Phase IIa Study of ISIS 721744 in Patients with HAE
Research type
Research Study
Full title
A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema
IRAS ID
272209
Contact name
Seema Patel
Contact email
Sponsor organisation
Ionis Pharmaceuticals, Inc.
Eudract number
2019-001044-22
Clinicaltrials.gov Identifier
Duration of Study in the UK
1 years, 3 months, days
Research summary
Summary of Research
The study involves the use of an investigational medicinal product known as ISIS 721744. This research study is being conducted to determine the safety, tolerability and efficacy of the study drug, ISIS 721744. ISIS 721744 is not approved for sale by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or other regulatory agencies, and can only be used for research. The study drug is designed to lower the amount of a protein known as prekallikrein produced by the liver. When prekallikrein is made by the liver and released into your blood stream, it can lead to hereditary angioedema (HAE)attacks. The purpose of this study is to assess if reducing the amount of prekallikrein can reduce HAE attacks and to see how safe ISIS 721744 is for patients with HAE.
Participants will receive 4 doses of the study drug or placebo (an inactive substance that contains no medicine) as an 80 mg subcutaneous (under the skin) injection in abdomen (stomach area), thigh, or upper arm.
This study will have two parts, Part A and Part B. The study doctor will inform the participant which part of the study they are participating in, this is based on the type of HAE identified through genetic testing results during screening. The visit schedule and procedures are almost exactly same for the two parts.
Part A is randomised (randomly assigned by chance to receive either study drug or placebo, double-blind (participant and study doctor will not know the if the study drug or placebo is given), and placebo-controlled (an inactive substance that contains no medicine)
Part B of the study is open label. All participants will receive study drug for Part B.Summary of Results
Purpose and Study Design The ISIS 721744-CS2 study involved the use of an investigational medicinal product known as ISIS 721744. ISIS 721744 is not approved for sale by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or other regulatory agencies. ISIS 721744 is designed to lower the amount of a protein known as prekallikrein produced by the liver. When prekallikrein is made by the liver and released into the blood stream, it can lead to Hereditary Angioedema (HAE) attacks. The purpose of the study was to assess if reducing the amount of prekallikrein can reduce the number of HAE attacks and to see how safe ISIS 721744 is for patients with HAE. The study was funded by Ionis Pharmaceuticals, Inc.
The study enrolled 23 participants, ages 18 and older, who had HAE and met the additional criteria to enter the study. Multiple research sites located in the United States and one site in the Netherlands participated in the study. Participant eligibility was determined during the Screening period, where tests and procedures were performed to determine if the participant could move forward to receive study treatment. The overall length of participation for each participant was approximately 33 weeks.
If confirmed eligible, participants entered the treatment period where they were split into two separate groups. Group A, which consisted of 23 participants with HAE-1/HAE-2, received four doses of either ISIS 721744 or placebo through a subcutaneous (under the skin) injection over a 13-week period. The participants, Study Doctor, nor the Sponsor knew if the participants received ISIS 721744 or placebo. Group B consisted of 3 participants with HAE-nC1-INH. All Group B participants received four doses of 80mg ISIS 721744 over a 13-week period. Following the treatment period, all participants entered a post-treatment period where tests and procedures were performed to make sure they could leave the study safely.
Participants also had the option to enter into the ISIS 721744-CS3 study instead of entering the Post-Treatment Period. The ISIS 721744-CS3 study is an open-label study, meaning all participants enrolled in this study receive ISIS 721744. This study is currently ongoing at research sites in the United States and the Netherlands.Results
Participants who received ISIS 721744 had significantly reduced HAE attacks and improved quality of life, compared to participants who received placebo. In addition, treatment with ISIS 721744 was well tolerated by participants and no severe adverse events were reported.
Blood samples taken from participants were tested for prekallikrein activity and plasma proenzyme activation (an additional indicator of prekallikrein activity). Test results showed that both prekallikrein activity and plasma proenzyme activation were significantly reduced in participants who received ISIS 721744, compared to the placebo group. Pharmacokinetic studies demonstrated that ISIS 721744 was rapidly absorbed into the blood stream following administration, and levels of ISIS 721744 in the bloodstream correlated with reduction in prekallikrein activity over time.
The overall safety profile of ISIS 721744 in participants with HAE was favorable and the study drug was well tolerated. The majority of adverse events that were reported after ISIS 721744 treatment was initiated were considered mild (29 of 40 adverse events), with the rest reported as moderate (11 of 40). No serious adverse events were reported in participants who received ISIS 721744 and no participants discontinued ISIS 721744 due to an adverse event.Overall Conclusion
Treatment with ISIS 721744 in the ISIS 721744-CS2 study significantly reduced the angioedema attack rate and improved quality of life in participants with HAE. ISIS 721744 had a favorable safety profile and no serious adverse events were reported in this study.REC name
London - Central Research Ethics Committee
REC reference
20/LO/0083
Date of REC Opinion
27 Mar 2020
REC opinion
Further Information Favourable Opinion