Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MBF-015 in Huntington's Disease: A Phase IIa Open-Label Study
- Trial ID
- 2023-505241-10-00
- Protocol
- MBF-015CT-02
- Sponsor
- Medibiofarma S.L.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase IIa, open-label, single-center study is to evaluate the **safety** and **tolerability** of MBF-015 in participants with **Huntington's disease** over a 28-day period, with a follow-up extending to day 43. This assessment is clinically relevant as it aims to determine the potential of MBF-015 as a safe and tolerable treatment option for patients with Huntington's disease, which is crucial for advancing therapeutic strategies in this neurodegenerative disorder.
Secondary objectives include:
- Characterizing the **pharmacokinetic** profile of MBF-015 in plasma, which is essential for understanding the drug's absorption, distribution, metabolism, and excretion.
- Characterizing the exposure of MBF-015 in **cerebrospinal fluid (CSF)**, providing insights into the drug's ability to penetrate the central nervous system, which is particularly important for treating neurological conditions such as Huntington's disease.
Participants
The clinical trial involves participants diagnosed with **Huntington's disease**, focusing on evaluating the safety and tolerability of MBF-015. The study population includes both male and female subjects, aged between 25 and 60 years. Participants are required to be ambulatory and must not be pregnant or lactating. The trial does not involve a vulnerable population. Participants must have documented CAG triplet repeats of 39 or more in the HTT gene and exhibit clinical diagnostic motor features of Huntington's disease. They should have a UHDRS Total Functional Capacity score between 7 and 13, indicating mild to moderate cognitive impairment. The trial requires participants to be able to undergo MRI scans, tolerate blood draws, and lumbar punctures. If participants are on treatment for Huntington's disease, they must be on a stable dose for at least three months prior to the study. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a **phase IIa**, open-label, single-center study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the investigational drug **MBF-015** in patients with **Huntington's disease**. The trial involves the oral administration of MBF-015 in the form of hard capsules. The study is structured to last for a total of 43 days, with the primary treatment period spanning 28 days, followed by a 15-day follow-up period. The primary endpoint focuses on assessing the safety and tolerability of MBF-015, with secondary endpoints including pharmacokinetic parameters and changes in various biomarkers and clinical scores.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as age, genetic markers, and the ability to tolerate study procedures. Following successful screening, participants will commence the treatment phase, with visits scheduled on Day 1-2, Day 28, and Day 43. These visits will involve comprehensive assessments, including blood draws, lumbar punctures, and MRI scans, to monitor the drug's effects and gather data on secondary endpoints. The end-of-study visit on Day 43 will conclude the participant's involvement, with final evaluations conducted to ensure safety and collect endpoint data.
Participant involvement is expected to last approximately 43 days, with conditions for early termination including the occurrence of adverse events that compromise safety or the inability to comply with study procedures. The trial's design ensures rigorous monitoring and data collection to achieve its objectives, contributing valuable insights into the potential therapeutic benefits of MBF-015 for Huntington's disease.
Treatment
The clinical trial involves the administration of the experimental medication **MBF-015**, which is provided in the form of **HARD CAPSULES**. The active substance, also named MBF-015, is of chemical origin. Each capsule contains 16 mg of the active substance. The medication is administered orally, with a maximum daily dose of 32 mg, equating to two capsules per day. The total maximum dose over the treatment period is 896 mg. The treatment duration is set for a maximum of 4 weeks, with the primary objective being to evaluate the safety and tolerability of MBF-015 in patients with Huntington's Disease.
In addition to the experimental treatment, participants will continue to receive their standard-of-care therapy for Huntington's Disease. This standard treatment will be maintained throughout the study to ensure that the effects of MBF-015 can be accurately assessed in conjunction with existing therapeutic regimens. No placebo or comparator treatment is utilized in this open-label study design.
Participant compliance with the dosing schedule will be monitored through regular follow-up visits and assessments. The study protocol includes measures to ensure adherence to the prescribed dosing regimen, with any deviations being documented and analyzed as part of the trial's safety and efficacy evaluations.
Efficacy
The efficacy of MBF-015 in the clinical trial will be assessed through a series of secondary endpoints. These include pharmacokinetic parameters such as Cmax, Tmax, Area under the curve (AUC), and Cmin in plasma at specified timepoints, including Day 1-2, Day 28, and a single-point concentration on Day 43. Additionally, the concentration of MBF-015 in cerebrospinal fluid (CSF) will be measured on Day 28, four hours post-dose. Changes from baseline in various neuronal biomarkers, including Nfl levels in CSF and/or blood, will be evaluated at Day 28.
Further assessments will involve changes from baseline in several neurophysiological and cognitive parameters at Day 28, such as absolute delta, theta, alpha, and beta power, aperiodic exponent, offset, and global coherence. Functional connectivity across the default mode network and the fronto-parietal network will also be analyzed. Cognitive and motor function will be evaluated using the Unified Huntington's Disease Rating Scale (UHDRS), with specific focus on total motor score (UHDRS-TMS), functional assessment checklist, independence scale, and total functional capacity (UHDRS-TFC) at Day 28 and Day 43. Additional cognitive assessments include the Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), and composite UHDR score (c-UHDRS).
Other efficacy measures include changes in apathy severity score in the PBA-s, various PD-CRS subtests, and histone activity or H3K9 acetylation or selected mRNAs in blood at Day 28 and Day 43. These assessments will provide a comprehensive evaluation of the preliminary efficacy of MBF-015 in patients with **Huntington's disease**.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Ambulatory male or nonpregnant, nonlactating females, age ≥25 to ≤60 years old
- Males and females of childbearing potential must agree to use adequate birth control measures during the study. Females of childbearing potential must have a negative serum pregnancy test prior to Visit 2 and either be sexually abstinent or must use a hormonal (oral, implantable, or injectable) or double barrier method of birth control throughout the study, and until 60 days after the last dose of study drug. Females unable to bear children must have documentation of such in the source records (i.e., tubal ligation, hysterectomy, or postmenopausal [defined as a minimum of 1 year since the last menstrual period]).
- Documented CAG triplet repeats ≥39 in the HTT gene. Clinical diagnostic motor features of HD, defined as UHDRS-TMS > 5 with Diagnostic Confidence Score = 4
- UHDRS Total Functional Capacity (TFC) scores ≥7 and ≤13 with mild-moderate cognitive impairment (MoCA score 10-25).
- In the opinion of the Investigator, the patient can tolerate all study procedures and is willing to comply with all other protocol requirements.
- Able to undergo MRI scans and able to tolerate them (e.g., no metal implants including MRI incompatible IUDs, chorea of a severity that precludes MRI scans or any condition that renders testing intolerable for the patient.
- Able to tolerate blood draws and lumbar puncture (LP).
- If participants are using a treatment for HD, they should be on a stable dose for at least 3 months prior to study commencement. Acceptable treatments include Dopamine D2 receptor blockers or reverse agonists, vesicular monoamine transporter 2 blockers or γ-aminobutyric acid (GABA) agonists.
- Ability to participate fully, in the opinion of the Investigator, in all aspects of this clinical trial. Full comprehension of consent language and written informed consent must be obtained from the participant and documented.
Exclusion Criteria
- Clinically significant medical finding on the physical examination other than HD that, in the judgment of the Investigator, will make the patient unsuitable for participation in and/or completion of the study procedures.
- Clinically significant laboratory abnormality at Screening.
- Clinically significant abnormality at Screening electrocardiogram (ECG), including but not necessarily limited to a confirmed QT interval corrected for heart rate (QTc) ≥450 msec for males or ≥470 msec for females. Clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the opinion of the Investigator, precludes the patient’s safe participation in the study or would interfere with the study assessments. Mental status, psychiatric medical history, and eligibility for the study must be documented in the screening questionnaire.
- Pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening Visit, or plans to become pregnant during the course of the study.
- Deemed to be at significant risk for suicidal behaviour based on any the following criteria: a. The opinion of the Investigator b. Answers “yes” to Actual Suicide Attempts or Suicidal Behaviors in the Suicidal Behaviors section of the Columbia-Suicide Severity Rating Scale (C-SSRS) with reference to a 2-year period prior to the Screening Visit c. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS with reference to a 6-month period prior to the Screening Visit. d. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS at the Baseline Visit since the last visit (Screening Visit).
- Positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
- Known to be positive for human immunodeficiency virus (HIV).
- Evidence of Clostridioides difficile toxin or treatment for C. difficile infection, or other intestinal bacterial pathogen, within 30 days prior to Screening.Any condition that increases risk of meningitis unless patient is receiving appropriate prophylactic treatment.
- A medical history of brain or spinal disease that would interfere with lumbar puncture, CSF circulation or safety assessment. History of post-lumbar-puncture headache of moderate or severe intensity and/or blood patch.
- Contraindication for MRI (claustrophobia, pacemaker, aneurism clips, cardiac mechanical valve).
- Contraindication for lumbar puncture (anticoagulation, coagulation disease): Must not be taking anticoagulant treatment.
- Concurrent or previous participation in another clinical trial and received investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to Screening.
- Any major surgery, in the investigator’s opinion, performed within 8 weeks prior to randomization or planned during the study (i.e., any surgical procedure requiring general anesthesia).
- Unwillingness to withhold protocol-prohibited medications during the trial.
- Started or changed dose for concomitant medication for the treatment of HD symptoms or psychiatric disorders within 30 days prior to the Screening Visit (concomitant medications that have been administered on a stable regimen for ≥30 days are permitted).
- History of excessive alcohol or drug abuse that, in the opinion of the investigator, may interfere with the participant’s ability to comply with the study procedures.
- Positive for opioids (unprescribed), cannabinoids, cocaine, amphetamines, methadone, barbiturates, methamphetamine, or phencyclidine at the Screening Visit.
- Known or suspected allergy, anaphylaxis, hypersensitivity or intolerance to the study drug excipients.
- Prior enrolment in the current study and had received study treatment.
- The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 20 Sept 2023 | 10 |