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

Overview

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).

Full Title of Study: “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”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Study Primary Completion Date: August 2023

Detailed Description

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.

Interventions

• Drug: NI006
  • NI006 will be administered intravenously
• Drug: Placebo
  • Formulation buffer of NI006, matching volume of NI006 doses will be administered intravenously

Arms, Groups and Cohorts

• Experimental: NI006
  • 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.
• Placebo Comparator: Placebo
  • 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.

Clinical Trial Outcome Measures

Primary Measures

• Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram
  • Time Frame: 4 months
  • 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
• Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram
  • Time Frame: 12 months
  • 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
• Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram
  • Time Frame: additional up to 10 months
  • 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

Secondary Measures

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

Participating in This Clinical Trial

Key Inclusion Criteria:

1. Age ≥18 years (and < 85 years only for cohort 7) 2. Confirmed diagnosis of ATTR-Cardiomyopathy 3. Known genotype (wild-type or hereditary form) 4. Chronic Heart Failure with LVEF ≥40%, LVWT ≥14 mm, NT-proBNP ≥ 600 pg/mL, 6-MWT ≥150 meter, no hospitalizations for cardiac disease for at least 30 calendar days prior to screening 5. Karnofsky Performance Status score ≥60% Key Exclusion Criteria:

1. Amyloid light-chain amyloidosis or any other non ATTR amyloidosis 2. New York Heart Association class IV 3. NT-proBNP ≥6000 pg/mL (NT-proBNP ≥8500 pg/mL only for cohort 7) 4. Heart failure not predominantly caused by ATTR-Cardiomyopathy 5. Any severe uncorrected valve disease 6. Chronic liver disease with liver function test abnormalities 7. Respiratory insufficiency requiring oxygen therapy 8. Renal insufficiency 9. Active malignancy with exception of: 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 10. Uncontrolled infection, HIV infection, seropositivity for HIV, hepatitis B and C, active hepatitis A 11. Autoimmune disease requiring immunosuppressive/modulating treatment in the last 2 years 12. History of organ transplantation or ventricular assist device 13. Polyneuropathy disability score > IIIA 14. Suspected or known drug or alcohol abuse, serious psychiatric or any other medical condition, which, in the opinion of the Investigator, makes the subject unsuitable

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Neurimmune AG
• Provider of Information About this Clinical Study
  • Sponsor