Dose-Escalation Study of ALXN1210 IV in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Study Overview
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Brief Summary
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This study evaluated the safety, tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of multiple intravenous (IV) doses of ALXN1210 administered to participants with PNH who have not previously been treated with complement inhibitor.

Detailed Description
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The data presented is up to the Primary Completion date of the study and is for the 24-week Primary Evaluation period. The study also includes an Extension Period of up to 5 years.

Official Title
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An Open-Label, Intrapatient, Dose-Escalation Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of ALXN1210 Administered Intravenously to Patients With Paroxysmal Nocturnal Hemoglobinuria

Conditions
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PNH

Intervention / Treatment
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* Biological: ALXN1210


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years of age PNH diagnosis confirmed by documented high-sensitivity flow cytometry Documented meningococcal vaccination not more than 3 years prior to dosing Female participants of childbearing potential used highly effective contraception starting at screening and continuing until at least 24-weeks after the last dose of ALXN1210 Willing and able to give written informed consent and comply with the study visit schedule Exclusion Criteria: Treatment with a complement inhibitor at any time Females who were pregnant, breastfeeding or who had a positive pregnancy test at screening or Day 1 Participation in an interventional clinical study within 30 days before initiation of dosing on Day 1, or use of any experimental therapy within 30 days prior to dosing on Day 1, or within 5 half-lives of the product, whichever is greater History of allergy to excipients of ALXN1210 or known allergy to Chinese hamster ovary cell proteins Inability to comply with study requirements History of any clinically significant cardiac, hepatic, immunologic, pulmonary, or rheumatoid disease that, in the Investigator's judgment, would preclude participation Other unspecified reasons that, in the opinion of the Investigator or Sponsor, made the participant unsuitable for enrollment

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Participants were administered ALXN1210 900 mg. In the Extension period participants continued at the same dose and frequency as the Primary Evaluation Period. | Biological: ALXN1210<br>* Participants were administered ravulizumab as an IV infusion every 4 weeks.<br>|
| Experimental: Cohort 2<br>Participants were administered ALXN1210 1800 mg. In the Extension period participants continued at the same dose and frequency as the Primary Evaluation Period. | Biological: ALXN1210<br>* Participants were administered ravulizumab as an IV infusion every 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change In Lactate Dehydrogenase (LDH) Levels From Baseline To Day 169 | Baseline was defined as the average of all available assessments prior to first ALXN1210 infusion. | Baseline, Day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change In Free Hemoglobin Levels From Baseline To Day 169 And Day 1821 | Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion. | Baseline, Day 169, Day 1821 | 
| Percent Change In Haptoglobin Levels From Baseline To Day 169 And Day 1821 | Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion. | Baseline, Day 169, Day 1821 | 
| Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 169 And Day 1821 | Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion. | Baseline, Day 169, Day 1821 | 
| Percent Change In Paroxysmal Nocturnal Hemoglobinuria (PNH) Red Blood Cell (RBC) Clones From Baseline To Day 169 And Day 1933 | Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion. | Baseline, Day 169, Day 1933 | 
| Percent Change In D-dimer Levels From Baseline To Day 169 And Day 1821 | Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion. | Baseline, Day 169, Day 1821 | 
| Change In Clinical Manifestations Of PNH From Baseline To Day 169 And Day 1821 | Clinical manifestations are defined as fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction (ED) by cohort. Improvement is defined as present at baseline and absent at Day 169 endpoint. Worsening is defined as absent at Baseline and present at Day 169 endpoint. | Baseline, Day 169, Day 1821 | 
| Area Under The Serum Concentration-versus-time-curve From Time 0 (Dosing) To The Last Quantifiable Concentration (AUCt) At Day 1 | AUCt reported in hours*microgram/milliliter (h*ug/mL). | Day 1 | 
| AUCt/ Dose-normalized (D) At Day 1 |  | Day 1 | 
| Area Under The Serum Concentration-versus-time-curve From Time 0 (Dosing) To The End Of The Dosing Interval (AUCtau) At Day 141 |  | Day 141 | 
| AUCtau/D At Day 141 |  | Day 141 | 
| Maximum Observed Serum Concentration (Cmax) At Day 1 And Day 141 |  | Day 1 and Day 141 | 
| Cmax/D At Day 1 And Day 141 |  | Day 1 and Day 141 | 
| Concentration At The End Of The Dosage Interval (Ctrough) At Day 1 And At Day 141 |  | Day 1 and Day 141 | 
| Time To Maximum Observed Serum Concentration (Tmax) At Day 1 And Day 141 |  | Day 1 and Day 141 | 
| Percent Change In Chicken Red Blood Cell (cRBC) Hemolysis From Baseline To Day 1709 |  | Baseline, Day 1709 | 
| Percent Change In Free Complement Component 5 (C5) Concentration From Baseline To Day 1709 |  | Baseline, Day 1709 | 
| Percent Change In Total C5 Concentration From Baseline To Day 1709 |  | Baseline, Day 1709 | 
| Participants Experiencing Antidrug Antibodies (ADAs) |  | Day 1821 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paroxysmal Nocturnal Hemoglobinuria, PNH, complement inhibitor