A randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy, safety, and tolerability of iptacopan in patients with generalized Myasthenia Gravis, followed by an open label extension phase

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

26 Sep 2024 → ongoing

Decision date (initial)

2025-06-27

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Others, Pharmacoeconomic, Pharmacodynamic, Pharmacogenetic, Efficacy, Pharmacokinetic

To demonstrate efficacy of iptacopan compared to placebo in patients with gMG on stable SOC in reducing the total score of the Myasthenia Gravis Activity of Daily Living (MG-ADL) scale at 6 months (Day 180) of treatment

Secondary objectives 11

1. To assess whether iptacopan is superior to placebo in patients with gMG in reducing Quantitative MG (QMG) total score at 6 months of treatment
2. To assess whether iptacopan is superior to placebo on the proportion of study participants achieving a reduction from baseline to Month 6 of QMG total score ≥5 points without rescue medication and/or strongly confounding prohibited medication
3. To assess whether iptacopan is superior to placebo on the proportion of study participants achieving a reduction from baseline to Month 6 of MG-ADL total score ≥ 3 points without rescue medication and/or strongly confounding prohibited medication
4. To assess whether iptacopan is superior to placebo in reducing MGC total score at Month 6 of treatment
5. To assess whether iptacopan is superior to placebo in reducing MG-QOL15r survey score at Month 6 of treatment
6. To evaluate the safety and tolerability of Iptacopan compared to placebo in patients with gMG
7. To evaluate the efficacy of iptacopan compared to placebo in patients with gMG on other efficacy endpoints
8. To assess long-term effect of iptacopan in patients with gMG in reducing the total score of the MG-ADL during the Extension Part
9. To assess long-term effect of iptacopan in patients with gMG on the proportion of participants achieving a reduction in oral corticosteroids (OCS) dose compared to Core Part that was maintained up to end of Extension Part
10. To assess long-term safety and tolerability of iIptacopan in patients with gMG
11. To assess whether iptacopan is superior to placebo in achieving Minimal Symptom Expression (MSE) at Month 6, defined as an MG-ADL of 0 or 1 at Month 6 without rescue therapy and/or strongly confounding prohibited medication

Conditions and MedDRA coding

generalized Myasthenia Gravis

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices, European Medicines Agency, Pharmaceuticals And Medical Devices Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provide in anonymized to respect the privacy of patients who have participated in the trail in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Adult patients with gMG (age 18-85 years) at screening
2. Positive serology testing for AChR+ antibody at screening
3. Myasthenia Gravis Foundation of America (MGFA) Class II-IV gMG at screening and likely not in need of a respirator for the duration of the study, as judged by the Investigator
4. The confirmation of the diagnosis of gMG should be documented and supported by ≥1 of the following 3 tests: • History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation. • History of positive test with short-acting acetylcholinesterase inhibitors (e.g. neostigmine or edrophonium chloride) • Patient has demonstrated improvement in MG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.
5. Baseline MG-ADL score ≥6, with ≥50% of the total score due to non-ocular symptoms
6. Participants receiving at least one of the following treatments for gMG for ≥ 6 months prior to baseline • One or more NSISTs; or • plasmapheresis, plasma exchange, or intravenous immunoglobulin (at least quarterly) to control symptoms despite treatment with steroids and NSISTs; or • an approved FcRN antagonist; or • rituximab; or • other approved gMG disease modifying therapies excluding complement inhibitors
7. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection is required prior to the start of study treatment. If the participant has not been previously vaccinated, or if a booster was required, the vaccine should be given according to local guidelines at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post-vaccination, prophylactic antibiotic treatment should be initiated at the start of the study treatment and continued until at least 2 weeks after vaccination or booster was completed.. Note: for US sites participating in Study CLNP023Q12301, the completion of the meningococcal vaccination or booster is required for patients with gMG prior to initiating study treatment, irrespective of prophylactic antibiotic use.
8. If not previously vaccinated, vaccination against Haemophilus influenzae infections should be given, if available and according to local guidelines, at least 2 weeks prior to first study drug administration.

Exclusion criteria 7

1. Have been treated with intravenous immunoglobulin (IVIG)/plasma exchange (PLEX) in the past month, with rituximab in the past 6 months, eculizumab in the past 2 months, ravulizumab or other complement inhibitors in the past 3 months, efgartigimod or other anti-FcRn therapies in the past 3 months, or had a thymectomy in the past 6 months or a planned thymectomy during the trial period.
2. Participants with clinically significant active or chronic uncontrolled bacterial, viral, or fungal infection at screening, including patients who test positive for an active viral infection at screening with: Active Hepatitis B Virus (HBV); Active Hepatitis C Virus (HCV); Human Immunodeficiency Virus (HIV) positive serology associated with an Acquired Immune Deficiency Syndrome (AIDS)-defining condition or with a cluster of differentiation 4 (CD4) count ≤200 cells/mm3
3. Female participants who are pregnant or lactating, or are intending to become pregnant
4. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment and an additional one week following cessation of study treatment.
5. Active systemic bacterial, viral (including COVID-19) or fungal infection or any major episode of infection that required hospitalization or injectable antimicrobial therapy within 14 days prior to study drug administration
6. History of recurrent invasive infections caused by encapsulated organisms, e.g., N. meningitidis and S. pneumoniae
7. Presence of fever ≥ 38 °C (100.4 °F) within 7 days prior to study drug administration

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline to Month 6 in Myasthenia Gravis Activity of Daily Living (MG-ADL) total score

Secondary endpoints 14

1. Change from baseline to Month 6 in Quantitative MG (QMG) total score
2. Proportion of participants with ≥5 points reduction from baseline to Month 6 of QMG total score without rescue medication and/or strongly confounding prohibited medication
3. Proportion of participants with ≥3 points reduction from baseline to Month 6 of MG-ADL total score without rescue medication and/or strongly confounding prohibited medication
4. Change from baseline to Month 6 in Myasthenia Gravis Composite (MGC) total score
5. Change from baseline to Month 6 in revised MG Quality of Life Questionnaire (MG-QOL15r) survey score
6. Incidence of adverse events and changes in clinical laboratory values, vital signs, and electrocardiograms, Columbia Suicide Severity Rating
7. Proportion of time during which participants showed a reduction of ≥ 2 points in MG-ADL total score that was maintained up to Month 6
8. Proportion of early MG-ADL responders during treatment (early responders with first MG-ADL improvement from baseline of ≥2 points occurring by week 4）
9. Change from baseline to Month 6 in EuroQol-5 Dimensions-5 Level (EQ-5D-5L)
10. Change from baseline in MG-ADL total score
11. Proportion of participants achieving a reduction in oral corticosteroids (OCS) dose compared to Core Part that was maintained up to end of Extension Part
12. Incidence of adverse events and changes in clinical laboratory values, vital signs, and electrocardiograms, Columbia Suicide Severity Rating
13. Proportion of participants achieving MSE at Month 6, defined as MG-ADL score of 0 or 1 at Month 6 without rescue therapy and/or strongly confounding prohibited medication
14. Proportion of participants with reduction of ≥ 3 points from baseline to Month 6 in MGC total score

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 16

Locations

9 EU/EEA countries · 55 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 91 files

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

Application history

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