First-in-Human Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy

Study Overview
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Brief Summary
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A phase 1, randomized, placebo-controlled, double-blind, dose escalation trial combining single-ascending dose and multiple-ascending dose phases of NI006 or placebo, followed by an open-label extension phase in subjects with Amyloid Transthyretin Cardiomyopathy (ATTR-CM).

Detailed Description
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This phase 1, randomized, placebo-controlled, double-blind trial in subjects with Amyloid Transthyretin Cardiomyopathy (ATTR-CM) consists of single-ascending dose (SAD) and multiple-ascending dose (MAD) phases, followed by an open-label extension (OLE) phase. In the SAD phase subjects are randomized in a 4:2 ratio to receive a single infusion of NI006 or placebo. Subjects completing the SAD phase will be enrolled in the MAD phase upon evaluation of all available safety data and receive a maximum of 3 additional infusions of NI006 or placebo every 28 days. Subjects completing the MAD phase will have the possibility to continue in an OLE phase with treatment up-titrations and switch from placebo to NI006 and receive up to 8 infusions of NI006 every 28 days. Subjects of cohort 1 to 5 who received at least one dose of NI006 during the OLE phase will have the possibility for a second OLE phase (OLE2) after completing the OLE phase and receive up to 10 additional infusions of NI006 every 28 days. In total, about 42 subjects are planned to be enrolled in 7 cohorts of 6 subjects each, at 6 ascending dose levels.

Official Title
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A Phase 1, First-in-Human, Double-Blind, Placebo-Controlled, Multicenter, Single and Multiple Ascending Dose Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy Followed by an Open-Label Extension

Conditions
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Amyloid Transthyretin Cardiomyopathy

Intervention / Treatment
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* Drug: NI006
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained from the subject prior to any trial-related procedure indicating that he/she understands the purpose of, and procedures required for the trial and is willing to participate in it Male or female subjects aged ≥18 years (and < 85 years only for cohort 7) at the time of obtaining informed consent and with confirmed availability for the scheduled trial visits Confirmed ATTR-Cardiomyopathy diagnosis established by: Polarizing light microscopy of green birefringent material in Congo red-stained tissue specimens and confirmed diagnosis of ATTR amyloidosis by IHC or mass spectrometry OR positive bone scintigraphy using either DPD, HMDP or PYP, with cardiac signal intensity indicative of ATTR-Cardiomyopathy (early phase imaging: cardiac mediastinum ratio > 1.21; late phase imaging: Perugini Grade 2 or 3) and absence of gammopathy (negative serum and urine immunofixation electrophoresis plus normal free light chain serum ratio). If a gammopathy is detected, diagnosis must be established based on tissue biopsy as indicated above Known genotype as follows: Known pathogenic TTR mutation for subjects with hereditary ATTR- Cardiomyopathy Known negative genetic testing for a TTR mutation for subjects with sporadic, WT- ATTR-Cardiomyopathy Chronic Heart Failure with all of the following characteristics: LVEF ≥40% LVWT ≥14 mm, measured by echocardiography NT-proBNP level ≥600 pg/mL Able to walk ≥150 meter in the 6-MWT NYHA class III (applicable only for cohort 7) No hospitalizations for cardiac disease for at least 30 calendar days prior to screening General health status acceptable for a participation in a clinical trial with a Karnofsky Performance Status ≥60% Stable pharmacological treatment of any other chronic condition for at least 30 calendar days prior to screening, with the exclusion of immunomodulatory and immunosuppressive treatments ANC ≥1000 cells/mm³, platelet count ≥100,000 cells/mm³, and hemoglobin ≥10 g/dL Women of childbearing potential must have a negative serum pregnancy test at screening and must agree to use highly effective physician-approved contraception from screening to 5 months after ending trial participation Males must be surgically sterile or must agree to use highly effective physician-approved contraception throughout of the trial participation, and for 5 months after ending trial participation Exclusion Criteria: Amyloid light-chain amyloidosis or any other non ATTR amyloidosis Heart failure corresponding to NYHA class IV Uncontrolled hypertension with systolic pressure ≥180 mmHg or diastolic pressure ≥110 mmHg confirmed by 3 measurements in supine position recorded with 5 minutes break in between the measurements Hypotension with systolic pressure ≤ 90 mmHg or diastolic pressure ≤ 60 mmHg confirmed by 3 measurements in supine position recorded with 5 minutes break in between the measurements NT-proBNP ≥6'000 pg/mL (NT-proBNP ≥8'500 pg/mL applicable only for cohort 7) Heart failure not predominantly caused by ATTR-Cardiomyopathy Any severe uncorrected valve disease Chronic liver disease with liver function test abnormalities: ALT and AST > 2.5 × ULN Total bilirubin > 2 × ULN Respiratory insufficiency requiring oxygen therapy Renal insufficiency with eGFR < 30 mL/min/1.73 m2 using the CKD-EPI equation Active malignancy with exception of the following: Adequately treated basal cell carcinoma Squamous cell carcinoma of the skin In situ cervical cancer Low risk prostate cancer with Gleason score < 7 and prostate specific antigen < 10 mg/mL Any other cancer from which the subject has been disease-free for ≥ 2 years Uncontrolled infection as per Investigator's judgement Known HIV infection, seropositivity for HIV, hepatitis B and C as well as active hepatitis A Autoimmune disease requiring immunosuppressive/modulating treatment in the last 2 years History of organ transplantation or ventricular assist device Polyneuropathy disability score > IIIA Suspected or known intolerance/allergy to proteins or any components of the investigational medicinal product Concomitant immunosuppressant therapy e.g., corticosteroids, prednisone, dexamethasone except as indicated in low dose (i.e., up to 10 mg prednisone or equivalent daily is allowed) for other medical conditions such as inhaled steroid for asthma Use of the following drugs acting on TTR or ATTR: tolcapone, diflunisal, patisiran, inotersen, and long-term doxycycline, in the 30 calendar days prior to signing informed consent form. Tafamidis is permitted if it is given as standard of care in a stable dose for at least 30 calendar days prior to signing the informed consent form Participation in another investigational clinical trial or intake of investigational drug within 30 calendar days before signing the informed consent form Suspected or known drug or alcohol abuse Serious psychiatric or any other medical condition (including laboratory abnormalities), which, in the opinion of the Investigator, makes the subject unsuitable for inclusion and puts the subject at an unacceptable risk Subject is nursing or is considering becoming pregnant during the trial or in the 5 months after ending trial participation Unwillingness or inability to adhere to the trial requirements If subject is in any way dependent on Neurimmune AG or the principal Investigator or if the subject is accommodated in an establishment on judicial or administrative order Employee or immediate family (spouse, parent, child or sibling, whether biological or legally adopted) of an employee of Neurimmune AG, the contract research organization or the trial site

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NI006<br>Dose escalation in up to 6 dose cohorts. Subjects will be administered a single dose of NI006 in the SAD, multiple doses of NI006 in the MAD and OLE phases. | Drug: NI006<br>* NI006 will be administered intravenously<br>|
| Placebo Comparator: Placebo<br>Subjects will be administered a single dose of placebo in the SAD phase and multiple doses of placebo in the MAD phase. In the OLE phase, all subjects will be administered multiple doses of NI006. | Drug: Placebo<br>* Formulation buffer of NI006, matching volume of NI006 doses will be administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram | Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram | 4 months | 
| Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram | Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram | 12 months | 
| Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram | Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram | additional up to 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NI006 pharmacokinetic profile and parameters - Cmax | Maximum observed serum concentration (Cmax) of NI006 | 4 months | 
| NI006 pharmacokinetic profile and parameters - Tmax | Time to maximum observed serum concentration (Tmax) of NI006 | 4 months | 
| NI006 pharmacokinetic profile and parameters - AUCinf | Area under the serum concentration-time curve from zero to infinity (AUCinf) of NI006 | 1 month | 
| NI006 pharmacokinetic profile and parameters - CL | Serum clearance (CL) of NI006 | 4 months | 
| NI006 pharmacokinetic profile and parameters - Vz | NI006 apparent volume of distribution during terminal phase (Vz) | 4 months | 
| NI006 pharmacokinetic profile and parameters - Vss | NI006 apparent volume of distribution at steady state (Vss) | 4 months | 
| NI006 pharmacokinetic profile and parameters - t½ | Terminal elimination half-life (t½) of NI006 in serum | 4 months | 
| NI006 pharmacokinetic profile and parameters - AUCtau | Area under the serum concentration-time curve from time zero to the end of the dosing interval after the first dose (AUCtau) of NI006 | 4 months | 
| NI006 pharmacokinetic profile and parameters - RaccCmax | Accumulation ratio for maximum concentration (RaccCmax) of NI006 in serum | 4 months | 
| NI006 pharmacokinetic profile and parameters - RaccAUC | Accumulation ratio calculated from AUC (RaccAUC) of NI006 in serum | 4 months | 
| NI006 pharmacokinetic profile and parameters - Ctrough | Minimum observed concentration (Ctrough) of NI006 in serum | 12 months | 
| NI006 OLE2 pharmacokinetic profile and parameters - Ctrough | Minimum observed concentration (Ctrough) of NI006 in serum | up to 10 months | 
| NI006 pharmacokinetic profile and parameters - dose-normalized Ctrough | Dose-normalized minimum observed concentration (Ctrough) of NI006 in serum | 12 months | 
| NI006 OLE2 pharmacokinetic profile and parameters - dose-normalized Ctrough | Dose-normalized minimum observed concentration (Ctrough) of NI006 in serum | up to 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATTR, Transthyretin, Amyloidosis, Cardiomyopathy, ATTR-CM