The Safety and Tolerability Study With ER2001 Intravenous Injection in Adults With Early Manifest Huntington's Disease

An Open-Label, Dose Escalation Early Phase 1 Study of ER2001 Intravenous Injection in Adults With Early Manifest Huntington's Disease

This is an open label, dose escalation clinic trial of ER2001 intravenous injection to evaluate safety, tolerability and pharmacokinetics of ascending single and multiple doses of intravenously administered ER2001 in patients with early manifest Huntington's Disease. Furthermore, pharmacodynamics in particular target engagement, and early clinical signs of efficacy will be assessed. This study will evaluate increasing doses of ER2001 in sequential cohorts. ER2001 was escalated over 4 dose levels . The planned duration of this treatment is 14 weeks.

Participants will receive totally 8 intravenous injections of ER2001 on the first day of the study, after 2 weeks they will receive 6 injections at weekly intervals, followed by 1 injections at 6 weeks interval. The treatment period of 14 weeks will be followed by an observation phase of 84 days . A modified 3 plus 3 dose-escalation design will be employed with escalating rules set according to the incidence of dose-limiting toxicity (DLT). The first cohort of 1-6 participants will receive a low dose. After safety analysis the next cohort of 3-6 will received a higher dose. Planned doses for increase in subsequent cohorts are 0.04, 0.08, 0.16, and 0.32 mg/kg. Decision to proceed to the next higher dose cohort will be based upon a safety review of the included participants. Treatment will continue until intolerable toxicity or as per patient preference.

Inclusion Criteria:

1. Patient has documented ability to understand the written study informed consent forms (ICFs) at the time of screening and has provided signed written informed consent prior to any study procedures.
2. 25 Years to 55 Years. Gender is not limited.
3. Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and a diagnostic classification level (DCL) of 4.
4. HTT gene expansion testing with the presence of ≥40 CAG repeats.
5. Ability to undergo and tolerate MRI scans.
6. Ability to undergo and tolerate lumbar puncture.
7. All HD medications given for motor, behavioral, and cognitive symptoms have been stable for 3 months prior to Screening.
8. Other concomitant medications have been stable for 1 month prior to Screening.
9. organ function measured prior to administration of study treatment.
10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential. Male patients must use a condom during treatment and for 6 months after the last dose of ER2001 when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.

Exclusion Criteria:

1. History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening.
2. Current active psychosis, confusional state, or violent behavior.
3. Bleeding tendency or history of coagulation disorder; As long as the investigator confirms that there is no evidence of bleeding tendency or coagulation dysfunction at present.
4. ECG with corrected QT interval (QTc) > 480 ms and/or indication of uncontrolled cardiac conditions, as judged by the investigator (e.g. unstable ischemia, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction,congestive heart failure, electrolyte disturbances, etc.)
5. Patients with HIV, Treponema pallidum, Hepatitis B, or Hepatitis C infection.
6. Need to take antiretroviral drugs, including antiretroviral drugs as preventive treatment.
7. Current or recurrent disease, infection, or other significant concurrent medical condition or medications that could confound clinical and laboratory evaluations or could affect a subject's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule.
8. Clinical diagnosis of chronic migraines.
9. Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter.
10. Preexisting structural brain lesions (such as tumor, arteriovenous malformation) as assessed by a centrally read MRI scan during the screening period.
11. Any history of gene therapy, RNA or DNA investigational agents, such as antisense oligonucleotides (ASO), cell transplantation or any other experimental brain surgery.
12. Treatment with investigational therapy within 4 weeks prior to screening or 5 drug elimination half-lives of investigational therapy, whichever is longer.
13. Unable or unsafe to perform lumbar puncture on the patient.
14. In the Investigator's judgment, that Parkinson's disease, multiple system atrophy and other dystonia diseases may be combined.
15. Patients who are hypersensitive to any ingredients in the formulation of ER2001.
16. Malignancy within 5 years of screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
17. Concurrent or planned concurrent participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions. Observational studies are acceptable.
18. Any serious medical condition or clinically significant laboratory, vital signs, or abnormalities at screening that, in the Investigator's judgment, precludes the patient's safe participation in and completion of the study.