Inebilizumab efficacy and safety in adults with myasthenia gravis

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

22 Mar 2021 → ongoing

Decision date (initial)

2024-05-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Horizon Therapeutics Ireland DAC, Ireland

External identifiers

EU CT number

2023-510006-40-00

EudraCT number

2020-000949-14

ClinicalTrials.gov

NCT04524273

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Therapy, Pharmacokinetic

To assess whether inebilizumab can reduce MG-related disability.

Secondary objectives 6

1. 1. To evaluate whether inebilizumab can reduce the frequency of MG exacerbations
2. 2. To evaluate whether inebilizumab can improve MG-related quality of life.
3. 3. To evaluate the safety and tolerability of inebilizumab in MG.
4. 4. To characterize the pharmacokinetic (PK) profile and immunogenicity of inebilizumab in patients with MG.
5. 5. To evaluate the effect of inebilizumab on corticosteroid usage
6. 6. To evaluate the ability of inebilizumab to elicit minimal symptom expression.

Conditions and MedDRA coding

Myasthenia Gravis which is either due to acetylcholine receptor antibodies (AChR) or muscle specific kinase antibodies (MuSK).

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Diagnosis of MG with anti-AChR or anti-MuSK antibody
2. 2. MGFA Clinical Classification Class II, III, or IV.
3. 3. MG-ADL score at the time of screening and randomization between 6 and 10 with > 50% of this score attributed to non-ocular items, or an MG-ADL score ≥ 11.
4. 4. QMG score ≥ 11 or greater at the time of screening and at randomizatio
5. 5. Subjects must be on: a. Corticosteroids only, with no dose increase within 4 weeks prior to randomization, or b. One allowed non-steroidal IST, with continuous use for ≥ 6 months prior to randomization and no dose increase within 4 months prior to randomization, or c. Combination of (1) corticosteroids with no dose increase within 4 weeks prior to randomization and (2) one allowed non-steroidal IST with continuous use for ≥ 6 months prior to randomization and no dose increase within 4 months prior to randomization. Allowed ISTs, alone or in combination with corticosteroids, are azathioprine, mycophenolate mofetil, and mycophenolic acid.
6. 9. Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective contraception method from the time of screening and for 6 months after the final dose of IP. Periodic abstinence, the rhythm method, or the withdrawal method is not an acceptable methods of contraception

Exclusion criteria 12

1. 8. Thymectomy within the 12 months prior to baseline (Day 1) visit or planned thymectomy during the duration of the RCP.
2. 9. Receipt of the following medications or treatments at any time prior to randomization: a. Alemtuzumab, b. Total lymphoid irradiation, c. Bone marrow transplant, d. T-cell vaccination therapy, e. Natalizumab, 10. Receipt of rituximab, ocrelizumab, ofatumumab, obinutuzumab, inebilizumab, or any experimental B-cell depleting agent within the 6 months prior to Day 1, unless the subject has a CD19+ B-cell count ≥ 40 cells/μL according to the central laboratory at screening. 11. Receipt of Leflunomide within 1 year prior to Day 1. 12. Receipt of the following within the 3 months prior to Day 1: a. Tocilizumab, b. Belimumab, c. Eculizumab, d. Cyclophosphamide, e. Ravulizumab, f. Neonatal Fc receptor blockers (efgartigimod alfa) g. Abatacept, h. Etanercept, i. Mitoxantrone, j. Sirolimus
3. 10. Receipt of the following within the 4 weeks prior to Day 1: a. Cyclosporine (except eye drops) b. Tacrolimus (except topical) (tacrolimus ≤ 3 mg/day is allowed in Japan only; see inclusion criterion 7C) c. Methotrexate d. Intravenous immunoglobulin (IVIg) or SC Ig e. PLEX treatment f. Thalidomide g. Tofacitinib
4. 11. Current use of: a. Corticosteroids (prednisone > 40 mg/day or > 80 mg over a 2-day period, or equivalent dose of other corticosteroids) b. Acetylcholinesterase inhibitors (pyridostigmine > 480 mg/day) or unstable dose in the 2 weeks prior to Day 1 c. Azathioprine > 3 mg/kg/day d. Mycophenolate mofetil > 3 g/day or mycophenolic acid > 1440 mg/day e. Any IST, alone or in combination with corticosteroids, except for azathioprine, mycophenolate mofetil, and mycophenolic acid.
5. 12. Concurrent/previous enrollment in another clinical study involving an investigational treatment within 4 weeks or 5 half-lives of the investigational treatment, whichever is longer, prior to Day 1.
6. 13. Receipt of a live attenuated vaccine within 4 weeks prior to randomization. Administration of inactivated (killed) vaccines is acceptable.
7. 14. History of untreated hepatitis C infection, or positive antibody test for hepatitis C virus (HCV) unless patient is considered to be cured following antiviral therapy and has a HCV viral load below the limit of detection ≥ 24 weeks after completion of treatment at site or central lab
8. 15. Hospitalization for any reason < 30 days prior to randomization
9. 16. Current or recent myasthenia gravis exacerbationdeterioration that has not returned to baseline/resolved within at least 30 days prior to randomization.
10. 25. History of untreated hepatitis C infection, or positive antibody test for hepatitis C virus (HCV) unless the subject is considered to be cured following antiviral therapy and has an HCV viral load below the limit of detection ≥ 24 weeks after completion of treatment at site or central lab.
11. 30. Hospitalization for any reason < 30 days prior to randomization.
12. 31. Current or recent MG deterioration that has not returned to baseline/resolved within ≥ 30 days prior to randomization.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at Week 26 in the overall study population (ie, the AChR-Ab+ and MuSK-Ab+ populations).

Secondary endpoints 17

1. 1 (Key). Change from baseline in Quantitative Myasthenia Gravis (QMG) score at Week 26 in the overall study population
2. 2 (Key). Change from baseline in MG-ADL score at Week 26 in the AChR-Ab+ population.
3. 3 (Key). Change from baseline in QMG score at Week 26 in the AChR-Ab+ population
4. 4 (Key). Change from baseline in MG-ADL score at Week 26 in the MuSK-Ab+ population.
5. 5 (Key). Change from baseline in QMG score at Week 26 in the MuSK-Ab+ population
6. 1 (Additional). The proportion of subjects with ≥ 3-point improvement in MG-ADL score at Week 26 and no use of rescue therapy between Day 28 and Week 26 in the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and at Week 52 and no use of rescue therapy between Day 28 and Week 52 in the AChR-Ab+ population.
7. 2 (Additional). Change from baseline in MG-ADL score at Week 52 in the AChR-Ab+ population.
8. 3 (Additional). Change from baseline in QMG score at Week 52 in the AChR-Ab+ population
9. 4 (Additional). Change from baseline in Myasthenia Gravis Composite (MGC) score at Week 26 in the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and at Week 52 in the AChR-Ab+ population.
10. 5 (Additional). Change from baseline in Myasthenia Gravis Quality of Life-15, revised score at Week 26 in the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and at Week 52 in the AChR-Ab+ population
11. 6 (Additional). Patient Global Impression of Change score at Week 26 in the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and at Week 52 in the AChR-Ab+ population.
12. 7 (Additional). Time to first MG exacerbation by Week 26 in the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and by Week 52 in the AChR-Ab+ population.
13. 8 (Additional). The safety and tolerability of inebilizumab as measured by the incidence of treatment-emergent adverse events, adverse events of special interest, and treatment-emergent serious adverse events. Laboratory measurements will also be evaluated as part of safety
14. 9 (Additional). The proportion of subjects with steroid tapered to ≤ 5 mg/day at Week 26 for the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and at Week 52 for the AChR-Ab+ population.
15. 10 (Additional). The proportion of subjects in whom steroid dose was reduced by ≥ 50% by Week 26 for the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population and by Week 52 for the AChR-Ab+ population.
16. 11 (Additional). The proportion of subjects achieving minimal symptom expression, defined as MG-ADL = 0 or 1, at Week 26.
17. 12 (Additional). Anti-drug antibody status and titer during the study in the overall study population, the AChR-Ab+ population, and the MuSK-Ab+ population.

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

Sue Cheng

Public contact point

Organisation

Horizon Therapeutics Ireland Designated Activity Company

Contact name

Medical Information

Third parties 9

Locations

5 EU/EEA countries · 13 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

Documents 40 files

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

Application history

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