The Medicines Company Is Making A

Dangerous Bet On A Drug To Lower LDL

Cholesterol
John LaMattina, CONTRIBUTOR
I cover news on drugs and R&D in the pharma industry
Opinions expressed by Forbes Contributors are their own.

Once heralded as the coming of the next

blockbusters in treating heart disease, the PCSK9
inhibitors Repatha (Amgen) and Praluent
(Sanofi/Regeneron) have had a
disappointing performance both therapeutically
and commercially.

These drugs, when combined with statins, have

shown the ability to lower LDL-cholesterol (LDL-
c) to unprecedented levels with many patients
seeing their LDL-c drop to as low as 30mg/dL.
Yet, at least based on data from Amgens
FOURIER trial which was designed to measure
reduction in cardiovascular events in heart
patients, Repathas medical impact has been less
than hoped for. While there was a drop in
cardiovascular events in this high risk patient
population, the magnitude of the drop was
disappointing with a 11.3% decrease in
cardiovascular events in the patients only
receiving statins vs. a 9.8% drop in the Repatha
plus statin arm a 15% reduction. Given the low
LDL-c levels for the PSCK9-treated patients,
better results were expected.
John Maraganore, chief executive officer of Alnylam Pharmaceuticals
Inc. (Photographer: Scott Eisen/Bloomberg)

Commercially, these drug sales have also lagged

expectations. While early in their lifecycles, the
combined sales of these drugs in 2016 was about
$250 million, a pittance compared to peak annual
sales of statins such as Pfizers Lipitor which at
one point reached $12.9 billion. The reason for
the slow uptake of PCSK9 inhibitors is cost. The
list prices for these drugs are on the order of
$14,000/year although it is rumored that the
negotiated price to payers is closer to $9,000.
Nevertheless, this is still an expensive drug and
payers are throwing up large hurdles before
allowing patient access to them. At the recent
Cowen Conference in NYC, one cardiologist
commented that his experience has been that all
first prescription requests are denied and then an
appeal process ensues. Thus, sales growth for
PCSK9 inhibitors will likely be slow.

There is another PCSK9 blocker on the horizon.

Inclisiran, being jointly developed by The
Medicines Company and Alnylam, is a first-in-
class PCSK9 synthesis inhibitor with the potential
for a highly competitive profile as compared with
anti-PCSK9 monoclonal antibodies. Data
presented last August at the European Society of
Cardiology Conference in Barcelona supported
this assertion. In the ORION 1 phase 2 study, a
two dose 300 mg regimen produced average time
adjusted LDL-c reductions of almost 50% at one
year.

Based on the ORION 1 data, The Medicines

Company and Alnylam have begun an ambitious
phase 3 program. The key components of the
phase 3 program are what would be expected: a
3,000 patient study with half randomly assigned
to receive a 300 mg dose of inclisiran four times
over 18 months while the other half receive
placebo to confirm the potent LDL-c lowering
potential of this drug over time. The second major
component, reminiscent of the FOURIER trial, is
a 14,000 patient cardiovascular outcome (CVOT)
study in patients with confirmed atherosclerotic
heart disease to measure the reduction of
cardiovascular events in the inclisiran patients
compared to those on placebo. These will not be
cheap to run. It likely that the price tag for the
inclisiran phase 3 program will be close to $1
billion.

Watch on Forbes: One Pharmaceutical

Company's Approach To Keeping
Healthcare Affordable

To pay for these studies, The Medicines Company

has announced a drastic downsizing with the
reduction of its workforce to 60 people (it had 410
back in February) and the sale of its infectious
disease group. Basically, it's betting its future on
inclisiran. But how risky is this bet? There is
definitely a high probability of clinical success
with inclisiran based on the previous results seen
with Repatha and Praluent. One can expect the
drug will successfully lower LDL-c over 18
months and that the CVOT will also result in a
better outcome than seen with statins. However,
will the inclisiran CVOT be significantly better
than the results seen in FOURIER? Furthermore,
by the time the inclisiran study reads out, the
results of the Praluent CVOT will also be in hand.
Whether inclisiran will be significantly
differentiated from the already marketed
compounds will be a big challenge.

An even bigger challenge will come from payers.

They dont really care about a mechanistically
different compound that provides the same
outcome. Nor do they care about a drug dosed
twice a year vs. one dosed twice a month.
Convenience isnt at the top of their minds. What
they DO care about is price. Will The Medicines
Company be willing to charge significantly less
than the price currently commanded by Repatha
and Praluent? Perhaps, but then again, early signs
are that this isnt going to be a huge market.
Getting into a price war would limit the returns
on this investment.

Another issue is timing. The launch of inclisiran

will occur when Repatha and Praluent will have
been on the market for 6 7 years. By then, these
drugs will be entrenched with patients, physicians
and payers. Dislodging these drugs, particularly if
there is no major difference in efficacy will be
tough to do. Unless, of course, you are counting
on competing on price.
So, The Medicines Company has made a big bet.
Its placed all of its chips in the middle of the
table, hoping that the inclisiran phase 3 program
will lead to an inside straight. Thats certainly a
possibility. But, how often does that happen?