Efficacy and safety of NNC6019-0001 at two dose levels in participants with
transthyretin amyloid cardiomyopathy (ATTR CM)

Transthyretin amyloid cardiomyopathy (ATTR CM)
Transthyretin amyloid (ATTR) amyloidosis is a rare and progressive disease
characterised by deposition of aggregates of misfolded transthyretin protein
(amyloid). Transthyretin (TTR) is a naturally occurring protein, which may
misfold to form toxic soluble monomers that subsequently may aggregate and form
fibrils with resultant TTR amyloid deposition into tissues (e.g., heart,
nerves, gastrointestinal tract) with disrupted organ structure and function as
the consequence. The TTR protein is produced primarily in the liver and in its
normal tetrameric form serves as a carrier for thyroxin and vitamin A, the
latter via the binding of retinol binding protein.
ATTR amyloidosis can be hereditary (hATTR) due to rare genetic variants or
occur sporadically as wild type (wtATTR).
In hATTR amyloidosis, the body makes a mutant form of the TTR protein. There
are more than 100 reported types of TTR mutations that promote amyloid fibril
formation. The predominant organ involvement for hATTR amyloidosis is either
the nervous system (hATTR PN amyloidosis) or the heart (hATTR CM amyloidosis),
although other organ systems are also often involved. Depending on the specific
mutation, some patients predominantly have cardiac symptoms, some predominantly
have symptoms from the nervous system, and some have a combination of both. In
one study of approximately 500 patients with the hATTR V30M mutation, one third
of patients had clinical nephropathy based on elevated levels of proteinuria,
and 10% progressed to end-stage renal disease. A significant number of TTR
mutations associated with a clinical phenotype cause a restrictive
cardiomyopathy.
Wild-type ATTR is similar to hATTR except that the protein that is deposited is
the misfolded, non-mutated transthyretin protein. The misfolding is thought to
be caused by age-related impaired proteostasis. The predominant effect of
wtATTR amyloidosis is on the heart.

This study has been transitioned to CTIS with ID 2023-506824-96-00 check the CTIS register for the current data.

• safety and tolerability from baseline to week 64 in participants with hATTR
or wtATTR cardiomyopathy

Primary
• To compare the effect of two dose levelsof NNC6019-0001 (30 mg/kg and 100
mg/kg) versus placebo on:
• change in 6-minute walk test and
• change in NT-proBNP
from baseline to week 52 in participants with hATTR or wtATTR cardiomyopathy.

Secondary
• To compare the effect of two dose levels of NNC6019-0001 (30 mg/kg and 100
mg/kg) versus placebo on:
• biomarkers
• pharmacodynamic endpoints
from baseline to week 52 in participants with hATTR or wtATTR cardiomyopathy.

This is an interventional, randomised, multinational, multicentre, three-arm
parallel-group, double-blind, placebo-controlled study comparing i.v.
NNC6019-0001 Q4W at two dose levels (30 mg/kg and 100 mg/kg) versus placebo in
participants with hATTR or wtATTR CM.
The study consists of a screening period of up to 8 weeks, followed by a
52-week intervention period. When participants discontinue study intervention
according to protocol, an end of treatment visit should be carried out 4 weeks
after administration of the last dose and a follow-up visit should be carried
out 16 weeks after administration of the last dose.

Patient will be randomised 1:1:1 to receive i.v. 30 mg/kg NNC6019-0001, 100
mg/kg NNC6019-0001 or placebo Q4W added to standard of care accroding to the
following treatment arms:


30 mg/kg NNC6019-0001
100 mg/kg NNC6019-0001
placebo

Potential risk:
Hypersensitivity: As expected for a protein-based drug, participants treated
with NNC6019-0001 may develop localised (to the infusion site) or generalised
hypersensitivity reactions.
Myocardial Inflammation: The intended action of the NNC6019-0001 in clearing
amyloid through macrophage activation and phagocytosis may result in a
theoretical risk of myocardial inflammation.
Pro-arrhythmic risk: Based on the potential mechanism of action of NNC6019-0001
and the underlying disease pathophysiology of ATTR cardiomyopathy, there is a
theoretical risk of arrhythmogenicity.
To mitigate these potential risks participants will be followed closely and
carefully by qualified medical staff. Additionally standard safety surveillance
activities and medical monitoring will be performed by Novo Nordisk.
Preliminary efficacy results from the FHD study (study NN6019-4965) for 7
evaluable participants treated with NNC6019-0001 were favourable. NNC6019-0001
was associated with a mean change of - 1.21% in GLS from baseline to 9 months
indicating a possible benefit in cardiac systolic function. Six (6) of the 7
efficacy evaluable participants had no change in their baseline New York Heart
Association (NYHA) class at month 9. Participation in this study is
contributing to the process of developing a new therapy option for patients
with ATTR CM with a proposed amyloid-depleting mode of action. Expected
benefits associated with treatment with NNC6019-0001 include those associated
with removal of amyloid in tissues, specifically in the myocardium.
It is expected that all participants will benefit from participation through
frequent and close contact with investigators and other site staff who will
ensure that the participants are treated to
recommended standard of care for their conditions, including ATTR CM, and
disease development and progression will be closely monitored and treated.
Taking into account the measures taken to minimise risk and burden to
participants participating in this study, the potential risks identified in
association with NNC6019-0001 are justified by the anticipated benefits that
may be afforded to participants with ATTR CM