ive)surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis
resulted in no adverse effects on fertility or on embryofetal development.
Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeksproduced no adverse effects on male reproductive organs or on sperm morphology or count.
14 CLINICAL STUDIES
The efficacy of ONPATTRO was demonstrated in a randomized, double-blind, placebo-controlled, multicenter clinicaltrial in adult patients with polyneuropathy caused by hATTR amyloidosis (NCT 01960348). Patients were randomized in
a 2:1 ratio to receive ONPATTRO 0.3 mg/kg (N=148) or placebo (N=77), respectively, via intravenous infusion onceevery 3 weeks for 18 months. All patients received premedication with a corticosteroid, acetaminophen, and H1 and H2blockers. Ninety-three percent of ONPATTRO-treated patients and 62% of placebo-treated patients completed 18 monthsof the assigned treatment.
The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy ImpairmentScore +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 (+7)composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nervefunction, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, andperipheral nerve electrophysiology. The maximum possible score was 304 points, with higher scores representing agreater severity of disease.
The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 18 in NorfolkQuality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessmentthat eva luates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the
Norfolk QoL-DN that was used in the trial had a total score range from -4 to 136, with higher scores representing greater
impairment.
The changes from baseline to Month 18 on both the mNIS+7 and the Norfolk QoL-DN significantly favored ONPATTRO(Table 2, Figure 1 and Figure 3). The distributions of changes in mNIS+7 and Norfolk QoL-DN scores from baseline toMonth 18 by percent of patients are shown in Figure 2 and Figure 4, respectively.
The changes from baseline to Month 18 in modified body mass index (mBMI) and gait speed (10-meter walk test)significantly favored ONPATTRO (Table 2).
Table 2: Clinical Efficacy Results from the Placebo-Controlled Study
Endpointa
Baseline, Mean (SD) Change from Baseline to
Month 18, LS Mean (SEM)
ONPATTROPlacebo
Treatment
Difference,
LS Mean
(95% CI)
p-value
ONPATTRO
N=148
Placebo
N=77 ONPATTRO Placebo
Primary
mNIS+7 b 80.9 (41.5) 74.6 (37.0) -6.0 (1.7) 28.0 (2.6) -34.0
(-39.9, -28.1) p<0.001
Secondary
Norfolk
QoL-DN b 59.6 (28.2) 55.5 (24.3) -6.7 (1.8) 14.4 (2.7) -21.1
(-27.2, -15.0) p<0.001
10-meter
walk test
(m/sec) c
0.80 (0.40) 0.79 (0.32) 0.08 (0.02) -0.24 (0.04) 0.31
(0.23, 0.39) p<0.001
mBMI d 970 (210) 990 (214) -3.7 (9.6) -119 (14.5) 116
(82, 149) p<0.001
CI, confidence interval; LS, least squares; mBMI, modified bod |
