Efficacy and Safety of IONIS-PKKRx for Preventive Treatment of Chronic Migraine

This is a double-blind, placebo-controlled, randomized, multi-center study in subjects with
chronic migraine. The study will consist of 7 office visits, 6 Sample collection visits and 3
phone call assessments. Subjects agreeing to participate in the study and meeting the entry
criteria assessed at the screening visit, will begin a 28 day baseline period to confirm
their diagnosis, and establish a baseline frequency of migraine and headache days. During the
baseline period, subjects will continue treating their migraines in their usual manner. They
will monitor headache activity, migraine related symptoms, and medication usage with an
electronic daily headache diary.

Subjects who, after completing the baseline, continue to meet entrance criteria will be
eligible to enter into the 4 month treatment phase. They will be randomized according to the
Clinvest generated randomization schedule. A total of 30 randomized subjects will enter the
treatment phase receiving IONIS-PKKRx (ISIS 546254; SC) or placebo in a 1:1 design. Study
drug or placebo will be administered weekly for 16 weeks. A short phone call to assess any
treatment related adverse events will take place 1 and 2 days after randomization. Daily
electronic diary assessments will collect headache frequency and severity, associated
migraine symptoms, acute medication usage, and the emergence of unusual symptoms and adverse
events. Subjects will return to the site at weeks 4, 8, and 12 for investigational product
(IP) accountability/dispensing, medication and medication updates, biomarker/lab sample
collection, and assessment of adverse events. An end of treatment visit will take place 16
weeks after randomization.

Subjects will have a follow-up safety visit one month after their last dosage of IP ) for
assessment of any adverse events (AE) and satisfaction and a final safety phone call 2 months
following their last office visit (3 months after last dose of IP) for assessment of any
adverse events (AE). Subjects will continue to complete headache diaries through Visit 7.
Subjects will also have hematology samples collected every other week starting after Visit 2
through Day 154.

Safety and tolerability will be monitored by the Investigators. Patients who discontinue
study treatment prematurely should complete any follow-up visits associated with the most
recent dose and should move into and complete the Follow-up Phase.

Subjects will undergo sampling for (pharmacokinetics) PK, coagulation, chemistry, hematology,
and optional future biomedical research, as specified in the schedule of procedures.

Inclusion Criteria:

Potential subjects must meet the following criteria at the screening visit to enter this
study:

1. male or female, in otherwise good health, 18 to 65 years of age.

2. history of chronic migraine meeting the diagnostic criteria listed in the
International Classification of Headache Disorders (ICHD-III beta version, 2013), as
follows:

a. History of frequent headaches suggestive of chronic migraine (15 or greater days of
qualifying headaches per month) for at least three months prior to screening b.
Verification of headache frequency through prospectively collected baseline
information during the 28-day run-in phase demonstrating headaches on at least 15
days, with at least 8 days per month fulfilling any ONE of the following; i. Qualify
as being a migraine attack ii. Relieved by migraine specific acute medications

3. onset of migraine before age 50.

4. stable pattern of migraine pattern for at least 3 months prior to screening.

5. not currently taking a migraine preventive OR has been taking a stable dose of a
preventive for at least 30 days prior to screening and agrees to not start, stop, or
change medication and/or dosage during the study period.

i. Subjects on migraine preventative should have stable headache pattern ii.
Injections of onabotulinumtoxinA are allowable if subject has completed at least 2
injection cycles and agrees to maintain a regular injection cycle for the duration of
the study

Exclusion Criteria:

Potential subjects meeting any of the following criteria will be excluded from entering
this study:

1. unable to understand the study requirements, the informed consent, or complete
headache records as required per protocol.

2. pregnant, actively trying to become pregnant, or breast-feeding.

3. history of medication overuse (MO) of opioids, or butalbital, as defined by ICHD-3
beta criteria and/or MO during baseline period.

4. history of substance abuse and/or dependence, in the opinion of the Investigator.

5. unstable neurological condition or a significantly abnormal neurological examination
with focal signs or signs of increased intracranial pressure.