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

Amyloid Transthyretin (ATTR)-Cardiomyopathy (CM) is an age-associated fatal
disease with a mean subject survival of 3 to 5 years and limited treatment
options available. There is currently (July 2019) no specific treatment for
ATTR-CM approved in Europe. Standard treatments for heart failure such as
beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers are poorly tolerated in ATTR-CM and should be avoided. Heart
transplantation is in principle the only available approach to restore cardiac
function but has poor applicability to this elderly and fragile subject
population. Liver transplantation, which is used for patients with hereditary
ATTR amyloidosis with peripheral neuropathy, unfortunately does not prevent
progression of cardiac amyloidosis. Tafamidis (Vyndaqel® and Vyndamax®) has
been approved by the Food and Drug Administration (FDA) in May 2019 for the
treatment of patients with ATTR-CM based on clinical trial data showing higher
survival rates and reduced number of hospitalizations for cardiovascular
problems in the tafamidis group than in the placebo group. Approval of
tafamidis is also expected in Europe.
NI006, a human monoclonal immunoglobulin-1 (IgG1) antibody derived using
Neurimmune*s proprietary technology, binds ATTR in cardiac and non-cardiac
tissues from subjects with sporadic and hereditary forms of the disease,
including binding similarly wild-type (WT) and mutant ATTR fibrils. NI006 has
the capacity to activate the elimination of ATTR fibrils by immune cells.
Removal of ATTR deposits from tissues, especially in the heart, is expected to
reduce myocardium stiffness, leading to improved cardiac function and symptom
regression in subjects.

Primary objective:
Determine the short- and long-term safety and tolerability of single and
multiple doses of NI006 in subjects with ATTR-CM by evaluating adverse events
(AE) and serious adverse events (SAE) and changes in laboratory parameters
(hematology,clinical chemistry, immunology, and urinalysis), cardiac
biomarkers, vital signs, electrocardiogram (ECG), and echocardiogram

Secondary objective:
Determine the pharmacokinetic (PK) profile and PK parameters of NI006 in
subjects with ATTR-CM

Exploratory objective:
-Explore the efficacy of multiple doses of NI006 in subjects with ATTR-CM on
clinical, imaging, ECG and laboratory variables
-Confirm absence of effect on physiological TTR
-Evaluate the immunogenicity of NI006
-Characterize target engagement and immune activation on tissue biopsies
(OPTIONAL)

This is a randomized, placebo-controlled, double-blind trial combining SAD and
MAD phases, followed by an OLE phase in subjects with ATTR-CM.
Subjects completing the SAD phase will be enrolled in the MAD phase upon
evaluation of all available safety data by the DEC.
Subjects completing the MAD phase will have the possibility to continue in an
OLE phase with dose up-titrations and switch from placebo to NI006 treatment,
upon cumulative safety data evaluation by the DEC.
About 30 to 36 subjects are planned to be enrolled in 5 to 6 ascending dose
cohorts of 6 subjects each. This number does not include subjects who need to
be replaced as explained in section 6.3.3 of the protocol.
The dose cohorts planned in mg/kg body weight are: 0.3 mg/kg (cohort 1), 1
mg/kg (cohort 2), 3 mg/kg (cohort 3), 10 mg/kg (cohort 4), 30 mg/kg (cohort 5),
and potentially 60 mg/kg (cohort 6, in case of absence of safety signals at 30
mg/kg).
The trial schema is provided in Table 5 and Table 6 of the protocol. These
schemata are to visualize the planned trial but are presenting a best-case
scenario and do not take possible delays into account.

SAD Phase
For each dose cohort, the first 2 subjects are randomized in a 1:1 ratio to
receive a single dose of NI006 or placebo. The decision to dose additional
subjects at the same dose level is based on 5-day post-dose safety data. The
following 4 subjects are randomized in a 3:1 ratio to receive a single dose of
NI006 or placebo, with a minimum 7-day enrolment interval. When at least 5
subjects were dosed in a dose cohort, with a minimum of 29 days after the first
subject was treated with IMP in the dose cohort, the DEC will review all
available safety data and decide on the initiation of the next higher dose
cohort (regular DEC meeting). Under specific circumstances the DEC will be
convened earlier than 29 days after the first subject was treated with IMP in
the dose cohort (ad-hoc DEC meeting).
If 5 SAD cohorts are performed, 20 subjects will receive 1 dose of NI006, and
10 subjects will receive placebo. If 6 SAD cohorts are performed, 24 subjects
will receive 1 dose of NI006 and 12 subjects will receive placebo; both cases
listed are excluding replacement subjects.

MAD Phase
Subjects completing the SAD phase will continue in the MAD phase of the trial
35 calendar days after their first dose of NI006 and receive 3 additional
administrations of NI006 at their assigned dose or placebo with an
inter-treatment interval of 28 days (±2 days - all procedures on the
same day).
The decision to enter the MAD phase will rely on the evaluation of the
cumulative safety data available by the DEC. In case no DEC decision is
available at this time or the DEC decided to postpone start of the MAD for
specific subject(s), the first treatment of the subjects in the MAD must be
delayed accordingly until the decision to enter the MAD is taken.
If all 5 SAD and MAD cohorts are performed, 20 subjects will receive 4 doses of
NI006, and 10 subjects will receive 4 doses of placebo. If 6 SAD and MAD
cohorts are performed, 24 subjects will receive 4 doses of NI006 and 12
subjects will receive 4 doses of placebo; both cases listed are excluding
potential replacement subjects.

OLE Phase
Subjects completing the MAD phase will have the possibility to continue in the
OLE phase of the trial. Subjects who received placebo during SAD and MAD phases
will be switched to NI006 during the OLE phase. During the OLE, based on the
evaluation of the cumulative safety data by
the DEC, subjects will be up-titrated continuously to the highest doses deemed
safe and well tolerated in repeated dosing (as evaluated in the MAD of the
specific dose cohort) at their dosing visit. During the OLE phase all subjects
may have the chance to be dosed with the maximum tolerated dose (MTD) depending
on the timepoint when the MTD is reached.
The OLE phase includes 8 additional administrations of NI006 with an
inter-treatment interval of 28 days (±2 days; all procedures on the same day).

Hospitalization for Safety Surveillance
The hospitalization schedule for safety surveillance is summarized in Table 4
of the protocol.
-SAD: 5 days (4 nights) (first IMP administration on the first day [V1] and
discharge on the 5th day [V5])
-MAD: For the second IMP administration, all subjects will be hospitalized for
3 days (2 nights) (drug administration on the first day [V9] and
discharge on the 3rd day [V11]); For the third and fourth drug administration,
all subjects will be hospitalized for 2 days (1 night) (drug administration on
first day [V14, V18] and discharge on the second day [V15, V19])
-OLE: 5 days (4 nights) after the first treatment in the OLE phase (drug
administration on the first day [V23] and discharge on the 5th day [V27]); No
hospitalization is mandatory for all following treatments provided no safety
issues have previously been detected and according to the Investigator*s
judgement

Patients will receive the following interventions:
-NI006/placebo dosing
-vital signs and physical examination
-Questionnaires & 6-minute walking test
-MRI or Bone Scintigraphy
-Echocardiography
-continuous ECG telemonitoring
-5-days holter
-12-lead ECG
-salivary gland biopsy (optional) - note: no cardiac biopsy in The Netherlands
-Blood / urine draws
-pregnancy testing (serum/urine for WOCBP)

Risk-benefit assessment:
The available non-clinical data indicate that NI006 selectively binds
pathological WT and mutant ATTR amyloid. This was confirmed by IHC with NI006
showing selective staining of amyloid deposits in tissues collected from
subjects with both sporadic and hereditary ATTR amyloidosis.
NI006 binding selectivity was further evaluated in good laboratory practice
(GLP) tissue crossreactivity experiments using frozen human tissue panels. An
ex vivo assay was developed consisting of human subject-derived cardiac tissue
sections incubated with human-derived macrophages in the presence of NI006. In
this assay, NI006 triggered rapid, dose-dependent and nearly complete removal
of ATTR amyloid from heart tissues by macrophages within 14 days, which
confirmed expected MOA.
Proof-of-mechanism for antibody-mediated removal of amyloid deposits has been
recently established in Alzheimer disease (Panza et al, 2014; Ostrowitzki et
al, 2012; Sevigny et al, 2016) and in treatment with anti-serum amyloid P
antibody (Richards et al, 2015; Richards et al, 2018).
The capacity of NI006 to bind amyloid deposits in subject*s cardiac tissues and
trigger their elimination by macrophages demonstrated ex vivo indicate a
promising therapeutic potential for the treatment of diseases caused by ATTR
amyloidosis.
The sentinel dosing at the beginning of each dose cohort, the proposed clinical
safety monitoring, and the use of a Data Evaluation Committee (DEC), provide
for a comprehensive safety risk minimization to address any uncertainties with
the administration of NI006.
Based on the current absence of approved treatment options for ATTR-CM in
Europe, the limited numbers of therapeutic mechanisms currently tested in
clinical studies, the rapid lethality of this disease, and the promising
non-clinical data observed with NI006, there is a demand from the medical
community to move forward with the clinical evaluation of NI006.