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

Study Overview
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Brief Summary
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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
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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)

Official Title
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Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Symptomatic Generalized Myasthenia Gravis

Conditions
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Generalized Myasthenia Gravis

Intervention / Treatment
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* Drug: Pozelimab + Cemdisiran
* Drug: Cemdisiran
* Other: Placebo
* Drug: Pozelimab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female patients ≥18 years of age at screening (or ≥ legal age of adulthood based on local regulations, whichever is older) Patient with documented diagnosis of myasthenia gravis (MG) based on medical history and supported by previous evaluations as described in the protocol Documented prior history of positive serologic test or a positive result during screening of anti-acetylcholine receptor (AChR) antibodies or anti-LRP4 antibodies. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa at screening 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 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: 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 History of thymectomy within 12 months prior to screening or planned during the study 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 Myasthenic crisis or Myasthenia Gravis Foundation of America (MGFA) Class V within 1 month of screening 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 Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) as described in the protocol 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 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 History of HIV infection or a positive test at screening per local requirements NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Placebo in DBTP; Re-randomized to Combination or Cemdisiran in ETP and OLTP | Drug: Pozelimab + Cemdisiran<br>* Subcutaneous administration as described in the protocol<br>Drug: Cemdisiran<br>* SC administration as described in the protocol<br>* Other names: ALN-CC5;Other: Placebo<br>* SC administration as described in the protocol<br>|
| Experimental: Group 2<br>Combination regimen throughout the study | Drug: Pozelimab + Cemdisiran<br>* Subcutaneous administration as described in the protocol<br>|
| Experimental: Group 3<br>Cemdisiran throughout the study | Drug: Cemdisiran<br>* SC administration as described in the protocol<br>* Other names: ALN-CC5;|
| Experimental: Group 4<br>Pozelimab monotherapy in DBTP followed by combination in ETP and OLTP | Drug: Pozelimab<br>* SC administration as described in the protocol<br>* Other names: REGN3918;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score | The total MG-ADL score ranges from 0 to 24 points, with higher scores indicating greater functional impairment and disability | From baseline to week 24 | 

Secondary Outcome Measures

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