IONIS PHARMACEUTICALS,INC. (NASDAQ:IONS) Files An 8-K Other Events

Item8.01Other Events.

On March27, 2017 Ionis Pharmaceuticals, Inc’s subsidiary, Akcea
Therapeutics, Inc., filed a registration statement on FormS-1
with the U.S. Securities and Exchange Commission relating to a
proposed initial public offering of Akcea’s common stock. The
registration statement contains, among other things, a
description of Akcea’s business. Ionis is filing the following
information with the Securities and Exchange Commission for the
purpose of updating certain aspects of its publicly disclosed
descriptions of its Akcea Therapeutics,Inc. business to include
portions of the description contained therein.

In this report, “Akcea Therapeutics,” “Akcea,” “Company,”
“we,” “us” and “our” refer to Akcea Therapeutics,Inc.,
unless the context requires otherwise.

We are a late stage biopharmaceutical company focused on
developing and commercializing drugs to treat patients with
serious cardiometabolic diseases caused by lipid disorders. Our
goal is to become the premier company offering treatments for
inadequately treated lipid disorders. We are advancing a mature
pipeline of four novel drugs with the potential to treat multiple
diseases. Our drugs, volanesorsen, AKCEA-APO(a)-L_Rx,
AKCEA-ANGPTL3-L_Rx and AKCEA-APOCIII-L_Rx,
are all based on antisense technology developed by
IonisPharmaceuticals, Inc., or Ionis. Our most advanced drug,
volanesorsen, has completed a Phase3 clinical program for the
treatment of familial chylomicronemia syndrome, or FCS, and is
currently in Phase3 clinical development for the treatment of
familial partial lipodystrophy, or FPL. FCS and FPL are both
severe, rare, genetically defined lipid disorders characterized
by extremely elevated levels of triglycerides. Both diseases have
life-threatening consequences and the lives of patients with
these diseases are impacted daily by the associated symptoms. In
our clinical program, we have observed consistent and substantial
(70%) decreases in triglycerides and improvements in other
manifestations of FCS, including pancreatitis attacks and
abdominal pain. We believe the safety and efficacy data from the
volanesorsen program demonstrate a favorable risk-benefit profile
for patients with FCS. In the third quarter of 2017, we plan to
file for marketing authorization for volanesorsen to treat
patients with FCS. We plan to report data from the Phase3 study
in patients with FPL in 2019. If the data are positive, in 2019
we plan to file for marketing authorization for volanesorsen to
treat patients with FPL.

We are assembling the infrastructure to commercialize our drugs
globally with a focus on lipid specialists as the primary call
point. A key element of our commercial strategy is to provide the
specialized, patient-centric support required to successfully
address rare disease patient populations. We believe our focus on
treating patients with inadequately addressed lipid disorders
will allow us to partner efficiently and effectively with the
specialized medical community that supports these patients. In
the future, this global infrastructure may support
commercialization of additional drugs within and outside the
cardiometabolic arena.

To maximize the commercial potential of two of the drugs in our
pipeline, we initiated a strategic collaboration with Novartis
PharmaAG, or Novartis, for the development and commercialization
of AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx.
We believe Novartis brings significant resources and expertise to
the collaboration that can accelerate our ability to deliver
these potential therapies to the large populations of patients
who have high cardiovascular risk due to inadequately treated
lipid disorders. As part of our collaboration, we received
$75.0million in an upfront option payment, of which we will
retain $60.0million and will pay $15.0million to Ionis as a
sublicense fee. After we complete Phase2 development of each of
AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx, if,
on a drug by drug basis, Novartis exercises its option to license
a drug and pays us the $150.0million license fee to do so,
Novartis plans to conduct and pay for a Phase3 cardiovascular
outcome study in high-risk patients and, if approved, to
commercialize such drug worldwide. We plan to co-commercialize
any licensed drug commercialized by Novartis in selected markets
through the specialized sales force we are building to
commercialize volanesorsen. Overall, we are eligible to receive
significant license fees,

milestone payments and royalties on sales of each drug Novartis
licenses if and when it meets the development, regulatory and
sales milestones specified in our agreement. We will share any
license fees, milestone payments and royalties equally with
Ionis.

Cardiometabolic disease, which includes cardiovascular diseases
and metabolic diseases, is the number one cause of death
globally. According to the American Heart Association, or AHA,
cardiovascular disease, or CVD, alone accounts for 17.3million
deaths per year globally, a number that the AHA expects to grow
to more than 23.6million by 2030. Further, between 2010 and 2030,
total direct medical costs of CVD in the United States alone are
projected to triple from $272.5billion to $818.1billion,
according to the AHA. In addition, the number of individuals with
metabolic diseases, including diabetes, is rising dramatically.
According to a 2010 study published in Population Health
Metrics, the number of people in the United States with
diabetes is projected to grow from approximately 20million in
2010 to between 46million and 87million by 2050. Cardiometabolic
risk factors include metabolic syndrome, dyslipidemia,
hypertension, obesity and insulin resistance. Lipid risk factors
driven by abnormalities in lipid molecules or the processing of
lipid molecules contribute to cardiometabolic diseases, with
elevated low density lipoprotein cholesterol, or LDL-C, being the
most widely recognized. Despite the availability of powerful
drugs to lower LDL-C, many people remain at significant risk due
to other lipid disorders that are not adequately addressed with
current therapies. We believe this treatment gap represents a
significant commercial opportunity both in rare and in broader
patient populations.

Each of the four drugs in our pipeline targets the specific
ribonucleic acid, or RNA, that encodes for a unique protein
associated with lipid dysfunction, robustly and selectively
inhibiting the production of such protein. These drugs were
designed and developed at Ionis, and use Ionis’ proprietary
antisense technology, which is a potent and specific way of
reducing disease-causing proteins. Specifically, our drugs
utilize Ionis’ generation 2.0 antisense technology, which is
designed for increased potency and enhanced safety
characteristics relative to Ionis’ generation 2.0 technology.
Additionally, AKCEA-APO(a)-L_Rx,
AKCEA-ANGPTL3-L_Rx and AKCEA-APOCIII-L_Rx
utilize Ionis’ advanced Ligand Conjugated Antisense, or LICA,
technology. We believe the enhancements offered by Ionis’ LICA
technology can provide greater patient convenience by allowing
for significantly lower doses and less frequent administration.
Our current pipeline includes drugs with the potential to treat
patients with a wide range of lipid disorders associated with
cardiometabolic disease that other technologies, such as small
molecules and antibodies, have not been able to adequately
address. Our development approach and commercialization strategy
include:

Commercial Approach

We plan to commercialize volanesorsen ourselves globally, with a
specialized and comprehensive patient-centric approach. Our
orphan-focused commercial model will include a small highly
focused salesforce in each country that we are targeting,
complemented by medical affairs and patient and healthcare
provider services. We plan to provide high touch patient and
healthcare provider support through reimbursement assistance,
partnerships with specialty pharmacies, injection training,
routine platelet monitoring and dietary counseling, which we
believe will enable strong integration with treating physicians
and facilitate patient uptake and compliance. Reimbursement
assistance may include activities such as a reimbursement
hotline, patient assistance, co-pay assistance through
foundations and

insurance verification. We plan to include dedicated case
managers as part of our support team who will work directly with
patients, caregivers and healthcare providers to help patients
start and stay on therapy. Our global commercial organization is
initially focused on our nearest term opportunities with
volanesorsen to treat patients with FCS and FPL. Our initial plan
is to focus on lipid specialists, specialized endocrinologists
and pancreatologists as our primary call points. At the outset,
we plan to focus our commercial efforts in the United States,
Canada and Europe, and intend to expand over time to other
relevant geographies. We believe the relatively small number of
specialized physicians treating FCS and FPL patients will allow
us to address this market with a nimble, scalable organization.
We are currently identifying patients and having them referred to
specialists for treatment, which we believe will facilitate
successful commercialization. Building awareness of these orphan
diseases among not only lipid specialists, but also referring
physicians, is a key element of our pre-commercial and commercial
plans. We are focused on disease education and market access,
with the goal of ensuring that identified patients can most
effectively obtain our drugs once commercialized. We are also
creating the specialized support required to potentially address
other rare disease patient populations.

We plan to commercialize by ourselves any approved drugs with a
rare disease or specialty focus. We may enter into additional
strategic relationships to commercialize certain of our drugs,
particularly in indications with large patient populations, as
evidenced by our collaboration with Novartis. We believe Novartis
brings significant resources and expertise to the collaboration
that can accelerate our ability to deliver
AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx to
the large populations of patients who have high cardiovascular
risk due to inadequately treated lipid disorders. We also plan to
co-commercialize any such drug in selected markets through the
specialized sales force we are building to commercialize
volanesorsen.

Integrated Development and Commercial Opportunities

Our drugs are designed to target a variety of lipid disorders,
present in both orphan and broad patient populations, which
available therapies do not adequately address. We are initially
focused on developing volanesorsen and
AKCEA-ANGPTL3-L_Rx for orphan indications that will not
require large cardiovascular outcome studies. The smaller, orphan
size populations allow a potentially rapid path to
commercialization and we believe will allow us to address the
commercial market with a nimble, scalable organization. At the
same time, we initiated a strategic collaboration with Novartis
for AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx,
allowing development of these drugs in larger populations with
the potential to expand the commercial opportunity.

While preparing to commercialize volanesorsen, we are building
relationships with specialist physicians. These specialists
influence and drive treatment practice across lipid disorders.
Accordingly, we believe that we will be able to leverage these
relationships in commercializing all of the drugs in our
pipeline.

Our Strategy

Our goal is to become the premier company offering treatments for
previously inadequately treated lipid disorders. The critical
components of our business strategy to achieve this goal include
the following:

Sales and Marketing

Our goal is to become the premier company offering treatments for
previously inadequately treated lipid disorders. We are
assembling the global infrastructure to develop the drugs in our
pipeline and to commercialize them with a focus on lipid
specialists, specialized endocrinologists and pancreatologists as
our primary call points. We are also creating the specialized
support required to potentially address other rare disease
patient populations. We plan to build a small, highly-focused
salesforce to support the commercialization of volanesorsen, if
approved, which would serve as the foundation of our sales,
marketing and patient support efforts for all of the drugs in our
pipeline, including our co-commercialization activities with
Novartis for AKCEA-APO(a)-L_Rx and
AKCEA-APOCIII-L_Rx, if and when approved.

Global Commercialization Infrastructure

We plan to commercialize volanesorsen ourselves globally, with a
specialized and comprehensive patient-centric approach. Our
orphan-focused commercial model will include a small highly
focused salesforce in each country that we are targeting,
complemented by medical affairs and patient and healthcare
provider services. We plan to provide high touch patient and
healthcare provider support through reimbursement assistance,
partnerships with specialty pharmacies, injection training,
routine platelet monitoring and dietary counseling, which we
believe will enable strong integration with treating physicians
and facilitate patient uptake and compliance. Reimbursement
assistance may include activities such as a reimbursement
hotline, patient assistance, co-pay assistance through
foundations and insurance verification. We plan to include
dedicated case managers as part of our support team who will work
directly with patients, caregivers and healthcare providers to
help patients start and stay on therapy. Our global commercial
organization is initially focused on our nearest term
opportunities with volanesorsen to treat patients with FCS and
FPL. Our initial plan is to focus on lipid specialists,
specialized endocrinologists and pancreatologists as our primary
call points. At the outset, we plan to focus our commercial
efforts in the United States, Canada and Europe, and intend to
expand over time to other relevant geographies. We believe the
relatively small number of specialized physicians treating FCS
and FPL patients will allow us to address this market with a
nimble, scalable organization. We are currently identifying
patients and having them referred to specialists for treatment,
which we believe will facilitate successful commercialization.
Building awareness of these orphan diseases among not only lipid
specialists, but also referring physicians, is a key element of
our pre-commercial and commercial plans. We are focused on
disease education and market access, with the goal of ensuring
that identified patients can most effectively obtain our drugs
once commercialized. We are also creating the specialized support
required to potentially address other rare disease patient
populations.

Due to the specialized nature of managing FCS and FPL, there are
a limited number of treating physicians.

In North America and Europe, we are planning for an overall field
force size of between 75 and 100 individuals for the initial
launch of volanesorsen in FCS, which we expect to be sufficient
to target

substantially all of the potential volanesorsen prescribers. This
field force would include sales representatives, medical
liaisons, and personnel for reimbursement assistance and patient
support.

In August 2016, we formed Akcea UK, our wholly-owned subsidiary
located in the United Kingdom. Akcea UK is supporting our initial
pre-commercialization activities in Europe, and will serve as a
potential entity for future United Kingdom and/or European
operations.

We expect to market our drugs to the same specialist call point
as volanesorsen, enabling us to leverage this commercial
organization as the core global infrastructure for all of our
drugs. We plan to commercialize by ourselves any approved drugs
with a rare disease or specialty focus. We may enter into
strategic relationships to commercialize certain of our drugs,
particularly in indications with large patient populations, as
evidenced by our collaboration with Novartis. We believe Novartis
brings significant resources and expertise to the collaboration
that can accelerate our ability to deliver
AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx to
the large populations of patients who have high cardiovascular
risk due to inadequately treated lipid disorders. We also plan to
co-commercialize any such drug in selected markets through the
specialized sales force we are building to commercialize
volanesorsen.

Preparing for Successful Commercialization

A key aspect of successfully commercializing therapies for orphan
diseases is to identify eligible patients. Patient populations
are frequently very small and sometimes heterogeneous. Our
management team is experienced in maximizing patient
identification for both clinical development and commercial
purposes in orphan diseases. We also have significant experience
in establishing the burden of disease in support of securing
orphan pricing and reimbursement.

Our commercial organization is focused on the following
priorities to prepare for the launch of volanesorsen:

Clinical Pipeline

Cardiometabolic disease, which includes cardiovascular diseases
and metabolic diseases such as diabetes, is the number one cause
of death globally. According to the AHA, CVD alone accounts for
17.3million deaths per year globally, a number that the AHA
expects to grow to more than

23.6million by 2030. Further, the number of individuals with
metabolic diseases, including diabetes, is also rising
dramatically. According to a 2010 study published in
Population Health Metrics, the number of people in the
United States with diabetes is projected to grow from
approximately 20million in 2010 to between 46million and
87million by 2050. Cardiometabolic risk factors include metabolic
syndrome, dyslipidemia, hypertension, obesity and insulin
resistance.

Lipid risk factors driven by abnormalities in lipid molecules
contribute to cardiometabolic diseases, with elevated LDL-C being
the most widely recognized. Despite the availability of powerful
drugs to lower LDL-C, many people remain at significant risk due
to other lipid disorders that are not adequately addressed with
current therapies. This treatment gap represents a significant
commercial opportunity both in orphan and in broader diseases,
with new therapies needed.

The following figure illustrates our pipeline:

(1)

We have used alternate names for our drugs:

Volanesorsen also has been known as
IONIS-APOCIII_Rx, ISIS-APOCIII_Rx and
ISIS304801.

AKCEA-APO(a)-L_Rx also has been known as
IONIS-APO(a)-L_Rx, ISIS-APO(a)-L_Rx and
ISIS 681257.

AKCEA-ANGPTL3-L_Rx also has been known as
IONIS-ANGPTL3-L_Rx, ISIS-ANGPTL3-L_Rx
and ISIS 703802.

AKCEA-APOCIII-L_Rx also has been known as
IONIS-APOCIII-L_Rx , ISIS-APOCIII-L_Rx
and ISIS 678354.

(2)

We have initiated a strategic collaboration with Novartis for
AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx.

Note:

The arrows designate the current phase of development for each
drug and indication, and do not represent the extent of
completion of the activities we are currently conducting within
the phase.

Note:

The “L” designation indicates drugs that use Ionis’ LICA
technology.

Volanesorsen

We are developing volanesorsen to treat patients with FCS and
FPL, orphan diseases characterized by extremely elevated
triglyceride levels and a high risk of life-threatening
pancreatitis. Patients with

FCS and FPL live with daily and chronic manifestations of their
disease that negatively affect their lives, including severe,
recurrent abdominal pain and cognitive impairment. Volanesorsen
acts to reduce triglyceride levels by inhibiting the production
of apolipoprotein C-III, or ApoC-III, a protein that is a key
regulator of triglyceride clearance. People who have low levels
of ApoC-III or reduced ApoC-III function have lower levels of
triglycerides and a lower incidence of CVD.

We believe volanesorsen has the potential to significantly
improve the lives of patients with FCS and FPL. We demonstrated
in Phase2 studies that volanesorsen robustly reduced ApoC-III and
triglycerides in patients, including in FCS patients, and also
had a beneficial impact on insulin sensitivity. Further, in a
Phase2 study, the triglyceride levels in all patients with FCS
treated with volanesorsen were reduced to levels below 500 mg/dL,
which is a commonly accepted level associated with reduced risk
of pancreatitis. We published our findings from the Phase2
studies with volanesorsen in two publications in the New England
Journal of Medicine.

We recently completed the Phase3 program for volanesorsen to
treat patients with FCS and are planning to file for regulatory
approval in multiple jurisdictions for this indication in the
third quarter of 2017. The Phase3 program consisted of two
studies, the APPROACH study and the COMPASS study. The APPROACH
study, a one year randomized, placebo-controlled study in 66
patients with FCS (average incoming triglycerides of 2,209
mg/dL), achieved its primary endpoint of reduction in
triglycerides at three months, with a 77% mean reduction in
triglycerides (p0.0001), which translated into a 1,712 mg/dL mean
absolute triglyceride reduction in volanesorsen-treated patients
(p0.0001). In the study, we observed that more than 75% of
treated patients achieved triglyceride levels below 750 mg/dL,
the level at which chylomicron formation begins to become
significant, and 50% of treated patients achieved triglyceride
levels below 500 mg/dL, a commonly accepted threshold for
pancreatitis risk. Each of these results was statistically
significant compared to placebo-treated patients, none of whom
achieved triglyceride levels below 500 mg/dL. In addition, in the
APPROACH study, treatment with volanesorsen was associated with a
statistically significant reduced rate of pancreatitis attacks in
the group of patients who had a documented history of recurrent
pancreatitis attacks in the 5years prior to the study (p=0.02).
Patients treated with volanesorsen who had reported abdominal
pain before treatment in the study, also experienced reduced and
less frequent pain than their placebo-treated counterparts, a
difference that was more evident as the study progressed. The
triglyceride lowering effects we observed were maintained
throughout the 12month study period. The COMPASS study, a six
month randomized placebo-controlled study in 113patients with
very high triglycerides (500 mg/dL), also achieved its primary
endpoint of reduction in triglycerides at three months, with a
71% mean reduction in triglycerides. In the COMPASS study,
treatment with volanesorsen was associated with a statistically
significant reduction in pancreatitis attacks (p=0.01). The data
from the COMPASS and APPROACH studies is consistent with and
supports the robust triglyceride lowering we observed in the
Phase2 program for volanesorsen. Overall in our volanesorsen
program, data are available for 43patients with FCS treated with
volanesorsen, including 33 in the APPROACH study, seven in the
COMPASS study and three in Phase2 studies. In these patients,
treatment with volanesorsen was associated with robust reduction
of triglyceride levels.

The most common adverse event in the studies was injection site
reactions, which were mostly mild. In addition, declines in
platelet counts were observed in many patients. These platelet
declines were not clinically significant in most patients and
were generally well managed with monitoring and dose adjustment.
Five patients discontinued participation in the APPROACH study
due to platelet count declines and four patients discontinued due
to other non-serious adverse events, including one case each of
sweating and chills, severe fatigue, rash and injection site
reaction. In the volanesorsen program as a whole (approximately
280 individuals who received volanesorsen), there were five
treatment-related or potentially treatment-related SAEs. Two of
the SAEs were described by the investigators as serum
sickness-like reaction and serum sickness, respectively. Both
patients fully recovered. The other three SAEs were serious
platelet events (grade4 thrombocytopenia): two in

APPROACH and one in the APPROACH open label extension study
(where a deviation from the protocol occurred in a patient who
was on placebo during APPROACH). These events resolved without
incident following cessation of dosing. We believe our current
regimen of platelet monitoring is designed to adequately identify
any such potential event and to provide patient safety. There
have been no deaths and no cardiovascular events in any
volanesorsen clinical study. We have now simplified our platelet
monitoring program such that monitoring is expected to occur once
weekly in all patients on volanesorsen. We believe our greater
involvement with physicians and patients, which will be a core
focus of the education and support provided by our
patient-centric commercial approach, should allow us to better
maintain patients on volanesorsen therapy.

Based on what we believe is a favorable risk-benefit profile
supported by data from both APPROACH and COMPASS, we are actively
preparing our regulatory filings in multiple jurisdictions for
volanesorsen in FCS. If approved, we plan to globally
commercialize volanesorsen ourselves for both FCS and FPL. The
FPL study, called BROADEN, is currently enrolling and we plan to
report data from this study in 2019. If the data are positive, in
2019 we plan to file for marketing authorization for volanesorsen
to treat patients with FPL. The FDA and EMA have granted orphan
drug designation to volanesorsen for the treatment of patients
with FCS. The EMA has granted orphan drug designation to
volanesorsen for the treatment of patients with FPL and we are in
the process of applying for orphan drug status for FPL in the
United States.

AKCEA-APO(a)-L_Rx

We are developing AKCEA-APO(a)-L_Rx for patients who
are at significant risk of CVD because of their elevated levels
of Lp(a). AKCEA-APO(a)-L_Rx inhibits the production of
the Apo(a) protein, thereby reducing Lp(a). Apo(a) is a very
atherogenic and thrombogenic form of LDL. Elevated Lp(a) is
recognized as an independent, genetic cause of coronary artery
disease, heart attack, stroke and peripheral arterial disease.
Inhibiting the production of Apo(a) in the liver reduces the
level of Lp(a) in blood, potentially slowing down or reversing
cardiovascular disease in patients with hyperlipoproteinemia(a),
a condition in which individuals have levels of Lp(a) greater
than 60 mg/dL. Lp(a) is difficult to inhibit using other
technologies, such as small molecules and antibodies; there are
multiple genetically-determined forms of the Apo(a) molecule and
creating a small molecule or antibody that can interact with
multiple targets is difficult. We believe antisense technology is
particularly well suited to address hyperlipoproteinemia(a)
because it specifically targets the RNA that codes for all forms
of the Apo(a) molecule. As a result, it can stop the production
of all of the forms of the protein. Furthermore, we believe
addressing elevated Lp(a) is the next important horizon in
lipid-focusedtreatment and, through our collaboration with
Novartis, we plan to develop AKCEA-APO(a)-L_Rx to treat
patients with established cardiovascular disease in whom
hyperlipoproteinemia(a)likely plays a causal role.

We have completed a Phase1/2 study with
AKCEA-APO(a)-L_Rx in patients with
hyperlipoproteinemia(a) and we reported the results at the AHA
meeting in November 2015. In this clinical study, we observed
significant and sustained reductions in Lp(a) of up to 97% with a
mean reduction of 79% after only a single, small volume dose of
AKCEA-APO(a)-L_Rx. With multiple doses of
AKCEA-APO(a)-L_Rx, we observed even greater reductions
of Lp(a) of up to 99% with a mean reduction of 92%. Based on
these results, we have started a Phase2b dose-ranging study of
AKCEA-APO(a)-L_Rx in patients with
hyperlipoproteinemia(a) and established CVD. We have initiated a
strategic collaboration with Novartis for this drug. In this
collaboration, we intend to complete the above-referenced Phase2b
study. Following completion of this study, Novartis has an option
to license the drug. If Novartis exercises its option to license
AKCEA-APO(a)-L_Rx and pays us the $150.0million license
fee to do so, Novartis plans to conduct and pay for a Phase3
cardiovascular outcome study in high-risk patients and, if
approved, to commercialize AKCEA-APO(a)-L_Rx worldwide.
We plan to co-commercialize AKCEA-APO(a)-L_Rx with
Novartis in selected markets through the specialized sales

force we are building to commercialize volanesorsen. We believe
Novartis brings significant resources and expertise to the
collaboration that can accelerate our ability to deliver this
potential therapy to patients at significant cardiovascular risk
due to their high Lp(a) levels.

AKCEA-ANGPTL3-L_Rx

We are developing AKCEA-ANGPTL3-L_Rx to treat multiple
lipid disorders. Studies have shown that elevated levels of the
ANGPTL3 protein are associated with an increased risk of
premature heart attacks, increased arterial wall thickness and
multiple metabolic disorders, such as insulin resistance. In
contrast, people with lower levels of ANGPTL3 have lower LDL-C
and triglyceride levels and thus lower risk of heart attacks and
multiple metabolic disorders. In preclinical studies, an analog
of AKCEA-ANGPTL3-L_Rx inhibited the production of the
ANGPTL3 protein in the liver, inhibiting liver fat accumulation
and lowering blood levels of triglycerides, LDL-C and very low
density lipoprotein cholesterol, or VLDL-C. In addition, our
preclinical data and initial Phase1 data suggest that inhibiting
the production of ANGPTL3 could improve other lipid parameters,
including triglyceride levels and total cholesterol.

We are conducting a Phase 1/2 program for
AKCEA-ANGPTL3-L_Rx in people with elevated
triglycerides. We reported results for the initial cohort from
this study at the AHA meeting in November 2016. We observed that
the people with elevated triglycerides achieved dose-dependent,
statistically significant mean reductions in ANGPTL3 of up to
83%. Treatment with AKCEA-ANGPTL3-L_Rx was also
associated with statistically significant mean reductions in
triglycerides of up to 66%, in LDL-C of up to 35% and in total
cholesterol of up to 36%. In this study,
AKCEA-ANGPTL3-L_Rx was reported to be well tolerated.
The most common adverse events in the
AKCEA-ANGPTL3-L_Rx treated group of patients were mild
headaches and dizziness that were approximately equal to the rate
observed in the placebo group. In the second half of 2017, we
plan to begin a study of AKCEA-ANGPTL3-L_Rx in patients
with hyperlipidemia with metabolic complications including
insulin resistance and fatty liver, in which we plan to include
patients with NAFLD or NASH. We plan to report data from this
study in 2019. Further, in the second half of 2017, we also plan
to study AKCEA-ANGPTL3-L_Rx in patients with rare
hyperlipidemias, including patients with FCS, and we plan to
report data from this study in 2018. If we find that
AKCEA-ANGPTL3-L_Rx can effectively lower triglyceride
levels in patients with rare hyperlipidemias, including patients
with FCS, through a different mechanism of action from
volanesorsen, it may represent an opportunity to expand our FCS
franchise. Additional potential indications for which we may
consider developing AKCEA-ANGPTL3-L_Rx include other
rare hyperlipidemias and lipodystrophies.

AKCEA-APOCIII-L_Rx

We are developing AKCEA-APOCIII-L_Rx to inhibit the
production of ApoC-III, the same protein inhibited by
volanesorsen, for the broad population of patients who have
cardiometabolic disease due to their elevated triglyceride
levels. ApoC-III impacts triglyceride levels and may also
increase inflammatory processes. This combination of effects
makes ApoC-III a promising target for patients with LDL-C already
controlled on statin therapy, but for whom triglycerides remain
poorly controlled. We believe that the enhancements offered by
Ionis’ LICA technology can provide greater patient convenience
by allowing for significantly lower doses and less frequent
administration, compared to volanesorsen. We are conducting a
Phase 1/2 study of AKCEA-APOCIII-L_Rx in people with
elevated triglycerides and plan to report results from this study
in the second half of 2017. We have initiated a strategic
collaboration with Novartis for this drug. In this collaboration,
we intend to complete the Phase2 program required to define the
appropriate dose and regimen to support a planned cardiovascular
outcome study. We plan to initiate a Phase2b dose-ranging study
of AKCEA-APOCIII-L_Rx in patients with
hypertriglyceridemia and established CVD in the second half of
2017 and plan to report data from this study in 2019. At the
completion of Phase2 development, Novartis has an

option to license the drug. If Novartis exercises its option to
license AKCEA-APOCIII-L_Rx and pays us the
$150.0million license fee to do so, Novartis plans to conduct and
pay for a Phase3 cardiovascular outcome study in high-risk
patients and, if approved, to commercialize
AKCEA-APOCIII-L_Rx worldwide. We plan to
co-commercialize AKCEA-APOCIII-L_Rx with Novartis in
selected markets through the specialized sales force we are
building to commercialize volanesorsen. We believe Novartis
brings significant resources and expertise to the collaboration
that can accelerate our ability to deliver this potential therapy
to patients at significant cardiovascular risk due to their
elevated triglyceride levels.

FORWARD-LOOKING STATEMENT

This report includes forward-looking statements regarding the
business of Ionis Pharmaceuticals,Inc. and Akcea
Therapeutics,Inc., a subsidiary of Ionis Pharmaceuticals, and the
therapeutic and commercial potential of volanesorsen and other
products in development. Any statement describing the companies’
goals, expectations, financial or other projections, intentions
or beliefs is a forward-looking statement and should be
considered an at-risk statement. Such statements are subject to
certain risks and uncertainties, particularly those inherent in
the process of discovering, developing and commercializing drugs
that are safe and effective for use as human therapeutics, and in
the endeavor of building a business around such drugs. The
companies’ forward-looking statements also involve assumptions
that, if they never materialize or prove correct, could cause its
results to differ materially from those expressed or implied by
such forward-looking statements. Although the companies’
forward-looking statements reflect the good faith judgment of its
management, these statements are based only on facts and factors
currently known by the companies. As a result, you are cautioned
not to rely on these forward-looking statements. These and other
risks concerning the companies’ programs are described in
additional detail in Ionis Pharmaceuticals,Inc.’s annual report
on Form10-K for the year ended December31, 2016, which is on file
with the SEC. Copies of this and other documents are available
from Ionis.

to the requirements of the Securities Exchange Act of 1934, as
amended, the registrant has duly caused this report to be signed
on its behalf by the undersigned, thereunto duly authorized.

QuickLinks

About IONIS PHARMACEUTICALS, INC. (NASDAQ:IONS)

Ionis Pharmaceuticals, Inc. is engaged in discovering and developing ribonucleic acid (RNA)-targeted therapeutics. The Company, using its drug discovery platform, has developed a pipeline of drugs for patients with unmet medical needs. The Company’s segments include Ionis Core and Akcea Therapeutics. In the Ionis Core segment, the Company is engaged in exploiting a drug discovery platform to generate a pipeline of drugs for the Company and its partners. The Akcea Therapeutics segment includes the operations of the Company’s subsidiary, Akcea Therapeutics, Inc. (Akcea Therapeutics). Akcea Therapeutics is focused on developing and commercializing volanesorsen and other clinical-stage drugs for serious cardiometabolic diseases caused by lipid disorders. The Company is developing volanesorsen to treat two severe and rare, genetically defined diseases, familial chylomicronemia (FCS) and familial partial lipodystrophy (FPL). The Company offers SPINRAZA, a Generation 2.0+ antisense drug.

IONIS PHARMACEUTICALS, INC. (NASDAQ:IONS) Recent Trading Information

IONIS PHARMACEUTICALS, INC. (NASDAQ:IONS) closed its last trading session up +1.05 at 38.98 with 1,502,171 shares trading hands.