An Open-Label, Phase 2 study of REGN3918 in adults with PNH

• Research type

  Research Study

• Full title

  An Open Label, Single Arm Study to Evaluate the Efficacy and Safety of REGN3918 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Are Complement Inhibitor Naive or Have Not Recently Received Complement Inhibitor Therapy

• IRAS ID

  260893

• Contact name

  Peter Hillmen

• Contact email

  peter.hillmen@nhs.net

• Sponsor organisation

  Regeneron Pharmaceuticals, Inc.

• Eudract number

  2018-002734-20

• ISRCTN Number

  ISRCTN00000000

• Clinicaltrials.gov Identifier

  NCT00000000

• Duration of Study in the UK

  2 years, 2 months, 18 days

• Research summary

  Research Summary

  This study is a phase 2, open-label study of REGN3918 (study drug) for adults with Paroxysmal Nocturnal Haemoglobinuria (PNH). PNH is a rare and life threatening blood condition characterised by the destruction of red blood cells (RBC) by the immune system and complement activation of white cells and platelets. The estimated incidence of PNH is 1.3 cases per million individuals per year, and the estimated prevalence is 15.9 cases per million individuals per year (Preis, 2014).

  Currently, eculizumab (marketed under the brand name Soliris®) is the approved treatment of PNH in many countries worldwide, including the UK.

  The main purpose of this study is to determine if REGN3918 will reduce the breakdown of RBCs and reduce the requirement for transfusion with red blood cells in patients with active PNH.

  The study will include up to42 participants in 2 cohorts (Cohort A – dose confirmation and Cohort B – dose expansion) in around 30 centres worldwide.

  Participation may last up to 30 weeks (a 4 week screening period and 26 weeks of treatment). Participants will then have the option to enroll in a separate open label extension study which will provide uninterrupted treatment of REGN3918. Participants will be allowed to self-administer the subcutaneous injection at home after set time points defined by what cohort they are allocated.

  REGN3918 will be administered by a single intravenous (IV, injection into a vein) dose followed by subcutaneous (SC, injection into fat underneath the skin) doses on a weekly basis. Other study procedures include physical examinations, blood and urine samples, vital signs, ECG, and completion of patient questionnaires.

  Summary of Results

  "Treatment Studied: Pozelimab
  Study Purpose: This study was designed to learn about the safety of pozelimab and if it was able to improve a certain type of hemoglobinuria.
  Regeneron reviewed the results of the study when it ended. An independent non-profit organization called the Center for Information and Study on Clinical Research Participation (CISCRP) helped prepare this summary of the study results.
  Who took part in this study?
  The researchers asked for the help of men and women with a certain type of hemoglobinuria called paroxysmal nocturnal hemoglobinuria, also known as PNH.
  The participants in this study were 19 to 76 years old when they joined the study.
  The participants could join the study if they:
  • had PNH and were experiencing symptoms, or had been given blood transfusions to manage their condition
  • had high levels of lactate dehydrogenase, also known as LDH, in their blood

  The study included 24 participants in Hong Kong, Hungary, Malaysia, South Korea, Taiwan, and the United Kingdom.

  Why was the research needed?
  PNH is a serious and life-threatening blood condition that can result in fatigue, severe pain, high blood pressure, and blood clots.
  PNH happens because of missing proteins, known as CD55 and CD59, on the surface of red blood cells. When these proteins are missing, the body’s natural defenses do not recognize the red blood cells and attack them, which breaks them down.
  The breakdown of red blood cells is known as hemolysis. Hemolysis leads to low levels of red blood cells in the body, known as anemia. It also leads to high levels of red blood cells in the urine, known as hemoglobinuria. This lack of healthy red blood cells causes a lower oxygen supply to the body’s tissues.
  Researchers are looking for better ways to manage PNH. Current treatments are not always effective for people with PNH. Also, current treatment schedules are difficult and take a lot of time for patients, including regular trips to the doctor. Before a treatment is available to patients, researchers study the treatment to learn more about it.
  The study drug, pozelimab, is an antibody designed to block hemolysis and stop the breakdown of red blood cells. Researchers wanted to find out if pozelimab could provide a better way to manage PNH, as well as provide an easier way to manage treatment for people with PNH.

  What was the purpose of this study?
  The researchers in this study wanted to learn how pozelimab works in a small number of participants with PNH. They also wanted to find out if the participants had any unwanted health effects during the study.
  The main questions the researchers wanted to answer in this study were:
  • Did pozelimab affect how many participants had healthy levels of LDH in their blood?
  • Did pozelimab affect how many participants needed additional blood transfusions during the study?
  • How did the participants feel about their symptoms and quality of life during the study?
  • Did pozelimab potentially cause any unwanted health effects during this study?

  What treatments did the participants receive?
  All 24 of the participants in this study received pozelimab as follows:
  • 1 initial dose (30 mg/kg) of pozelimab as an intravenous (IV) infusion
  • Starting 1 week after the initial dose, a dose of pozelimab (800 mg) by injection under the skin, given every week for 25 weeks

  This was an open-label study. This means each participant knew what they were receiving, and the doctors and study staff also knew.
  The dose of pozelimab was measured in milligrams per kilogram (mg/kg) for the IV infusion, and milligrams (mg) for the injections.

  What happened during this study?
  Each participant was in the study for up to about 7 months.
  Overall, the entire study took over 2 years to finish. This study started enrolling participants in May 2019 and ended in June 2021.
  Before the participants received their study treatment, they visited their study site 1 time. This part of the study lasted up to 1 month. At this visit, the study doctors made sure the participants could join the study. They also:
  • did a physical exam and asked about the participants’ medications, medical history, and any unwanted health effects
  • checked the participants’ heart health using an electrocardiogram, also known as an ECG
  • asked the participants to answer some questionnaires about their quality of life and their PNH symptoms
  • took blood and urine samples

  While the participants received their study treatment, they visited their study site 26 times. This part of the study lasted for around 6 months. At these visits, the doctors gave the participants their study treatment. They also:
  • did a physical exam and asked about the participants’ medications and any unwanted health effects
  • asked the participants to answer some questionnaires about their quality of life and their PNH symptoms
  • took blood and urine samples

  After the participants finished receiving treatment, they visited their study site 1 time. This part of the study happened at week 26, 1week after the participants received their final dose of study treatment. At this visit, the doctors:
  • did a physical exam and asked about the participants’ medications and any unwanted health effects
  • checked the participants’ heart health using an ECG
  • asked the participants to answer some questionnaires about their quality of life and their PNH symptoms
  • took blood and urine samples

  What were the results of this study?
  This is a summary of the main results from this study. The individual results of each participant might be different and are not in this summary.
  The results from several studies are needed to decide which treatments work. Other studies may provide new information or different results.

  Did pozelimab affect how many participants had healthy levels of LDH in their blood?
  Yes. The researchers found that 75.0% of participants had healthy levels of LDH in their blood while receiving pozelimab. This was 18 out of 24 participants.
  To answer this question, the researchers measured the levels of LDH in the participants’ blood throughout the study. This was done by taking blood samples.
  LDH is a protein found in red blood cells. In people with PNH, red blood cells become damaged and break down, releasing LDH into the blood. By measuring how much LDH is in the blood, the researchers can find out how much the red blood cells are being damaged.
  Did pozelimab affect how many participants needed additional blood transfusions during the study?
  Yes. The researchers found that 87.5% of participants did not need additional blood transfusions while receiving pozelimab. This was 21 out of 24 participants.
  To answer this question, the researchers measured the levels of hemoglobin in the participants’ blood throughout the study. This was done by taking blood samples.
  Hemoglobin is a protein found in red blood cells that carries oxygen to the body’s tissues and carbon dioxide to the lungs to be removed from the body. The researchers measured the levels of hemoglobin in the blood to find out whether the participants needed a blood transfusion or not. If a participant had low levels of hemoglobin or was showing signs of anemia, such as looking pale, fatigue, and shortness of breath, the participant was given a blood transfusion.

  How did the participants feel about their symptoms and quality of life during the study?
  Over the course of the study, the participants reported a clinically meaningful increase in their quality of life while receiving pozelimab.
  To answer this question, the researchers asked the participants to answer some questionnaires about their quality of life and their PNH symptoms. The participants answered these questionnaires at the beginning of the study and while they received pozelimab. These questionnaires were:
  • Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire, also known as FACIT-Fatigue
  • European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, also known as EORTC-QLQ-C30
  • European Quality of Life 5 Dimensions 3 Levels Questionnaire, also known as EQ-5D-3L

  FACIT-Fatigue
  The participants gave responses to each question in the FACIT-Fatigue questionnaire on a scale from 0 to 4. From the responses, the researchers calculated the total FACIT-Fatigue score for each participant. A higher score meant that the participant was not fatigued and had a better quality of life. A lower score meant that the participant was fatigued and had a worse quality of life.
  The researchers then calculated the average FACIT-Fatigue score for all of the participants. They compared the participants’ scores before receiving pozelimab to their scores while they were receiving pozelimab. An increase in average FACIT-Fatigue score meant that the participants felt that pozelimab helped their fatigue and quality of life.
  Overall, the researchers found that that the increase in average FACIT-Fatigue score was 9.9, which was considered to be clinically meaningful.
  EORTC-QLQ-C30
  The participants gave responses to each question on the EORTC-QLQ-C30 based on how much they agreed with a statement. These statements were divided into separate health groups that focused on overall health, physical health, emotional health, thinking ability, social health, fatigue, pain, and shortness of breath.
  The answers from each participant for each health group were turned into a score, which was a number between 0 and 100.
  Researchers then calculated the average EORTC-QLQ-C30 score for each health group. The researchers then compared the participants’ scores before receiving pozelimab to their scores while they were receiving pozelimab.
  By the end of the study, these changes were found to be clinically meaningful and are listed below.
  A higher score for fatigue, pain, and shortness of breath meant that the participant had a worse quality of life, while a lower score meant a better quality of life. The average changes were:
  • Fatigue decreased by 18.9
  • Pain decreased by 13.5
  • Shortness of breath decreased by 15.9

  But, a higher score for overall health, physical health, emotional health, thinking ability, and social health meant the participant had a better quality of life, while a lower score meant a worse quality of life. The average changes were:
  • Overall health increased by 12.5
  • Physical health increased by 17.5
  • Emotional health increased by 14.5
  • Thinking ability increased by 9.8
  • Social health increased by 15.8

  All of these changes in average EORTC-QLQ-C30 score (whether an increase or decrease) indicated a better quality of life while receiving pozelimab.

  EQ-5D-3L
  As part of the EQ-5D-3L questionnaire, participants reported their health by marking a point on a line between “The best health you can imagine” and “The worst health you can imagine”. This is called a visual analogue scale (VAS). The placement of these lines was turned into a number between 1 and 100.
  From these responses, the researchers calculated the total EQ-5D-3L score for each participant. A higher score meant that the participant had a better quality of life, while a lower score meant a worse quality of life. The researchers then calculated the average EQ-5D-3L score for all of the participants. The researchers then compared the participants’ scores before receiving pozelimab to their scores while they were receiving pozelimab.
  An increase in average EQ-5D-3L score meant that the participants felt that pozelimab helped their quality of life.
  Overall, the researchers found that the average increase in EQ-5D-3L score was 8.4, which was considered to be clinically meaningful.

  Did pozelimab potentially cause any unwanted health effects during this study?
  This section is a summary of the unwanted health effects the participants had during the study that the study doctors thought could potentially be related to the study treatment. These unwanted health effects that could potentially be related to the study treatment are called adverse reactions. An adverse reaction is considered “serious” when it is life-threatening, causes lasting problems, or requires hospital care.
  These adverse reactions may or may not be caused by the treatment in the study.

  Did any adverse reactions happen during this study?
  There were 41.7% of participants who had adverse reactions during this study. This was 10 out of 24 participants.
  None of the participants had serious adverse reactions.
  None of the participants left the study due to adverse reactions.

  What serious adverse reactions happened during the study?
  There were no serious adverse reactions or deaths in this study.

  What adverse reactions happened during the study?
  The most common adverse reactions were headache and injection site reaction.
  The list below shows all of the adverse reactions to pozelimab that happened during the study. Some participants had more than 1 adverse reaction.
  • Headache in 29.2% of participants (7 out of 24)
  • Injection site reaction in 12.5% of participants (3 out of 24)
  • Nausea in 8.3% of participants (2 out of 24)
  • Chest discomfort in 4.2% of participants (1 out of 24)
  • Itchy skin at injection site in 4.2% of participants (1 out of 24)
  • Fever in 4.2% of participants (1 out of 24)
  Stomach pain in 4.2% of participants (1 out of 24)
  • Diarrhea in 4.2% of participants (1 out of 24)
  • Vomiting in 4.2% of participants (1 out of 24)
  • Decreased amount of a type of white blood cell called neutrophils in the blood in 4.2% of participants (1 out of 24)
  • Muscle and bone discomfort in 4.2% of participants (1 out of 24)

  How has this study helped patients and researchers?
  This study helped researchers learn more about using pozelimab for people with PNH.
  The results from several studies are needed to decide which treatments work best and are safest. This summary shows only the main results from this one study. Other studies may provide new information or different results.
  Further clinical studies with pozelimab in people with PNH are planned.
  Where can I learn more about this study?
  You can find more information about this study on the websites listed below. If a full report of the study results is available, it can also be found here.
  • http://www.clinicaltrials.gov/ct2/show/study/NCT03946748
  • http://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-002734-20

  Full Study Title: An open-label, single arm study to evaluate the efficacy and safety of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria (PNH) who are complement inhibitor-naïve or have not recently received complement inhibitor therapy
  National Clinical Trials Number: NCT03946748
  EudraCT Number: 2018-002734-20
  Regeneron Protocol Number: R3918-PNH-1852
  Regeneron Pharmaceuticals, Inc. sponsored this study and has its headquarters in Tarrytown, NY, USA.
  The phone number for Regeneron Medical Information is +1-844-734-6643 and the email is clinicaltrials@regeneron.com.

  Participants in clinical studies belong to a large community of people who take part in clinical research around the world. They help researchers answer important health questions and find medical treatments for patients."

• REC name

  Yorkshire & The Humber - Leeds East Research Ethics Committee

• REC reference

  19/YH/0133

• Date of REC Opinion

  24 Jul 2019

• REC opinion

  Further Information Favourable Opinion