FIELD OF THE DISCLOSURE
[0001] This disclosure relates to an anti-IL-23pl9 antibody hum13B8-b or antigen binding
fragment thereof and its use in the treatment of psoriatic arthritis. In some embodiments, the
disclosure relates to a method of treating psoriatic arthritis wherein the treatment results in
improvement from the baseline value of both tender joint count and swollen joint count. In some
embodiments, the disclosure relates to a method of determining the efficacy of an anti-IL-23pl9
antibody for the treatment of psoriatic arthritis.
BACKGROUND
[0002] Psoriasis (PsO) is a chronic inflammatory skin disorder affecting approximately 1% to
2% of people worldwide. Psoriatic arthritis (PsA) has been defined as a unique inflammatory
arthritis associated with PsO. The precise prevalence is unknown, but estimates vary from 0.3%
to 1% of the population; among patients with PsO, the observed prevalence of inflammatory
arthritis varies from 6% to 42%. The clinical features typically present as an oligoarticular and
mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at
least 20% of patients. Gladman et al., Ann. Rheum. Dis. 64(Suppl II): iil4-iil7 (2005).
Symptoms include tenderness, pain and stiffness in and around the joints, dactylitis, spondylitis,
pain and swelling in the heels, nail disfiguration (discoloration, splitting, or pitting), and
generalized fatigue. Patients with PsA who present with polyarticular disease are at risk for
disease progression. In addition to progression of clinical and radiological damage, health
related quality of life is reduced among patients with PsA. Gladman et al. (2005).
[0003] Current treatment choices for PsA include non-steroidal anti-inflammatory drugs
(NSAIDs), corticosteroids, topical treatments (for skin), light therapy (for skin), physiotherapy,
and disease-modifying anti-rheumatic drug (DMARDs). There are also two types ofbiologics
approved for the use in treating PsA, and more recently an agent that targets interleukin-12 (IL-
12) and IL-23. Methotrexate (MTX) is approved by the U.S. Food and Drug Administration
(FDA) for the skin condition PsO, but it is frequently used off-label for PsA. Methotrexate has
been reported as providing symptomatic relief to some patients with multiple joint involvement
and PsO but there is little scientific evidence to support the use as a disease-modifying agent for
PsA.
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SUMMARY
[0004] Provided herein is a method of treating psoriatic arthritis comprising administering an
anti-IL-23p19 antibody huml3B8-b to a patient in need thereof, wherein the patient is
subcutaneously administered a first dose of the antibody on week 0 and a subsequent dose at
every 12 weeks thereafter; and wherein the antibody huml3B8-b comprises: (i) a light chain
polypeptide comprising the amino acid sequence of SEQ ID NO: 1; and (ii) a heavy chain
polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
[0005] Also provided herein is a method of treating psoriatic arthritis comprising
administering to a patient in need thereof a therapeutically effective amount of an anti -IL-23p 19
antibody huml3B8-b, wherein the treatment results in at least 20% improvement from baseline
value of tender joint count and swollen joint count; and wherein the antibody huml3B8-b
comprises: (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1;
and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
[0006] Further provided herein is a method of treating psoriatic arthritis comprising
administering to a patient in need thereof a therapeutically effective amount of an anti -IL-23p 19
antibody huml3B8-b, wherein the treatment results in at least 50% improvement from baseline
value of tender joint count and swollen joint count; and wherein the antibody huml3B8-b
comprises: (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1;
and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
[0007] Further provided herein is a method of treating psoriatic arthritis comprising
administering to a patient in need thereof a therapeutically effective amount of an anti -IL-23p 19
antibody huml3B8-b, wherein the treatment results in at least 70% improvement from baseline
value of tender joint count and swollen joint count; and wherein the antibody huml3B8-b
comprises: (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1;
and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
[0008] Further provided herein is a method of determining the efficacy of an anti-IL-23p 19
antibody for the treatment of psoriatic arthritis comprising administering an anti-IL-23p19
antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a first dose
of the antibody on week 0 and a subsequent dose at every 12 weeks after the first dose; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2, and wherein an ACR20 response value of at least about 40% at week
24 or week 52 indicates the efficacy of the antibody.
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[0009] Further provided herein is a method of determining the efficacy of an anti-IL-23p19
antibody for the treatment of psoriatic arthritis comprising administering an anti-IL-23p19
antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a first dose
of the antibody on week 0 and a subsequent dose at every 12 weeks after the first dose; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2, and wherein an ACR50 response value of at least about 20% at week
24 or week 52 indicates the efficacy of the antibody.
[001 0] Further provided herein is a method of determining the efficacy of an anti-IL-23p 19
antibody for the treatment of psoriatic arthritis comprising administering an anti-IL-23p19
antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a first dose
of the antibody on week 0 and a subsequent dose at every 12 weeks after the first dose; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2, and wherein an ACR70 response value of at least 10% at week 24 or
week 52 indicates the efficacy ofthe antibody.
[0011] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein at least a 75% improvement from baseline value in
Psoriasis Area and Severity Index at week 52 indicates the efficacy of the antibody. In some
embodiments, at least 90% improvement from baseline value in Psoriasis Area and Severity
Index at week 52 indicates the efficacy of the antibody. In some embodiments, a 100%
improvement from baseline value in Psoriasis Area and Severity Index at week 52 indicates the
efficacy ofthe antibody.
[0012] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
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acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein a reduced DAS28-CRP score from baseline value at
week 52 indicates the efficacy of the antibody. In some embodiments, the patient may
experience a DAS28 score reduced by 1, 2, 3, 4, 5, 6, 7, 8, or 9 units.
[0013] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23pl9 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein a statistically significant improvement in disease
activity as determined by the minimal disease activity (MDA) criteria at week 52 indicates the
efficacy of the antibody.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0014] Figure 1 is a schematic showing the study design. Abbreviations: B/1 =Baseline;
LTE = long-term extension; mg =milligram; PtGA =Patient Global Assessment; q = every;
Tildra = tildrakizumab; Wk =Week.
[0015] Figure 2 shows the ACR20/50/70 for patients through week 52 across treatments and
time points. Abbreviations: Q4W, every 4 weeks; Q 12W, every 12 weeks; TIL, tildrakizumab.
[0016] Figure 3 shows the ACR20/50/70 for patients through week 24 across treatments and
time points. Abbreviations: PBO, placebo; Q4W, every 4 weeks; Q 12W, every 12 weeks; TIL,
tildrakizumab. *P <0.05; tP <0.001; tP <0.0001 vs placebo.
[0017] Figure 4 shows minimal disease activity response rates from baseline to week 52 in
PsA patients across treatments and time points. Error bars represent the 95% confidence interval.
Abbreviations: PsA, psoriatic arthritis; Q4W, every 4 weeks; Q 12W, every 12 weeks; TIL,
tildrakizumab.
[0018] Figure 5 shows PASI 75/90/100 response rates up to week 52 across treatments and
time points. Response rates were calculated in patients with BSA 2:: 3% at baseline. Black
symbols corresponding p-values were analyzed using nonresponse imputation for missing
responses. P-values are based on Cochran-Mantel-Haenszel test (with prior anti-TNF use and
baseline weight as stratification factors) for nonresponse imputation dataset. *P <0.05; tP
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<0.001; tP <0.0001 versus placebo. Abbreviations: BSA, body surface area; PASI, Psoriasis
Area and Severity Index; Q4W, every 4 weeks; Q 12W, every 12 weeks; TIL, tildrakizumab.
[0019] Figure 6 shows DAS28-CRP response rates across treatments and time points. Error
bars represent 95% confidence interval. Abbreviations: Q4W, every 4 weeks; Q 12W, every 12
weeks; TIL, tildrakizumab.
DETAILED DESCRIPTION
[0020] The present disclosure relates to an anti-IL-23p19 antibody huml3B8-b or antigen
binding fragment thereof and its use in the treatment of psoriatic arthritis. In some embodiments,
provided herein is a method of treating psoriatic arthritis comprising administering an anti-IL-
23p19 antibody huml3B8-b to a patient in need thereof, wherein the patient is subcutaneously
administered a first dose of the antibody on week 0 and a subsequent dose at every 12 weeks
thereafter; and wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide
comprising the amino acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide
comprising the amino acid sequence of SEQ ID NO: 2.
[0021] As utilized in accordance with the present disclosure, unless otherwise indicated, all
technical and scientific terms shall be understood to have the same meaning as commonly
understood by one of ordinary skill in the art. Unless otherwise required by context, singular
terms shall include pluralities and plural terms shall include the singular.
[0022] The term "antibody" as used herein refers to a protein that is capable of recognizing
and specifically binding to an antigen. Ordinary or conventional mammalian antibodies
comprise a tetramer, which is typically composed oftwo identical pairs of polypeptide chains,
each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa)
and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms
"heavy chain" and "light chain," as used herein, refer to any immunoglobulin polypeptide having
sufficient variable domain sequence to confer specificity for a target antigen. The aminoterminal
portion of each light and heavy chain typically includes a variable domain of about 100
to 110 or more amino acids that typically is responsible for antigen recognition. The carboxylterminal
portion of each chain typically defines a constant domain responsible for effector
function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin
polypeptide includes a variable domain (VH) and three constant domains (CH1, CH2, and CH3) and
a hinge region between CHJ and CH2, wherein the VH domain is at the amino-terminus of the
polypeptide and the CH3 domain is at the carboxyl-terminus, and a full-length light chain
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immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL),
wherein the VL domain is at the amino-terminus of the polypeptide and the CL domain is at the
carboxyl-terminus.
[0023] Within full-length light and heavy chains, the variable and constant domains typically
are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a
"D" region of about 10 more amino acids. The variable regions of each light/heavy chain pair
typically form an antigen binding site. The variable domains of naturally occurring antibodies
typically exhibit the same general structure of relatively conserved framework regions (FR)
joined by three hypervariable regions, also called complementarity determining regions or CDRs.
The CDRs from the two chains of each pair typically are aligned by the framework regions,
which may enable binding to a specific epitope. From the amino-terminus to the carboxylterminus,
both light and heavy chain variable domains typically comprise the domains FRl,
CDRl, FR2, CDR2, FR3, CDR3, and FR4.
[0024] The term "antigen binding fragment" as used herein refers to a portion of an intact
antibody and/or refers to the antigenic determining variable domains of an intact antibody. It is
known that the antigen binding function of an antibody can be performed by fragments of a fulllength
antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab',
F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, diabodies, and multispecific
antibodies formed from antibody fragments.
[0025] In particular embodiments, the anti-IL-23pl9 antibody hum13B8-b is tildrakizumab.
The term "tildrakizumab" as used herein refers to a humanized anti-IL-23pl9 monoclonal
antibody, also known as SCH 900222 or MK-3222. Tildrakizumab is a high-affinity (297
picomolar [pM]) humanized immunoglobulin G 1/kappa (lgG l!K) antibody that specifically binds
to the pl9 protein of the IL-23 heterodimer but does not bind human IL-12 (IL-12/23p40 and
IL12p35 heterodimer) or human IL-12/23p40.
[0026] In particular embodiments, tildrakizumab comprises a light chain polypeptide
comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain polypeptide comprising
the amino acid sequence of SEQ ID NO: 2, and which is disclosed in U.S. Patent Nos. 8,404,813
and 8,293,883, the disclosures of each of which are hereby incorporated by reference in their
entireties. In other embodiments, tildrakizumab or an antigen-binding fragment thereof
comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy
chain variable domain comprises CDRl, CDR2, and CDR3 sequences of the amino acid
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sequences of SEQ ID NOs: 3-5, and wherein the light chain variable domain comprises CDRl,
CDR2, and CDR3 sequences of the amino acid sequences of SEQ ID NOs: 6-8.
[0027] As used herein, the term "subject" and "patient" are interchangeable. In some
embodiments, subjects and/or patients are mammals.
[0028] A "disorder" is any condition that would benefit from treatment using the antibodies
of the disclosure. "Disorder" and "condition" are used interchangeably herein and include
chronic and acute disorders or diseases, including those pathological conditions that predispose a
patient to the disorder in question.
[0029] The terms "treatment" or "treat" as used herein refer to both therapeutic treatment and
prophylactic or preventative measures. Those in need of treatment include patients having
psoriatic arthritis as well as those prone to have psoriatic arthritis or those in which psoriatic
arthritis is to be prevented.
[0030] The terms "administration" or "administering" as used herein refer to providing,
contacting, and/or delivering an antibody or fragment thereof by any appropriate route to achieve
the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral
(e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial,
intrasynovial, intrastemal, intrathecal, intralesional, or intracranial injection), transdermal,
topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants.
[0031] In some embodiments, the anti-IL-23pl9 antibody huml3B8-b or an antigen-binding
fragment thereof is administered every two weeks, every four weeks, every six weeks, every
eight weeks, every ten weeks, or every twelve weeks.
[0032] As used herein, the term "Week 0" refers to the first day the anti-IL-23pl9 antibody
huml3B8-b or an antigen-binding fragment thereof is administered.
[0033] In some embodiments, the anti-IL-23pl9 antibody huml3B8-b or an antigen-binding
fragment thereof is administered over a two week treatment period, over a four week treatment
period, over a six week treatment period, over an eight week treatment period, over a twelveweek
treatment period, over a twenty-four week treatment period, over a thirty-six week
treatment period, over a forty-eight week treatment period, over a sixty week treatment period
over a seventy-two week treatment period, or over a one year or more treatment period.
[0034] The therapy dose of the anti-IL-23pl9 antibody huml3B8-b or an antigen-binding
fragment thereof will vary depending, in part, upon the size (body weight, body surface, or organ
size) and condition (the age and general health) ofthe patient. In some embodiments, the patient
is administered one or more doses of the anti-IL-23pl9 antibody huml3B8-b or an antigen-
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binding fragment thereof wherein the dose is 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140
mg, 160 mg, 180 mg, or 200 mg. In some embodiments, the first dose and the subsequent dose
of the anti-IL-23pl9 antibody huml3B8-b or an antigen-binding fragment thereof are the same.
In some embodiments, the first dose and the subsequent dose of the anti-IL-23pl9 antibody
huml3B8-b or an antigen-binding fragment thereof are different. In some embodiments, the first
dose is 100 mg. In some embodiments, the first dose is 200 mg. In some embodiments, the
subsequent dose is 100 mg. In some embodiments, the subsequent dose is 200 mg. In some
embodiments, the first dose and the subsequent dose are 100 mg. In some embodiments, the first
dose and the subsequent dose are 200 mg.
[0035] In some embodiments, provided herein is a method of treating psoriatic arthritis
comprising administering to a patient in need thereof a therapeutically effective amount of an
anti-IL-23pl9 antibody huml3B8-b, wherein the treatment results in at least 20%, at least 50%,
or at least 70% improvement from baseline value of tender joint count and swollen joint count;
and wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the
amino acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 2.
[0036] For joint counts, five clinical patterns have been described among patients with PsA:
distal interphalangeal (DIP), asymmetrical oligoarticular, symmetric polyarticular, spondylitis,
and arthritis mutilans. Peripheral joints are assessed for tenderness and swelling. There is no
validated measure to assess peripheral joints in PsA; the measure used is the ACRjoint count
initially developed for the assessment of patients with rheumatoid arthritis (RA). The ACRjoint
count ranges from 28, 44, 68, and 78 for tenderness, and 28, 44, 66, and 76 for swelling
(excluding hips from the assessment of swelling, which cannot be felt at the hip joints). The
ACRjoint count of68 tender and 66 swollen joints count includes the majority of joints affected
in PsA, and it can be readily performed in a clinic visit. It includes the temporomandibular,
sternoclavicular, acromioclavicular, shoulder, elbow, wrist (including the carpometacarpal and
intercarpal joints as 1 unit), metacarpophalangeal (MCP), proximal interphalangeal (PIP), DIP,
hip, knee, talotibial, midtarsal (including subtalar), metatarsophalangeal, and interphalangeal
joints of the toes (proximal and distal joints of each toe is counted as 1 unit).
[0037] The American College of Rheumatology 20/50/70 Response Criteria (ACR20/50/70)
measures the percentage of subjects with at least a 20%, 50%, or 70% improvement from
Baseline in tender joints (68) and swollen joints (66) along with associated percentage
improvements in three of five other items: 1) the PGA of disease activity (as measured using a
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VAS), 2) the PtGA of disease activity (as measured using a VAS), 3) patient pain assessment (as
measured using a VAS), 4) patient self-assessed disability (as measured using the HAQ-DI), and
5) acute-phase c-reactive protein (CRP).
[0038] C-reactive protein (CRP) or high sensitivity C-reactive protein (hsCRP) is an acute
phase reactant, a protein made by the liver and released into the blood within a few hours after
tissue injury, the start of an infection, or other cause of inflammation, such as an autoimmune
disorder. Markedly increased levels are observed in active Psoriatic Arthritis patients and serves
as one of the biomarkers of the Psoriatic Arthritis disease condition.
[0039] Physician Global Assessment (PGA) of Disease Activity refers to an assessment
wherein a physician evaluates the status of a subject's PsA by means of a visual analog scale
(VAS). The subject is assessed according to how the subject's current arthritis is. The VAS is
anchored with verbal descriptors of "very good" to "very poor."
[0040] Patient Global Assessment of Disease Activity (PtGA) refers to an assessment
wherein a subject assesses their current global status of PsA by means of a VAS ("Considering
all the ways your arthritis affects you, on average, how have you been doing today?"), anchored
with verbal descriptors of "very well" to "very poorly".
[0041] Patient Pain Assessment refers to an assessment wherein a subject assesses their level
of present pain ("How much pain due to your arthritis are you currently experiencing?") using a
VAS. The subject rates their pain at that time on the scale that is anchored with verbal
descriptors of "no pain" to "worst possible pain".
[0042] Patient Self-assessed Disability refers to an assessment wherein subjects assess their
general disability over the past week using the HAQ-DI questionnaire.
[0043] In some embodiments, the methods disclosed herein result in at least 20%, at least
50%, or at least 70% improvement from baseline for at least three of the five parameters selected
from the group consisting of (i) Physician Global Assessment of disease activity, (ii) Patient
Global Assessment of disease activity, (iii) Patient pain assessment, (iv) patient self-assessed
disability, and (v) acute-phase CRP.
[0044] The Health Assessment Questionnaire- Disability Index (HAQ-DI) is designed to
assess patients' usual abilities using their usual equipment. Patients usually find the HAQ-DI
self-explanatory, and clarifications are seldom required. There are eight categories assessed by
the HAQ-DI: 1) dressing and grooming, 2) arising, 3) eating, 4) walking, 5) hygiene, 6) reach, 7)
grip, and 8) common daily activities. For each of these categories, patients report the amount of
difficulty they have in performing two or three specific activities. The time frame for the
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disability questions is the PAST WEEK and each question can be scored as 0 (without any
difficulty), 1 (with some difficulty), 2 (with much difficulty) or 3 (unable to do). The use of aids
and devices for these activities is also recorded. Use of any device or aid will result in a
minimum score of 2 for that category. The score for the disability index is the mean of the eight
category scores. If more than two ofthe categories, or 25%, are missing, the scale is not scored.
If fewer than two of the categories are missing, the sum of the categories is divided by the
number of answered categories. A higher score indicates greater disability.
[0045] The Disease Activity Score 28-item C-Reactive Protein (DAS28-CRP) refers to the
measurement of disease activity as assessed across 28 joints including the shoulder, elbow, wrist,
MCP (1 through 5), PIP (1 through 5), and knee, with all fourteen joints assessed for each side of
the body. It is a composite score derived from examination of the 28 joints for swelling and
tenderness, global assessment of pain and overall status using a VAS, and a blood marker of
inflammation (hsCRP).
[0046] The Leeds dactylometer refers to a validated tool for assessing dactylitis. The
dactylometer is used to measure the circumference of the base of the affected digit and is
compared to the contralateral digit. The LDI is a measure of this comparison along with a
tenderness score (0 =no tenderness, 1 =tender, 2 =tender and wince, and 3 =tender and
withdraw) for joints deemed to have dactylitis (where dactylitis is defined as a 10% difference in
the ratio of circumference of the affected digit compared to the contralateral digit). The LEI
examines tenderness at six sites: two sites (left and right) at each of the lateral epicondyles of the
humerus, medial condyles of the femur and the insertion of the Achilles tendon. For each
entheseal site, assessment is made of the adjacent joint in terms of tenderness and soft-tissue
swelling, with a score of 1 if present. The LEI score range is 0-6.
[004 7] The Psoriasis Area and Severity Index (PASI) is a measure of the average redness,
thickness, and scaliness of the lesions (each graded on a 0-4 scale), weighted by the area of
involvement. A 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 75)
is a current benchmark of primary endpoints for most clinical trials of psoriasis.
[0048] Minimal Disease Activity (MDA) is a measure for disease remission. A patient is
classified as having achieved MDA when 5 out of7 ofthe following criteria are met: tender
joint count ~1; swollen joint count ~1; psoriasis activity and severity index ~1 or body surface
area ~3; patient pain visual analog scale (VAS) score of ~15; patient global disease activity VAS
score of~20; Health Assessment Questionnaire (HAQ) score ~0.5; and tender entheseal points
~1.
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[0049] The terms "pharmaceutical composition" or "therapeutic composition" as used herein
refer to a compound or composition capable of inducing a desired therapeutic effect when
properly administered to a patient. One embodiment of the disclosure provides a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a therapeutically effective
amount of at least one antibody ofthe disclosure.
[0050] The terms "pharmaceutically acceptable carrier" or "physiologically acceptable
carrier" as used herein refer to one or more formulation materials suitable for accomplishing or
enhancing the delivery of one or more antibodies of the disclosure.
[0051] Pharmaceutical compositions comprising tildrakizumab, either alone or in
combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable
carriers are provided. The pharmaceutical compositions comprising tildrakizumab provided
herein are for use in, but not limited to, diagnosing, detecting, or monitoring a disorder, in
preventing, treating, managing, or ameliorating a disorder or one or more symptoms thereof,
and/or in research. The formulation of pharmaceutical compositions, either alone or in
combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable
carriers, is known to one skilled in the art.
[0052] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; wherein
the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein an ACR20 response value of at least about 40% at week
24 or week 52 indicates the efficacy of the antibody. In some embodiments, an ACR20 response
value of at least about 50% at week 24 or week 52 indicates the efficacy of the antibody. In
some embodiments, an ACR20 response value of at least about 60% at week 24 or week 52
indicates the efficacy of the antibody.
[0053] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
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sequence of SEQ ID NO: 2; and wherein an ACR50 response value of at least about 20% at week
24 or week 52 indicates the efficacy of the antibody. In some embodiments, an ACR50 response
value of at least about 25% at week 24 or week 52 indicates the efficacy of the antibody. In
some embodiments, an ACR50 response value of at least about 30% at week 24 or week 52
indicates the efficacy of the antibody.
[0054] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein an ACR70 response value of at least about 10% at week
24 or week 52 indicates the efficacy of the antibody. In some embodiments, an ACR70 response
value of at least about 12% at week 24 indicates the efficacy of the antibody. In some
embodiments, an ACR70 response value of at least about 15% at week 24 or week 52 indicates
the efficacy of the antibody.
[0055] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein at least a 75% improvement from baseline value in
Psoriasis Area and Severity Index at week 52 indicates the efficacy of the antibody. In some
embodiments, at least 90% improvement from baseline value in Psoriasis Area and Severity
Index at week 52 indicates the efficacy of the antibody. In some embodiments, a 100%
improvement from baseline value in Psoriasis Area and Severity Index at week 52 indicates the
efficacy ofthe antibody.
[0056] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23p19 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
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acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein a reduced DAS28-CRP score from baseline value at
week 52 indicates the efficacy of the antibody. In some embodiments, the patient may
experience a DAS28 score reduced by 1, 2, 3, 4, 5, 6, 7, 8, or 9 units.
[0057] In some embodiments provided herein is a method of determining the efficacy of an
anti-IL-23p 19 antibody for the treatment of psoriatic arthritis comprising administering an antiIL-
23pl9 antibody huml3B8-b to a patient, wherein the patient is subcutaneously administered a
first dose of the antibody on week 0 and a subsequent dose at every 12 weeks thereafter; and
wherein the antibody huml3B8-b comprises: (i) a light chain polypeptide comprising the amino
acid sequence of SEQ ID NO: 1; and (ii) a heavy chain polypeptide comprising the amino acid
sequence of SEQ ID NO: 2; and wherein a statistically significant improvement in disease
activity as determined by the minimal disease activity (MDA) criteria at week 52 indicates the
efficacy ofthe antibody.
EXAMPLES
[0058] The Examples that follow are illustrative of specific embodiments of the disclosure,
and various uses thereof. They are set forth for explanatory purposes only and should not be
construed as limiting the scope of the disclosure in any way.
Example 1: Administration of Tildrakizumab in Subjects with Active Psoriatic
Arthritis
1. Design of the Study
[0059] A randomized, double-blind, placebo-controlled, multiple-dose, Phase 2b study was
conducted to evaluate the efficacy of four dose groups oftildrakizumab administered by
subcutaenous injection in subjects with active PsA (NCT02980692). Subjects with active PsA
were randomized 1: 1: 1: 1: 1 to receive 200 milligram (mg) tildrakizumab administered by
subcutaneous (SC) injection every (q) 4 weeks up until Week 52, 200 mg tildrakizumab
administered SC ql2 weeks up until Week 52, 100 mg tildrakizumab administered SC ql2 weeks
up until Week 52, 20 mg tildrakizumab administered SCat Weeks 0 and 12, then tildrakizumab
200 mg at Weeks 24 and ql2 weeks thereafter up until Week 52, or placebo administered SCat
Weeks 0, 4, 8, 12, 16, 20, and 24, and then tildrakizumab 200 mg ql2 weeks thereafter up until
Week 52. All subjects received injections q4 weeks; subjects randomized to the 12-weekly
active treatment groups received placebo injections at Weeks 4, 8, 16, 20, 28, 32, 40, and 44.
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[0060] The study consisted of a Screening Period (Days -28 to 0); Part 1, a double-blind,
placebo-controlled period (Day 1 to Week 24); Part 2, a double-blind follow-up period (Week 25
to 52); and Part 3, a 20-week wash-out period (Week 53 to 72). During the wash-out period,
subjects no longer received tildrakizumab. Subjects who showed clinical response to treatment
(defined as 2::20% improvement from Baseline in both the swollen and tender joint counts and 2::
20% improvement from Baseline in the Patient Global Assessment [PtGA] of disease activity) at
Week 24 entered Part 2 ofthe study. Subjects receiving tildrakizumab (100 mg ql2 weeks or
200 mg [q4 and ql2 weeks] dose groups) during Part 1 who failed to show clinical response to
treatment at Week 24 were discontinued from the study drug. Subjects receiving placebo or 20
mg tildrakizumab during Part 1 who failed to show clinical response to treatment at Week 24
entered Part 2 and received 200 mg tildrakizumab q 12 weeks until Week 52. Subjects in Part 2
who were not deriving sufficient clinical benefit at any time after Week 24, were discontinued
from study drug.
[0061] The primary endpoint was measured by the proportion of subjects achieving 20%
improvement from Baseline in American College of Rheumatology response criteria (ACR20)
response rate at Week 24 and 52. Secondary efficacy endpoints included ACR50, ACR70
response rates, and the components of ACR response; proportion of subjects who require
adjustment of background therapy; proportion of subjects who achieved a DAS28-CRP < 3.2;
proportion of subjects who achieved minimal disease activity (MDA) criteria; Leeds Dactylitis
Index (LDI) and Leeds Enthesitis Index (LEI) change from Baseline; HAQ-DI change from
Baseline, and 7 5%/90%/100% improvement in the Psoriasis Area and Severity Index (PAS I).
The PK and immunogenicity oftildrakizumab and Treatment-emergent adverse events (TEAEs)
were also be evaluated.
2. Selection of Study Population
[0062] The subject population included subjects 2:: 18 years of age, with a diagnosis of PsA
(by the Classification of Psoriatic Arthritis [CASPAR] criteria) with symptoms present for at
least 6 months, 2:: 3 tender and 2:: 3 swollen joints at Screening and Baseline.
[0063] Subjects were excluded from participation in the study if aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) 2::2 times upper limit of normal (ULN), creatinine 2::
1.5 times the ULN, serum direct bilirubin 2:: 1.5 mg/dL, white blood cell (WBC) count< 3.0 x
1 03/j..lL, or positive test result for rheumatoid factor.
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[0064] Table 1 provides a summary of the demographic characteristics by treatment for the
selected subjects. Table 2 provides a summary of the baseline disease characteristics for the
selected subjects. N=number of subjects in the treatment group analysis set and n=number of
subjects in the specified category with non-missing values. Baseline is defined as the last
available value before the first dose of study drug.
Table 1: Summary of Demographic Characteristics by Treatment Full Analysis Set
Characteristic 200mg 200mg 100 mg 20 mg -> 200 mg Placebo -> 200 mg Total
Tildrakizumab Tildrakizumab Tildrakizumab Tildrakizumab Tildrakizumab (N=391)
q4wk q12wk (N=77) (N=78) (N=79)
N=78) N=79)
~ge (years)
N 78 79 77 78 79 391
Mean(SD) 50.1 (13.28) 49.3 (11.24) 49.2 (11.85) 4 7.2 (13.35) 48.1 (13.30) 48.8 (12.61)
Median 50.0 49.0 50.0 47.5 47.0 48.0
Min, Max 20,90 26,71 18,77 18,71 18,75 18,90
Sex n (%)
Male 32 (41.0) 42 (53.2) 30 (39.0) 37 (47.4) 35 (44.3) 176 (45.0)
Female 46 (59.0) 37 (46.8) 47 (61.0) 41 (52.6) 44 (55.7) 215 (55.0)
!Race n(%)
White 76 (97.4) 78 (98.7) 75 (97.4) 75 (96.2) 74 (93.7) 378 (96.7)
Black or African 0 0 1 ( 1.3) 1 ( 1.3) 3 ( 3.8) 5 ( 1.3)
American
Asian 0 0 0 0 0 0
Other 2 ( 2.6) 1 ( 1.3) 1 ( 1.3) 2 ( 2.6) 2 ( 2.5) 8 ( 2.0)
IEthnicitv n (%)
Hispanic/Latino 12 (15.4) 16 (20.3) 11 (14.3) 9 (11.5) 11 (13.9) 59 (15.1)
Not Hispanic/ Latino 66 (84.6) 63 (79.7) 66 (85.7) 69 (88.5) 68 (86.1) 332 (84.9)
!Height (em)
N 78 79 77 78 79 391
Mean(SD) 167.95 (8.944) 169.93 (9.930) 168.54 (8.921) 169.99 (10.064) 169.86 (9.896) 169.26
(9.556)
Median 168.00 170.00 168.00 168.46 170.00 168.00
Min, Max 150.0, 189.0 140.0, 190.0 150.5, 191.8 151.3, 195.0 147.2, 189.0 140.0, 195.0
Weight(kg)
N 78 79 77 78 79 391
Mean(SD) 85.05 (19.690) 87.09 (19.513) 83.59 (18.904) 85.13 (18.109) 85.31 (20.213) 85.24
(19.236)
Median 85.70 85.00 84.30 84.25 83.00 85.00
Min, Max 44.5, 135.0 48.7, 157.8 52.0, 147.0 50.4, 142.5 50.0, 140.3 44.5, 157.8
IBM! (kg/m**2)
N 78 79 77 78 79 391
Mean(SD) 30.11 (6.523) 30.19 (6.462) 29.48 (6.846) 29.37 (5.192) 29.46 (5.958) 29.72
(6.199)
Median 30.01 29.31 27.84 28.89 27.79 28.91
Min, Max 17.8, 49.5 18.6, 51.4 20.6, 50.8 18.1, 43.6 19.3, 46.3 17.8, 51.4
~bbreviations: q~every; wk-week; BMI-body mass index; SD-Standard Deviation; Min-Minimum; Max-Maximum.
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T a bl e 2 Ba se me 1sease Cha ract enst 1cs Fui lAn alySI.S se t
Characteristics 200mg 200mg 100 mg 20 mg -> 200 mg Placebo -> 200 mg Total
Tildrakizumab Tildrakizumab Tildrakizumab Tildrakizumab Tildrakizumab (N=391)
lq4wk (N =78) lq12wk(N=79) N=77) I (N=78) N=79)
!Baseline Rheumatoid Factor
(IU/mL)
N 77 79 77 75 79 387
Mean 20.00 20.00 21.40 20.60 24.53 21.32
SD 0.000 0.000 9.242 5.173 23.333 11.614
Median 20.00 20.00 20.00 20.00 20.00 20.00
Min, Max 20.0, 20.0 20.0, 20.0 20.0, 95.2 20.0, 64.8 20.0, 168.8 20.0, 168.8
Missing 1 0 0 3 0 4
!Baseline BSA Affected(%)
N 78 79 77 78 79 391
Mean 11.9 9.0 12.8 10.4 8.2 10.4
SD 16.02 12.38 16.01 14.11 12.18 14.26
Median 5.0 4.0 8.0 4.0 3.0 5.0
Min, Max 0,85 0,56 0, 90 0, 70 0, 80 0, 90
!Baseline BSA Affected
>=3%n(%)
Yes 53 (67.9) 44 (55.7) 54 (70.1) 41 (52.6) 42 (53.2) 234 (59.8)
No 25 (32.1) 35 (44.3) 23 (29.9) 37 (47.4) 37 (46.8) 157 (40.2)
!Baseline Tendor Joint Counts
N 78 79 77 78 79 391
Mean 16.6 19.5 21.3 19.0 19.7 19.2
SD 11.93 13.90 14.80 12.95 14.66 13.70
Median 13.5 15.0 19.0 14.0 15.0 15.0
Min, Max 3, 64 4, 63 3,59 4,54 3,64 3, 64
!Baseline Swollen Joint Counts
N 78 79 77 78 79 391
Mean 10.4 10.0 11.0 9.4 11.8 10.5
SD 7.43 7.95 8.21 6.41 9.75 8.03
Median 8.0 7.0 8.0 8.0 8.0 8.0
Min, Max 3,35 3,45 0,38 3,38 3,42 0, 45
!Baseline PGA of Disease
k\ctivity Score
N 78 79 77 78 79 391
Mean 54.0 55.4 57.3 59.4 59.5 57.1
SD 16.12 16.21 17.31 14.44 15.59 16.02
Median 55.5 56.0 59.0 60.5 58.0 57.0
Min, Max 9,88 20,83 3,95 25,94 19,93 3, 95
!Baseline PtGA of Disease
l".ctivitv Score
N 78 79 77 78 79 391
Mean 57.8 61.1 60.3 61.9 65.2 61.3
SD 18.31 20.74 20.24 17.36 18.12 19.05
Median 57.5 66.0 65.0 62.0 66.0 62.0
Min, Max 13,90 5, 94 16, 100 21, 100 21, 100 5, 100
!Baseline Patient's Pain
k\ssessment Score
N 78 79 77 78 79 391
Mean 55.4 59.6 59.2 60.9 64.2 59.9
SD 19.09 23.54 22.08 19.70 20.36 21.10
Median 57.0 65.0 60.0 63.0 68.0 62.0
Min, Max 9,97 4, 98 5, 100 16, 100 13, 100 4, 100
!Baseline HAQ-DI
N 78 79 77 78 79 391
Mean 1.0481 1.0111 1.0471 1.0545 1.1614 1.0646
SD 0.61806 0.64307 0.71031 0.60255 0.59584 0.63384
Median 1.1250 1.0000 1.1250 1.0000 1.2500 1.1250
Min, Max 0.000, 2.875 0.000, 2.500 0.000, 2. 750 0.000, 2.375 0.000, 2.500 0.000, 2.875
!Baseline hsCRP (mg/L)
N 78 79 77 78 79 391
Mean 7.827 10.483 10.587 10.733 13.002 10.533
SD 18.6437 14.4210 20.0102 13.9524 20.8016 17.7744
Median 3.310 3.720 4.880 5.145 5.720 4.390
Min, Max 0.30, 156.50 0.27, 85.04 0.10, 155.87 0.22, 67.43 0.21, 123.95 0.10, 156.50
~bbreviations: BSA=Body Surface Area; hsCRP=C-reactive protein; HAQ-DI=Health Assessment Questionnaire Disability Index;
IPGA=Physician Global Assessment; PtGA=Patient Global Assessment;q=every; wk=week; SD=Standard Deviation; Min= Minimum;
!Max= Maximum.
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3. Statistical Analysis
[0065] The primary efficacy analysis population was the Full Analysis Set (F AS) defined as
all randomized subjects who have received at least 1 dose of Investigational Medicinal Product
(IMP). The primary analysis was based on the Cochran-Mantel-Haenszel test, incorporating
prior anti-TNF use and Baseline weight as stratification factors, to compare response rates for the
primary endpoint (ACR20 at Week 24 and Week 52) between placebo and each of the respective
active dose arms. In addition, response rate difference between placebo and each of the
respective active dose arms and the corresponding confidence interval (CI) was estimated. Early
withdrawals and any other subjects with incomplete data at Week 24 were classified as nonresponders
for the primary endpoint (ACR20). Subjects who failed to show minimal response to
treatment (defined as< 10% improvement from Baseline in either swollen or tender joint counts)
at Week 16 may have had their background medications adjusted according to the maximum
permitted daily dose and continue in the study. Any subjects requiring these adjustments were
counted as non-responders for the primary analysis.
[0066] Analyses ofthe primary endpoint will be based on the FAS. A sensitivity analysis
was performed based on PP AS.
4. Results up to Week 24
[0067] The summary of the subject status at Week 24 is presented in Table 3. The safety
analysis set consisted of all randomized subjects who received at least 1 dose ofiMP. The full
analysis set consisted of all randomized subjects who received at least 1 dose of investigational
medicinal product (IMP). The per-protocol analysis set consisted of all subjects in the full
analysis set without any major protocol deviations that could have influenced the validity of the
data for the primary efficacy variables. Percentages were based on the number of subjects
randomized except for Completers and Discontinuation where percentages are based on the
number of subjects in the safety analysis set. Part 1 is a double-blind placebo-controlled period
from baseline to Week 24, and Part 2 is a double-blind follow-up period from Week 25 to Week
52.
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Table 3: Summary of Subject Status at Week 24
!Population Subset 200mg 200mg 100 mg 20 mg -> 200 mg Placebo -> 200 mg Total
Tildrakizumab Tildrakizumab Tildrakizumab Tildrakizumab Tildrakizumab n(%)
q4wk q12wk n(%) n(%) n(%)
n(%) n(%)
!Number of Subject Screened 500
!Number of Screen Failure 109
!Number of Subject 78 79 77 78 79 391
!Randomized
Did not take study drug 0 0 0 0 0 0
Safety Analysis Set (a) 78 (100.0) 79 (100.0) 77 (100.0) 78 (100.0) 79 (100.0) 391 (100.0)
Full Analysis Set (b) 78 (100.0) 79 (100.0) 77 (100.0) 78 (100.0) 79 (100.0) 391 (100.0)
Per Protocol Analysis Set 78 (100.0) 79 (100.0) 77 (100.0) 78 (100.0) 79 (100.0) 391 (100.0)
(c)
Completers for Treatment 5 ( 6.4) 2 ( 2.5) 5 ( 6.5) 5 ( 6.4) 9 (11.4) 26 ( 6.6)
Discontinued from Treatment 16 (20.5) 17 (21.5) 21 (27.3) 7 ( 9.0) 7 ( 8.9) 68 (17.4)
Completed Part 1 Treatment 61 (78.2) 64 (81.0) 60 (77.9) 71 (91.0) 74 (93.7) 330 (84.4)
!Discontinued Treatment in 16 (20.5) 15 (19.0) 17 (22.1) 7 ( 9.0) 5 ( 6.3) 60 (15.3)
!Part 1
Completed Part 2 Treatment 5 ( 6.4) 2 ( 2.5) 5 ( 6.5) 5 ( 6.4) 9 (11.4) 26 ( 6.6)
!Discontinued Treatment in 0 2 ( 2.5) 4 ( 5.2) 0 2 ( 2.5) 8 ( 2.0)
!Part 2
Completers for Study 8 (10.3) 6 ( 7.6) 9 (11.7) 6 ( 7.7) 8 (10.1) 37 ( 9.5)
!Discontinued from Study 7 ( 9.0) 5 ( 6.3) 11 (14.3) 4 ( 5.1) 6 ( 7.6) 33 ( 8.4)
~bbreviations: q~every; wk=week; IMP-Investigational Medicinal Product.
[0068] The Cochran-Mantel Haenszel (CMH) analysis of ACR20 response rates up to Week
24 is illustrated in Table 4. ACR20 was calculated as a >=20% improvement from baseline in
tender and swollen joint counts and >=20% improvement from baseline in three of the five
remaining ACR-core set measures: patient and physician global assessments, pain, disability, and
an acute-phase CRP. Subjects receiving tildrakizumab (100 mg ql2 weeks or 200 mg [q4 and
ql2 weeks] dose groups) during Part 1 who failed to show clinical response to treatment at Week
24 were discontinued study drug and entered the washout period per protocol. Week 24
assessments for subjects who discontinue study drug were recorded at Week 52/EOT. Two-sided
95% CI and p-value were based on the CMH test with prior anti-TNF use and Baseline weight as
stratification factors. IfMantel-Fleiss criterion was less than 5, pairwise comparisons were based
on Fisher's exact tests after collapsing across levels of the stratification factors. This is noted
with a"*" for p-value. Baseline is defined as the last available value before the first dose of
study drug.
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Table 4: CMH Analysis of ACR20 Response Rates up to Week 24 (Missing Response= Nonresponse
) -Pn .m ary An al1y SI.S Fu 11 An al1y SI.S Se t
Comparison to Placebo
95% Confidence
Interval
Visit Treatment Group N n Response SE(%) Difference SE of Lower Upper p-value
Rate(%) %) Difference(%) %) %)
Week 1 200 mg tildrakizumab q4wk 78 8 10.26 3.44
200 mg tildrakizumab q 12wk 79 9 11.39 3.57
100 mg tildrakizumab 77 5 6.49 2.81
20 mg tildrakizumab 78 5 6.41 2.77
Placebo 79 4 5.06 2.47
200 mg tildrakizumab q4wk vs Placebo 5.18 4.20 -3.05 13.41 0.2235
200 mg tildrakizumab q 12wk vs Placebo 6.34 4.35 -2.18 14.86 0.1504
100 mg tildrakizumab vs Placebo 1.43 3.74 -5.90 8.76 0.7441 *
20 mg tildrakizumab vs Placebo 1.35 3.71 -5.93 8.62 0.7458*
Week4 200 mg tildrakizumab q4wk 78 17 21.79 4.67
200 mg tildrakizumab q 12wk 79 16 20.25 4.52
100 mg tildrakizumab 77 23 29.87 5.22
20 mg tildrakizumab 78 14 17.95 4.35
Placebo 79 15 18.99 4.41
200 mg tildrakizumab q4wk vs Placebo 2.85 6.31 -9.53 15.22 0.6553
200 mg tildrakizumab q 12wk vs Placebo 1.31 6.38 -11.19 13.81 0.8378
100 mg tildrakizumab vs Placebo 11.04 6.90 -2.49 24.57 0.1125
20 mg tildrakizumab vs Placebo -0.96 6.27 -13.25 11.32 0.8777
WeekS 200 mg tildrakizumab q4wk 78 35 44.87 5.63
200 mg tildrakizumab q 12wk 79 30 37.97 5.46
100 mg tildrakizumab 77 37 48.05 5.69
20 mg tildrakizumab 78 29 37.18 5.47
Placebo 79 22 27.85 5.04
200 mg tildrakizumab q4wk vs Placebo 16.89 7.49 2.22 31.56 0.0261
200 mg tildrakizumab q 12wk vs Placebo 10.09 7.48 -4.57 24.75 0.1812
100 mg tildrakizumab vs Placebo 20.49 7.53 5.74 35.24 0.0086
20 mg tildrakizumab vs Placebo 9.46 7.47 -5.18 24.09 0.2091
Week 12 200 mg tildrakizumab q4wk 78 41 52.56 5.65
200 mg tildrakizumab q 12wk 79 39 49.37 5.62
100 mg tildrakizumab 77 36 46.75 5.69
20 mg tildrakizumab 78 32 41.03 5.57
Placebo 79 26 32.91 5.29
200 mg tildrakizumab q4wk vs Placebo 19.37 7.68 4.31 34.43 0.0144
200 mg tildrakizumab q 12wk vs Placebo 16.25 7.73 1.11 31.39 0.0395
100 mg tildrakizumab vs Placebo 13.90 7.76 -1.30 29.11 0.0759
20 mg tildrakizumab vs Placebo 8.03 7.69 -7.05 23.11 0.3019
Week 16 200 mg tildrakizumab q4wk 78 54 69.23 5.23
200 mg tildrakizumab q 12wk 79 45 56.96 5.57
100 mg tildrakizumab 77 42 54.55 5.67
20 mg tildrakizumab 78 36 46.15 5.64
Placebo 79 27 34.18 5.34
200 mg tildrakizumab q4wk vs Placebo 34.51 7.39 20.02 48.99 <.0001
200 mg tildrakizumab q 12wk vs Placebo 22.34 7.65 7.34 37.34 0.0047
100 mg tildrakizumab vs Placebo 20.34 7.79 5.07 35.61 0.0114
20 mg tildrakizumab vs Placebo 11.81 7.76 -3.40 27.03 0.1349
Week20 200 mg tildrakizumab q4wk 78 57 73.08 5.02
200 mg tildrakizumab q 12wk 79 54 68.35 5.23
100 mg tildrakizumab 77 46 59.74 5.59
20 mg tildrakizumab 78 42 53.85 5.64
Placebo 79 28 35.44 5.38
200 mg tildrakizumab q4wk vs Placebo 37.19 7.29 22.90 51.48 <.0001
200 mg tildrakizumab q 12wk vs Placebo 32.71 7.49 18.03 47.39 <.0001
100 mg tildrakizumab vs Placebo 24.05 7.69 8.99 39.11 0.0026
20 mg tildrakizumab vs Placebo 18.09 7.75 2.89 33.29 0.0228
Contd.
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Comparison to Placebo
95% Confidence
Interval
Visit Treatment Group N n Response SE Difference SEof Lower Upper p-value
Rate(%) (%) (%) Difference(%) (%) (%)
Week24 200 mg tildrakizumab q4wk 78 62 79.49 4.57
200 mg tildrakizumab q 12wk 79 61 77.22 4.72
100 mg tildrakizumab 77 55 71.43 5.15
20 mg tildrakizumab 78 57 73.08 5.02
!Placebo 79 40 50.63 5.62
200 mg tildrakizumab q4wk vs Placeb 28.42 7.16 14.39 42.45 0.0002
0
200 mg tildrakizumab q 12wk vs Place 26.22 7.33 11.85 40.58 0.0006
~0
100 mg tildrakizumab vs Placebo 20.54 7.54 5.75 35.32 0.0085
20 mg tildrakizumab vs Placebo 22.21 7.53 7.44 36.98 0.0043
Abbreviations: q=every; wk=week; ACR=American College of Rheumatology; CMH=Cochran-Mantel-Haenszel; CRP=Creactive
protein; SE=Standard Error.
N=number of subjects in full analysis set. n=number of responders.
[0069] Table 5 illustrates CMH analysis of the ACR 50 response rates up to Week 24.
ACR50 is calculated as a >=50% improvement from baseline in tender and swollen joint counts
and >=50% improvement from baseline in three of the five remaining ACR-core set measures:
patient and physician global assessments, pain, disability, and an acute-phase CRP. The ACR50
analysis was implemented in the same way as described above for the ACR20 analysis.
[0070] Subjects receiving tildrakizumab (100 mg ql2 weeks or 200 mg [q4 and ql2 weeks]
dose groups) during Part 1 who fail to show clinical response to treatment at Week 24 will
discontinue the study drug and enter the washout period per protocol. Week 24 assessments for
subjects who discontinue the study drug are recorded at Week 52/EOT. These assessments will
be reported as part of the Week 24 visit. Two-sided 95% CI and p-value are based on the CMH
test with prior anti-TNF use and Baseline weight as stratification factors. IfMantel-Fleiss
criterion is less than 5, pairwise comparisons will be based on Fisher's exact tests after collapsing
across levels of the stratification factors. This is noted with a"*" for p-value. Baseline is
defined as the last available value before the first dose of study drug.

WHAT IS CLAIMED IS:
1 1. A method oftreating psoriatic arthritis comprising administering an anti-IL-23pl9
2 antibody huml3B8-b to a patient in need thereof, wherein the patient is subcutaneously
3 administered a first dose of the antibody on week 0 and a subsequent dose at every 12 weeks
4 thereafter; and wherein the antibody huml3B8-b comprises:
5
6
7
8
1 2.
(i)
1; and
(ii)
a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
2.
The method according to claim 1, wherein the first dose and the subsequent dose are
2 the same.
1 3. The method according to claim 1, wherein the first dose and the subsequent dose are
2 different.
1
1
1
1
4.
5.
6.
7.
The method according to claim 1, wherein the first dose is 100 mg.
The method according to claim 1, wherein the first dose is 200 mg.
The method according to claim 1, wherein the subsequent dose is 100 mg.
The method according to claim 1, wherein the subsequent dose is 200 mg.
1 8. The method according to claim 2, wherein the first dose and the subsequent dose are
2 100 mg.
1 9. The method according to claim 2, wherein the first dose and the subsequent dose are
2 200 mg.
1 10. The method according to claim 3, wherein the first dose is 100 mg and the subsequent
2 dose is 200 mg.
1 11. The method according to claim 3, wherein the first dose is 200 mg and the subsequent
2 dose is 100 mg.
1 12. The method according to claim 1, wherein the treatment comprises administration of
2 the subsequent dose at every 12 weeks at least up to 24 weeks.
1 13. The method according to claim 1, wherein the treatment comprises administration of
2 the subsequent dose at every 12 weeks at least up to 36 weeks.
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1 14. The method according to claim 1, wherein the treatment comprises administration of
2 the subsequent dose at every 12 weeks at least up to 48 weeks.
1 15. The method according to claim 1, wherein the treatment comprises administration of
2 the subsequent dose at every 12 weeks at least up to 60 weeks.
1 16. The method according to claim 1, wherein the treatment comprises administration of
2 the subsequent dose at every 12 weeks at least up to 72 weeks.
1 17. A method of treating psoriatic arthritis comprising administering to a patient in need
2 thereof a therapeutically effective amount of an anti-IL-23pl9 antibody huml3B8-b, wherein
3 the treatment results in at least 20% improvement from baseline value of tender joint count
4 and swollen joint count; and wherein the antibody huml3B8-b comprises:
5
6
7
8
1
2
3
4
5
1
2
3
4
5
6
7
(i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
1; and
(ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
2.
18. The method according to claim 17, wherein the treatment further results in at least
20% improvement from baseline for at least three of the five parameters selected from the
group consisting of (i) Physician Global Assessment of disease activity, (ii) Patient Global
Assessment of disease activity, (iii) Patient pain assessment, (iv) patient self-assessed
disability, and (v) acute-phase CRP.
19. A method of treating psoriatic arthritis comprising administering to a patient in need
thereof a therapeutically effective amount of an anti-IL-23pl9 antibody huml3B8-b, wherein
the treatment results in at least 50% improvement from baseline value of tender joint count
and swollen joint count; and wherein the antibody huml3B8-b comprises:
(i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
1; and
(ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
8 2.
1 20. The method according to claim 19, wherein the treatment further results in at least
2 50% improvement from baseline for at least three of the five parameters selected from the
3 group consisting of (i) Physician Global Assessment of disease activity, (ii) Patient Global
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4 Assessment of disease activity, (iii) Patient pain assessment, (iv) patient self-assessed
5 disability, and (v) acute-phase CRP.
1 21. A method of treating psoriatic arthritis comprising administering to a patient in need
2 thereof a therapeutically effective amount of an anti-IL-23p19 antibody hum13B8-b, wherein
3 the treatment results in at least 70% improvement from baseline value of tender joint count
4 and swollen joint count; and wherein the antibody hum13B8-b comprises:
5
6
7
8 2.
1 22.
(i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
1; and
(ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
The method according to claim 21, wherein the treatment further results in at least
2 70% improvement from baseline for at least three of the five parameters selected from the
3 group consisting of (i) Physician Global Assessment of disease activity, (ii) Patient Global
4 Assessment of disease activity, (iii) Patient pain assessment, (iv) patient self-assessed
5 disability, and (v) acute-phase CRP.
1 23. A method of determining the efficacy of an anti-IL-23p19 antibody for the treatment
2 of psoriatic arthritis comprising administering an anti-IL-23p19 antibody hum13B8-b to a
3 patient, wherein the patient is subcutaneously administered a first dose of the antibody on
4 week 0 and a subsequent dose at every 12 weeks after the first dose; and wherein the antibody
5 hum13B8-b comprises:
6
7
8
9
10
11
1
2·
'
24.
(i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
1; and
(ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
and wherein an ACR20 response value of at least about 40% at week 24 or week 52
indicates the efficacy of the antibody.
The method according to claim 23, wherein an ACR20 response value of at least about
2 50% at week 24 or week 52 indicates the efficacy of the antibody.
1 25. The method according to claim 23, wherein an ACR20 response value of at least about
2 60% at week 24 or week 52 indicates the efficacy of the antibody.
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1 26. A method of determining the efficacy of an anti-IL-23p 19 antibody for the treatment
2 of psoriatic arthritis comprising administering an anti-IL-23pl9 antibody huml3B8-b to a
3 patient, wherein the patient is subcutaneously administered a first dose of the antibody on
4 week 0 and a subsequent dose at every 12 weeks after the first dose; and wherein the antibody
5 huml3B8-b comprises:
6
7
8
9
10
1 27.
(i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
1; and
(ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
2; and wherein an ACR50 response value of at least about 20% at week 24 or week 52
indicates the efficacy of the antibody.
The method according to claim 26, wherein an ACR50 response value of at least about
2 25% at week 24 or week 52 indicates the efficacy of the antibody.
1 28. The method according to claim 26, wherein an ACR50 response value of at least about
2 30% at week 24 or week 52 indicates the efficacy of the antibody.
1 29. A method of determining the efficacy of an anti-IL-23pl9 antibody for the treatment
2 of psoriatic arthritis comprising administering an anti-IL-23pl9 antibody huml3B8-b to a
3 patient, wherein the patient is subcutaneously administered a first dose of the antibody on
4 week 0 and a subsequent dose at every 12 weeks after the first dose; and wherein the antibody
5 huml3B8-b comprises:
6
7
8
9
10
11
1
2·
'
30.
(i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:
1; and
(ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:
and wherein an ACR70 response value of at least 10% at week 24 or week 52 indicates
the efficacy of the antibody.
The method according to claim 29, wherein an ACR50 response value of at least about
2 12% at week 24 or week 52 indicates the efficacy of the antibody.
1 31. The method according to claim 29, wherein an ACR50 response value of at least about
2 15% at week 24 or week 52 indicates the efficacy of the antibody.
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1 32. The method according to any one of claims 23-31, wherein the first dose and the
2 subsequent dose are same.
1 33. The method according to any one of claims 23-31, wherein the first dose and the
2 subsequent dose are different.
1
1
1
34.
35.
36.
2 mg.
1 37.
2 mg.
1 38.
The method according to any one of claims 23-31, wherein the first dose is 100 mg.
The method according to any one of claims 23-31, wherein the first dose is 200 mg.
The method according to any one of claims 23-31, wherein the subsequent dose is 100
The method according to any one of claims 23-31, wherein the subsequent dose is 200
The method according to any one of claims 23-31, wherein the first dose and the
2 subsequent dose are 100 mg.
1 39. The method according to any one of claims 23-31, wherein the first dose and the
2 subsequent dose are 200 mg.
1 40. A method of determining the efficacy of an anti-IL-23pl9 antibody for the treatment
2 of psoriatic arthritis comprising administering an anti-IL-23pl9 antibody huml3B8-b to a
3 patient, wherein the patient is subcutaneously administered a first dose of the antibody on
4 week 0 and a subsequent dose at every 12 weeks thereafter; and wherein the antibody
5 huml3B8-b comprises:
6 (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1;
7 and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID
8 NO: 2;
9 and wherein at least a 75% improvement from baseline value in Psoriasis Area and
10 Severity Index at week 52 indicates the efficacy of the antibody.
1 41. The method according to claim 40, wherein at least 90% improvement from baseline
2 value in Psoriasis Area and Severity Index at week 52 indicates the efficacy of the antibody.
1 42. The method according to claim 40, wherein at least 100% improvement from baseline
2 value in Psoriasis Area and Severity Index at week 52 indicates the efficacy of the antibody.
1 43. A method of determining the efficacy of an anti-IL-23pl9 antibody for the treatment
2 of psoriatic arthritis comprising administering an anti-IL-23pl9 antibody huml3B8-b to a
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3 patient, wherein the patient is subcutaneously administered a first dose of the antibody on
4 week 0 and a subsequent dose at every 12 weeks thereafter; and wherein the antibody
5 hum13B8-b comprises:
6 (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1;
7 and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID
8 NO: 2; and
9 wherein a reduced DAS28-CRP score from baseline value at week 52 indicates the
10 efficacy of the antibody.
1 44. A method of determining the efficacy of an anti-IL-23p19 antibody for the treatment
2 of psoriatic arthritis comprising administering an anti-IL-23p19 antibody hum13B8-b to a
3 patient, wherein the patient is subcutaneously administered a first dose of the antibody on
4 week 0 and a subsequent dose at every 12 weeks thereafter; and wherein the antibody
5 hum13B8-b comprises:
6 (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1;
7 and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID
8 NO: 2; and
9 wherein a statistically significant improvement in disease activity as determined by the
10 minimal disease activity (MDA) criteria at week 52 indicates the efficacy of the
11 antibody.