Dinner W/ Mgt . Says Much Ado About Nothing On Concerns
Following Recently Released Onpattro Approval Package By FDA
MS / Sept 17, 2018

FDA documents highlighted in process deliberations on safety
& patient deaths but mgt. indicates that any concerns held by
agency were not broached with company and never made it to
the labeling. This suggests that the agency believed that risks
were not substantial enough a concern.

Dinner with management relieves cardiac concerns that arose last week
followingrelease of the Onpattro Approval Package by the FDA:Last week, we
hosted Alnylam mgt. for a dinner during their attendence at the Morgan Stanley
Healthcare Conference. During the dinner, mgt. discussed the recent release of
the Onpattro (patisiran) approval package, which contained commentary
regarding safety that contributed to volatility in the shares. After our discussions,
their presentation at the conference as well as Friday morning's release of
exploratory cardiac data on Onpattro via its publishing in the journal Circulation,
we see it as unlikely that cardiac safety should be a concern for Onpattro.

Although we have yet to project sales numbers for Onpattro in the hereditary
transthyretin amyloidosis with cardiomyopathy (hATTR-CM) population, we
expect that last week's noise will not impact uptake in hATTR with
polyneuropathy population who have cardiac symptoms. Attending the
conference and dinner were Chief Executive Officer John Maraganore, PhD and
Chief Medical Officer Pushkal Garg, MD.

Document's commentary on cardiac safetyevents represents in process FDA
deliberations, but not conclusions:Last week, investors cited concerns following
a read of the FDA's /Drug Approval Package' for Onpattro (find ithere). As part
of the FDA Application Review Files can be found the 'Multi-Discipline
Review/Summary, Clinical, Non-Clinical (find ithere).' In the safety discussion –
which begins on page 18 – the document addresses patient deaths from the PhIII
APOLLO trial. Alnylam stock has been under pressure due to the
disproportionate number of cardiovascular heart failure deaths noted in the
Onpattro arm versus the number observed in the placebo arm (7 to 1) (Exhibit 1).

In the text of the FDA's document, A reviewer suggests this differential is
'concerning'. However, the numbers are not high enough to be considered for the
labeling. When this death imbalance with regards to heart failure is juxtaposed
versus the PhIII ENDEVOUR trial for revusiran in cardiomyopathy – which was
discontinued to a mortality imbalance favoring placebo – investors became
concerned that the large hATTR-CM and wild type TTR populations could
potentially be contraindicated.

Let's have a dose of perspective: The specific documents in question are in house
(FDA's house) deliberations of a drug's dataset. They do not represent the
agency's conclusions. It is the FDA's responsibility to vet and fully scrutinize each
aspect of a dataset. If the concerns rise to a substantive level, the company will
be engaged in the subject matter and if the company cannot resolve the concern
it would be likely that a black box warning for cardiac toxicity would be included
in the label. This did not occur. In fact, this line of commentary was never
broughtup to management during the entire deliberative process for the NDA
application. In other words, the concerns regarding cardiac toxicity were examined
and mostly dismissed internally by the agency. This would likely be because the
actual mortality imbalance heavily favored Onpattro who had seven patient
deaths (of 148 enrolled in this arm) as compared to 6 deaths on placebo (of 77)
(Exhibit 1).Further accentuating this, is that there were many more
discontinuations on placebo than Onpattro. Outright cardiovascular deaths
between the two arms (including stroke) were essentially even, 7 on drug versus
3 on placebo. To take matters one step further, this was a randomized trial for a
highly heterogenous population that includes numbers mutations of varying
levels of severity. The Onpattro arm had a disproportionate number of patients
with non-V30M mutations, which are considered to be more aggressive than
most included in this trial. 4 of the 7 of the patients that died from the Onpattro
arm had T60 ALA mutation or a Glu 89 Gln mutation, which are also considered
to be aggressive.
Though weare not concerned on cardiac safety, ALN-TTRsc02 needed for
cardiomyopathy market penetration: Although we are not concerned regarding
the safety related noise from last week, we do not expect that Onpattro will get
substantial use in hATTR-CM patients. In order to maximize penetration into this
population, we hold the view that Alnylam will need to build its dataset
demonstrating efficacy in these patients through follow-on ALN-TTRsc02. A PhIII
trial for ALN-TTRsc02should begin later this year,examining the drug for hATTR
with polyneuropathy. A PhIII trial to examine ALN-TTRsc02for hATTR with
cardiomyopathy and wild type TTR is set to begin in the future. However, mgt.
wants to conduct this trial against tafamidis. As such, this trial is not likely to
begin until after tafamidis is approved. Mgt. is also considering a third PhIII trial
which would examine ALN-TTRsc02in patients with earlier diagnosed disease.

A handful of catalysts on tap: A busy couple months are ahead for the company.

Mgt.has indicated that Onpattro has already achieved first sales;although,
expectations for 3Q18 numbers should be held in check. When Alnylam reports
earnings in November, mgt. will announced the number of completed Onpattro
start forms. This should allow us some insight into the drug's early launch.

Before the end of this month, we expect to see interim PhIII data from the
ENVISION trial examining givosiran for hepatic porphyrias. Sufficient ALA
reduction seen in this study could provide the basis for an early FDA submission,
although with final data expected 1H19, timingupside is minimal.

Beyond givosiran,a competitive decision for Ionis's Tegsedi for hATTR-PN is
expected by October 6. We continue to expect approval for the competitor.
Although with Ionis's recent receipt of a complete response letter for Waylivra,
investors are a bit more unsure on Tegsedi's fate.