22104: A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2b/3 Study to Evaluate the Efficacy and Safety of Izokibep in Subjects with Active Psoriatic Arthritis

Trial ID: 2022-501362-22-00
Protocol: 22104
Sponsor: Acelyrin Inc.

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Diseases & Conditions

Psoriatic arthropathy

Objectives

The primary objective of this study is to demonstrate the efficacy of one or both regimens of **izokibep** (160 mg weekly and 160 mg every two weeks) compared to placebo in subjects with active **psoriatic arthritis**. This is measured by the proportion of subjects achieving a 50% improvement in ACR core set measurements (ACR50) at Week 16. This objective is clinically relevant as achieving ACR50 indicates a significant reduction in disease activity, which can lead to improved patient outcomes and quality of life.

The secondary objectives include:

Demonstrating the efficacy of izokibep regimens compared to placebo, as measured by various clinical endpoints such as resolution of enthesitis, improvement in PsAID, PASI score reductions, changes in physical function, and achievement of minimal disease activity (MDA) at Week 16.
Assessing the safety and tolerability of izokibep through the incidence of treatment-emergent adverse events (TEAEs), events of interest, serious adverse events (SAEs), and clinically significant laboratory values and vital signs.
Evaluating the immunogenicity of izokibep by the presence of anti-drug antibodies (ADAs).
Investigating the efficacy of an 80 mg every four weeks regimen compared to placebo and comparing the three izokibep regimens for dose-response relationships.
Evaluating the pharmacokinetics of izokibep in subjects with psoriatic arthritis.

Participants

The clinical trial for **Psoriatic Arthritis** involves a total of 234 participants, comprising both male and female subjects. The study population includes individuals aged between 18 and 75 years, who have been clinically diagnosed with Psoriatic Arthritis with symptom onset at least six months prior to the first dose of the study drug. Participants were selected based on their inadequate response, intolerance, or contraindication to at least one prior treatment, such as NSAIDs, csDMARDs, or TNFi. The trial includes individuals who have maintained stable doses of certain medications, such as methotrexate or corticosteroids, for specified periods before the study's commencement. The trial population is not limited by gender, and both male and female subjects are included, provided they adhere to contraceptive guidelines as per local regulations. Participants are required to have a negative tuberculosis test at screening and must not have a known history of active tuberculosis. The study does not exclude vulnerable populations, ensuring a comprehensive assessment of the investigational drug's efficacy across a diverse group of individuals.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **Izokibep** in subjects with active **psoriatic arthritis**. The trial is structured in a Phase 2b/3 format and aims to demonstrate the efficacy of two dosing regimens of Izokibep (160 mg weekly and 160 mg every two weeks) compared to a placebo. The primary endpoint is the proportion of subjects achieving a 50% improvement in ACR core set measurements (ACR50) at Week 16. Secondary endpoints include the resolution of enthesitis, PsAID response, PASI90, HAQ-DI change from baseline, ACR20, and the assessment of treatment-emergent adverse events (TEAEs), events of interest, and serious adverse events (SAEs).

The trial duration is estimated to span from April 13, 2023, to November 23, 2023. Participants will be involved in the study for a maximum treatment period of 51 weeks. The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, clinical diagnosis, and active disease status. Following the screening, participants will undergo baseline assessments before randomization. Subsequent follow-up visits will occur at regular intervals to monitor efficacy and safety outcomes, with the final visit marking the end of the study.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions include the development of significant adverse events, withdrawal of consent, or non-compliance with study protocols. The study is conducted under strict adherence to ethical guidelines, ensuring that all participants provide informed consent and meet the eligibility criteria, including a negative tuberculosis test and appropriate contraceptive measures for those of childbearing potential.

Treatment

The clinical trial involves the administration of **Izokibep**, an experimental medication formulated as a **solution for injection**. Izokibep is a protein-based therapeutic agent developed by ACELYRIN, INC. The medication is administered via the **subcutaneous** route. Participants in the trial will receive a dosage of 160 mg, with two different dosing regimens being evaluated: once weekly (QW) and once every two weeks (Q2W). The maximum treatment period for Izokibep is 51 weeks. The study aims to assess the efficacy of Izokibep in subjects with active **psoriatic arthritis**, with the primary endpoint being the proportion of subjects achieving a 50% improvement in ACR core set measurements (ACR50) at Week 16.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the experimental treatment in appearance and administration method, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the true efficacy of Izokibep. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

Efficacy

The efficacy of the clinical trial evaluating **Izokibep** in subjects with active Psoriatic Arthritis will be assessed using several parameters. The primary endpoint is the proportion of subjects achieving a 50% improvement in ACR core set measurements (ACR50) at Week 16. Secondary endpoints include the resolution of enthesitis (LEI = 0) at Week 16, PsAID response at Week 16, PASI90 at Week 16, and the change in HAQ-DI from baseline to Week 16. Additionally, ACR20 at Week 16, treatment-emergent adverse events (TEAEs), events of interest, serious adverse events (SAEs), laboratory values, vital signs at collected timepoints, and treatment-emergent anti-drug antibodies (ADAs) will be evaluated.

The efficacy parameters will be measured and collected at specified timepoints, with the primary assessment occurring at Week 16. The trial employs a randomized, double-blind, placebo-controlled design to ensure the reliability of the results. The methods for measuring these endpoints include validated scales and laboratory tests, ensuring the accuracy and consistency of the data collected throughout the study. The trial aims to demonstrate the efficacy of two dosing regimens of Izokibep (160 mg weekly and 160 mg every two weeks) compared to placebo, with the primary objective being the achievement of ACR50 at the designated timepoint.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject has provided signed informed consent including consenting to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Subject must be ≥18 (or the legal age of consent in the jurisdiction in which the study is taking place) and ≤75 years of age, at the time of signing the informed consent.
Clinical diagnosis of PsA with symptom onset at least 6 months prior to first dose of study drug and fulfillment of the ClASsification for Psoriatic ARthritis (CASPAR) criteria at Screening.
Active PsA as defined by: a. ≥3 swollen joints out of 66 joints (SJC66) at screening and baseline visits. b. ≥3 tender joints out of 68 joints (TJC68) at screening and baseline visits.
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) negative at screening.
Subject must have had an inadequate response, intolerance, or contraindication to at least one of the following: a. NSAID b. csDMARD (i.e. methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, cyclosporine A) c. TNFi (e.g. adalimumab, infliximab, etanercept, golimumab, certolizumab).
For subjects using methotrexate, leflunomide, sulfasalazine, hydroxychloroquine or apremilast, treated for ≥3 months and a stable dose (not to exceed 25 mg methotrexate per week, 20 mg leflunomide per day, sulfasalazine 3 g per day, hydroxychloroquine 400 mg per day or apremilast 60 mg per day) for ≥4 weeks prior to first dose of study drug.
For subjects using corticosteroids, must have been on a stable dose and regimen and not to exceed 7.5 mg per day of prednisone (or other corticosteroid equivalent to 7.5 mg per day of prednisone) for ≥4 weeks prior to first dose of study drug.
Subjects using NSAIDs ,or low potency opioid medications (tramadol, paracetamol in combination with hydrocodone or with codeine) must have been on a stable dose and regimen for ≥ 2 weeks prior to first dose of study drug.
No known history of active tuberculosis (TB).
Subject has a negative TB test at screening, as defined by1: o Negative QuantiFERON test OR o Subjects with a positive QuantiFERON test are allowed if all of the following is satisfied: * No symptoms of TB as determined by the investigator. * Documented history of adequate prophylaxis initiation prior to receiving study drug per local guidelines. * No known exposure to a case of active TB after most recent prophylaxis. * No evidence of active TB on chest radiograph within 3 months prior to first dose of study drug. o Subjects with an indeterminate QuantiFERON test are permitted to retest once. If the retest result is indeterminate, subject may be randomized if all of the following is satisfied: * No symptoms of TB as determined by the investigator. * Documented history of adequate prophylaxis initiation prior to receiving study drug per local guidelines. * No known exposure to a case of active TB. If subject has previously received TB prophylaxis, no known exposure to active TB after most recent prophylaxis. * No evidence of active TB on chest radiograph within 3 months prior to first dose of study drug. * Deemed to be low risk per risk determination questionnaire and medical monitor review 1 T-SPOT TB test may be used to establish eligibility if agreed upon with the medical monitor.
Male and female subjects: Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. Male subjects: Male subjects are eligible to participate if they agree to the following during the study drug period and for at least 8 weeks after the last dose of study drug: • Refrain from donating semen, plus either: o Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR o Must agree to use contraception/barrier as detailed below: § Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. b. Female subjects: A female subject is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: • Is a woman of nonchildbearing potential as defined in Section 10.4 (Contraceptive and Barrier Guidance). OR • Is a WOCBP and uses a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4 during the study drug period and for at least 8 weeks after the last dose of study drug. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study drug. A WOCBP must have a negative highly sensitive serum pregnancy test at screening and a negative urine pregnancy test on Day 1 prior to the first dose of study drug, see Section 8.3.5.

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Exclusion Criteria

Any history or current confirmed diagnosis of IBD OR Any of the following symptoms (of unknown etiology) or any signs or symptoms within the last year that in the opinion of the Investigator may be suggestive of IBD, with fecal calprotectin > 500 µg/g; OR if fecal calprotectin > 150 to 500 µg/g without confirmed approval from a GI consult that an IBD diagnosis is clinically unlikely (see Section 8.2.11) when the following clinical signs and symptoms are present: a. prolonged or recurrent diarrhea b. prolonged or recurrent abdominal pain c. blood in stool
History of fibromyalgia or any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint disease other than PsA (including, but not limited to rheumatoid arthritis, gout, connective tissue diseases). Prior history of axial spondyloarthritis or fibromyalgia is permitted if documentation of change in diagnosis to PsA or documentation that the diagnosis was made incorrectly. Prior history of reactive arthritis or axial spondyloarthritis is permitted if an additional diagnosis of PsA is made. Chronic osteoarthritis symptoms that in the Investigator’s opinion may interfere with study assessments.
Uncontrolled, clinically significant system disease such as: a. diabetes mellitus b. hypertension c. cardiovascular disease including moderate to severe heart failure (New York Heart Association class III/IV) d. renal disease e. moderate to severe liver disease.
Malignancy within 5 years except treated and considered cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer, or in situ breast ductal carcinoma.
Severe, uncontrolled, medically unstable mood disorder, such as severe depression.
History or evidence of any clinically significant disorder (including psychiatric), condition, or disease that, in the opinion of the investigator, may pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
Active infection or history of infection as follows: a. Any active infection for which oral anti-infectives (antibiotics, antivirals, antifungals) were used ≤14 days prior to first dose of study drug. b. A serious infection requiring hospitalization or IV anti-infectives (antibiotics, antivirals, antifungals) ≤30 days prior to first dose of study drug. c. Recurrent or chronic infections or other active infections that in the opinion of the investigator might cause this study to be detrimental to the subject.
Candida infection requiring systemic treatment within 3 months prior to first dose of study drug.
Tuberculosis or fungal infection seen on available chest x-ray taken within 3 months prior to first dose of study drug or at screening (Exception: documented evidence of completed treatment and clinically resolved).
Known history of human immunodeficiency virus (HIV) or positive HIV test at screening.
Positive hepatitis B surface antigen (HBsAg) or detected sensitivity on the hepatitis B virus (HBV) DNA polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBcAb)/hepatitis B surface antibody (HBsAb) positive subjects OR positive hepatitis C virus antibody test at screening.
Laboratory abnormalities at screening: a. hemoglobin <9 g/dL b. platelet count <100 000/mm3 c. white blood cell count <3 000 cells/mm3 d. aspartate aminotransferase and/or alanine aminotransferase ≥2.5 times the upper limit of normal e. estimated glomerular filtration rate <60 mL/min/1.73 m2 at screening f. 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. Note: Laboratory value(s) out of range due to sampling error or that might be within range after medically appropriate supplementation may be repeated up to 2 times within the screening window before the subject is considered a screen failure.
Previous exposure to izokibep or any other IL-17 inhibitor and IL-17 receptor inhibitors (eg, secukinumab, ixekizumab, bimekizumab, brodalumab).
Prior exposure to biologics that had a potential or known association with progressive multifocal leukoencephalopathy (ie, natalizumab [Tysabri], rituximab [Rituxan], or efalizumab [Raptiva]).
Exposure to the following within 24 weeks prior to first dose of study drug: a. intramuscular (IM) or oral gold b. cytotoxic agents such as cyclophosphamide, D-penicillamine.
Exposure to the following within 12 weeks prior to first dose of study drug: a. TNFi (except etanercept within 4 weeks) b. other experimental or commercially available biologic or biosimilar therapies (within 12 weeks or 5 half-lives, whichever is longer) c. cyclosporine, azathioprine, tacrolimus d. IV gamma-globulin or Prosorba column therapy.
Exposure to the following within 4 weeks prior to first dose of study drug: a. janus kinase (JAK) inhibitor (eg, tofacitinib, upadacitinib) b. any other conventional systemic DMARD not covered above (other than methotrexate and hydroxychloroquine unless maintaining on a stable dose through the study as allowed in inclusion criteria) c. IA hyaluronic acid injections d. IA, IM, or IV corticosteroids including adrenocorticotropic hormone e. other psoriasis treatments not listed above (eg, any other biological therapies, mycophenolate mofetil, retinoids, fumarates, or phototherapy [eg, PUVA, UVA, UVB, high potency topical corticosteroids]).
Exposure to leflunomide within 8 weeks prior to first dose of study drug (unless maintaining on a stable dose through the study as allowed in inclusion criteria).
Exposure to sulfasalazine and apremilast within 1 week prior to first dose of study drug (unless maintaining a stable dose through the study as allowed in inclusion criteria).
Chronic use of medium or high potency narcotic analgesics such as morphine or morphine-derived medications, fentanyl, hydromorphone, levorphanol, meperidine, methadone, or oxycodone, at screening, as determined by investigator.
Received live vaccination ≤12 weeks prior to dosing or scheduled to receive a live vaccine within 12 weeks following the last dose of study drug.
Participating in another interventional clinical study or participated in a clinical study involving administration of a study drug within the following time period prior to dosing: 12 weeks, 5 half-lives, or twice the duration of the biological effect of the study drug (whichever is longer).
History of hypersensitivity or allergy to izokibep or its excipients.
Previously randomized or withdrawn from this study.
Active substance abuse (drug or alcohol) within 24 weeks prior to first dose of study drug, as determined by the investigator.
Any condition that compromises the ability of the subject to give written informed consent and/or subject’s unwillingness or inability to comply with study procedures.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	13 Apr 2023	10
Czechia	Not Recruiting	13 Apr 2023	10
Germany	Not Recruiting	13 Apr 2023	16
Hungary	Not Recruiting	13 Apr 2023	14
Poland	Not Recruiting	13 Apr 2023	20
Spain	Not Recruiting	13 Apr 2023	8