ZX008 for Healthy Volunteers

Overseen By UCB Cares

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: UCB BIOSCIENCES, Inc.

Must not be taking: Hepatic enzyme-inducing drugs

Disqualifiers: Cardiovascular disease, Glaucoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies how the body processes three common drugs—midazolam, bupropion, and metformin—before and after repeated doses of a new treatment called ZX008 (an experimental treatment). The goal is to understand how ZX008 affects the breakdown of these drugs in the body. Individuals who are generally healthy and have no history of heart problems, high blood pressure, or certain medical conditions might be suitable candidates. Participants will receive the drugs at specific times, with breaks in between, to observe how ZX008 changes drug metabolism. As a Phase 1 trial, this research focuses on understanding how ZX008 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

Yes, you must stop taking prescription drugs, over-the-counter medications, herbal/traditional medicines, or dietary supplements 14 days before the trial, except for acetaminophen (up to 2 g/day).

Do I need to stop taking my current medications for the trial?

Yes, you will need to stop taking most medications, including prescription drugs, over-the-counter medications, and supplements, at least 14 days before the trial starts, except for acetaminophen (up to 2 g/day).

Is there any evidence suggesting that ZX008 is likely to be safe for humans?

Research has shown that ZX008, also known as fenfluramine, has undergone safety testing in several previous studies. In trials involving patients with Dravet syndrome and Lennox-Gastaut syndrome, ZX008 was generally well-tolerated. Common side effects included reduced appetite and tiredness, but these were usually mild.

Another study examined ZX008 in healthy adult recreational drug users. This research also indicated that ZX008 was safe for this group, with side effects similar to those in other studies and not severe.

Overall, these findings suggest that ZX008 is generally well-tolerated in both patients with certain conditions and healthy adults. However, as this is a Phase 1 trial, the main focus remains on understanding how the drug works in the body, and safety continues to be closely monitored. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

ZX008, also known as fenfluramine HCl, is unique because it offers a novel mechanism of action for conditions like epilepsy, potentially targeting serotonin pathways differently than existing treatments. Unlike standard anti-epileptic drugs that primarily focus on sodium channels or GABA receptors, ZX008 modulates serotonin levels, which could lead to improved seizure control. Researchers are excited about its potential to provide better efficacy and possibly fewer side effects for patients who do not respond well to current medications. This new approach could represent a significant advancement in epilepsy treatment, giving hope to individuals seeking alternative options.

What evidence suggests that ZX008 might be an effective treatment for pharmacokinetics?

Research has shown that ZX008, also known as fenfluramine, can help reduce certain types of seizures. In a study involving patients with Lennox-Gastaut syndrome (a type of epilepsy), those taking 0.7 mg/kg/day of fenfluramine experienced fewer drop seizures compared to those on a placebo. Additionally, research suggests ZX008 might improve learning, memory, and behavior. These findings come from both early studies and trials with healthy volunteers. Although this trial focuses on how ZX008 interacts with other medications, its past success in treating seizures remains promising. ^{5 6 7 8 9}

Who Is on the Research Team?

UCB Cares

Principal Investigator

001 844 599 2273 (UCB)

Are You a Good Fit for This Trial?

This trial is for healthy men and women aged 18 to 55, weighing at least 50 kg with a BMI of 18-32. Participants must understand the study and agree to its rules by signing a consent form.

Inclusion Criteria

I am either male or female.

I can sign and follow the study's consent form and rules.

I weigh at least 50 kg and my BMI is between 18 and 32.

Exclusion Criteria

Clinically significant history or presence of electrocardiogram (ECG) or echocardiogram (ECHO) findings as judged by the investigator or designee at the Screening Visit and Check-in

Bilirubin >ULN (isolated bilirubin <1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

Abnormal sinus rhythm (heart rate outside of 40bpm and 100bpm)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of the cocktail of probe drugs followed by a washout period, then repeated doses of ZX008 with additional probe drug administration

3 weeks

Multiple visits for drug administration and sampling

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ZX008

Trial Overview The study tests how ZX008 affects the body's handling of three drugs: midazolam (used for sedation), bupropion (an antidepressant), and metformin (for diabetes). It compares their levels in the blood before and after taking ZX008.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 4 Interventions

Study participants will receive a single dose of the cocktail of probe drugs at pre-specified timepoints followed by a wash out period. The same study participants will then receive repeated oral doses of fenfluramine HCl (ZX008) and a single dose of the cocktail of probe drugs at pre-specified time points during this Treatment Period.

Who Is Running the Clinical Trial?

UCB BIOSCIENCES, Inc.

Lead Sponsor

Trials

28

Recruited

7,200+

Published Research Related to This Trial

In a clinical development program involving 1684 subjects and 2038 injections, OptiMARK demonstrated a safety profile comparable to Magnevist, with 31% of its injections associated with adverse events.

OptiMARK was found to be safe and well-tolerated, showing fewer adverse events compared to Magnevist (35%) and placebo (48%), indicating its potential as a reliable imaging agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The OptiMARK clinical development program: summary of safety data. Brown, JJ., Kristy, RM., Stevens, GR., et al.[2019]

The proposed clinical trial procedures aim to improve the detection of effective treatments for lethal diseases by combining mortality and non-fatal outcomes into a worst-rank score, enhancing the ability to assess overall treatment efficacy.

By first testing for mortality differences before evaluating non-fatal outcomes, these methods help ensure that treatments are not falsely deemed beneficial when they may have harmful effects on survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Joint testing of mortality and a non-fatal outcome in clinical trials. McMahon, RP., Harrell, FE.[2017]

In a post hoc analysis of type 2 diabetes patients inadequately controlled on metformin, vildagliptin was more effective than glimepiride in achieving a composite endpoint of HbA1c<7.0% without causing hypoglycemia or weight gain after 2 years.

This finding suggests that vildagliptin may be a safer and more effective option for managing blood sugar levels in patients with type 2 diabetes, regardless of their age or how long they have had diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vildagliptin more effectively achieves a composite endpoint of HbA₁c Bader, G., Geransar, P., Schweizer, A.[2022]

In a study of 98 laryngeal cancer patients, a change of about 5% to 10% in quality of life (QOL) scores is considered clinically meaningful, helping clinicians estimate the minimal important difference (MID) when no empirical data is available.

Patients rated a 4% change in the FACT-H&N and FACT-G scales as 'a little bit better,' indicating that even small improvements can be significant, especially when assessing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interpreting clinically significant changes in patient-reported outcomes. Ringash, J., O'Sullivan, B., Bezjak, A., et al.[2022]

The study presents a curated and standardized version of the FDA Adverse Event Reporting System (FAERS) data, which enhances the quality and usability of drug safety surveillance by removing duplicates and standardizing drug and outcome vocabularies.

This new resource will facilitate faster and more reliable drug safety research by providing pre-computed statistics and reducing the time needed for data management, ultimately improving the identification of adverse drug reactions (ADRs) post-marketing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A curated and standardized adverse drug event resource to accelerate drug safety research. Banda, JM., Evans, L., Vanguri, RS., et al.[2020]

ZMYND8 plays a dual role in gene regulation, acting as both a transcriptional activator and repressor, depending on its association with different protein complexes.

The study reveals that ZMYND8's interaction with the P-TEFb complex is crucial for activating target genes, particularly in the context of neuronal precursor cell differentiation induced by all-trans retinoic acid (ATRA).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positive Regulation of Transcription by Human ZMYND8 through Its Association with P-TEFb Complex. Ghosh, K., Tang, M., Kumari, N., et al.[2022]

The Drug Adverse Reaction Database (DART) provides detailed information on 147 confirmed and 89 potential protein targets associated with adverse drug reactions (ADRs), which is crucial for understanding the mechanisms behind these reactions and aiding in drug discovery.

DART includes extensive data on 257 drugs and 1080 ligands, offering insights into their binding properties, physiological functions, and the specific adverse effects they may cause, making it a valuable resource for researchers and developers in pharmacology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug Adverse Reaction Target Database (DART) : proteins related to adverse drug reactions. Ji, ZL., Han, LY., Yap, CW., et al.[2018]

ZMYND11 is a protein that plays a crucial role in repressing gene expression by specifically binding to a modified form of histone H3.3 (H3.3K36me3).

By binding to this histone modification, ZMYND11 prevents the elongation of transcription, which is the process of copying DNA into RNA, thereby regulating gene activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The putative tumor suppressor ZMYND11 recognizes H3.3K36me3. [2020]

Accurate and objective assessment of clinical outcomes in randomized controlled trials is crucial, with a strong emphasis on using major (hard) endpoints as the gold standard for measuring effectiveness.

While surrogate and composite endpoints can be useful for improving statistical precision and reducing sample sizes, they must be carefully selected to ensure they reliably predict major clinical outcomes, as they may not always reflect true patient benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evaluation of the results of clinical trials: surrogate end points and composite end points. Gensini, GF., Conti, AA.[2019]

The safety of marketed drugs is a significant concern, as some commonly prescribed medications can lead to serious or life-threatening side effects in patients.

The ChEMBL resource will provide a curated drug safety data set, including toxicity classifications and black box warnings, which will be freely available and regularly updated to aid in drug safety research and discovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug Safety Data Curation and Modeling in ChEMBL: Boxed Warnings and Withdrawn Drugs. Hunter, FMI., Bento, AP., Bosc, N., et al.[2023]

Cbx8, a Polycomb protein, is identified as a crucial regulator of aggressive breast cancer, being overexpressed in human cases and linked to poorer survival outcomes.

Cbx8 enhances Notch signaling by maintaining specific histone modifications, and its depletion reduces tumor formation, suggesting it plays a significant role in breast tumor development through a non-canonical mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis. Chung, CY., Sun, Z., Mullokandov, G., et al.[2020]

ZMYND8 is a key player in regulating gene expression by interacting with specific epigenetic marks on histones, particularly H3.1K36Me2 and H4K16Ac, which helps it bind to developmental genes.

This study reveals that ZMYND8 can influence transcription independently of the CHD4 component of the NuRD complex, highlighting its unique role in modulating gene activity, especially in response to all-trans-retinoic acid (ATRA).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8. Adhikary, S., Sanyal, S., Basu, M., et al.[2021]

This study identified critical laboratory result thresholds for various substances in adult patients, which are associated with a 90% predicted probability of death, helping clinicians recognize life-threatening conditions.

The thresholds include specific values for sodium, potassium, bicarbonate, and other key indicators, providing a practical framework for assessing patient risk in intensive care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome-Based Critical Result Thresholds in the Adult Patient Population. Tan, EH., Yang, Z., Li, Y., et al.[2020]

Variants in the ZMYND8 gene were identified in 11 individuals, leading to a novel neurocognitive disorder characterized by intellectual disability and associated physical anomalies, highlighting the gene's critical role in brain development and function.

Functional studies showed that specific missense variants disrupt important protein interactions, which may underlie the cognitive deficits observed, as demonstrated by decreased learning in a Drosophila model with ZMYND8 knockdown.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations. Dias, KR., Carlston, CM., Blok, LER., et al.[2022]

The review of clinical research data from 1977 to 2011 highlights significant inconsistencies in how adverse reactions (AR) to drugs are assessed, which can affect the reliability of safety information provided to patients.

To improve the safety profiles of medications, the authors advocate for the establishment of a common European standard for the structured assessment of adverse reactions in clinical research, as no such standard currently exists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Assessing adverse reactions in clinical trials]. Harnisch, S., Schade-Brittinger, C., Rief, W.[2013]

In a review of 24 First-in-Man studies involving 1,017 healthy male volunteers, the incidence of adverse events (AEs) was low, with 98.3% of AEs being mild or moderate, indicating a favorable safety profile for small molecules in Phase I trials.

Only 0.4% of treatments resulted in serious adverse events, all of which were not medically concerning and did not require hospitalization, suggesting that small molecule trials can be conducted safely in healthy volunteers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of healthy volunteers in First-in-Man trials - an analysis of studies conducted at the Bayer in-house ward from 2000 to 2005. Wensing, G., Ighrayeb, IA., Boix, O., et al.[2019]

In a survey of 459 members of the British Pharmacological Society, it was found that drugs were administered to 8163 healthy volunteers, with only 6.9% experiencing minor adverse effects and 0.04% facing potentially life-threatening effects, indicating a very low risk associated with these studies.

Among 7607 healthy student volunteers, only 6.0% reported minor adverse effects during drug administration for educational purposes, with no severe adverse effects noted, reinforcing the overall safety of drug administration in healthy volunteer studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Healthy volunteer studies in Great Britain: the results of a survey into 12 months activity in this field. Orme, M., Harry, J., Routledge, P., et al.[2019]

In a comprehensive review of 54 phase-I studies involving 1015 healthy volunteers over 10 years, the overall incidence of adverse events was found to be 12.8%, with a higher rate for active drugs (13.7%) compared to placebo (7.9%).

Most adverse events were minor, with only 3% classified as severe, and no deaths or life-threatening events reported, highlighting that while adverse events are common in phase-I trials, they are typically not serious.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in phase-I studies: a report in 1015 healthy volunteers. Sibille, M., Deigat, N., Janin, A., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03355209

NCT03355209 | A Study to Investigate the Efficacy and ... This is a two-part, multicenter, double-blind, parallel-group, placebo controlled study to evaluate the effect of ZX008 when used as adjunctive therapy for ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9062770/

Efficacy and Safety of Fenfluramine for the Treatment ... In this randomized clinical trial of 263 patients with LGS, use of 0.7-mg/kg/d fenfluramine resulted in a greater reduction in drop seizures than with placebo.

3. ctv.veeva.com ctv.veeva.com/study/a-study-to-investigate-the-efficacy-and-safety-of-zx008-fenfluramine-hydrochloride-as-an-adjunctiv

A Study to Investigate the Efficacy and Safety of ZX008 ... This is a two-part, multicenter, double-blind, parallel-group, placebo controlled study to evaluate the effect of ZX008 when used as adjunctive ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1525505022004437

Fenfluramine treatment is associated with improvement in ... Data from preclinical studies and clinical studies in healthy volunteers suggest that this unique pharmacology may mediate learning, memory, and behavioral ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02682927

Study Details | NCT02682927 | A Trial of Two Fixed Doses ... ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03467113

NCT03467113 | A Study to Assess the Safety and ... This is an open label study to evaluate the safety of ZX008 (fenfluramine) in patients with Dravet syndrome (DS) or Lennox Gastaut syndrome (LGS) who are being ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2020/212102Orig1s000OtherR.pdf

212102Orig1s000 - accessdata.fda.gov study of ZX008 (fenfluramine HCl) and CBD in otherwise healthy, adult recreational drug users. Inclusion criteria: Healthy male or female ...

8. jamanetwork.com jamanetwork.com/journals/jamaneurology/fullarticle/2791918

Efficacy and Safety of Fenfluramine for the Treatment ... Meaning Findings from this trial suggest that fenfluramine may be a safe and effective treatment option for patients with LGS.

9. mayo.edu mayo.edu/research/clinical-trials/cls-20316205

Clinical Trials This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with Dravet syndrome who have ...