Preclinical and Clinical Studies Employing RNA Interference as a Therapeutic for Respiratory Syncytial Virus (RSV) Infection in the Lung - RNA Interference from Biology to Therapeutics - page 317

15.3 Overview of Clinical Development for ALN-RSV01

15.3.1 Summary of Phase I Studies

To date, over 270 subjects have been exposed to ALN-RSV01 via nasal spray or
inhalation in the setting of clinical studies. The safety and pharmacokinetic distribu-
tion of intranasal and inhaled ALN-RSV01 was evaluated in four Phase 1 studies.
In the early clinical studies, ALN-RSV01-101 and ALN-RSV01-102, ALN-RSV01
was administered intranasally to 65 adult healthy male volunteers in single and
multiple ascending doses ranging from 1.5 to 150 mg. Nasal administration was
done with nasal spray devices (Becton-Dickinson Accuspray) that were filled with
siRNA diluted in saline. ALN-RSV01 was found to be safe and well-tolerated at
doses up to 150 mg once daily for 5 days. Systemic exposure of ALN-RSV01 was
very low as only trace amounts of ALN-RSV01 were detected shortly after adminis-
tration in the serum of a few patients at the highest dose level [ 27 ] .
The next Phase I studies, ALN-RSV01-104 and ALN-RSV01-107, administered
single and multiple doses of inhaled ALN-RSV01 ranging from 0.01 to 3.0 mg/kg
using an investigational PARI eFlow ® nebulizer (PARI Pharma) to a total of 107
adult male and female healthy volunteers. Administration of ALN-RSV01 by inha-
lation was generally safe and well-tolerated. At higher inhaled doses (1 mg/kg and
above), transient flu-like symptoms were noted, including headache, chills, cough,
noncardiac chest, and throat pain. Similar to the i.n. studies, little systemic exposure
was observed after inhalation of ALN-RSV01. A dose of 0.6 mg/kg was well-
tolerated and anticipated to be active based on allometric scaling of ALN-RSV01
doses that were effective in the mouse RSV model.

15.3.2 Experimental RSV Infection Model

An RSV experimental infection model was utilized in ALN-RSV01-105 to explore
the effectiveness of ALN-RSV01 in healthy human volunteers inoculated with RSV
[ 28 ]. In this double-blind placebo-controlled trial, 85 healthy male volunteers
received either 75 or 150 mg ALN-RSV01 or placebo per nasal administration for
2 days. This was followed by i.n. inoculation with log3 to log5 PFU of RSV A strain
(Memphis 37, GMP manufactured), as well as 3 more days of ALN-RSV01 or pla-
cebo administration. RSV infection was detected in 72% of the volunteers with a
mean incubation period of 3 days. Overall, the proportion of subjects infected with
RSV was significantly lower in those treated with ALN-RSV01 compared to pla-
cebo as determined by qRT-PCR (data not shown) and quantitative culture
(Fig. 15.3a ). The proportion of subjects that remained uninfected after RSV inocu-
lation was also significantly greater in ALN-RSV01-treated than placebo as deter-
mined by quantitative culture (Fig. 15.3b ). Measurements of viral load, viral