A Study to Examine the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Symptomatic Generalized Myasthenia Gravis (NIMBLE)

• ClinicalTrials.gov Identifier: NCT05070858
• Recruitment Status: Recruiting
• First Posted: October 7, 2021
• Last Update Posted: April 8, 2024
• Sponsor: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Tracking Information

• First Submitted Date: September 27, 2021
• First Posted Date: October 7, 2021
• Last Update Posted Date: April 8, 2024
• Actual Study Start Date: December 14, 2021
• Estimated Primary Completion Date: August 29, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 27, 2021)

Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score [ Time Frame: From baseline to week 24 ]

The total MG-ADL score ranges from 0 to 24 points, with higher scores indicating greater functional impairment and disability

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 27, 2021)

• Change from baseline in Quantitative Myasthenia Gravis (QMG) score [ Time Frame: Week 24 ]
  QMG total scores range from 0 to 39, with higher scores representing greater impairment
• Proportion of patients responding on the MG-ADL [ Time Frame: From baseline to week 24 ]
  ≥3-point improvement
• Proportion of patients responding on the QMG [ Time Frame: From baseline to week 24 ]
  ≥5-point improvement
• Proportion of patients with consistent response on the MG-ADL [ Time Frame: From baseline to week 24 ]
  At least a 2-point MG-ADL improvement on 2 or more consecutive assessments spanning 4 or more weeks during the DBTP
• Proportion of patients with minimal symptom expression (MSE) [ Time Frame: Week 24 ]
  Score of 0 to 1 on the MG-ADL
• Change from baseline in the Myasthenia Gravis Composite (MGC) total score [ Time Frame: Week 24 ]
  MGC score ranges from 0 to 50, with higher score indicating higher impairment
• Change from baseline in Myasthenia Gravis Quality of Life (MG QOL15r) total score [ Time Frame: Week 24 ]
  Total score ranges from 0 to 30 points; a higher score represents greater impairment
• Proportion of patients with improvement point thresholds on MG-ADL [ Time Frame: From baseline to week 24 ]
  ≥2, 4, 5, 6, 7, 8, 9, or 10
• Proportion of patients with improvement point thresholds on QMG [ Time Frame: From baseline to week 24 ]
  ≥3, 4, 6, 7, 8, 9, or 10
• Incidence and severity of treatment-related adverse events (TEAEs) in patients treated with pozelimab + cemdisiran or placebo [ Time Frame: Through week 24 ]
• Incidence and severity of serious adverse events (SAEs) in patients treated with pozelimab + cemdisiran or placebo [ Time Frame: Through week 24 ]
• Incidence and severity of adverse events of special interest (AESIs) in patients treated with pozelimab + cemdisiran or placebo [ Time Frame: Through week 24 ]
• Concentrations of total pozelimab in serum [ Time Frame: Through study duration, approximate 172 weeks ]
• Concentrations of cemdisiran and its metabolites in plasma [ Time Frame: Through study duration, approximate 172 weeks ]
• Incidence of treatment-emergent anti-drug antibodies (ADAs) to pozelimab over time [ Time Frame: Through study duration, approximately 172 weeks ]
• Incidence of treatment-emergent ADAs to cemdisiran over time [ Time Frame: Through study duration, approximate 172 weeks ]
• Change in CH50 over time [ Time Frame: Through study duration, approximately 172 weeks ]
• Percent change in CH50 over time [ Time Frame: Through study duration, approximately 172 weeks ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Examine the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Symptomatic Generalized Myasthenia Gravis
• Official Title: Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Symptomatic Generalized Myasthenia Gravis

Brief Summary

The primary objective is:

To evaluate the effect of pozelimab + cemdisiran on daily functioning that is impacted by signs and symptoms in patients with symptomatic generalized myasthenia gravis (gMG)

The secondary objectives of the study are:

• To evaluate the effect of pozelimab + cemdisiran (ie, combination) and cemdisiran monotherapy on:

  • Clinician-assessed signs of myasthenia gravis (MG) and muscle strength
  • Daily functioning that is impacted by signs and symptoms in patients with symptomatic gMG (cemdisiran monotherapy only).
  • Proportion of patients with improvements in daily function that is impacted by signs and symptoms of MG
  • Proportion of patients that have improvements in clinician-assessed signs of MG and muscle strength
  • Health related quality of life
  • Proportion of patients with minimal MG symptoms
  • Patient- and clinician-reported signs and symptoms of MG
• To evaluate the safety and tolerability of pozelimab + cemdisiran and cemdisiran monotherapy
• To assess the concentration of total pozelimab in serum
• To assess the concentrations of cemdisiran and its metabolites in plasma
• To assess the immunogenicity of pozelimab
• To assess the concentration of total C5 in plasma
• To assess the immunogenicity of cemdisiran
• To study the effect of pozelimab + cemdisiran and cemdisiran monotherapy on complement activation

• Detailed Description: DBTP- Double blind treatment plan (24 weeks) ETP - Extension treatment plan (28 weeks) OLTP- Open label treatment plan (68 weeks) Off-treatment follow up period (52 weeks)
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Generalized Myasthenia Gravis

Intervention

• Drug: Pozelimab + Cemdisiran
  Subcutaneous administration as described in the protocol
• Drug: Cemdisiran
  SC administration as described in the protocol
  Other Name: ALN-CC5
• Other: Placebo
  SC administration as described in the protocol
• Drug: Pozelimab
  SC administration as described in the protocol
  Other Name: REGN3918

Study Arms

• Experimental: Group 1
  Placebo in DBTP; Re-randomized to Combination or Cemdisiran in ETP and OLTP
  Interventions:

  • Drug: Pozelimab + Cemdisiran
  • Drug: Cemdisiran
  • Other: Placebo
• Experimental: Group 2
  Combination regimen throughout the study
  Intervention: Drug: Pozelimab + Cemdisiran
• Experimental: Group 3
  Cemdisiran throughout the study
  Intervention: Drug: Cemdisiran
• Experimental: Group 4
  Pozelimab monotherapy in DBTP followed by combination in ETP and OLTP
  Intervention: Drug: Pozelimab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 13, 2022): 235
• Original Estimated Enrollment (submitted: September 27, 2021): 210
• Estimated Study Completion Date: March 23, 2028
• Estimated Primary Completion Date: August 29, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

1. Male or female patients ≥18 years of age at screening (or ≥ legal age of adulthood based on local regulations, whichever is older)
2. Patient with documented diagnosis of myasthenia gravis (MG) based on medical history and supported by previous evaluations as described in the protocol
3. Documented prior history of positive serologic test or a positive result during screening of anti-acetylcholine receptor (AChR) antibodies or anti-LRP4 antibodies.
4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa at screening
5. Myasthenia Gravis-Activities of Daily Living (MG-ADL) score ≥6 at screening. Ocular items should not contribute more than 50% of MG-ADL total score
6. Currently receiving an acetylcholinesterase inhibitor or documented reason for not using acetylcholinesterase inhibitor therapy per investigator 7. Currently receiving an immunosuppressive therapy (IST) for MG, or documented reason why the patient is not taking an IST per investigator

8. If currently receiving an IST, not anticipated to have IST dosage changed before randomization or during double-blind treatment period (DBTP).

Key Exclusion Criteria:

1. Patients with antibody profile that is only positive for muscle specific tyrosine kinase (MuSK) (MuSK positivity is based on a documented prior history of positive serologic test for antibodies to MuSK or a positive result during screening
2. History of thymectomy within 12 months prior to screening or planned during the study
3. History of malignant thymoma (patients with stage 1 may be enrolled), or history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
4. Myasthenic crisis or Myasthenia Gravis Foundation of America (MGFA) Class V within 1 month of screening
5. No documented meningococcal vaccination within 5 years prior to screening visit unless vaccination will be administered during the screening period and prior to initiation of study treatment
6. Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) as described in the protocol
7. Patients who require antibiotics for meningococcal prophylaxis and have a contraindication, warning, or precaution precluding the use of penicillin class and penicillin-alternative antibiotics planned to be used for prophylaxis, or a history of intolerance leading to the discontinuation of these antibiotics
8. Positive hepatitis B surface antigen or hepatitis C virus ribonucleic acid (RNA) during screening. NOTE: Cases with unclear interpretation should be discussed with the medical monitor
9. History of HIV infection or a positive test at screening per local requirements

NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Clinical Trials Administrator; 844-734-6643; clinicaltrials@regeneron.com

• Listed Location Countries: Australia, Belgium, Canada, Czechia, Denmark, France, Georgia, Germany, India, Italy, Japan, Korea, Republic of, Poland, Serbia, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05070858
• Other Study ID Numbers: R3918-MG-2018; 2020-003272-41 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
• Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• URL: https://vivli.org/

• Current Responsible Party: Regeneron Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Regeneron Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

• PRS Account: Regeneron Pharmaceuticals
• Verification Date: March 2024