A phase IIa, open label, single centre study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of orally dosed MBF-015 in Huntington's disease patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medibiofarma S.L.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

30 Jan 2024 → 4 Dec 2024

Decision date (initial)

2023-09-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacokinetic, Pharmacodynamic

To evaluate safety and tolerability of MBF-015 in participants with Huntington’s Disease (HD) on top of standard of care over 28 days, with follow-up to day 43.

Secondary objectives 2

1. To characterize the pharmacokinetic profile of MBF-015 in plasma.
2. To characterize exposure of MBF-015 in CSF fluid

Conditions and MedDRA coding

Huntington's disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Ambulatory male or nonpregnant, nonlactating females, age ≥25 to ≤60 years old
2. 2. 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]).
3. 3. 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
4. 4. UHDRS Total Functional Capacity (TFC) scores ≥7 and ≤13 with mild-moderate cognitive impairment (MoCA score 10-25).
5. 5. In the opinion of the Investigator, the patient can tolerate all study procedures and is willing to comply with all other protocol requirements.
6. 6. 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.
7. 7. Able to tolerate blood draws and lumbar puncture (LP).
8. 8. 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.
9. 9. 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 20

1. 1. 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.
2. 2.     Clinically significant laboratory abnormality at Screening.
3. 3.     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.
4. 4.     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.
5. 5. 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).
6. 6.     Positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
7. 7.     Known to be positive for human immunodeficiency virus (HIV).
8. 8.     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.
9. 9.     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.
10. 10.  Contraindication for MRI (claustrophobia, pacemaker, aneurism clips, cardiac mechanical valve).
11. 11.  Contraindication for lumbar puncture (anticoagulation, coagulation disease): Must not be taking anticoagulant treatment.
12. 12.  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.
13. 13.  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).
14. 14.  Unwillingness to withhold protocol-prohibited medications during the trial.
15. 15.  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).
16. 16.  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.
17. 17.  Positive for opioids (unprescribed), cannabinoids, cocaine, amphetamines, methadone, barbiturates, methamphetamine, or phencyclidine at the Screening Visit.
18. 18.  Known or suspected allergy, anaphylaxis, hypersensitivity or intolerance to the study drug excipients.
19. 19.  Prior enrolment in the current study and had received study treatment.
20. 20.  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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is safety and tolerability of MBF-015 administration for 28 days from baseline to end of the follow-up period at Day 43. Number and severity of AEs reported including Clinically Significant Changes in vital signs, physical examination, Laboratory Measurements, ECGs, and Columbia-Suicide Severity Rating Scale (C-SSRS).

Secondary endpoints 16

1. • Plasma: Cmax, Tmax, Area under curve (AUC) and Cmin in plasma at Day 1-2 and Day 28, and single-point concentration on Day 43.
2. • CSF: concentration of MBF-015 on Day 28 at [+ 4h] post-dose.
3. • Change from baseline of neuronal biomarkers including Nfl levels measured in CSF and/or blood at Day 28.
4. • Change from baseline of absolute delta, theta, alpha and beta power, aperiodic exponent, offset and global coherence.
5. • Change from baseline of the strength of functional connectivity across the nodes comprising the default mode network and the fronto-parietal network. at Day 28.
6. • Change from baseline of the total PD-CRS score at Day 28.
7. • Change from baseline in the UHDRS total motor score (UHDRS-TMS) at Day 28 (EoT, V4), and day 43 (EoS, V5).
8. • Change from baseline in the UHDRS Functional assessment checklist at Day 28 (EoT, V4).
9. • Change from baseline in the UHDRS independence scale at Day 28 (EoT, V4), and day 43 (EoS, V5).
10. • Change from baseline in the UHDRS total functional capacity (UHDRS-TFC) at Day 28 (EoT, V4), and day 43 (EoS, V5).
11. • Change from baseline in the Stroop word reading test (SWR) at Day 28 (EoT, V4), and day 43 (EoS, V5).
12. • Change from baseline in the Symbol Digit Modalities Test (SDMT) at Day 28 (EoT, V4), and day 43 (EoS, V5).
13. • Change from baseline in the composite UHDR score (c-UHDRS).
14. • Change from baseline of apathy severity score in the PBA-s at Day 28 (EoT, V4), and day 43 (EoS, V5).
15. • Change from baseline of the different PD-CRS subtests at day 28.
16. • Change from baseline of histone activity or H3K9 acetylation or selected mRNAs in blood, at Day 28 (EoT, V4), and day 43 (EoS, V5).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medibiofarma S.L.

Sponsor organisation

Medibiofarma S.L.

Address

Poligono Industrial Mocholi 2 B, Noain C Noain C

City

Noain (Valle De Elorz)

Postcode

31110

Country

Spain

Scientific contact point

Organisation

Medibiofarma S.L.

Contact name

Richard Roberts

Public contact point

Organisation

Medibiofarma S.L.

Contact name

Richard Roberts

Third parties 5

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications