New Drug Effectively Lowers Cholesterol

Thu, 10/03/201

Alnylam Pharmaceuticals Inc., an RNAi therapeutics company, announced
the publication in The Lancet of complete study results from a Phase 1
trial with ALN-PCS, a systemically administered RNAi therapeutic
targeting PCSK9 for the treatment of hypercholesterolemia.

The paper, titled “Effect of an RNA interference drug on the synthesis
of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the
concentration of serum LDL cholesterol in healthy volunteers: a
randomized, single-blind, placebo-controlled, phase 1 trial,” reports
the results of a study evaluating single intravenous dose administration
of ALN-PCS, in the absence of concomitant lipid-lowering agents such as
statins.

Specifically, ALN-PCS administration resulted in a rapid, dose-dependent
reduction in plasma PCSK9 of up to 84 percent relative to baseline and
placebo, with a corresponding reduction in serum levels of low-density
lipoprotein cholesterol (LDL-C) – a clinically validated endpoint– of up
to 57 percent relative to baseline and placebo. The knockdown of PCSK9
and lowering of LDL-C were also found to be durable, with effects
lasting for weeks after a single dose. This new paper documents the
first human proof of concept for an RNAi therapeutic impacting a
clinically validated endpoint.

“Our data with ALN-PCS demonstrate that inhibition of PCSK9 synthesis by
an RNAi therapeutic may be a potentially safe and novel approach to
reduce LDL-C. The study also documents the first human proof of concept
for an RNAi therapeutic toward a clinically validated endpoint, namely
LDL-C,” said Kevin Fitzgerald, senior director of research at Alnylam
and lead author on the paper. “We believe that the unique mechanism of
action for ALN-PCS, which inhibits the synthesis of PCSK9 inside liver
cells– thereby reducing both its intracellular and extracellular
functions– provides a differentiated strategy for PCSK9 antagonism. This
mechanism of action results in consistent clinical activity across a
wide range of baseline PCSK9 plasma levels, including in individuals
with very high PCSK9 levels. Together with The Medicines Company, we are
now advancing ALN-PCSsc, a GalNAc-siRNA targeting PCSK9, which we
believe will enable subcutaneous dose administration with a wide
therapeutic index, and expect to designate our development candidate by
the end of this year.”

“Cardiovascular disease remains the leading cause of mortality
worldwide, with elevated LDL-C a well validated and modifiable risk
factor. A substantial number of patients, especially those at high risk
for cardiovascular disease, are unable to achieve target LDL levels with
current drugs, such as statins, and it is clear that new therapeutic
options are needed,” said Daniel Rader, professor of Medicine and chief,
Division of Translational Medicine and Human Genetics, at the Perelman
School of Medicine at the University of Pennsylvania. Rader also serves
on Alnylam’s Scientific Advisory Board. “As a key regulator of LDL
receptor levels, liver-expressed PCSK9 is one of the most important and
best validated novel targets in molecular medicine for the treatment of
hypercholesterolemia. An RNAi therapeutic targeting PCSK9 expression in
the liver has the potential to rapidly and durably lower LDL
cholesterol, thereby having the potential to reproduce the beneficial
effects observed in individuals with loss-of-function PCSK9 mutations. I
am very encouraged by the ALN-PCS Phase I safety and efficacy data
generated to date and look forward to continued clinical advancement of
RNAi therapeutics toward this important disease target.”

ALN-PCS is a systemically delivered RNAi therapeutic targeting PCSK9, a
target validated by human genetics that is involved in the metabolism of
LDL-C, or “bad” cholesterol. ALN-PCS inhibits the synthesis of PCSK9,
thereby reducing intracellular and extracellular levels of PCSK9,
resulting in lowered levels of LDL-C.

The Phase 1 study was conducted as a randomized, single-blind,
placebo-controlled, single-ascending dose study in healthy volunteer
subjects with elevated baseline LDL-C (greater than 116mg/dL). The
primary objective of the study was to evaluate the safety and
tolerability of a single dose of ALN-PCS. Secondary objectives of the
study included assessment of pharmacodynamic effects of ALN-PCS on
plasma PCSK9 protein levels and evaluation of clinical activity as
measured by LDL-C levels. A total of 32 subjects were enrolled into six
sequential dose cohorts ranging from 0.015 to 0.400 mg/kg in a 3:1
randomization of drug to placebo.

Results of the Phase 1 study showed that single dose administration of
ALN-PCS achieved rapid, dose-dependent, and durable knockdown of PCSK9
protein levels in plasma of up to 84 percent relative to baseline and
placebo, with a statistically significant mean reduction of 70 percent
in the highest dose group of 0.400 mg/kg. In addition, ALN-PCS
administration resulted in rapid, dose-dependent, and durable reductions
in LDL-C of up to 57 percent relative to baseline and placebo, with a
statistically significant mean reduction of 40 percent at the 0.400
mg/kg dose level.

Importantly, ALN-PCS demonstrated consistent clinical activity toward
both PCSK9 and LDL-C in a manner that was independent of baseline levels
of PCSK9, highlighting the unique mechanism of action for a PCSK9
synthesis inhibitor. In other words, subjects with high levels of PCSK9
at baseline achieved a comparable degree of knockdown of plasma PCSK9
and reductions in LDL-C as those with low levels of baseline PCSK9.
Furthermore, there was no significant change in plasma levels of
transthyretin (TTR), a liver-secreted protein that is not expected to
change upon silencing PCSK9, thus confirming that the effects of ALN-PCS
on plasma PCSK9 levels were specific to the target gene. In addition,
data from pre-clinical studies in non-human primates were shown to be
highly predictive of the clinical results, demonstrating that non-human
primate data from studies with RNAi therapeutics translate to human data
on a roughly equivalent mg/kg basis.

ALN-PCS was shown to be generally safe and well tolerated in this Phase
I study and there were no serious adverse events related to study drug
administration. There were no drug-related discontinuations and no liver
enzyme elevations. In addition, there were no clinically significant,
dose-dependent changes in any laboratory indices– including liver
function tests, creatine phosphokinase, C-reactive protein, and
hematological parameters– or cytokines. There was also no statistically
significant change compared to baseline in levels of high-density
lipoprotein (HDL), or “good” cholesterol, consistent with the phenotype
observed in human PCSK9 loss-of-function mutations.

Alnylam is currently advancing ALN-PCSsc, an RNAi therapeutic targeting
PCSK9 that utilizes the company’s proprietary GalNAc conjugate delivery
platform enabling subcutaneous dose administration with a wide
therapeutic index. At its R&D Day in July 2013, the company presented
pre-clinical data from non-human primate studies performed in the
absence of concomitant statin therapy, showing that subcutaneous
administration of ALN-PCSsc resulted in greater than 80 percent
knockdown of plasma PCSK9 with greater than 50 percent reductions in
LDL-C. The company expects to nominate a development candidate for
ALN-PCSsc in late 2013.

In February 2013, Alnylam formed an exclusive global alliance with The
Medicines Company for the development and commercialization of the
ALN-PCS program. Alnylam will lead the program through the completion of
Phase 1. The Medicines Company is responsible for leading and funding
development from Phase 2 forward and commercializing the ALN-PCS program
if successful.

“We are very excited by the pre-clinical and early clinical data that
our partner Alnylam has generated to date with ALN-PCS as reported in
The Lancet, in addition to the more recent progress with ALN-PCSsc,
which we believe has the potential to deliver a highly competitive
profile with subcutaneous dose administration. We have seen that
inhibition of PCSK9 by various therapeutic approaches, such as
monoclonal antibodies and gene silencing, can substantially reduce LDL-C
in patients. Epidemiological and disease mechanism studies suggest this
reduction in LDL-C can further reduce the risks of the world’s number
one killer, coronary artery disease,” said David Kallend, vice president
and global medical director for the lipid programs at The Medicines
Company. “Our focus on acute and intensive care medicine has led us to a
leadership position in the management of patients who are at extreme
risk as a consequence of the rupture of their vulnerable coronary artery
plaque at and around the time of acute coronary syndromes. We look
forward to working with Alnylam in advancing ALN-PCSsc to patients.”

Source: Alnylam Pharmaceuticals Inc.