name includes the strength, if part of the generic name (e.g., betamethasone phosphate 0.1%). The dose is recorded as number of drops. 50  Patent Application 5) For VEGF therapies, all doses administered within 1 year prior to study entry are recorded.

[0262] Concomitant Therapies

[0263] Subjects are allowed to continue on 1 ongoing non-biologic immunosuppressive therapy at study entry provided the dose has been stable within the 4 weeks prior to day 1 and must remain unchanged throughout the study. In addition, doses must be within the acceptable limits listed below: Methotrexate ≤ 25 mg / week Cyclosporine ≤ 4 mg / kg / day Mycophenolate mofetil ≤ 3 mg / day Azathioprine ≤ 175 mg / day Tacrolimus (oral formulation) ≤ 8 mg / day

[0264] There is no required washout period for the discontinued concomitant immunosuppressive.

[0265] Subjects who enter the study receiving topical corticosteroids (eye drops) undergo a standardized taper schedule beginning at week 1 until all subjects are off topical corticosteroids by week 10. Depending on the dose that the subject is on at day 1 visit, the number of drops per day is decreased every week until eye drops are discontinued by week 10. An example tapering schedule is provided in Table 11. Table 11 D (N f dr / d ) r W k

[0266] Investigators consider supplementation in line with standard medical practice, with agents such as calcium, Vitamin D3 and proton pump inhibitors, as appropriate, if there is a concern for or clinical suspicion or evidence of osteopenia or gastritis. 51  Patent Application

[0267] Subjects who meet the treatment failure criteria may receive rescue medications at the investigator’s discretion. If the rescue medication is a biologic, the subject discontinues from study drug and all activities listed in the early termination visit (week 52) is completed within 2 weeks. If the rescue medication is a non-biologic, the subject can continue on study and continue receiving study drug. Subjects should continue to complete study assessments as outlined in the SoA. Only the efficacy assessments of BCVA and VFQ-25 are completed at week 24 and week 52; all other efficacy assessments will not be completed.

[0268] Upon initiation or discontinuation of investigational product, investigators consider potential effects on metabolism of cytochrome P450 substrates with narrow therapeutic indexes such as methotrexate, tacrolimus, cyclosporine, certain tricyclic antidepressants (including amitriptyline and nortriptyline), baricitinib, warfarin and tamoxifen.

[0269] Prohibited Medications

[0270] The following medications are prohibited from enrollment through week 52: All other biologic therapies with a potential therapeutic impact on uveitis including but not limited to: ^ TNF-α inhibitors (e.g., adalimumab, cyclosporine, mycophenolate mofetil etanercept, infliximab, golimumab); or an equivalent drug to ^ Abatacept; mycophenolate mofetil (e.g., ^ Secukinumab; mycophenolic acid) at an equivalent ^ Ixekizumab; dose, azathioprine and tacrolimus ^ Bimekizumab; (oral formulation); ^ Anakinra; ^ Live vaccines (during the study and ^ Rituximab; for 2 months after the last dose of ^ Natalizumab; study drug); ^ Tocilizumab; ^ Implantable corticosteroids; ^ Certolizumab pegol; ^ Any investigational agents; and ^ Ustekinumab; ^ Procedures including: ^ Belimumab; and o refractive laser surgery; ^ Anti-VEGF therapy; o retinal laser ^ All other immunosuppressive photocoagulation; therapy other than methotrexate, 52  Patent Application o neodymium-doped yttrium o laser surgery of the macula aluminum garnet posterior including photodynamic capsulotomy; therapy or focal laser; and photocoagulation.

[0271] Discontinuation of Study Drug and Subject Discontinuation / Withdrawal

[0272] Discontinuation of specific sites or of the study as a whole are detailed herein.

[0273] Discontinuation of Study Drug

[0274] In rare instances, it may be necessary for a subject to permanently discontinue study drug. The reason for permanent discontinuation of study drug is documented. If study drug is permanently discontinued, the subject is encouraged to remain in the study to be evaluated for safety and efficacy. Subjects continue to complete study assessments as outlined in the SoA where possible, with the exception of study drug administration. Study visits at weeks 10, 24, 48 and 52 are prioritized. Reasons for removal from study drug include any of the following: ^ Subject request; ^ Safety concern (e.g., due to an AE [including laboratory abnormality], ineligibility determined, protocol deviation, noncompliance, pregnancy, hepatotoxicity); ^ Death; ^ Lost to follow-up; ^ Decision by sponsor (other than subject request, safety concern, lost to follow-up); ^ Subject who meets the criteria of non-response; ^ Subject who meets the criteria of treatment failure and receives a biologic as a rescue medication; 53  Patent Application

[0275] Subjects with newly diagnosed IBD or with IBD flares during the study: ^ Discontinue study drug and be followed-up until resolution of active IBD symptoms; and ^ Are referred, as appropriate, to a health care professional treating IBD, such as a gastroenterologist;

[0276] Liver Chemistry Stopping Criteria

[0277] Discontinuation of study drug for abnormal liver tests is required by the investigator when a subject meets one of the conditions outlined in the algorithm or in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the investigator believes that it is in the best interest of the subject (Fig.2). The investigator may consider rechallenge if a reasonable alternative explanation is identified and after consultation with the medical monitor.

[0278] Study Drug Restart or Rechallenge After Liver Stopping Criteria Are Met

[0279] Study drug restart / rechallenge after liver chemistry stopping criteria are met is allowed in this study. If the subject meets liver chemistry stopping criteria, there is no restart / rechallenge for the subject with study drug unless: Sponsor medical monitor approval is granted; and IEC and / or IRB approval is obtained, if required. NOTE: If study drug was interrupted for suspected study drug-induced liver injury, the subject is informed of the risk of death, liver transplantation, hospitalization and jaundice before resumption of dosing.

[0280] Refer to Liver Safety: Required Actions and Follow-up Assessments and Study drug Restart / Rechallenge Guidelines for details on the restart / rechallenge process, as provided herein.

[0281] If sponsor medical monitor approval to restart / rechallenge the subject with study drug is not granted, then the subject must permanently discontinue study drug and may continue in the study for protocol-specified study assessments.

[0282] Subject Discontinuation / Withdrawal from the Study Reasons for removal of a subject from the study are: ^ Decision by sponsor 54  Patent Application ^ Decision by investigator (following discussion with sponsor) ^ Death ^ Withdrawal of consent from study ^ Lost to follow-up

[0283] Withdrawal of consent from study: A subject may withdraw from the study at any time without jeopardizing subsequent medical care.

[0284] At the time of discontinuing from the study, if possible, an early termination visit is conducted, as shown in the SoA. See the SoA for data to be collected at the time of study discontinuation and follow-up and for any further evaluations that need to be completed.

[0285] The subject is permanently discontinued from the study drug and the study at that time.

[0286] If the subject withdraws consent for disclosure of future information, the sponsor may retain and continue to use any data collected before such a withdrawal of consent.

[0287] If a subject withdraws from the study, he / she may request destruction of any samples taken and not tested, and the investigator documents this in the site study records and notify the sponsor or its designee.

[0288] Lost to Follow-up

[0289] A subject will be considered lost to follow-up if he / she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site.

[0290] The following actions must be taken if a subject fails to return to the clinic for a required study visit: ^ The site must attempt to contact the subject and reschedule the missed visit as soon as possible, counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether the subject wishes to and / or should continue in the study. ^ Before a subject is deemed lost to follow-up, the investigator or designee must make every effort to regain contact with the subject (where possible, 3 attempts at known effective points of contact [e.g., phone, email, text], and if necessary, a certified letter to the subject’s last known mailing address or local equivalent methods). These contact attempts should be documented in the subject’s medical record. ^ Should the subject continue to be unreachable, he / she will be considered lost to follow-up. 55  Patent Application

[0291] Study Assessments and Procedures

[0292] Informed consent is obtained before any study-related procedures are performed. In regions where the legal age of consent is older than 18 years, informed consent is obtained from and signed by the subject.

[0293] Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions are not allowed.

[0294] All assessments are completed before study drug administration, unless otherwise specified. Patient-reported outcome assessments are completed first.

[0295] The order of the eye examinations occurs according to established site procedures as long as the slit lamp examination for anterior chamber cell (ACC) count is performed prior to the application of mydriatic eye drops to dilate the subject’s pupils for further assessment.

[0296] At screening, the central reading center assessment based on fundus photography, FA and / or SD-OCT is required to confirm eligibility prior to day 1.

[0297] Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or awareness to determine if the subject should continue or discontinue study drug.

[0298] Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct.

[0299] All screening evaluations are completed and reviewed to confirm that potential subjects meet all eligibility criteria. The investigator maintains a screening log to record details of all subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.

[0300] Procedures conducted as part of the subject’s routine clinical management (e.g., x-rays) and obtained before signing of the ICF are utilized for screening or baseline purposes provided the procedures meet the protocol-specified criteria and are performed within the timeframe defined in the SoA.

[0301] Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.

[0302] Efficacy Assessments

[0303] Planned timepoints for all efficacy assessments are provided in the SoA. The order of the eye examinations occurs according to established site procedures. However, paracenteses of 56  Patent Application anterior chamber fluid is performed until after all examinations and testing have been completed, including FA. This test series is completed prior to study drug administration and oral prednisone / prednisolone.

[0304] These tests are performed by named, qualified, health care professional member(s) of the site’s study team. If possible, all evaluations for a specific test procedure within a subject are performed by the same authorized member of the site’s team, using the same equipment. If a staff member who was involved in these tests leaves the site, appropriate measures are taken to assign and train a successor who continues the testing already started with the least possible disruption while well-adherent to the originally agreed standardization rulings.

[0305] Independent sequential masked efficacy evaluations by the central reading center are established for SD-OCT, fundus photography and FA measurement in order to standardize and strengthen the validity of efficacy evaluations.

[0306] For the purpose of the efficacy endpoints and assessment of non-response, the principal investigator’s assessment of vitreous haze and inflammatory lesions, based on fundus photographs, and if required FA and / or SD-OCT, takes precedence over the central reading center assessment of vitreous haze and inflammatory lesions.

[0307] If a subject meets non-response criteria during the eye examination, all activities listed in the early termination visit (week 52) are completed within 2 weeks.

[0308] Best Corrected Visual Acuity

[0309] Refraction and assessment of BCVA will be assessed at the timepoints indicated in the SoA. At each visit, subjects undergo refraction and result of refraction for each eye recorded on the CRF. Using the appropriate corrective lenses based on the visit’s refraction, the subject’s BCVA is measured using an ETDRS chart.

[0310] Slit Lamp Exam

[0311] The slit lamp exam is completed to measure the following findings: bilateral ACC and Age-Related Eye Disease Study (AREDS) lens opacity grading. Results are evaluated by the investigator.

[0312] Anterior Chamber Cell Count

[0313] Slit lamp examination for ACC is performed prior to application of mydriatic eye drops to dilate the subject’s pupils for further assessment. 57  Patent Application

[0314] A slit lamp biomicroscopy is carried out aiming a 1 × 1-mm slit beam through the anterior chamber to count the number of cells visible in the lit area for each eye. The reported number will be used to determine the grade according to the SUN criteria (Jabs et al, 2005). Table 11 – ACC Grading Grade ACC Count

[0315] Lens Opacity Gg

[0316] The degree of lens opacity is graded using the AREDS standard photographs as reference (AREDS, 2001). Lenses are examined at the slit lamp for the presence and severity of 3 types of opacity: nuclear, cortical and posterior subcapsular. For each type of opacity, the examiner compares the lens being examined with a series of 3 standard photographs of increasing severity (Chew et al, 2010). Table 12 – Lens Opacity Grading Patent Application Grading for Posterior Subcapsular Opacity <1.0 no PSC opacity, or opacity obviously less than PSC Std. No.1

[0318] Intraocular pressure is performed for both eyes at the timepoints indicated in the SoA. Applanation tonometry is preferred but non-contact tonometry is also be used if the site does not have equipment to perform applanation tonometry.

[0319] Dilated Indirect Ophthalmoscopy

[0320] Dilated indirect ophthalmoscopy is performed at the timepoints indicated in the SoA. The subject’s eyes are dilated in preparation for indirect ophthalmoscopy. Dilated indirect ophthalmoscopy is performed to determine both vitreous haze grading and the absence / presence of active, inflammatory, chorioretinal and / or inflammatory retinal vascular lesions.

[0321] Vitreous haze is graded according to the NEI criteria adapted by the SUN working group (Jabs et al, 2005; Nussenblatt et al, 1985). Standard photographs are used. Table 13 - Vitreous Haze Grading59  Patent Application

[0322] Spectral-Domain Optical Coherence Tomography

[0323] Bilateral SD-OCT is performed at the timepoints indicated in the SoA. The SD-OCT is carried out for each eye to determine central retinal thickness (CRT [mm]), excess central subfield thickness and the presence of macular edema (yes / no). In addition, SD-OCT is also be used as a complementary assessment when determining the presence / absence of active inflammatory chorioretinal and / or inflammatory retinal vascular lesions.

[0324] The measurement of retinal thickness is carried out with 1 of the following permissible devices: Cirrus HD-OCT (Carl Zeiss Meditec, Inc.) Spectralis (Heidelberg Engineering)

[0325] SD-OCT measurements are sent to the central reading center for assessment.

[0326] Although it is preferred to complete the SD-OCT measurements following pupil dilation, it is important that the site conducts the scans consistently across each subject (using the same model of SD-OCT device for each subject) throughout the study.

[0327] Fundus Photography

[0328] Bilateral fundus photography isperformed at timepoints indicated in the SoAto assess the presence / absence of active inflammatory chorioretinal and / or inflammatory retinal vascular lesions and vitreous haze grading for each eye. All fundus photographs are sent to the central reading center for assessment.

[0329] Fluorescein Angiography

[0330] Fluorescein angiography is a technique for examining the circulation of the retina and choroid using a fluorescent dye and a specialized camera. Sodium fluorescein isadded into the systemic circulation, the retina is illuminated with blue light at a wavelength of 490 nanometers, and an angiogram is obtained by photographing the fluorescent green light that is emitted by the dye. The fluorescein isadministered by IV. The subject is monitored per standard practice.

[0331] Dye tracing by FA serves to evidence the presence / absence of active inflammatory chorioretinal and / or inflammatory retinal vascular lesions. FA is performed at screening. FA is only be repeated after screening if the screening FA shows signs of inflammation. In such event, FA is scheduled at week 10, week 24 and at the end of treatment (week 52). FA is performed at any unscheduled visit if there is concern about the condition of the eye. FA is performed for 60  Patent Application subjects who meet the treatment failure criteria and are continuing on study. The FA is completed as soon as feasible from the time the subject meets the treatment failure criteria.

[0332] FA is complementary to dilated indirect ophthalmoscopy and fundus photography, providing further supportive documentation / evidence of whether a chorioretinal / retinal vascular lesion is active or inactive. Fluorescein angiography photographs are sent to the central reading center for assessment.

[0333] Visual Functioning Questionnaire

[0334] The VFQ-25 will be administered at the timepoints indicated in the SoA. The VFQ-25 is completed at every visit prior to any study procedure or examination. The questionnaire is interviewer-administered.

[0335] Short Form 12

[0336] The acute Short Form-12v2™ Health Survey (SF-12) is a 7-day recall, 12-item subset of the Short-Form-36v2™ questionnaire that measures the same 8 domains of health including physical functioning, role-function, bodily pain, general health, vitality, social functioning, role-emotional and mental health. The SF-12 is a brief, reliable measure of overall health status with scores general for physical component and mental components. Each item on the SF-12 is score on 3- or 5-item Likert scales and the domain scales are standardized to 0 to 100 scale, where 0 represents lower quality of life and 100 represents higher quality of life. The subject completes the questionnaire before site personnel perform any clinic assessments and before any interaction with the site personnel has occurred to avoid biasing the subject’s response.

[0337] European Quality of Life-5 Dimensions

[0338] The European Quality of Life-5 Dimensions (EQ-5D) comprises 5 questions on mobility, self-care, pain, usual activities and psychological status with 3 possible answers for each item (1=no problem, 2=moderate problem, 3=severe problem). A summary index with a maximum score of 1 can be derived from these 5 dimensions by conversion with a table of scores. The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems. In addition, there is a visual analog scale to indicate the general health status with 100 indicating the best health status.

[0339] Safety Assessments

[0340] Planned timepoints for all safety assessments are provided in the SoA. 61  Patent Application

[0341] Medical and Surgical History

[0342] A complete medical and surgical history, as well as history of alcohol and nicotine use, isobtained from each subject during the screening visit. An updated medical history is obtained at the day 1 visit prior to study drug administration and updated as necessary throughout the study.

[0343] A uveitis history obtained at screening captures date of onset of uveitis, which eye(s) is / are affected, type of uveitis, the nature of diagnosis, subject history of infectious uveitis, cause of previous infection (if applicable), number of flares within the past 12 months (including the current flare), date of last flare prior to current flare, prednisone / prednisolone dose at time of last flare (or equivalent prednisone / prednisolone dose), if subject was on another corticosteroid, and date of onset of current flare.

[0344] Physical Examination

[0345] A complete physical examination includes, at a minimum, assessments of the dermatological, cardiovascular, respiratory, gastrointestinal and neurological systems. At specified timepoints in the SoA, physical examinations will also include assessment of skin and mucus membranes.

[0346] Clinically significant findings observed prior to first dose of study drug should be listed as medical history in the CRF and reported as AEs if observed after first dose of study drug.

[0347] Physical Measurements

[0348] Height and weight measurements are performed at the timepoints indicated in the SoA and data will be recorded in cm and kg, respectively. Height and weight are measured without shoes.

[0349] Vital Signs

[0350] Vital signs are measured in a sitting position after 5 minutes’ rest and will include temperature, systolic and diastolic blood pressure, pulse and respiratory rate.

[0351] Electrocardiograms

[0352] Triple 12-lead ECGs are obtained as outlined in the SoA using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT intervals.

[0353] Clinical Safety Laboratory Tests

[0354] The investigator reviews the laboratory report, documents this review, and records any clinically significant changes occurring during the study as an AE. The laboratory reports is filed with the source documents. 62  Patent Application

[0355] Abnormal laboratory findings associated with the underlying disease are not considered clinically significant unless judged by the investigator to be more severe than expected for the subject’s condition.

[0356] All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 8 weeks after the last dose of study drug are repeated until the values return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor. a. If clinically significant values do not return to normal / baseline within a period of time judged reasonable by the investigator, the etiology should be identified, and the sponsor notified. b. All protocol-required laboratory tests, as defined herein, must be conducted in accordance with the laboratory manual and the SoA. c. If laboratory values from non-protocol-specified laboratory tests performed at the institution’s local laboratory require a change in subject management or are considered clinically significant by the investigator (e.g., SAE or AE), then the results must be recorded within source documents.

[0357] Pregnancy Testing

[0358] Pregnancy testing in WOCBP is conducted throughout the study. A serum pregnancy test will be performed at screening and urine pregnancy testing is performed at subsequent visits as detailed in the SoA.

[0359] Additional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation or regulatory agency, to establish the absence of pregnancy at any time during the subject’s participation in the study.

[0360] The investigator is responsible for review of medical history, menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

[0361] Hepatitis Testing

[0362] All subjects are tested for the presence of HBV and hepatitis C virus at screening. A positive result for HBsAg will be exclusionary. Samples negative for HBsAg are tested for HBsAb and HBcAb. If test results are positive for HBcAb or HBsAb, then HBV DNA PCR is performed and any result that meets or exceeds detection sensitivity will be exclusionary. 63  Patent Application

[0363] Antinuclear Antibodies / Anti-double-stranded DNA

[0364] Blood for antinuclear antibodies (ANAs) / anti-double-stranded DNA is collected at screening. These tests are markers, and the results are not exclusionary; therefore, waiting for the results should not delay enrollment or randomization. If a subject develops signs and symptoms of lupus on-study, an ANA test may is repeated based on the investigator's clinical judgment.

[0365] Herpes Simplex Virus (Immunoglobulin M / Immunoglobulin G)

[0366] Subjects aretested for herpes simplex virus to rule out a potential infectious etiology of the uveitis.

[0367] Varicella Zoster Virus (Immunoglobulin M / Immunoglobulin G)

[0368] Subjects are tested for varicella zoster virus to rule out a potential infectious etiology of the uveitis.

[0369] Home Study Drug Administration Diary

[0370] Study site staff administer study drug at the first 2 visits. Thereafter, if home dosing is a consideration, the subject or subject's caregiver or designee administers and demonstrates competency for at least 2 visits prior to being allowed to dose at home. Otherwise, the subject returns to the site for all injections. The subject (or caregiver / designee) completes a diary for every study dose taken outside of the study site (i.e., at home). The study drug is administered on the dates as directed by the site staff. Information regarding the study drug administration (e.g., date and time of study drug administration, if the full dose was administered) is recorded on the study drug administration diary. Instructions on proper study drug administration are provided to the subject (caregiver / designee). Subjects are instructed to call the study site if they are having problems administering the study drug or have missed or delayed administering a dose. Subjects are instructed to bring the study drug administration diary to each study visit.

[0371] Adverse Events, Serious Adverse Events and Other Safety Reporting

[0372] The definitions of AEs and SAEs can be found herein.

[0373] Adverse events are reported by the subject (or, when appropriate, by a caregiver or surrogate).

[0374] The investigator and any qualified designees are responsible for detecting, documenting and recording events that meet the definition of an AE or SAE. The investigator is responsible for following up all AEs that are serious, considered related to the study drug or study procedures, or that caused the subject to discontinue the study drug. 64  Patent Application

[0375] The method of recording, evaluating and assessing causality of AEs and SAEs and the procedures for completing and transmitting SAE reports are provided herein.

[0376] Time Period and Frequency for Collecting AE and SAE Information

[0377] All SAEs are collected from the signing of the ICF until the 8-week follow-up visit at the timepoints specified in the SoA.

[0378] All AEs are collected from the first dose of study drug until the 4 weeks after the last dose of study drug as specified in the SoA.

[0379] Medical occurrences that begin before the start of study drug but after obtaining informed consent are recorded as medical history / current medical conditions, not as AEs.

[0380] All SAEs are recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours from investigator’s knowledge of the event, as indicated herein. The investigator submits any updated SAE data to the sponsor within 24 hours of it being available.

[0381] Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of the study participation. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he / she considers the event to be reasonably related to the study drug or study participation, the investigator must promptly notify the sponsor / designee.

[0382] Method of Detecting AEs and SAEs

[0383] Care is taken not to introduce bias when detecting AEs and / or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrences.

[0384] Follow-up of AEs and SAEs

[0385] After the initial AE / SAE report, the investigator is required to proactively follow each subject at subsequent visits / contacts. All SAEs and AEs of special interest will be followed until resolution, stabilization, the event is otherwise explained or the subject is lost to follow-up.

[0386] Regulatory Reporting Requirements for SAEs

[0387] Prompt notification by the investigator to the sponsor or designee of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of subjects and the safety of a study drug under clinical investigation are met. 65  Patent Application

[0388] The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study drug under clinical investigation. The sponsor complies with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs / IECs and investigators. This includes reporting of events that meet suspected unexpected serious adverse reaction (SUSAR) criteria via Eudravigilance, as applicable.

[0389] An investigator who receives an investigator safety report describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from the sponsor or designee reviews and then files it along with the Investigator’s Brochure and notifies the IRB / IEC, if appropriate, according to local requirements.

[0390] Investigator safety reports are prepared for SUSARs according to local regulatory requirements and sponsor or designee policy and forwarded to investigators as necessary.

[0391] Pregnancy

[0392] Details of all pregnancies in female subjects and, if indicated, female partners of male subjects are collected after the start of study drug and until 8 weeks after the last dose of study drug.

[0393] If a pregnancy is reported, the investigator records pregnancy information on the appropriate form and submit it to the sponsor or designee within 24 hours of learning of the female subject or female partner of male subject (after obtaining the necessary signed informed consent from the female partner).

[0394] While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons is reported as an AE or SAE.

[0395] Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and are reported as such.

[0396] The subject / pregnant female partner will be followed to determine the outcome of the pregnancy. The investigator will collect follow-up information on the subject / pregnant female partner and the neonate, and the information will be forwarded to the sponsor or designee.

[0397] Any poststudy pregnancy-related SAE considered reasonably related to the study drug by the investigator will be reported to the sponsor or designee. While the investigator is not obligated to actively seek this information in former study subjects / pregnant female partners, he / she may learn of an SAE through spontaneous reporting. 66  Patent Application

[0398] Any female subject who becomes pregnant while participating in the study will discontinue study drug.

[0399] Events of Special Interest

[0400] Based on the class effects or potential risks with IL-17 inhibitors, the following events of special interest (preferred term) are monitored: ^ Candida infection; ^ Major cardiovascular and ^ IBD; cerebrovascular events; ^ In addition, based on the potential risk ^ TB; with an IL-17 receptor inhibitor, the ^ Infections (including opportunistic following events of special interest infections and serious infections); will also be monitored: ^ Cytopenias; and ^ Suicidal ideation; ^ Hypersensitivity reactions. ^ Malignancies;

[0401] Pharmacokinetic Assessments

[0402] Blood samples are collected for measurement of plasma concentrations of izokibep as specified in the SoA.

[0403] Instructions for the collection and handling of biological samples are provided in the Laboratory Manual by the sponsor or designee. The actual date and time (24-hour clock time) of each sample is recorded.

[0404] Samples are used to evaluate the PK of izokibep. Each plasma sample will be divided into 2 aliquots (1 each for PK, and a backup). Samples collected for analyses of izokibep (plasma) concentration may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.

[0405] Genetic analyses are not be performed on these plasma samples.

[0406] Study drug concentration information are not be reported to investigative sites.

[0407] Pharmacokinetic samples collected may be used for assay validation and related assay development purposes.

[0408] Pharmacokinetic samples are shipped frozen from clinical sites to the central laboratory and later shipped from the central laboratory to the PK laboratory for analysis. The PK plasma samples are stored in a secure storage space with adequate measures to protect confidentiality. 67  Patent Application

[0409] The PK samples are retained while research on izokibep or study drugs of this class or uveitis continues but no longer than 20 years or other period as per local requirements.

[0410] Immunogenicity Assessments

[0411] Antibodies to izokibep are evaluated in serum samples collected from all subjects according to the SoA. Additionally, serum samples are collected at the final visit from subjects who discontinued study drug or were withdrawn from the study. These samples are tested by the sponsor or sponsor’s designee.

[0412] Instructions for the collection and handling of biological samples are provided in the Laboratory Manual by the sponsor or designee.

[0413] Samples testing positive for binding antibodies are further characterized and may be tested for neutralizing antibodies.

[0414] The detection and characterization of antibodies to izokibep are performed using a validated assay method by or under the supervision of the sponsor.

[0415] Antibody samples collected are used for assay validation and related assay development purposes.

[0416] ADA serum samples are shipped frozen from clinical sites to the central laboratory and later shipped from the central laboratory to the ADA laboratory for analysis. The ADA serum samples are stored in a secure storage space with adequate measures to protect confidentiality.

[0417] Samples are retained while research on izokibep or drugs of this class or uveitis continues but no longer than 20 years or other period as per local requirements. 68  Patent Application

[0418] Statistical Considerations

[0419] This section is a summary of the planned statistical analyses of the most important endpoints including primary and secondary endpoints.

[0420] Statistical Hypotheses

[0421] The hypotheses tested for the primary endpoint are: H0: λIzo / λPbo = 1 versus H0: λIzo / λPbo ≠ 1, where λIzoand λPboare the hazard rates for 1 regimen of izokibep and combined regimens of placebo, respectively. The hypotheses tested for the first secondary endpoint of quiescence rate at week 10 are: H0: πIzo - πPbo = 0 versus H0: πIzo - πPbo ≠ 0, where πIzoand πPboare the response rates for 1 regimen of izokibep and combined regimens of placebo, respectively. The hypotheses tested for the second secondary endpoint of change in BCVA are: H0: µIzo- µPbo= 0 versus H0: µIzo- µPbo≠ 0, where µIzo and µPbo are the mean changes in BCVA in an eye for 1 regimen of izokibep and combined regimens of placebo, respectively. Analogous hypotheses will be tested for the third secondary endpoint of change in NEI-VFQ-25 in a subject at week 24, the fourth secondary endpoint of change in SD-OCT in an eye at week 10 and the fifth secondary endpoint of change in SD-OCT in an eye at week 52.

[0422] Multiplicity Adjustment and Type I Error Rate

[0423] Hypothesis tests are adjusted to control the familywise error rate in the strong sense at α = 0.050, 2 sided.

[0424] An adjustment of 0.0001 is made to account for the unblinded data summaries reviewed by the DMC. The hypotheses is therefore be tested at α = 0.0499.

[0425] The statistical comparisons of the primary efficacy endpoint and the secondary endpoints is carried out in sequential order. All endpoints starting with the primary endpoint and moving 69  Patent Application through the secondary endpoints are tested sequentially for comparison of izokibep dosed QW to placebo. For each comparison, significance concluded if p < 0.0499 and if all prior comparisons in the testing sequence also showed p < 0.0499. Specifically, the testing order are: ^ The primary endpoint, time to treatment failure, comparing izokibep dosed QW to placebo dosed QW. ^ The first secondary endpoint, quiescence at week 10, comparing izokibep dosed QW to placebo dosed QW. ^ The second secondary endpoint, change in BCVA, comparing izokibep dosed QW to placebo dosed QW. ^ The third secondary endpoint, change in NEI-VFQ-25, comparing izokibep dosed QW to placebo dosed QW. ^ The fourth secondary endpoint, change in CRT at week 10, comparing izokibep dosed QW to placebo dosed QW. ^ The fifth secondary endpoint, change in CRT at week 52, comparing izokibep dosed QW to placebo dosed QW.

[0426] If a hypothesis is not rejected, p-values for subsequent hypotheses in the sequence are reported but not used to assess objectives or make determinations of efficacy. For any subjects enrolled before amendment v2.0 and randomized to receive izokibep Q2W, these efficacy data are listed but not used in any summaries or comparisons.

[0427] Analysis Sets

[0428] Full Analysis Set

[0429] For assessing the primary and secondary efficacy objectives, all subjects randomized are included in the analyses as the Full Analysis Set. Intercurrent events (ICEs) such as missed or discontinued treatment and protocol deviations are addressed as described in the definition of the estimands. Subjects are included according to randomized treatment assignment.

[0430] Safety Analysis Set

[0431] For assessing the safety objectives, all subjects randomized who receive at least 1 administration of test material are included in the summaries and analyses. In the event that a 70  Patent Application subject receives incorrect study drug, that subject is be grouped according to treatment received, and such subjects are listed and counted in the final report.

[0432] PK Analysis Set

[0433] For assessing PK parameters, all subjects who receive at least 1 administration of test material and have at least 1 sample collected and analyzed for drug concentration areincluded in summaries and analyses.

[0434] ADA Analysis Set

[0435] For assessing ADA, all subjects who receive at least 1 administration of test material and have both baseline ADA and at least 1 post-dose ADA measurement are included in summaries and analyses.

[0436] Statistical Analyses

[0437] General Considerations

[0438] All data collected are summarized by planned timepoint without imputation. Continuous data are summarized with count, mean, median, standard deviation, minimum and maximum. Change from baseline additionally include standard error. Categorical data are summarized with count and percent. Time to event data are summarized with product-limit estimators of median and quartiles. Placebo subjects assigned to receive doses QW are summarized both separately and combined, with hypotheses tested using both placebo dosing frequencies combined.

[0439] All hypothesis tests will be reported with 2-sided p-values. Comparison of QW dosing to placebo will use only subjects assigned to receive izokibep QW or placebo. All confidence intervals will be 2-sided with nominal 95% coverage.

[0440] Data will be summarized by planned timepoint, using data collected at the visit. Study day will be calculated as post-baseline date minus randomization date, plus 1 (except that study day for pre-randomization dates will not include the plus 1). Day range windows will not be applied for summaries (but may be applied for protocol deviations). Baseline values will be the last value collected before randomization and change from baseline will be calculated as post-baseline value minus baseline value. 71  Patent Application

[0441] Primary Endpoint and Estimand

[0442] The treatment policy strategy for ICEs is used in general to define the estimand, so subjects are included using observed treatment failure data at or after week 10 regardless of treatment compliance, use of rescue medications or any other protocol deviations. Subjects who discontinue the study or who have not completed week 52 at the time of the primary analysis are censored at the last assessment. The population for the estimand is subjects with uveitis who did not meet the criteria for non-response. That is, subjects who meet the criteria for non-response are omitted from the analysis of the primary endpoint. Because this omits some subjects based on events after randomization, another analysis including these subjects as events at time non-response is determined also is reported to confirm that omission of such subjects did not change the conclusions.

[0443] The null hypothesis of equal hazard rates compares each dosing regimen of izokibep to the combined placebo group using the logrank test. Factors used for stratification of the randomization are included as strata in the model.

[0444] Supportive analyses using other assumptions about ICEs (including use of prohibited concomitant medications due to efficacy considerations, inability to taper steroids due to efficacy considerations, withdrawal from treatment due to lack of efficacy and AEs related to treatment) are also be reported. These are defined before the database is locked and treatment assignments are unblinded for the primary analysis.

[0445] Secondary Endpoints and Estimands

[0446] The secondary endpoints are quiescence at week 10, change in BCVA at week 24, change in NEI-VFQ-25 at week 24, change in CRT at week 10 and change in CRT at week 52. The treatment policy strategy for ICEs is used to construct estimands for each. Unlike the primary endpoint estimand, subjects who are early treatment failures are not excluded from the population for any secondary endpoint. For quiescence rate at week 10 and change in NEI-VFQ-25 at week 24, the analysis unit will be subject; for change in BCVA at week 24, change in CRT at week 10 and change in CRT at week 52, the analysis unit is eye and analyses includes all eyes from subjects that meet entry criteria.

[0447] The first secondary endpoint of quiescence at week 10 is analyzed in a stratified analysis. Within each of the 4 strata used for the randomization, the risk difference and associated standard error are calculated. The analysis combines the 4 risk differences using Cochran-Mantel-Haenszel 72  Patent Application weighting, assuming a common risk difference within each of the strata. The 4 standard errors are similarly combined, and the test statistic calculated. Subjects who do not have an assessment for quiescence at week 10 are included as non-responders (nonresponse imputation [NRI]). The number of subjects included with NRI is reported by treatment group, along with reasons for missed assessments.

[0448] The secondary endpoints of change in BCVA, change in NEI-VFQ-25 and change in CRT are analyzed as continuous variables. The baseline value for change is the best reported value, including all timepoints starting with the last value obtained before randomization through the last value obtained before week 10 for BCVA and NEI-VFQ-25. Change in CRT includes all timepoints starting with the last value obtained before randomization through the last value obtained at or before week 10. Change at week 24 (week 52) is calculated as week 24 (week 52) value minus baseline value. The analysis is reported using mixed effects model with repeated measures (MMRM), using observed change at all scheduled assessments at and after week 10, up to and including week 24, and using eye within subject as a nested effect to account for correlation between eyes within a subject for BCVA and CRT. A contrast at week 24 is used to estimate the effect at week 24. Covariates in the MMRM analysis will be the stratification factors used in the randomization and the baseline value. Eyes (BCVA and CRT) or subjects (NEI-VFQ-25) with no values at or after week 10 are included by imputing a change of 0 at the first planned assessment at or after week 10.

[0449] Safety Analyses

[0450] Safety data includes summaries of exposure, AEs, SAEs and laboratory data. Subjects who received placebo QW are used for summaries during the placebo controlled portion of the study. Subjects receiving izokibep Q2W before initiation of protocol amendment v2.0 are listed only. No inferential statistics (p-values) are reported for safety data.

[0451] Exposure includes the number of doses administered (including complete and incomplete doses) and reasons for missed or incomplete doses. Exposure is reported through the planned collection of the primary endpoint and for the entire study.

[0452] Serious AEs reported before first administration of study drug are listed. All summaries include only treatment-emergent events. The number of subjects who report 1 or more AEs, the number who report 1 or more severe AEs, the number who report 1 or more SAEs and the number 73  Patent Application who report 1 or more AEs that leads to discontinuation of study drug are summarized by treatment during the primary phase of the study and overall.

[0453] Laboratory data including ADAs are summarized at each planned collection timepoint.

[0454] Interim Analysis and Early Stopping Rules

[0455] No interim analyses is conducted for the purpose of stopping the study or altering the study design.

[0456] The primary analysis of primary and secondary endpoints occurs after all subjects have had an opportunity to complete the week 24 assessments (have completed the week 24 assessments, or have completed a subsequent timepoint assessment, or permanently discontinued the study before week 24). For the secondary endpoints, this includes all data for all subjects for the final analysis, and so it will be the final analysis. For the primary endpoint, all available data at visits after week 24 is included, but some subjects are ongoing and may have data collected after the primary analysis is reported. All data collected for the primary endpoint for all subjects through week 52 is reported in a subsequent analysis, but the p-values from each comparison of a regimen of izokibep to placebo in this subsequent analysis are not be used for any alpha-preserving hypothesis testing. Investigators, site personnel and all sponsor personnel who have contact with subjects remain blinded to individual subject treatment assignments until the final analysis.

[0457] When the primary efficacy analysis is conducted, safety data are summarized. Summaries include all safety data through week 24 and all available data on all subjects through week 52. All safety data is summarized through week 52 when all subjects have completed through week 52.

[0458] Sample Size Determination

[0459] The analysis uses a logrank test. An assessment of power by the logrank test, assuming a hazard ratio of 35.78 (consistent with the assumed event rates) and a 10% dropout rate at week 24 (treated as censored in the analysis), results in 90% power, using only events through week 24 and calculated using PASS software. Events in some subjects after week 24 are included, further increasing the power. 74  Patent Application

[0460] Supporting Documentation and Operational Considerations

[0461] Regulatory, Ethical and Study Oversight Considerations

[0462] Regulatory and Ethical Considerations

[0463] This study is conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences international ethical guidelines Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines Applicable laws and regulations. The protocol, protocol amendments, ICF, Investigator’s Brochure and other relevant documents (e.g., advertisements) are submitted to an IRB / IEC by the investigator and reviewed and approved by the IRB / IEC before the study is initiated.

[0464] Any amendments to the protocol require IRB / IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study subjects.

[0465] Approval for protocols and any substantial amendments to the protocol that require health authority approval prior to initiation will be obtained except for changes necessary to eliminate an immediate hazard to study subjects.

[0466] The investigator is responsible for the following: ^ Providing written summaries of the status of the study to the IRB / IEC annually or more frequently in accordance with the requirements, policies and procedures established by the IRB / IEC ^ Notifying the IRB / IEC of SAEs or other significant safety findings as required by IRB / IEC procedures Providing oversight of the conduct of the study at the site and adherence to requirements of 21 Code of Federal Regulations, ICH guidelines, the IRB / IEC, European regulation 536 / 2014 for clinical studies (if applicable) and all other applicable local regulations.

[0467] Financial Disclosure

[0468] Investigators and subinvestigators provide the sponsor or designee with sufficient, accurate financial information as requested to allow the sponsor to submit complete and accurate financial certification or disclosure statements to the appropriate regulatory authorities. 75  Patent Application Investigators are responsible for providing information on financial interests during the course of the study and for 1 year after completion of the study.

[0469] Informed Consent Process

[0470] The investigator or his / her representative explain the nature of the study, including the risks and benefits, to the subject and answer all questions regarding the study.

[0471] Subjects are informed that their participation is voluntary. Subjects are required to sign a statement of informed consent.

[0472] The medical record must include a statement that written informed consent was obtained before the subject was enrolled in the study and the date the written consent was obtained. The authorized person obtaining the informed consent must also sign the ICF.

[0473] Subjects are reconsented to the most current version of the ICF(s) during their participation in the study.

[0474] A copy of the ICF(s) is provided to the subject.

[0475] A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 30 days from the previous ICF signature date.

[0476] Data Protection

[0477] Subjects are assigned a unique identifier by the sponsor. Any subject records or datasets that are transferred to the sponsor contain the identifier only; subject names or any information which would make the subject identifiable are not be transferred.

[0478] The subject is informed that the subject’s personal study-related data will be used by the sponsor in accordance with local data protection law. The level of disclosure must also be explained to the subject who is required to give consent for their data to be used as described in the informed consent.

[0479] The subject is informed that the subject’s medical records may be examined by Clinical Quality Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate IRB / IEC members and by inspectors from regulatory authorities.

[0480] The sponsor and investigator implement appropriate measures to monitor and identify any breach of security leading to accidental or unlawful destruction, loss, alteration, unauthorized disclosure or access to that data. In the event of a personal data breach, the sponsor 76  Patent Application and investigator will take appropriate measures to address the breach, including measures to mitigate its adverse effects. The investigator will notify the sponsor without undue delay after having become aware of the breach. Such notification will contain the details of a contact point where more information can be obtained, a description of the nature of the breach (including, where possible, categories and approximate number of data subjects and personal data records concerned), its likely consequences and the measures taken or proposed to address the breach including, where appropriate, measures to mitigate its possible adverse effects. Upon becoming aware of any data breach, the sponsor will notify all competent data protection authorities of the breach, where required by local regulations. Where feasible and permissible by applicable law, such notification will occur within 72 hours of becoming aware of the breach. Such notification will contain the details of a contact point where more information can be obtained, a description of the nature of the breach (including, where possible, categories and approximate number of data subjects and personal data records concerned), its likely consequences and the measures taken or proposed to address the breach including, where appropriate, measures to mitigate its possible adverse effects.

[0481] Taking into account the nature, scope, context and purpose of the processing, and the risks for the rights and freedoms of natural persons, the investigator will implement technical and organizational measures to ensure adequate security and confidentiality of the data. Such measures will include without limitation pseudonymization and data encryption in transit and at rest, identity and access management procedures to restrict physical and logical access to the data, network perimeter and endpoint protection using firewalls and other intrusion detection systems, documented policies taking account of the state of the art, and regular training of all personnel responsible for the processing of personal data.

[0482] Dissemination of Clinical Study Data

[0483] The results of the study are reported in a clinical study report generated by the sponsor and will contain CRF data from all study sites that participated in the study. Recruitment performance or specific expertise related to the nature and the key assessment parameters of the study is used to determine a coordinating investigator. Study subject identifiers are not be used in publication of results. Any work created in connection with the performance of the study and 77  Patent Application contained in the data that can benefit from copyright protection (except any publication by the investigator) is the property of the sponsor as author and owner of copyright in such work.

[0484] Registration of Clinical Studies and Disclosure of Results

[0485] The sponsor registers and / or discloses the existence of and the results of clinical studies as required by law including posting company-sponsored study information in the US National Institutes of Health website www.clinicaltrials.gov.

[0486] Monitoring and Data Quality Assurance

[0487] Qualified, assigned monitors from the sponsor (or designee) conduct regular on-site and remote monitoring visits to monitor various aspects of the study. These visits and communications, along with regular inspection of the electronic CRFs, are conducted to assess subject enrollment, compliance with protocol procedures, completeness and accuracy of data entered on the electronic CRFs, verification of data against source documents, and occurrence of AEs, etc. The investigator provides the monitor with full access to all source and study documents.

[0488] All subject data relating to the study is recorded on CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is responsible for verifying that data entries are accurate and correct by signing the CRF.

[0489] Guidance on completion of CRFs is provided.

[0490] The investigator or site staff promptly report to the sponsor (or designee) all deviations that occur at their clinical site, and report protocol deviations to their IRB / IEC according to local requirements.

[0491] The sponsor (or designee) may audit investigator sites regarding, but not limited to, the informed consent process, presence of required documents, adherence to protocol, accountability and storage of drug supplies, comparison between electronic CRF with source documents, etc. All medical records and study related documents must be available for audit, and the investigator and study staff agree to participate and cooperate in audits conducted in a reasonable manner.

[0492] Government regulatory authorities and ethics committees may also inspect the investigator site during or after the study. The investigator or designee should contact the 78  Patent Application sponsor (or its designee) immediately if this occurs. The investigator must cooperate fully with regulatory authorities or other audits conducted in a reasonable manner.

[0493] The sponsor or designee is responsible for the data management of this study, including quality checking of the data.

[0494] The sponsor assumes accountability for actions delegated to other individuals (e.g, CROs).

[0495] Records and documents, including signed ICFs, pertaining to the conduct of this study must be retained by the investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the study drug. These documents should be retained for a longer period, however, if required by the applicable regulatory requirements or by an agreement with the sponsor.

[0496] No records may be destroyed during the retention period without the written approval of the sponsor. No records may be transferred to another location or party without written notification to the sponsor.

[0497] Quality Tolerance Limits will be defined before the start of the study and monitored by the CRO and sponsor during the course of the study. They will also be reported in the clinical study report.

[0498] Source Documents

[0499] Source documents provide evidence for the existence of the subject and substantiate the integrity of the data collected. Source documents are filed at the investigator’s site.

[0500] Source documents contain the results of original observations and activities of a clinical investigation. Source documents include, but are not limited to, medical records (progress notes), computer printouts, screening logs and recorded data from automated instruments. Information from medical records and other source documents will be promptly transcribed to the appropriate section of the electronic CRF. The electronic CRF is not considered and should not be used as source documentation. 79  Patent Application

[0501] Data reported on the CRF that are transcribed from source documents must be consistent with the source documents or the discrepancies must be explained. The investigator may need to request previous medical records or transfer records, depending on the study. Also, current medical records must be available.

[0502] The investigator must maintain accurate documentation (source data) that supports the information entered in the CRF.

[0503] Study monitors will perform ongoing source data verification to confirm that data entered into the CRF by authorized site personnel are accurate, complete and verifiable from source documents; that the safety and rights of subjects are being protected; and that the study is being conducted in accordance with the currently approved protocol and any other study agreements, ICH GCP and all applicable regulatory requirements.

[0504] Study and Site Start and Closure

[0505] Study Start

[0506] The study start date is the date on which the first subject is enrolled into the study.

[0507] Study / Site Termination

[0508] The sponsor reserves the right to close the study site or terminate the study at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A study site is considered closed when all required documents and study supplies have been collected and a study-site closure visit has been performed.

[0509] The investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination.

[0510] Reasons for the early closure of a study site by the sponsor or investigator may include but are not limited to:

[0511] For study termination: Discontinuation of further study drug development.

[0512] For site termination: ^ Failure of the investigator to comply with the protocol, the requirements of the IRB / IEC or local health authorities, the sponsor’s procedures or GCP guidelines ^ Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by the investigator 80  Patent Application ^ Total number of subjects included earlier than expected

[0513] If the study is prematurely terminated or suspended, the sponsor shall promptly inform the investigators, the IECs / IRBs, the regulatory authorities and any CRO(s) used in the study of the reason for termination or suspension, as specified by the applicable regulatory requirements. The investigator shall promptly inform the subject and should assure appropriate subject therapy and / or follow-up.

[0514] Publication Policy

[0515] The results of this study may be published or presented at scientific meetings. If this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. This allows the sponsor to protect proprietary information and to provide comments. The clinical study agreement / site contract will cover additional details regarding publications.

[0516] The sponsor will comply with the requirements for publication of study results. In accordance with standard editorial and ethical practice, the sponsor will generally support publication of multi-center studies only in their entirety and not as individual site data. In this case, a coordinating investigator will be designated.

[0517] Authorship will be determined by mutual agreement and in line with International Committee of Medical Journal Editors authorship requirements.

[0518] Clinical Laboratory Tests

[0519] The tests detailed in Table 14 are performed by the central laboratory.

[0520] Protocol-specific requirements for inclusion or exclusion of subjects are detailed hereinabove as part of the subject protocol.

[0521] Additional tests may be performed at any time during the study as determined necessary by the investigator or required by local regulations. Table 14 L T P l81  Patent Application Clinical chemistry1Blood urea Potassium Aspartate Total and nitrogen aminotransferase / serum direct lutamic-oxaloacetic bilirubin te ng l)Patent Application NOTES: 1 Details of liver chemistry stopping criteria and required actions and follow-up are provided herein in the Liver Chemistry Stopping Criteria and Liver Safety: Required Actions and Follow-up Assessments and Study, , and Reporting

[0523] AE Definition

[0524] An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of study drug.

[0525] Events Meeting the AE Definition

[0526] The following meet the AE definition: ^ Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or other safety assessments (e.g., ECG, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the investigator (i.e., not related to progression of underlying disease); ^ Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition; ^ New condition detected or diagnosed after study drug administration even though it may have been present before the start of the study; ^ Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction; ^ Signs, symptoms or the clinical sequelae of a suspected overdose of either study drug or a concomitant medication. Overdose per se will not be reported as an AE / SAE unless it is an intentional overdose taken with possible suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae; Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 83  Patent Application symptoms and / or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE.

[0527] Events NOT Meeting the AE Definition A) Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition B) The disease / disorder being studied or expected progression, signs or symptoms of the disease / disorder being studied, unless more severe than expected for the subject’s condition C) Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the AE D) Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital) E) Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen

[0528] An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more of the criteria listed: A) Results in death B) Is life threatening The term life threatening in the definition of serious refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. C) Requires inpatient hospitalization or prolongation of existing hospitalization In general, hospitalization signifies that the subject has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and / or treatment that would not have been appropriate in the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. 84  Patent Application Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. D) Results in persistent or significant disability / incapacity The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption. E) Is a congenital anomaly / birth defect

[0529] Other situations: Medical or scientific judgment should be exercised by the investigator in deciding whether SAE reporting is appropriate in other situations such as significant medical events that may jeopardize the subject or may require medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. These events should usually be considered serious. Examples of such events include invasive or malignant cancers, intensive treatment for allergic bronchospasm, blood dyscrasias, convulsions or development of study drug dependency or study drug abuse.

[0530] AE and SAE Recording: When an AE / SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory reports and diagnostics reports) related to the event.

[0531] The investigator will then record all relevant AE / SAE information in the required CRF / SAE form.

[0532] It is not acceptable for the investigator to send photocopies of the subject’s medical records to the sponsor or designee in lieu of completion of the required CRF / SAE form.

[0533] There may be instances when copies of medical records for certain cases are requested by the sponsor or designee. In this case, all subject identifiers, with the exception of the subject number, will be redacted on the copies of the medical records before submission. 85  Patent Application

[0534] The investigator will attempt to establish a diagnosis of the event based on signs, symptoms and / or other clinical information. Whenever possible, the diagnosis (not the individual signs / symptoms) will be documented as the AE / SAE.

[0535] Assessment of Intensity

[0536] The investigator will make an assessment of intensity for each AE and SAE reported during the study and assign it to 1 of the following categories: Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with everyday activities. Moderate: Sufficient discomfort is present to cause interference with normal activity. Severe: Extreme distress, causing significant impairment of functioning or incapacitation; prevents normal everyday activities.

[0537] Assessment of Causality

[0538] The investigator is obligated to assess the relationship between study drug and each occurrence of each AE / SAE. The investigator will use clinical judgment in the assessment of causality according to the following categories: ^ Not related: A causal relationship can be excluded, and another documented cause of the AE is most plausible ^ Related: A causal relationship is clinically / biologically plausible and there exists a plausible time sequence between onset of the AE and administration of the study drug Additional factors in the assessment of causality include the following: ^ A reasonable possibility of a relationship conveys that there are facts, evidence, and / or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. ^ Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship of the event to study drug administration, will be considered and investigated. ^ The investigator will also consult the Investigator’s Brochure and / or product information, for marketed products, in his / her assessment. ^ For each AE / SAE, the investigator must document in the medical notes that he / she has reviewed the AE / SAE and has provided an assessment of causality. 86  Patent Application ^ There may be situations in which an SAE has occurred and the investigator has minimal information to include in the initial report to the sponsor or designee. However, it is very important that the investigator always make an assessment of causality for every event before the initial transmission of the SAE data to the sponsor or designee. ^ The investigator may change his / her opinion of causality in light of follow-up information and send an SAE follow-up report with the updated causality assessment. ^ The causality assessment is 1 of the criteria used when determining regulatory reporting requirements.

[0539] Follow-up of AEs and SAEs

[0540] The investigator is obligated to perform or arrange for the conduct of supplemental measurements and / or evaluations as medically indicated or as requested by the sponsor to elucidate the nature and / or causality of the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.

[0541] If a subject dies during participation in the study or during a recognized follow-up period, the investigator will provide the sponsor or designee with a copy of any postmortem findings including histopathology.

[0542] New or updated information will be recorded in the originally submitted documents.

[0543] The investigator will submit any updated SAE data to the sponsor or designee within 24 hours of receipt of the information.

[0544] SAE Reporting to Sponsor / Designee via the SAE Report Form

[0545] The primary mechanism for reporting an SAE to the sponsor / designee will be the SAE Report Form.

[0546] All SAEs will be recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours from investigator’s knowledge of the event.

[0547] Email transmission of the SAE Report Form is the preferred method to transmit this information to the sponsor / designee. 87  Patent Application

[0548] In the rare circumstance email is not available, the SAE Report Form may be sent by facsimile as a back-up reporting method.

[0549] Investigator signature is required to be collected on the SAE Report Form prior to submission. With rare exception, the form may be sent without signature in order to meet the reporting deadline; however, investigator signature is required to be obtained as soon as possible after submission.

[0550] Contacts for SAE reporting can be found on the SAE Report Form. Table 15 CONTRACEPTIVESaALLOWED DURING THE STUDY INCLUDE: r n e88  Patent Application Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The dPatent Application Table 16 - Liver Chemistry Stopping Criteria ALT AST Ab lALT A T ^ Ly , e of n,Patent Application ^ Monitor subject twice weekly until liver counter medications) on the chemistry test abnormalities resolve, stabilize concomitant medications CRF. n r yPatent Application ALT = alanine transaminase; AST = aspartate transaminase; CRF = case report form; INR = international normalized ratio; ULN = upper limit of normal 1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is unavailable, record the absence / presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 2. All events of ALT or AST ^ 3 × ULN and total bilirubin ^ 2 × ULN (> 35% direct bilirubin) or ALT or AST ^ 3 × ULN and INR > 1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to the sponsor in an expedited manner and as an SAE if SAE criteria are met (excluding studies of hepatic impairment or cirrhosis). The INR stated threshold value will not apply to subjects receiving anticoagulants. 3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 4. Record the date / time of the PK blood sample draw and the date / time of the last dose of study drug prior to the blood sample draw on the CRF. If the date / time of the last dose is unclear, provide the subject’s best approximation. If the date / time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the Study Laboratory Manual. Table 17 - Definitions Abbreviation Definition y92  Patent Application Table 17 - Definitions Abbreviation DefinitionPatent Application Table 17 - Definitions Abbreviation DefinitionPatent Application References ACELYRIN Inc, Izokibep Investigator’s Brochure. Age-Related Eye Disease Study Research Group. The age-related eye disease study (AREDS) system for classifying cataracts from photographs: AREDS report No.4. American Journal of Ophthalmology.2001;131(2):167–75. Amadi-Obi A, Yu C-R, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27 / STAT1. Nature Medicine.2007;13(6):711–18. Barisani-Asenbauer T, Maca SM, Mejdoubi L, Emminger W, Machold K, Auer H. Uveitis-a rare disease often associated with systemic diseases and infections-a systematic review of 2619 patients. Orphanet Journal of Rare Diseases.2012;7:57. Chew EY, Kim J, Sperduto RD, Datiles MB, Coleman HR, Thompson DJS, et al. Evaluation of the age-related eye disease study clinical lens grading system: AREDS report No.31. Ophthalmology.2010;117(11):2112-9.e3. Chi W, Zhu X, Yang P, Liu X, Lin X, Zhou H, et al. Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Investigative Ophthalmology and Visual Science. 2008;49(7):3058–64. Dick AD, Tugal-Tutkun I, Foster S, Zierhut M, Melissa Liew SH, Bezlyak V, et al. Secukinumab in the treatment of noninfectious uveitis: Results of three randomized, controlled clinical trials. Ophthalmology.2013;120(4):777–87. Durrani OM, Tehrani NN, Marr JE, Moradi P, Stavrou P, Murray PI. Degree, duration, and causes of visual loss in uveitis. In British Journal of Ophthalmology.2004;88(9):1159–62. Gritz DC and Wong IG. Incidence and prevalence of uveitis in Northern California: The Northern California Epidemiology of Uveitis Study. Ophthalmology.2004;111(3),491–500. Humira Summary of Product Characteristics. https: / / www.ema.europa.eu / en / documents / product- information / humira-epar-product-information_en.pdf 95  Patent Application Humira United States Prescribing Information (n.d.). Highlights of prescribing information. www.fda.gov / medwatch Jabs DA, Nussenblatt RB, Rosenbaum JT, Atmaca LS, Becker MD, Brezin AP, et al. Standardization of Uveitis Nomenclature for Reporting Clinical Data. Results of the First International Workshop. American Journal of Ophthalmology.2005;140(3):509–16. Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med.2016; 375:932-43. Lee RWJ and Dick AD. Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation. Eye (Lond).2012;26(1):17–28. Letko E, Yeh S, Stephen Foster C, Pleyer U, Brigell M, Grosskreutz CL. Efficacy and Safety of Intravenous Secukinumab in Noninfectious Uveitis Requiring Steroid-Sparing Immunosuppressive Therapy. Ophthalmology.2015;122(5):939–48. Lin P. Infectious Uveitis. Current Ophthalmology Reports.2015;3(3):170–83. Miossec P and Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nature Reviews Drug Discovery.2012;11(10):763–76. Miserocchi E, Fogliato G, Modorati G, Bandello F. Review on the Worldwide Epidemiology of Uveitis. European Journal of Ophthalmology.2013;23(5):705–17. Miserocchi, E, Modorati G, Mosconi P, Colucci A, Bandello F. Quality of Life in Patients with Uveitis on Chronic Systemic Immunosuppressive Treatment. Ocular Immunology and Inflammation.2010;18(4):297–304. Murphy CC, Hughes EH, Frost NA, Dick A. Quality of life and visual function in patients with intermediate uveitis. British Journal of Ophthalmology.2005;89(9):1161–65. Nguyen QD, Hatef E, Kayen B, MacAhilig CP, Ibrahim M, Wang J, et al. A Cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States. Ophthalmology.2011;118(1), 184–90. Nussenblatt RB, Palestine AG, Chan C-C, Roberge F. Standardizatlon of Vitreal inflammatory Activity in Intermediate and Posterior Uveitis. Ophthalmology.1985;92(4):467–71. 96  Patent Application Prete M, Dammacco R, Fatone MC, Racanelli V. Autoimmune uveitis: clinical, pathogenetic, and therapeutic features. Clinical and Experimental Medicine.2016;16(2):125–36. Rosenbaum JT. Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease. Clinical Rheumatology.2015;34(6):999–1002. Rosenbaum JT, Bodaghi B, Couto C, Zierhut M, Acharya N, Pavesio C, et al. New observations and emerging ideas in diagnosis and management of non-infectious uveitis: A review. Seminars in Arthritis and Rheumatism.2019;49(3):438–45. Rothova A, Suttorp-Van Schulten MSA, Treffers F, Kijlstra A, Treffers WF, Suttorp-Van Schulten A, et al. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Opthalmol.1996;80(4):332–36. Schiffman RM, Jacobsen G, Whitcup SM. Visual Functioning and General Health Status in Patients With Uveitis. Archives of Ophthalmology.2001;119(6):841–49. Thorne JE, Suhler E, Skup M, Tari S, Macaulay D, Chao J, et al. Prevalence of noninfectious uveitis in the United States: A claims-based analysis. JAMA Ophthalmology. 2016;134(11):1237–45. Wakefield D and Chang J. Epidemiology of Uveitis. International Ophthalmology Clinics. 2005;45(2):1–13. Zhang R, Qian J, Guo J, Yuan YF, Xue K. Suppression of experimental autoimmune uveoretinitis by anti-IL-17 antibody. Current Eye Research.2009;34(4):297–303. 97

Claims

Patent Application CLAIMS WHAT IS CLAIMED IS:

1. A method of treatment of uveitis by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep or a salt thereof.

2. The method of claim 1, wherein the composition comprises between about 155 and about 165 mg of izokibep or a salt thereof. 3 The method of claim 1 or claim 2, wherein the composition comprises between about 157 and about 162 mg of izokibep or a salt thereof. 4 The method of any one of claims 1-3, wherein the composition comprises about 160 mg of izokibep or a salt thereof. 5 The method of any one of claims 1-4, wherein the composition comprises 160 mg of izokibep or a salt thereof. 6 The method of any one of claims 1-5, wherein the composition further comprises one or more of sodium phosphate, NaCl, and EDTA. 7 The method of claim 6, wherein the composition comprises 10 mM sodium phosphate, 150 mM NaCl, and 0.5 mM EDTA. 8 The method of any one of claims 1-7, wherein the composition is administered to the patient subcutaneously. 9 The method of claim 8, wherein the composition is administered in an arm, upper thigh, and / or abdomen of the patient. 10 The method of any one of claims 1-9, wherein the composition is administered to the patient once weekly. 11 The method of any one of claims 1-9, wherein the composition is administered to patient twice weekly. 12 The method of any one of claims 1-11, wherein the composition is administered to a patient for between 1 and 52 weeks. 98Patent Application 13. The method of any one of claims 1-12, wherein the uveitis is one or more of the group consisting of an intermediate-uveitis, a posterior-uveitis, and a pan-uveitis.

14. The method of claim 13, wherein the uveitis is an intermediate-uveitis.

15. The method of claim 13, wherein the uveitis is a posterior-uveitis, and pan-uveitis.

16. The method of claim 13, wherein the uveitis is a pan-uveitis.

17. The method of any one of claims 1-16, wherein the uveitis is a non-infectious uveitis.

18. The method of any one of claim 1-17, wherein the treatment reduces IL-17 expression in the patient.

19. The method of any one of claims 1-18, wherein the treatment provides quiescence at between about 1 week and 15 weeks.

20. The method of any one of claims 1-19, wherein prior to administration, the patient received corticosteroid treatment.

21. The method of claim 20, wherein the patient tapers use of the corticosteroid during the administration.

22. The method of claim 21, wherein the patient discontinues use of the corticosteroid by a fifteenth week of administration.

23. The method of any one of claims 1-22, wherein the patient receives one or more doses of prednisone or prednisolone.

24. The method of claim 23, wherein the patient receives one dose of prednisone or prednisolone daily for a first fourteen days of the administration.

25. The method of any one of claims 1-24, wherein prior and / or during the administration, the patient receives an immunosuppressant.

26. A medicament for the treatment of uveitis in a human subject comprising between about 150 mg and about 170 mg izokibep or a salt thereof.

27. The medicament of claim 26, comprising between about 155 mg and about 165 mg of izokibep or a salt thereof. 99  Patent Application 28. The medicament of claim 26 or claim 27, comprising between about 157 mg and about 162 mg of izokibep or a salt thereof.

29. The medicament of any one of claims 26-28, comprising about 160 mg of izokibep or a salt thereof.

30. The medicament of any one of claims 26-29, comprising 160 mg of izokibep or a salt thereof.

31. The medicament of any one of claims 26-30, further comprising one or more of sodium phosphate, NaCl, and EDTA.

32. The medicament of claim 31, comprising 10 mM sodium phosphate, 150 mM NaCl, and 0.5 mM EDTA.

33. The medicament of any one of claims 26-32, wherein the medicament is formulated for subcutaneous administration.

34. The medicament of claim 33, wherein the subcutaneous administration is in an arm, upper thigh, and / or abdomen of the subject.

35. The medicament of any one of claims 26-34, wherein the medicament is administered to the subject once weekly.

36. The medicament of any one of claims 26-34, wherein the medicament is administered to the subject twice weekly.

37. The medicament of any one of claims 26-36, wherein the medicament is administered to the subject for between 1 and 52 weeks.

38. The medicament of any one of claims 26-37, wherein the uveitis is one or more of the group consisting of an intermediate-uveitis, a posterior-uveitis, and a pan-uveitis.

39. The medicament of claim 38, wherein the uveitis is an intermediate-uveitis.

40. The medicament of claim 38, wherein the uveitis is a posterior-uveitis, and pan-uveitis.

41. The medicament of claim 38, wherein the uveitis is a pan-uveitis.

42. The medicament of any one of claims 26-41, wherein the uveitis is a non-infectious uveitis.

43. The medicament of any one of claims 26-42, wherein administration of the medicament to the subject reduces IL-17 expression in the subject. 100  Patent Application 44. The medicament of any one of claims 26-43, wherein administration of the medicament to the subject provides quiescence at between about 1 week and 15 weeks.

45. The medicament of any one of claims 26-44, wherein prior to administration of the medicament, the subject received corticosteroid treatment.

46. The medicament of claim 45, wherein the subject tapers use of the corticosteroid during the administration of the medicament.

47. The medicament of claim 46, wherein the subject discontinues use of the corticosteroid by a fifteenth week of administration of the medicament.

48. The medicament of any one of claims 26-47, wherein the subject further receives one or more doses of prednisone or prednisolone during administration of the medicament.

49. The medicament of claim 48, wherein the subject receives one dose of prednisone or prednisolone daily for a first fourteen days of the administration.

50. The medicament of any one of claims 26-49, wherein prior and / or during the administration of the medicament to the subject, the subject further receives an immunosuppressant.

51. A composition comprising between about 150 mg and 170 mg of izokibep or a salt thereof for use in the treatment of uveitis.

52. A composition for use according to claim 51, wherein the composition comprises between about 155 and about 165 mg of izokibep or a salt thereof.

53. A composition for use according to claim 51 or claim 52, wherein the composition comprises between about 157 and about 162 mg of izokibep or a salt thereof.

54. A composition for use according to any one of claims 51-53, wherein the composition comprises about 160 mg of izokibep or a salt thereof.

55. A composition for use according to any one of claims 51-54, wherein the composition comprises 160 mg of izokibep or a salt thereof.

56. A composition for use according to any one of claims 51-55, wherein said treatment is as defined in any one of claims 8-25. 101  Patent Application 57. Use of a composition comprising between about 150 mg and 170 mg of izokibep or a salt thereof in the manufacture of a medicament for the treatment of uveitis.

58. Use according to claim 57, wherein the composition comprises between about 155 and about 165 mg of izokibep or a salt thereof.

59. Use according to claim 57 or claim 58, wherein the composition comprises between about 157 and about 162 mg of izokibep or a salt thereof.

60. Use according to any one of claims 57-59, wherein the composition comprises about 160 mg of izokibep or a salt thereof.

61. Use according to any one of claims 57-60, wherein the composition comprises 160 mg of izokibep or a salt thereof.

62. Use according to any one of claims 57-61, wherein said treatment is as defined in any one of claims 8-25. 102

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