A drug-drug interaction study of DNL343 in healthy volunteers
Research type
Research Study
Full title
A Fixed-Sequence, Drug-Drug Interaction Study Evaluating the Effect of the Cytochrome P450 3A Inhibitor Itraconazole on DNL343 in Healthy Participants
IRAS ID
310753
Contact name
Helen Philpott
Contact email
Sponsor organisation
Denali Therapeutics Inc.
Eudract number
2021-006382-37
ISRCTN Number
ISRCTN77943537
Duration of Study in the UK
0 years, 3 months, 5 days
Research summary
Research Summary\nThe purpose of this study is to investigate the study drug DNL343.\n\nThe objectives of this study are:\n- To determine if there any effects/interactions between DNL343 and a marketed oral drug, and to determine how the marketed drug affects the safety, tolerability (degree to which side effects of a drug can be tolerated) and concentration of DNL343 in the blood.\n\n- To determine the safety and tolerability of DNL343 when it is administered on two occasions; once when it is taken alone and when it is administered in the presence of a marketed oral drug.\n\n- To investigate the concentration of DNL343 in the blood, and to measure how this concentration differs when DNL343 is taken on its own versus in combination with a marketed oral drug.\n\nThis study is classed as a drug-drug interaction study where participants are given a drug which has known effects and a known method of breakdown (metabolism) in the body and then given the study drug (DNL343) to determine if there is any effect or interaction between the drugs in the body.\n\nIn the study, participants will take a single dose of DNL343 (40 milligrams - mg) on Day 1, followed by a 200 mg dose of the marketed drug twice daily on Day 15, then once daily (200 mg) from Days 16-17, then 200 mg dose of the marketed drug twice daily on Day 18, and then once daily from Days 19-28 in addition to taking a single dose of both DNL343 (40 mg, taken together with the morning dose of the marketed drug) on Day 18.\n\nBlood samples will be taken at set time points throughout the study in order to measure the concentration of DNL343 in the blood and to evaluate how the concentration of DNL343 differs when it is taken alone and in combination.\n\nSummary of Results\nThe purpose of this study was to investigate the study drug DNL343, and the overall objectives of the study were as follows:\n\n- To determine if there were any effects/interactions between DNL343 and itraconazole (ITZ - a drug commonly used in the treatment of different types of fungal infections), and to determine how ITZ affected the safety, tolerability (degree to which side effects of a drug can be tolerated) and concentration of DNL343 in the blood.\n\n- To determine the safety and tolerability of DNL343 when it was administered on two occasions; once when it was taken alone and when it was administered in the presence of ITZ.\n\n- To investigate the concentration of DNL343 in the blood, and to measure how this concentration differed when DNL343 was taken on its own versus in combination with ITZ.\n\nThis study was classed as a drug-drug interaction study. This means that participants were given a drug which has known effects and a known method of breakdown (metabolism) in the body (ITZ) and given the study drug (DNL343) to determine if there was any effect or interaction between the drugs in the body and whether administration of ITZ affected the safety, tolerability and concentration of DNL343 in the blood.\n\nThis study involved 24 healthy volunteers and during the study, participants were required to take a single dose of DNL343 (40 milligrams - mg) on Day 1, followed by a 200 mg dose of ITZ twice daily on Day 15 (200 mg per dose), then once daily (200 mg) from Days 16-17, then 200 mg of ITZ twice daily on Day 18 (200 mg per dose), and then once daily from Days 19-28 (200 mg per dose) in addition to taking a single dose of DNL343 (40 mg, taken together with the morning dose of ITZ) on Day 18.\n\nParticipants were administered DNL343 in the form of a single 40 mg capsule per dose and ITZ was administered in the form of two 100 mg capsules per dose. Blood samples were taken at set time points throughout the study in order to measure the concentration of DNL343 in the blood and to evaluate how the concentration of DNL343 differed when it was taken alone versus when it was taken with ITZ.\n\nThe purpose of this was to support the study Sponsor in developing guidance as to how the DNL343 product should be administered in future clinical trials of the product and to provide guidance as to how certain drugs may interact and impact the effectiveness of DNL343.\n\nWith respect to the assessment of the drug-drug interactions, DNL343 demonstrated a weak potential for drug-drug interaction for drugs such as ITZ, as the levels of DNL343 in the blood showed only a slight decrease when ITZ was administered in combination with DNL343. Therefore, it is unlikely that DNL343 has any major potential for drug-drug interactions with other drugs which are broken down in the same way as ITZ.\n\nWith respect to the safety objectives of the study, it was determined that DNL343 was considered to be safe and well tolerated, both in the presence and absence of ITZ. All adverse events (side effects) which were reported were considered to be Grade 1 in severity (with the exception of two reports which were classified as Grade 2) and resolved before the study completed, either without any treatment or treatment with some medications to manage the symptoms. Of the effects reported, two participants were withdrawn from the study (one due to a positive COVID-19 test and the other due to sickness considered to be related to the study drug).\n\nIn summary, the data gathered during the study was considered sufficient to meet the objectives of the study and results support further development of DNL343 for the treatment of Amyotrophic Lateral Sclerosis (ALS – also known as motor neurone disease (MND)).
REC name
Wales REC 2
REC reference
22/WA/0009
Date of REC Opinion
18 Jan 2022
REC opinion
Favourable Opinion