Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today final results from its completed Phase I
clinical trial with ALN-TTR01, an RNAi therapeutic targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis
(ATTR). The data
were presented at the XIII International Symposium on Amyloidosis held
May 6-10, 2012 in Groningen, The Netherlands. Data from this study show
that administration of ALN-TTR01 resulted in statistically significant
reductions in serum TTR protein levels, including both wild-type and
mutant TTR protein, in ATTR patients. Knockdown of TTR, the
disease-causing protein, was found to be dose dependent, rapid, and
durable after just a single dose. The full time course for TTR knockdown
reveals the potential for once monthly or possibly once every other
monthly dose regimens in further studies. ALN-TTR was found to be
generally safe and well tolerated in this study.
"These Phase I data from our ALN-TTR01 clinical study demonstrate rapid,
dose-dependent, and durable lowering of TTR protein levels after a
single dose in ATTR patients. The observed reduction of mutant and
wild-type TTR in patients with the V30M mutation is important, since
both contribute to amyloid deposition. Further, the full time course for
TTR knockdown after a single dose confirms our expectations for a once a
month or possibly even a once every two month dosing regimen in our
further studies," said Jared Gollob, M.D, Senior Director, Clinical
Research. "We believe these data with ALN-TTR01 provide key human proof
of concept as we advance ALN-TTR02 as our 'go-to-market' RNAi
therapeutic for the treatment of ATTR, a debilitating orphan genetic
disease. ALN-TTR02 uses our proprietary second-generation LNP
formulation which has demonstrated markedly improved potency in human
clinical studies, and we look forward to presenting results from an
ongoing Phase I clinical study in the third quarter of 2012. Alnylam is
committed to bringing this high impact medicine to patients afflicted
with ATTR."
This Phase I study was designed as a randomized, placebo-controlled,
single-dose escalation study in patients with ATTR. Patients were
enrolled in seven sequential cohorts of increasing doses ranging from
0.01 to 1.0 mg/kg. There were four patients per cohort, with patients
randomized to receive drug or placebo in a 3:1 ratio. Following the
completion of dose escalation, additional patients were enrolled at 1.0
mg/kg. Data were presented from 32 patients, including eight who
received placebo and 24 who received drug.
ALN-TTR01 clinical activity was assessed based on measurements of serum TTR protein levels. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day 7 to 10 in the 1.0 mg/kg group (geometric mean relative to placebo, p=0.01). The rapid onset and durable effect of ALN-TTR01 after a single dose was exemplified by one patient dosed at 1.0 mg/kg who showed 63% TTR lowering at 48 hours, peak TTR knockdown of 81% at day 10, approximately 50% lowering at 30 days post dose, and full recovery only at 60 days. In addition, analysis of serum samples by a liquid chromatography-mass spectrometry method revealed that both mutant and wild-type TTR were knocked down to the same extent in V30M patients; both wild-type and mutant TTR have been shown to cause amyloid plaques in ATTR patients.