A Phase 2 trial to evaluate the efficacy and safety of daxdilimab in participants with primary discoid lupus erythematosus.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Horizon Therapeutics Ireland Designated Activity Company

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

16 May 2023 → 9 May 2025

Decision date (initial)

2024-06-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Horizon Therapeutics Ireland Designated Activity Company

External identifiers

EU CT number

2023-509746-35-00

EudraCT number

2022-000831-21

ClinicalTrials.gov

NCT05591222

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Pharmacodynamic

To evaluate the effect of daxdilimab compared with placebo in reducing active disease activity at Week 24 in participants with primary DLE.

Secondary objectives 4

1. To evaluate the effect of daxdilimab compared with placebo in reducing DLE disease activity at Week 24 in participants with primary DLE.
2. To evaluate the effect of daxdilimab compared with placebo in disease activity and damage in participants with primary DLE.
3. Pharmacokinetics and Immunogenicity: To characterize the PK and immunogenicity of daxdilimab in participants with primary DLE.
4. Safety: To evaluate the safety and tolerability of daxdilimab in participants with primary DLE.

Conditions and MedDRA coding

Primary Discoid Lupus Erythematosus

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the United States) obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations.
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
3. Adult men or women ≥ 18 and ≤ 75 years of age.
4. A diagnosis of DLE for ≥ 6 months prior to Screening supported by a history of a. A biopsy or b. a clinical feature score of ≥ 7 on the DLE Classification Criteria (DLECC) scale if a biopsy is not available.
5. Currently active discoid lupus with all the following: a. Digital photography adjudicated with central reading to confirm a currently active discoid disease lesion. b. CLASI-A score ≥ 8 related to discoid lesions at Baseline.
6. Treatment refractory DLE defined as active disease despite current or historical treatment with a systemic treatment including, but not limited to antimalarial, methotrexate, mycophenolate, azathioprine, dapsone, corticosteroid, thalidomide, or lenalidomide, OR documented history of intolerance to antimalarials and/or immunosuppressive medications.
7. Participants with active disease who currently are on any of the following therapies must have been on a stable dosage prior to Screening and must remain on a stable dosage through Randomization and for the entire trial as described below: − Antimalarials (eg, hydroxychloroquine, chloroquine, quinacrine) must be at a stable dosage for at least 8 weeks prior to Screening and through Randomization. − Methotrexate ≤ 20 mg/week (oral or SC) at stable dosage and route of administration for at least 4 weeks prior to Screening and through Randomization. − Mycophenolate mofetil ≤ 2 g/day or mycophenolic acid ≤ 1.44 g/day at stable dosage for at least 4 weeks prior to Screening and through Randomization. − Azathioprine must be stable for at least 4 weeks prior to Screening and through Randomization. − Corticosteroid equivalent to prednisone ≤ 10 mg/day at stable dosage for at least 4 weeks prior to Screening and through Randomization. − Topical corticosteroids and calcineurin inhibitors at stable dosage for at least 1 week prior to Screening and through Randomization.
8. Vaccination status should be up to date per local standards.
9. Females are eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies: - Is a woman of non-childbearing potential (WONCBP) OR - Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (ie, has a failure rate of < 1%, as described in Appendix 1), during the study intervention period and for at least 6 months after the last dose of IP and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. o A WOCBP must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1. o Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5 Pregnancy Testing of the Study Protocol. o The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. The Investigator should also evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of IP.
10. Males are eligible to participate if they agree to the following during the study intervention period and for at least 3 months after the last dose of IP: − Refrain from donating fresh unwashed semen, PLUS either: − 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 − Must agree to use contraception/barrier as detailed below: o 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 WOCBP who is not currently pregnant. Effective methods of contraception are listed in Appendix 1 of the Study Protocol.

Exclusion criteria 27

1. Individuals involved in the conduct of the trial, their employees, or immediate family members of such individuals.
2. Participation in another clinical trial with an investigational drug within 4 weeks prior to Randomization or within 5 published half-lives, whichever is longer.
3. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of participant safety or trial results.
4. Weight > 160 kg (352 pounds) at Screening.
5. History of allergy, hypersensitivity reaction, or anaphylaxis to any component of the IP or to a previous mAb or human Ig therapy.
6. Breastfeeding or pregnant women or women who intend to become pregnant anytime from signing the ICF through 6 months after receiving the last dose of IP.
7. History of drug or alcohol abuse that, in the opinion of the Investigator, might affect participant safety or compliance with visits, or interfere with other trial assessments.
8. Major surgery within 8 weeks prior to Screening or elective surgery planned from Screening through end of Treatment Period.
9. Splenectomy
10. Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to Screening through Randomization.
11. History of clinically significant cardiac disease including unstable angina, myocardial infarction, congestive heart failure within 6 months prior to Randomization; arrhythmia requiring active therapy, except for clinically insignificant extra systoles, or minor conduction abnormalities; or presence of clinically significant abnormality on ECG if, in the opinion of the Investigator, it would increase the risk of trial participation.
12. History of cancer within the past 5 years, except as follows: − Cutaneous basal cell or squamous cell carcinoma treated with curative therapy.
13. Any underlying condition that in the opinion of the Investigator significantly predisposes the participant to infection.
14. Participant who has given > 499 mL of blood or plasma within 56 days of Screening (during a clinical trial or at a blood bank donation) or plans to give blood or plasma during their participation in the trial or up to 6 months after the last IP administration, whichever is longer.
15. Transfusion with blood, packed red blood cells, platelets or treatment with plasmapheresis, or plasma exchange within 8 weeks prior to Randomization and for the total duration of the trial participation.
16. Known history of a primary immunodeficiency or an underlying condition, such as known human immunodeficiency virus (HIV) infection, or a positive result for HIV infection per central laboratory.
17. At Screening, any of the following per central laboratory tests (may be repeated once within the same screening period to confirm results prior to Randomization): − Aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN) − Alanine aminotransferase (ALT) > 2.5 × ULN − Total bilirubin (TBL) > 1.5 × ULN (unless due to Gilbert’s syndrome) − Neutrophil count < 1500/μL (or < 1.5×109/L) − Platelet count < 135,000/μL (or < 135×109/L) − Hemoglobin < 10 g/dL (or < 100 g/L) − Total lymphocyte count < 800/μL (or < 0.8×109/L) − Antinuclear antibody titer > 1:320
18. All participants will undergo testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) during Screening. − Participants who are HBsAg positive are not eligible for the study. − Participants who are HBsAg negative and HBcAb positive will be reflex tested for hepatitis B surface antibody (HBsAb). If HBsAb is positive, may be enrolled in the study; if HBsAb is negative, the participant is not eligible for the study.
19. All participants will undergo testing for hepatitis C antibody (HCVAb) during Screening. − Participants who are HCVAb positive will be reflex tested for hepatitis C virus (HCV) RNA and if HCV RNA is positive, the participant is not eligible for the study .
20. Active tuberculosis (TB), or a positive IFNγ release assay (IGRA) test at Screening, unless documented history of appropriate treatment for active or latent TB. Participants with an indeterminate IGRA test result can repeat the test, but if the repeat test is also indeterminate, they will be excluded.
21. Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus [CMV]) at any time prior to Randomization, including, but not limited to, disseminated herpes, herpes encephalitis, recent recurrent herpes zoster (defined as 2 episodes within the last 2 years), or ophthalmic herpes.
22. Any herpes zoster, CMV, or Epstein-Barr virus infection that was not completely resolved 12 weeks prior to Randomization.
23. Any of the following within 30 days prior to signing the ICF and through Randomization: − Clinically significant active infection in the opinion of the Investigator, including ongoing, and chronic infection requiring antibiotics or antiviral medication (chronic nail infections are allowed). − Any infection requiring hospitalization or treatment with intravenous anti infectives. − A participant with a documented positive SARS-CoV-2 test may be rescreened at least 2 weeks after a positive test if the participant is asymptomatic or at least 3 weeks after symptomatic COVID-19 illness.
24. Opportunistic infection requiring hospitalization or parenteral antimicrobial treatment within 2 years prior to Randomization.
25. Any acute illness or evidence of clinically significant active infection on Day 1.
26. Participants who have COVID-19 or other significant infection, or in the judgment of the Investigator, may be at a high risk of COVID-19 or its complications should not be randomized.
27. NOTE: Other protocol defined Exclusion criteria may apply.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary Efficacy: Mean change in CLASI-A score from Baseline (Day 1) to Week 24

Secondary endpoints 8

1. Secondary Efficacy: Proportion of participants who achieve 0 or 1 on the CLA-IGA scale at Week 24 (5-point Likert scale [0-4]).
2. Secondary Efficacy: Proportion of participants who achieve a ≥ 50% reduction in CLASI-A score from Baseline (Day 1) at Week 24.
3. Secondary Efficacy: Mean change in the SADDLE from Baseline (Day 1) to Week 24.
4. Pharmacokinetics and Immunogenicity: Serum concentration of daxdilimab over time.
5. Pharmacokinetics and Immunogenicity: Incidence of ADA directed against daxdilimab over time.
6. Safety: Incidence of TEAEs.
7. Safety: Incidence of TESAEs
8. Safety: Incidence of TEAESIs: hypersensitivity reaction, including anaphylaxis, herpes zoster infection, serious (Grade 3 or higher) viral infection/reactivation, opportunistic infection, and malignancy (except non-melanoma skin cancer).

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Horizon Therapeutics Ireland Designated Activity Company

Sponsor organisation

Horizon Therapeutics Ireland Designated Activity Company

Address

Pottery Road, Dun Laoghaire Dun Laoghaire

City

Dublin

Postcode

A96 F2A8

Country

Ireland

Scientific contact point

Organisation

Horizon Therapeutics Ireland Designated Activity Company

Contact name

Medical Information

Public contact point

Organisation

Horizon Therapeutics Ireland Designated Activity Company

Contact name

Medical Information

Third parties 13

Locations

7 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

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

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

Documents 120 files

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

Application history

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