APOLLO: A Phase 3 Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Patisiran (ALN-TTR02) in Transthyretin (TTR)-Mediated Polyneuropathy (Familial Amyloidotic Polyneuropathy-FAP)

Transthyretin-mediated amyloidosis (ATTR) is an inherited, autosomal dominant,
systemic disease caused by a mutation in the transthyretin (TTR) gene, leading
to destabilization of the tetrameric form of TTR and tissue deposition of
amyloid fibrils. The particular TTR mutation and site of amyloid deposition
determines the clinical manifestations of the disease, which include sensory
and motor neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR is a
progressive disease associated with severe morbidity, with a life expectancy
limited to 5 to 15 years from symptom onset. There are over 100 reported TTR
mutations which are associated with 2 clinical syndromes: familial amyloidotic
polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). The
estimated worldwide prevalence of FAP is 5,000 to 10,000, with the majority of
cases in Portugal, Sweden, France, Japan, Brazil, and the United States.
There are multiple lines of evidence demonstrating that reduction of
circulating TTR improves outcomes in patients with ATTR. Because the liver is
the primary source of wildtype and mutant TTR, orthotopic liver transplantation
is the current standard of care in patients with minimal neuropathy symptoms
and no cardiac involvement. It is estimated that approximately two-thirds of
FAP patients are not transplant-eligible. Nonsurgical options that are used for
the treatment of FAP include tafamidis (Vyndaqel®; only approved in the EU for
early-stage FAP) and diflunisal (completed a phase III clinical trial). Due to
the restricted use of liver transplantation and tafamidis in patients with
early stage of disease, and the non-standard use of diflunisal among
practitioners, there remains an unmet medical need for a potent and effective
therapy for FAP that will have an impact on patients across a broad range of
neurologic impairment, regardless of their mutation.
Patisiran (ALN-TTR02) is being developed for the treatment of ATTR patients
with symptomatic FAP. Patisiran is a short interfering RNA (siRNA) specifically
targeting TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) for
intravenous (IV) administration. Following LNP-mediated delivery to the liver,
patisiran targets TTR mRNA for degradation, resulting in the potent and
sustained reduction of mutant and WT TTR protein via the RNA interference
(RNAi) mechanism. It is postulated that the suppression in both WT and mutant
TTR observed upon administration of patisiran once every 21 days may result in
clinical benefit in FAP patients with polyneuropathy.

This study aims to demonstrate the clinical efficacy of patisiran and to
establish the safety of chronic dosing in ATTR patients with FAP.

The primary objective of the study is to determine the efficacy of patisiran by
evaluating the difference between the patisiran and placebo groups in the
change from baseline of modified NIS+7 (mNIS+7) score at 18 months.

The secondary objectives of the study are to determine the effect of patisiran
on various clinical parameters by assessing the difference between patisiran
and placebo in the change from baseline in the following measurements at 18
months:
- Quality of Life
- Motor function
- Autonomic function

This is a multicenter, multinational, randomized, double-blind study comparing
patisiran to placebo in ATTR patients with symptomatic Familial Amyloidotic
Polyneuropathy (FAP).
Consented eligible patients will be randomized to receive either 0.3 mg/kg
patisiran or placebo in a blinded manner. Patients will receive patisiran or
placebo for 78 weeks.

Consented eligible patients will be randomized to receive either 0.3 mg/kg
patisiran or placebo in a blinded manner. Patients randomized to the active
treatment group will receive 0.3 mg/kg patisiran administered as an IV infusion
by a controlled infusion device.
Patients randomized to placebo will receive IV normal saline (0.9%).

Patients are required to visit the hospital more often than during standard
treatment, and will need to discontinue tafamidis or diflunisal if presently
used. The patient's participation in this study will last for approximately 78
weeks. Efficacy and safety testing will be performed. Visits involve the
administration of study medication and standard safety tests.