A study to test if izokibep improves psoriatic arthritis symptoms and to see how safe izokibep is

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acelyrin Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

18 Apr 2023 → 4 Oct 2024

Decision date (initial)

2023-04-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To demonstrate that 1 or both regimens of izokibep (160 mg QW and 160 mg Q2W) are efficacious compared to placebo, as measured by the proportion of subjects achieving 50%
improvement in ACR core set measurements (ACR50) at Week 16

Secondary objectives 6

1. To demonstrate that 1 or both regimens of izokibep (160 mg QW and 160 mg Q2W) are efficacious compared to placebo, as measured by: • Proportion of subjects with resolution of enthesitis at Week 16 as assessed by LEI in subpopulation that had enthesitis (LEI > 0) at baseline • Proportion of subjects achieving an improvement in PsAID of at least 3 units at Week 16 compared to baseline in subjects with PsAID ≥ 3 at baseline • Proportion of subjects achieving 90% or greater reduction in PASI score from baseline (PASI90) at Week 16 in subjects with ≥ 3% BSA psoriasis at baseline • Change in physical function as assessed by HAQ-DI change from baseline to Week 16 • Proportion of subjects achieving 20% improvement in ACR core set measurements (ACR20) at Week 16 • Proportion of subjects achieving minimal disease activity (MDA) at Week 16
2. To assess the safety and tolerability of izokibep as measured by the incidence of TEAEs, events of interest, SAEs, and clinically significant laboratory values and vital signs
3. To assess the immunogenicity of izokibep as measured by the presence of ADAs
4. To demonstrate that 1 or both regimens of izokibep (160 mg QW and 160 mg Q2W) are efficacious compared to placebo, as measured by: • Proportion of subjects achieving 70% improvement in ACR core set measurements (ACR70) at Weeks 16, 24, and 52 • Change in DAS28-CRP at Weeks 16, 24, and 52 as compared to baseline • Change in DAPSA score at Weeks 16, 24, and 52 as compared to baseline • Change in clinical DAPSA (cDAPSA) score at Weeks 16, 24, and 52, as compared to baseline • Proportion of subjects achieving DAPSA and proportion of subjects achieving cDAPSA low disease activity or remission at Weeks 16, 24, and 52 • Proportion of subjects achieving DAPSA and proportion of subjects achieving cDAPSA remission at Weeks 16, 24, and 52 • Change in PASDAS at Weeks 16, 24, and 52 as compared to baseline • Proportion of subjects achieving 75% or greater reduction in PASI score from baseline (PASI75) at Weeks 16, 24, and 52 in subjects with ≥3% BSA psoriasis at baseline • Proportion of subjects achieving 100% reduction in PASI score from baseline (PASI100) at Weeks 16, 24, and 52 in subjects with ≥3% BSA psoriasis at baseline • Proportion of subjects achieving MDA at Weeks 24, and 52 • Proportion of subjects achieving VLDA response at Weeks 16, 24, and 52 • Proportion of subjects with resolution of dactylitis at Weeks 16, 24, and 52 in subpopulation that had dactylitis at baseline (pooled izokibep doses), as assessed with LDI • Change from baseline in mNAPSI at Weeks 16, 24, and 52 in subpopulation with nail psoriasis at baseline (pooled izokibep doses) • Progression of structural damage assessed radiographically and expressed as the change in mTSS at Weeks 16 and 52, compared to baseline • Change in SPARCC enthesitis score at Weeks 16, 24, and 52, as compared to baseline in subpopulation with enthesitis (SPARCC > 0) at baseline • Change in spinal pain NRS at Weeks 16, 24, and 52, as compared to baseline in subjects reporting spinal pain at baseline • Change in quality of life as assessed by SF-36 total score, physical component summary (PCS), and mental component summary (MCS) change from baseline to Weeks 16, 24, and 52 • Fatigue as assessed by FACIT-F change from baseline to Weeks 16, 24, and 52 • Proportion of subjects achieving ACR50 at Weeks 24 and 52 • Proportion of subjects achieving PASI90 at Weeks 24 and 52 in subjects with ≥3% BSA psoriasis at baseline • Change in physical function as assessed by HAQ-DI change from baseline to Weeks 24 and 52 • Proportion of subjects with resolution of enthesitis at Weeks 24 and 52 as assessed by LEI in subpopulation that had enthesitis (LEI > 0) at baseline • Proportion of subjects achieving an improvement in PsAID of at least 3 units at Weeks 24 and 52 compared to baseline in subjects with PsAID ≥3 at baseline • Proportion of subjects achieving ACR20 at Weeks 24 and 52
5. To investigate that the 80 mg Q4W regimen is efficacious compared to placebo, as measured by the same primary, secondary and exploratory endpoints. To compare the three regimens of izokibep for assessment of dose-response relationships, as measured by the primary and secondary endpoints.
6. To evaluate the pharmacokinetics of izokibep in subjects with psoriatic arthritis

Conditions and MedDRA coding

Psoriatic Arthritis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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.
2. 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.
3. 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.
4. 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.
5. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) negative at screening.
6. 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).
7. 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.
8. 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.
9. 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.
10. No known history of active tuberculosis (TB).
11. 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.
12. 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.

Exclusion criteria 26

1. 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
2. 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.
3. 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.
4. 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.
5. Severe, uncontrolled, medically unstable mood disorder, such as severe depression.
6. 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.
7. 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.
8. Candida infection requiring systemic treatment within 3 months prior to first dose of study drug.
9. 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).
10. Known history of human immunodeficiency virus (HIV) or positive HIV test at screening.
11. 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.
12. 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.
13. Previous exposure to izokibep or any other IL-17 inhibitor and IL-17 receptor inhibitors (eg, secukinumab, ixekizumab, bimekizumab, brodalumab).
14. Prior exposure to biologics that had a potential or known association with progressive multifocal leukoencephalopathy (ie, natalizumab [Tysabri], rituximab [Rituxan], or efalizumab [Raptiva]).
15. 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.
16. 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.
17. 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]).
18. 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).
19. 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).
20. 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.
21. 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.
22. 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).
23. History of hypersensitivity or allergy to izokibep or its excipients.
24. Previously randomized or withdrawn from this study.
25. Active substance abuse (drug or alcohol) within 24 weeks prior to first dose of study drug, as determined by the investigator.
26. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ACR50 at Week 16

Secondary endpoints 1

1. • Resolution of enthesitis (LEI = 0) at Week 16 • PsAID response at Week 16 • PASI90 at Week 16 • HAQ-DI change from baseline to Week 16 • ACR20 at Week 16 • TEAEs, events of interest, and SAEs • Laboratory values and vital signs at collected timepoints • Treatment-emergent ADAs

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acelyrin Inc.

Sponsor organisation

Acelyrin Inc.

Address

23371 Mulholland Drive

City

Woodland Hills

Postcode

91364-2734

Country

United States

Scientific contact point

Organisation

Acelyrin Inc.

Contact name

Clinical Trials Information Desk

Public contact point

Organisation

Acelyrin Inc.

Contact name

Clinical Trials Information Desk

Third parties 6

Locations

6 EU/EEA countries · 49 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 31 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications