Updated the approximate anticipated number of subjects that may enroll into the study (approximately 70 subjects) so that the number of subjects is reflective of the estimated number of qualified subjects from the ISIS 304801-CS6 and ISIS 304801- CS16 Index Studies. • Defined the specific subject population from ISIS 304801-CS16 who will be allowed to enter the Open-label Extension Study. • Clarification of when final assessments from the ISIS 304801- CS6 and ISIS 304801-CS16 Index Studies may be used for enrollment into ISIS 304801-CS7. • Clarification of how food and alcohol were monitored during the study. • An addition to the platelet monitoring rule language to allow for more frequent monitoring was included. • Guidance to Investigators with enrolled FCS subjects who also had Type 2 diabetes mellitus. Specific glucose monitoring rules were provided for subjects on insulin and oral antidiabetic medications. The definition of documented severe hypoglycemia was included and safety monitoring rules were defined. Also, specific monitoring rules were incorporated into the protocol for hyperglycemic events.

Modified the clinical experience safety language to reflect updated blinded safety data from ongoing studies. •Indicated that the Data and Safety Monitoring Board (DSMB) was independent. •Revised the contraceptive requirements to state that abstinence is only acceptable as true abstinence, i.e., when it was in line with the preferred and usual lifestyle of the subject. • Added lipoprotein lipase activity as a qualification assessment for ISIS 304801-CS16 rollover subjects. • Added genetic testing as a qualification assessment for ISIS 304801-CS16 rollover subjects. • Increased the frequency of the pregnancy testing. • Added hematology blood draws at Weeks 12, 16, 22, 25, 29, 35, 41, 47, and 51 to more frequently assess platelet counts. • Allowed blood sampling at Weeks 4, 8, 12, 16, 19, 22, 25, 29, 32, 35, 41, 44, 47, 51, and 58 to be conducted by a home healthcare nurse. Allowed blood sampling at the 24-hour PK blood draw to be conducted by a home healthcare nurse. • Added language that each time a hematology lab was drawn and sent to the central laboratory for analysis, an additional sample should be collected in parallel and analyzed locally, to reduce the occurrence of unreportable hematology results. • Provided guidance that the length of fasting should preferably not be more than 12 hours. • Updated the platelet monitoring rule language to allow for more frequent monitoring as determined by the Sponsor Medical Monitor in consultation with the Investigator. • Added language to the safety monitoring for insulin, oral antidiabetic medication and glucose that all subjects, including those not on insulin, who use a glucometer should also bring their glucometer and/or glucometer log printout to every clinic visit. • Clarified guidance on determining relatedness of a suspected unexpected serious adverse event (SUSAR).

Added language that any case of a platelet count less than or equal to (≤) 50,000/ cubic millimeter (mm^3) should be reported in an expedited fashion to the Sponsor. • Added language regarding the frequency of obtaining platelet counts after a study drug dose pause and subsequent rechallenge. • Added language that any unreportable platelet count result must be rechecked and determined not to have met a stopping rule before treatment could continue.

Added hematology blood draws for platelet counts to be measured every 2 weeks during the treatment period and every 2 weeks for the first 6 weeks after the last dose of study drug. • Updated the platelet safety monitoring rules. • If there was no reportable platelet count within 14 days of the last platelet count, subject would hold treatment until a new platelet count is obtained and reviewed. • Added language to indicate that all platelet count results will be promptly reviewed by the Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that the subject could be approaching the dose pause rule of 75,000/mm^3. • Changed the platelet dose pause/stopping rule from 50,000/mm^3 to 75,000/mm^3 and that when platelet count returns to greater than or equal to (≥) 100,000/mm^3 treatment may be continued but at a reduced dose frequency of 300 mg every 2 weeks or a reduced dose of 150 mg per week and only if approved by the Sponsor Medical Monitor. • Added language to indicate that in the event of any platelet count less than 25,000/mm^3, or a platelet count less than 50,000/mm^3 that occured while the subject was on treatment at 300 mg every 2 weeks or 150 mg per week, then treatment of a subject with volanesorsen would be stopped permanently. Platelet count would be monitored daily until 2 successive values show improvement then monitored every 2-3 days until platelet count is stable. • Added language to indicate that administration of steroids was recommended for subjects whose platelet count was less than 25,000/mm^3 and to provide treatment guidelines for the administration of steroids. • Added a table summarizing actions to be taken in the event of a low platelet count. • Added language to indicate that subjects would receive a suitable dose or dose frequency of volanesorsen, when they enter this CS7 study, based on safety/tolerability or non safety/tolerability dosing rules.

Provisions to enroll FCS subjects in the open label study who did not participate in the ISIS 304801–CS6 or ISIS 304801–CS16 Index Studies. • Clarified the protocol which then specified 3 subject groups, with assignment based on prior involvement in Index Studies of ISIS 304801: - Group 1: ISIS 304801-CS6 (Index Study) rollover FCS subjects - Group 2: ISIS 304801-CS16 (Index Study) rollover FCS subjects - Group 3: FCS subjects who did not participate in the ISIS 304801-CS6 or ISIS 304801-CS16 Index Studies •Removed language that indicated that lipoprotein lipase (LPL) activity can be measured if needed for study qualification for subjects in Groups 2 and 3. • Added language to indicate that a second study drug rechallenge would not be allowed following a platelet count decrease below 75,000/mm^3. • Provided clarifications to the platelet safety monitoring rules. • Added language to indicate that subjects who discontinue early from study drug, or the study, should be followed as per the platelet monitoring rules for the first 6 weeks after discontinuing study drug and the next platelet count should be taken within at least 6 weeks so that subjects would be monitored for at least 12 weeks after discontinuing study drug.

Provision to allow subjects who complete the 52-week treatment period to participate in an expanded access program or continue treatment for up to an additional 52 weeks until an expanded access program was approved and available in their country. Subjects not participating in an expanded access program would enter the 13- week post treatment evaluation period. • The following assessments were added: Troponin I; labs to be performed in the event of a platelet count < 75,000/mm^3; platelet bound autoantibody testing at Baseline (may be done); plus medical history, hepatitis B, C, and human immunodeficiency virus (HIV) at Screening (Group 3 subjects).

Updated the platelet safety monitoring rules. • Added LPL activity of ≤ 20 percent (%) of normal in medical history as an inclusion criteria for Group 2 and 3 subjects as had been allowed for Group 1 subjects. • Added platelet count < lower limit of normal (LLN) for the central laboratory (i.e., < 140,000/mm^3) for Group 3 subjects. •Assessment of acute pancreatitis in medical history in Group 2 subjects. • Added archive blood sample for potential gene sequencing related to High Throughput Genomic (HTG) (Group 3; Group 2 if not available from Index Study). • Blood viscosity (may be done) to assess potential benefit of study drug administration, and platelet aggregation (may be done) to assess platelet function.

Prolonged the extended treatment period an additional 52 weeks.

Added the option for subjects to receive a study drug dose reduction as either 300 mg every two weeks (prefilled syringe) or 150 mg once-weekly (vial presentation), Clarified that discontinuation from the treatment period will be required for any subjects who are on a dose pause for ≥ 3 months, and removed the references to landmark visits (if subject stops drug treatment then they enter the follow-up period).

Added an up to 52 weeks of additional treatment to the extended treatment period. • Clarified the option for subjects to receive a volanesorsen dose reduction of 300 mg every two weeks. • Clarified discontinuation of subjects from the treatment period who were on a dose pause for ≥ 3 months. • Removed the references to landmark visits (if subject stops treatment then they enter the follow-up period).